Intratracheal budesonide mixed with surfactant to increase survival free of bronchopulmonary dysplasia in extremely preterm infants: statistical analysis plan for the international, multicenter, randomized PLUSS trial.

BACKGROUND: Bronchopulmonary dysplasia (BPD), an inflammatory-mediated chronic lung disease, is common in extremely preterm infants born before 28 weeks' gestation and is associated with an increased risk of adverse neurodevelopmental and respiratory outcomes in childhood. Effective and safe prophylactic therapies for BPD are urgently required. Systemic corticosteroids reduce rates of BPD in the short term but are associated with poorer neurodevelopmental outcomes if given to ventilated infants in the first week after birth. Intratracheal administration of corticosteroid admixed with exogenous surfactant could overcome these concerns by minimizing systemic sequelae. Several small, randomized trials have found intratracheal budesonide in a surfactant vehicle to be a promising therapy to increase survival free of BPD. The primary objective of the PLUSS trial is to determine whether intratracheal budesonide mixed with surfactant increases survival free of bronchopulmonary dysplasia (BPD) at 36 weeks' postmenstrual age (PMA) in extremely preterm infants born before 28 weeks' gestation. METHODS: An international, multicenter, double-blinded, randomized trial of intratracheal budesonide (a corticosteroid) mixed with surfactant for extremely preterm infants to increase survival free of BPD at 36 weeks' postmenstrual age (PMA; primary outcome). Extremely preterm infants aged < 48 h after birth are eligible if (1) they are mechanically ventilated, or (2) they are receiving non-invasive respiratory support and there is a clinical decision to treat with surfactant. The intervention is budesonide (0.25 mg/kg) mixed with poractant alfa (200 mg/kg first intervention, 100 mg/kg if second intervention), administered intratracheally via an endotracheal tube or thin catheter. The comparator is poractant alfa alone (at the same doses). Secondary outcomes include the components of the primary outcome (death, BPD prior to or at 36 weeks' PMA), and potential systemic side effects of corticosteroids. Longer-term outcomes will be published separately, and include cost-effectiveness, early childhood health until 2 years of age, and neurodevelopmental outcomes at 2 years of age (corrected for prematurity). STATISTICAL ANALYSIS PLAN: A sample size of 1038 infants (519 in each group) is required to provide 90% power to detect a relative increase in survival free of BPD of 20% (an absolute increase of 10%), from the anticipated event rate of 50% in the control arm to 60% in the intervention (budesonide) arm, alpha error 0.05. To allow for up to 2% of study withdrawals or losses to follow-up, PLUSS aimed to enroll a total of 1060 infants (530 in each arm). The binary primary outcome will be reported as the number and percentage of infants who were alive without BPD at 36 weeks' PMA for each randomization group. To estimate the difference in risk (with 95% CI), between the treatment and control arms, binary regression (a generalized linear multivariable model with an identity link function and binomial distribution) will be used. Along with the primary outcome, the individual components of the primary outcome (death, and physiological BPD at 36 weeks' PMA), will be reported by randomization group and, again, binary regression will be used to estimate the risk difference between the two treatment groups for survival and physiological BPD at 36 weeks' PMA.

Protocol for a randomised controlled trial comparing two CPAP levels to prevent extubation failure in extremely preterm infants.

INTRODUCTION: Respiratory distress syndrome is a complication of prematurity and extremely preterm infants born before 28 weeks' gestation often require endotracheal intubation and mechanical ventilation. In this high-risk population, mechanical ventilation is associated with lung injury and contributes to bronchopulmonary dysplasia. Therefore, clinicians attempt to extubate infants as quickly and use non-invasive respiratory support such as nasal continuous positive airway pressure (CPAP) to facilitate the transition. However, approximately 60% of extremely preterm infants experience 'extubation failure' and require reintubation. While CPAP pressures of 5-8 cm H2O are commonly used, the optimal CPAP pressure is unknown, and higher pressures may be beneficial in avoiding extubation failure. Our trial is the Extubation CPAP Level Assessment Trial (ÉCLAT). The aim of this trial is to compare higher CPAP pressures 9-11 cm H2O with a current standard pressures of 6-8 cmH2O on extubation failure in extremely preterm infants. METHODS AND ANALYSIS: 200 extremely preterm infants will be recruited prior to their first extubation from mechanical ventilation to CPAP. This is a parallel group randomised controlled trial. Infants will be randomised to one of two set CPAP pressures: CPAP 10 cmH2O (intervention) or CPAP 7 cmH2O (control). The primary outcome will be extubation failure (reintubation) within 7 days. Statistical analysis will follow standard methods for randomised trials on an intention to treat basis. For the primary outcome, this will be by intention to treat, adjusted for the prerandomisation strata (GA and centre). We will use the appropriate parametric and non-parametric statistical tests. ETHICS AND DISSEMINATION: Ethics approval has been granted by the Monash Health Human Research Ethics Committees. Amendments to the trial protocol will be submitted for approval. The findings of this study will be written into a clinical trial report manuscript and disseminated via peer-reviewed journals (on-line or in press) and presented at national and international conferences.Trial registration numberACTRN12618001638224; pre-results.

A multicentre, randomised trial of stabilisation with nasal high flow during neonatal endotracheal intubation (the SHINE trial): a study protocol.

INTRODUCTION: Neonatal endotracheal intubation is an essential but potentially destabilising procedure. With an increased focus on avoiding mechanical ventilation, particularly in preterm infants, there are fewer opportunities for clinicians to gain proficiency in this important emergency skill. Rates of successful intubation at the first attempt are relatively low, and adverse event rates are high, when compared with intubations in paediatric and adult populations. Interventions to improve operator success and patient stability during neonatal endotracheal intubations are needed. Using nasal high flow therapy extends the safe apnoea time of adults undergoing upper airway surgery and during endotracheal intubation. This technique is untested in neonates. METHODS AND ANALYSIS: The Stabilisation with nasal High flow during Intubation of NEonates (SHINE) trial is a multicentre, randomised controlled trial comparing the use of nasal high flow during neonatal intubation with standard care (no nasal high flow). Intubations are randomised individually, and stratified by site, use of premedications, and postmenstrual age (<28 weeks' gestation; ≥28 weeks' gestation). The primary outcome is the incidence of successful intubation on the first attempt without physiological instability of the infant. Physiological instability is defined as an absolute decrease in peripheral oxygen saturation >20% from preintubation baseline and/or bradycardia (<100 beats per minute). ETHICS AND DISSEMINATION: The SHINE trial received ethical approval from the Human Research Ethics Committees of The Royal Women's Hospital, Melbourne, Australia and Monash Health, Melbourne, Australia. The trial is currently recruiting in these two sites. The findings of this study will be disseminated via peer-reviewed journals and presented at national and international conferences. TRIAL REGISTRATION NUMBER: ACTRN12618001498280.

A multicentre, randomised controlled, non-inferiority trial, comparing high flow therapy with nasal continuous positive airway pressure as primary support for preterm infants with respiratory distress (the HIPSTER trial): study protocol.

INTRODUCTION: High flow (HF) therapy is an increasingly popular mode of non-invasive respiratory support for preterm infants. While there is now evidence to support the use of HF to reduce extubation failure, there have been no appropriately designed and powered studies to assess the use of HF as primary respiratory support soon after birth. Our hypothesis is that HF is non-inferior to the standard treatment--nasal continuous positive airway pressure (NCPAP)--as primary respiratory support for preterm infants. METHODS AND ANALYSIS: The HIPSTER trial is an unblinded, international, multicentre, randomised, non-inferiority trial. Eligible infants are preterm infants of 28-36(+6) weeks' gestational age (GA) who require primary non-invasive respiratory support for respiratory distress in the first 24 h of life. Infants are randomised to treatment with either HF or NCPAP. The primary outcome is treatment failure within 72 h after randomisation, as determined by objective oxygenation, blood gas, and apnoea criteria, or the need for urgent intubation and mechanical ventilation. Secondary outcomes include the incidence of intubation, pneumothorax, bronchopulmonary dysplasia, nasal trauma, costs associated with hospital care and parental stress. With a specified non-inferiority margin of 10%, using a two-sided 95% CI and 90% power, the study requires 375 infants per group (total 750 infants). ETHICS AND DISSEMINATION: Ethical approval has been granted by the relevant human research ethics committees at The Royal Women's Hospital (13/12), The Royal Children's Hospital (33144A), The Mercy Hospital for Women (R13/34), and the South-Eastern Norway Regional Health Authority (2013/1657). The trial is currently recruiting at 9 centres in Australia and Norway. The trial results will be published in peer-reviewed international journals, and presented at national and international conferences. TRIAL REGISTRATION NUMBER: Australian New Zealand Clinical Trials Registry ID: ACTRN12613000303741.

Establishment of hormone reference intervals for infants born < 30 weeks' gestation.

OBJECTIVE: Preterm infants, especially those born very preterm (<32 weeks' gestation), suffer a number of morbidities. Immaturity of the endocrine system and its potential impact on morbidity is the subject of numerous studies. Hormone concentrations are sometimes measured in very preterm infants, however there are little normative data available to be able to interpret the results. The aim of this study was to describe age appropriate hormone reference intervals for babies born less than 30 weeks' gestation. STUDY DESIGN: Samples were collected at 1, 4, 7, 14, 21, 28 and 42 days after birth from babies born 23-29 weeks' gestation. The serum was analyzed for seven hormones by automated chemiluminescent immunoassay (Siemens Immulite 2000). Results from the 107 infants who survived beyond 40 weeks' corrected gestational age were included in the data analysis. RESULTS: Cortisol, dehydroepiandrosterone sulfate, growth hormone and progesterone levels were highest during the first seven days with levels up to 10,801nmol/L; 26.6µmol/L; 343mU/L; and >63.6nmol/L respectively. Free thyroxine levels were as low as <2.6pmol/L for the first 28 days with the nadir at 7days. Estradiol levels ranged from <73 to 1626pmol/L over the six weeks. Reference intervals for IGF-1 could not be established as the levels were below the analyzer's sensitivity. There were no differences in reference intervals between male and female infants. CONCLUSIONS: We describe gestation appropriate reference intervals for six hormones measured in babies born <30 weeks' gestation. Utilization of these reference intervals permits the correct and timely interpretation of results to the clinician.

Maternal diet and breastfeeding: a case for rethinking physiological explanations for breastfeeding determinants.

BACKGROUND: Although some authors explain determinants of breastfeeding that occur in a dose-response manner as evidence of causality, we argue that dose-response relationships are not proof of a biological relationship between the variables. The relationship between maternal smoking and breastfeeding and maternal obesity and breastfeeding are similar: increasing levels of smoking or obesity are associated with shorter duration of breastfeeding. However, maternal infant feeding intention is a strong predictor of breastfeeding duration. AIMS: In this paper we present data on another variable with a clear dose-response relationship with breastfeeding duration--maternal diet--as a case study to argue that a dose-response relationship does not imply causality. STUDY DESIGN: Secondary analysis of cross-sectional survey. SUBJECTS: Nationally representative sample of 3544 singleton infants in Longitudinal Study of Australian Children, 2004. OUTCOME MEASURES: Maternal intake of fruit and vegetables; breastfeeding duration. RESULTS: Adjusted Odds Ratios (AOR) for breastfeeding at 6 months for daily maternal fruit and vegetable intake (reference group=no fruit/vegetables): 1 serve AOR 1.6 (95%CI 1.0, 2.6); 2 serves AOR 2.3 (1.5, 3.5); and 6 or more serves AOR 4.4 (2.8, 6.8). CONCLUSIONS: Although higher maternal intake of fruit/vegetables is associated with longer breastfeeding duration, this is not a biological causal relationship. There are possible biological explanations for altered milk supply in women who smoke or are obese, but not for fruit/vegetable intake. We call for a broader understanding of the social determinants of infant feeding and suggest that all breastfeeding studies measure maternal infant feeding intention as an important determinant.

Twenty-three years of single-stage end-to-side anastomosis repair of interrupted aortic arches.

OBJECTIVE: This study defined long-term results of a policy of single-stage repair of interrupted aortic arch with end-to-side anastomosis. METHODS: Records of 112 consecutive patients undergoing interrupted aortic arch repair between 1985 and 2007 were reviewed. Single-stage repair was performed in 95 patients, with 90 having end-to-side repair. RESULTS: There were 11 in-hospital deaths (10%). Twelve patients needed arch reintervention during the same hospital stay: 7 for residual arch obstruction and 5 for left main bronchus obstruction. Nine patients were unavailable for follow-up. After a mean of 10 +/- 7 years, 6 late deaths occurred, for 18-year survival of 92% (95% confidence interval [CI], 84%-97%). Patients with end-to-side anastomoses had better 18-year survival (97%, 95% CI, 87%-99%, vs 74%, 95% CI, 44%-89%, P < .01). After discharge, 19 patients underwent further aortic arch intervention. The only factors predictive of late arch reintervention were technique other than end-to-side (P < .001) and reoperation for left outflow tract obstruction. Freedom from arch reintervention after end-to-side repair was 78% at 18 years (95% CI, 59%-89%). Another 16 patients had significant residual obstruction. The 18-year freedom from hypertension was 88% (95% CI, 72%-95%). CONCLUSIONS: Single-stage repair with end-to-side anastomosis seems the best approach for most neonates with interrupted aortic arch, because it provides relief of the arch obstruction with low early mortality. After 2 decades of experience with this approach, incidence of late hypertension seems minimal. The need for further arch reintervention warrants close follow-up of these patients.

A systematic review of motor and cognitive outcomes after early surgery for congenital heart disease.

CONTEXT: Brain injury is the most common long-term complication of congenital heart disease requiring surgery during infancy. It is clear that the youngest patients undergoing cardiac surgery, primarily neonates and young infants, are at the greatest risk for brain injury. Developmental anomalies sustained early in life have lifelong repercussions. OBJECTIVE: We conducted a systematic review to examine longitudinal studies of cognitive and/or motor outcome after cardiac surgery during early infancy. METHODS: Electronic searches were performed in Medline, the Cumulative Index to Nursing and Allied Health Literature (Cinahl), and Embase (1998-2008). The search strategy yielded 327 articles, of which 65 were reviewed. Eight cohorts provided prospective data regarding the cognitive and/or motor outcome of infants who had undergone surgery for congenital heart disease before 6 months of age. Two authors, Ms Snookes and Dr Gunn, independently extracted data and presented results according to 3 subgroups for age of follow-up: early development (1 to <3 years); preschool age (3-5 years); and school age (>5 to 17 years). Weighted analysis was undertaken to pool the results of studies when appropriate. RESULTS: All of the identified studies reported results of the Bayley Scales of Infant Development for children younger than the age of 3. Outcome data as reported by the Bayley Scales were combined for infants assessed at 1 year of age, revealing a weighted mean Mental Development Index of 90.3 (95% confidence interval: 88.9-91.6) and Psychomotor Development Index of 78.1 (95% confidence interval: 76.4-79.7). Additional analysis was limited by a lack of data at preschool and school age. CONCLUSIONS: With this review we identified a limited number of prospective studies that systematically addressed outcome in patients at the highest risk. These studies consistently revealed cognitive and motor delay in children after cardiac surgery during early infancy. Additional investigation is required to ascertain the consequences of such impairment during later childhood and into adult life.

Physical activity in survivors of childhood acute lymphoblastic leukaemia.

AIM: To objectively measure levels of physical activity in children, following treatment for acute lymphoblastic leukaemia (ALL). METHODS: Nineteen children who had completed treatment for ALL 6 months-5 years prior to study enrollment wore an accelerometer for 2 weekdays and 2 weekend days. RESULTS: The children spent an average of 141 +/- 74 min/day engaged in moderate to vigorous physical activity (MVPA), an amount similar to that previously documented in healthy children. Only three of the 19 subjects averaged less MVPA than the recommended amount (at least 60 min/day). MVPA levels were significantly higher on weekdays than weekend days (P= 0.006). Overall, boys engaged in significantly more MVPA than girls (P= 0.029). MVPA time was negatively correlated with age (r =-0.80) and age at diagnosis (r =-0.87). No trend between MVPA and time off treatment or body mass index was identified. CONCLUSIONS: Survivors of childhood ALL appear to be engaging in similar amounts of MVPA as those of the healthy children and are meeting recommended levels of physical activity.

Symptoms and suffering at the end of life in children with cancer: an Australian perspective.

OBJECTIVE: To examine the symptoms, level of suffering, and care of Australian children with cancer at the end of life. DESIGN, SETTING AND PARTICIPANTS: In a study conducted at the Royal Children's Hospital, Melbourne, parents of children who had died of cancer over the period 1996-2004 were interviewed between February 2004 and August 2006. Parents also completed and returned self-report questionnaires. MAIN OUTCOME MEASURES: Proportions of children suffering from and treated for various symptoms; proportion of children receiving cancer-directed therapy at the end of life; proportion of children whose treatment of symptoms was successful; location of death. RESULTS: Of 193 eligible families, 96 (50%) were interviewed. All interviews were conducted in person, and occurred a mean of 4.5 years (SD, 2.1 years) after the child's death. Eighty-four per cent of parents reported that their child had suffered "a lot" or "a great deal" from at least one symptom in their last month of life--most commonly pain (46%), fatigue (43%) and poor appetite (30%). Children who received cancer-directed therapy during the end-of-life period (47%) suffered from a greater number of symptoms than those who did not receive treatment (P = 0.03), but the severity of symptoms did not differ between these groups. Of the children treated for specific symptoms, treatment was successful in 47% of those with pain, 18% of those with fatigue and 17% of those with poor appetite. Of the 61 families who felt they had time to plan where their child would die, 89% preferred to have their child die at home. The majority of children (61%) died at home. Of those who died in hospital, less than a quarter died in the intensive care unit. CONCLUSIONS: Relatively high rates of death at home and low rates of unsuccessful medical interventions suggest a realistic approach at the end of life for Australian children dying of cancer. However, many suffer from unresolved symptoms, and greater attention should be paid to palliative care for these children.

Quality of care at the end of life in children with cancer.

AIM: Current Australian guidelines for the provision of paediatric palliative care highlight the importance of services being focused on the needs of the child and family. We aimed to establish parents' level of satisfaction with the quality of care currently being provided to children dying of cancer. METHODS: We interviewed 96 parents of children who died of cancer in Melbourne, Australia between 1996 and 2004 to ascertain how they rated the care provided to their child during the end-of-life period. RESULTS: A majority of parents were satisfied with the care provided by their primary oncologist, local doctors, palliative care services and home-care nurses. Most parents felt that discussions about key medical and treatment decisions were appropriate and clearly understood. Parents were generally satisfied with the leadership roles undertaken in decision-making in the end-of-life period; however, parents who were not satisfied indicated that they would like additional involvement of their primary oncologist. CONCLUSIONS: Current approaches to end-of-life care in children with cancer appear to be satisfactory. The main focus should continue to be on open and honest communication.

Maternal obesity and initiation and duration of breastfeeding: data from the longitudinal study of Australian children.

The aim of this paper is to investigate whether the lower rate of breastfeeding at 6 months by overweight and obese mothers is primarily due to these women giving up breastfeeding in the first week postpartum using a cross-sectional population survey. The sample is children from the infant cohort (about 12 months of age) of Wave 1 (2004) of the Longitudinal Study of Australian Children for whom breastfeeding and maternal information were available (n = 3075). Definitions used: normal-weight body mass index (BMI, kg/m(2)) 20 to <25, overweight BMI 25 to <30, obese BMI > or =30. Breastfeeding initiation was 95.1% for normal-weight women, 92.8% for overweight women and 87.1% for obese women. At 6 months, 64% of normal-weight women were breastfeeding, compared with 54% of overweight and 44% of obese women. On multivariate analysis, for women who initiated breastfeeding, overweight women had an odds ratio (OR) of 1.52 [95% confidence interval (CI) 1.02, 2.28] and obese women had an OR of 2.54 (95% CI 1.70, 3.79) of stopping breastfeeding by 1 week compared with normal-weight women (adjusted for maternal age, education, smoking, level of socio-economic disadvantage, caesarean birth, admission to special care nursery). For women who breastfed for at least 1 week, overweight women had an adjusted OR of 1.26 (1.04, 1.53) and obese women had an adjusted OR of 1.38 (1.10, 1.73) of ceasing to breastfeed before 6 months, compared with normal-weight women. In conclusion, among overweight/obese women who initiate breastfeeding, higher rates of cessation of breastfeeding in both the immediate postpartum period and in the first 6 months contribute to the shorter duration.

Maternal employment and breastfeeding: results from the longitudinal study of Australian children.

AIM: To investigate the effect of maternal postnatal employment on breastfeeding duration in Australia in the first 6 months after birth. METHOD: Secondary data analysis of the infant data (2004) from the Longitudinal Study of Australian Children (LSAC). Complete maternal and breastfeeding data were available for 3,697 infants. Multivariable logistic regression was used to investigate the effect of timing of resumption of maternal employment and maternal employment status on breastfeeding at 6 months postpartum after adjustment for maternal education, maternal age, maternal smoking during pregnancy and socioeconomic status of the child's area of residence. RESULTS: Fewer women employed full-time were breastfeeding their infants at 6 months (39%) than nonemployed women (56%). Participation in full-time employment before 6 months had a strong, negative effect on the likelihood of continuing breastfeeding for 6 months, adjusted OR = 0.35 (95%CI: 0.22-0.55). Compared to nonemployed women, fewer women in part-time employment were breastfeeding at 6 months (44%), adjusted OR = 0.49 (95% CI: 0.37-0.64). CONCLUSIONS: Results from this large representative cohort of Australian infants confirm that maternal employment in the first 6 months of life contributes to premature cessation of breastfeeding even when known risk factors for breastfeeding cessation are controlled for.

Does maternal smoking have a negative physiological effect on breastfeeding? The epidemiological evidence.

Women who smoke are less likely to breastfeed their children than nonsmokers. It is thought that nicotine has a negative effect on breastmilk supply by suppressing prolactin levels. The aim of this review was to assess the epidemiological evidence that maternal smoking has a negative physiological effect on breastfeeding. The following data sources were searched: The Cochrane Library, Medline, CINAHL, Current Contents, Psychinfo, Sociological Abstracts and the Lactation Resource Centre (Australian Breastfeeding Association) using the key words 'smoking' and 'breastfeeding' or 'infant feeding'. The Journal of Human Lactation and Birth were hand searched. Women who smoke are less likely to intend to breastfeed, less likely to initiate breastfeeding, and likely to breastfeed for a shorter duration than nonsmokers. Several studies have found a dose-response relationship between the number of cigarettes smoked each day and breastfeeding intention, initiation, and duration that persists after adjusting for confounding factors. In some population groups a high proportion of smokers breastfeed successfully. The association between maternal smoking and lack of breastfeeding is consistent across different study designs in a range of countries. Given that women who smoke are less likely to intend to breastfeed, however, it cannot be assumed that the relationship between smoking and duration of breastfeeding is a physiological one. If smoking had a consistent negative physiological effect on lactation, one would not expect to see such wide variations in breastfeeding rates among women who smoke. Therefore, it is likely that psychosocial factors are largely responsible for the lower rates of breastfeeding found in women who smoke compared with those who do not.

Does maternal smoking have a negative physiological effect on breastfeeding? The epidemiological evidence.

BACKGROUND: Women who smoke are less likely to breastfeed their children than nonsmokers. It is thought that nicotine has a negative effect on breastmilk supply by suppressing prolactin levels. The aim of this review was to assess the epidemiological evidence that maternal smoking has a negative physiological effect on breastfeeding. METHODS: The following data sources were searched: The Cochrane Library, Medline, CINAHL, Current Contents, Psychinfo, Sociological Abstracts and the Lactation Resource Centre (Australian Breastfeeding Association) using the key words "smoking" and "breastfeeding" or "infant feeding." The Journal of Human Lactation and Birth were hand searched. RESULTS: Women who smoke are less likely to intend to breastfeed, less likely to initiate breastfeeding, and likely to breastfeed for a shorter duration than nonsmokers. Several studies have found a dose-response relationship between the number of cigarettes smoked each day and breastfeeding intention, initiation, and duration that persists after adjusting for confounding factors. In some population groups a high proportion of smokers breastfeed successfully. CONCLUSIONS: The association between maternal smoking and lack of breastfeeding is consistent across different study designs in a range of countries. Given that women who smoke are less likely to intend to breastfeed, however, it cannot be assumed that the relationship between smoking and duration of breastfeeding is a physiological one. If smoking had a consistent negative physiological effect on lactation, one would not expect to see such wide variations in breastfeeding rates among women who smoke. Therefore, it is likely that psychosocial factors are largely responsible for the lower rates of breastfeeding found in women who smoke compared with those who do not.