Randomized Trial of BCG Vaccine to Protect against Covid-19 in Health Care Workers.

BACKGROUND: The bacille Calmette-Guérin (BCG) vaccine has immunomodulatory "off-target" effects that have been hypothesized to protect against coronavirus disease 2019 (Covid-19). METHODS: In this international, double-blind, placebo-controlled trial, we randomly assigned health care workers to receive the BCG-Denmark vaccine or saline placebo and followed them for 12 months. Symptomatic Covid-19 and severe Covid-19, the primary outcomes, were assessed at 6 months; the primary analyses involved the modified intention-to-treat population, which was restricted to participants with a negative test for severe acute respiratory syndrome coronavirus 2 at baseline. RESULTS: A total of 3988 participants underwent randomization; recruitment ceased before the planned sample size was reached owing to the availability of Covid-19 vaccines. The modified intention-to-treat population included 84.9% of the participants who underwent randomization: 1703 in the BCG group and 1683 in the placebo group. The estimated risk of symptomatic Covid-19 by 6 months was 14.7% in the BCG group and 12.3% in the placebo group (risk difference, 2.4 percentage points; 95% confidence interval [CI], -0.7 to 5.5; P = 0.13). The risk of severe Covid-19 by 6 months was 7.6% in the BCG group and 6.5% in the placebo group (risk difference, 1.1 percentage points; 95% CI, -1.2 to 3.5; P = 0.34); the majority of participants who met the trial definition of severe Covid-19 were not hospitalized but were unable to work for at least 3 consecutive days. In supplementary and sensitivity analyses that used less conservative censoring rules, the risk differences were similar but the confidence intervals were narrower. There were five hospitalizations due to Covid-19 in each group (including one death in the placebo group). The hazard ratio for any Covid-19 episode in the BCG group as compared with the placebo group was 1.23 (95% CI, 0.96 to 1.59). No safety concerns were identified. CONCLUSIONS: Vaccination with BCG-Denmark did not result in a lower risk of Covid-19 among health care workers than placebo. (Funded by the Bill and Melinda Gates Foundation and others; BRACE ClinicalTrials.gov number, NCT04327206.).

Success of blinding a procedural intervention in a randomised controlled trial in preterm infants receiving respiratory support.

BACKGROUND: Blinding of treatment allocation from treating clinicians in neonatal randomised controlled trials can minimise performance bias, but its effectiveness is rarely assessed. METHODS: To examine the effectiveness of blinding a procedural intervention from treating clinicians in a multicentre randomised controlled trial of minimally invasive surfactant therapy versus sham treatment in preterm infants of gestation 25-28 weeks with respiratory distress syndrome. The intervention (minimally invasive surfactant therapy or sham) was performed behind a screen within the first 6 h of life by a 'study team' uninvolved in clinical care including decision-making. Procedure duration and the study team's words and actions during the sham treatment mimicked those of the minimally invasive surfactant therapy procedure. Post-intervention, three clinicians completed a questionnaire regarding perceived group allocation, with the responses matched against actual intervention and categorised as correct, incorrect, or unsure. Success of blinding was calculated using validated blinding indices applied to the data overall (James index, successful blinding defined as > 0.50), or to the two treatment allocation groups (Bang index, successful blinding: -0.30 to 0.30). Blinding success was measured within staff role, and the associations between blinding success and procedural duration and oxygenation improvement post-procedure were estimated. RESULTS: From 1345 questionnaires in relation to a procedural intervention in 485 participants, responses were categorised as correct in 441 (33%), incorrect in 142 (11%), and unsure in 762 (57%), with similar proportions for each of the response categories in the two treatment arms. The James index indicated successful blinding overall 0.67 (95% confidence interval (CI) 0.65-0.70). The Bang index was 0.28 (95% CI 0.23-0.32) in the minimally invasive surfactant therapy group and 0.17 (95% CI 0.12-0.21) in the sham arm. Neonatologists more frequently guessed the correct intervention (47%) than bedside nurses (36%), neonatal trainees (31%), and other nurses (24%). For the minimally invasive surfactant therapy intervention, the Bang index was linearly related to procedural duration and oxygenation improvement post-procedure. No evidence of such relationships was seen in the sham arm. CONCLUSION: Blinding of a procedural intervention from clinicians is both achievable and measurable in neonatal randomised controlled trials.

Two-Year Outcomes After Minimally Invasive Surfactant Therapy in Preterm Infants: Follow-Up of the OPTIMIST-A Randomized Clinical Trial.

Importance: The long-term effects of surfactant administration via a thin catheter (minimally invasive surfactant therapy [MIST]) in preterm infants with respiratory distress syndrome remain to be definitively clarified. Objective: To examine the effect of MIST on death or neurodevelopmental disability (NDD) at 2 years' corrected age. Design, Setting, and Participants: Follow-up study of a randomized clinical trial with blinding of clinicians and outcome assessors conducted in 33 tertiary-level neonatal intensive care units in 11 countries. The trial included 486 infants with a gestational age of 25 to 28 weeks supported with continuous positive airway pressure (CPAP). Collection of follow-up data at 2 years' corrected age was completed on December 9, 2022. Interventions: Infants assigned to MIST (n = 242) received exogenous surfactant (200 mg/kg poractant alfa) via a thin catheter; those assigned to the control group (n = 244) received sham treatment. Main Outcomes and Measures: The key secondary outcome of death or moderate to severe NDD was assessed at 2 years' corrected age. Other secondary outcomes included components of this composite outcome, as well as hospitalizations for respiratory illness and parent-reported wheezing or breathing difficulty in the first 2 years. Results: Among the 486 infants randomized, 453 had follow-up data available (median gestation, 27.3 weeks; 228 females [50.3%]); data on the key secondary outcome were available in 434 infants. Death or NDD occurred in 78 infants (36.3%) in the MIST group and 79 (36.1%) in the control group (risk difference, 0% [95% CI, -7.6% to 7.7%]; relative risk [RR], 1.0 [95% CI, 0.81-1.24]); components of this outcome did not differ significantly between groups. Secondary respiratory outcomes favored the MIST group. Hospitalization with respiratory illness occurred in 49 infants (25.1%) in the MIST group vs 78 (38.2%) in the control group (RR, 0.66 [95% CI, 0.54-0.81]) and parent-reported wheezing or breathing difficulty in 73 (40.6%) vs 104 (53.6%), respectively (RR, 0.76 [95% CI, 0.63-0.90]). Conclusions and Relevance: In this follow-up study of a randomized clinical trial of preterm infants with respiratory distress syndrome supported with CPAP, MIST compared with sham treatment did not reduce the incidence of death or NDD by 2 years of age. However, infants who received MIST had lower rates of adverse respiratory outcomes during their first 2 years of life. Trial Registration: anzctr.org.au Identifier: ACTRN12611000916943.

A randomized controlled trial of remote microphone listening devices to treat auditory deficits in children with neurofibromatosis type 1.

BACKGROUND: A high proportion of patients with neurofibromatosis type 1 (NF1) present with functional hearing deficiency as a result of neural abnormality in the late auditory brainstem. METHODS: In this randomized, two-period crossover study, we investigated the hypothesis that remote-microphone listening devices can ameliorate hearing and communication deficits in affected school-aged children (7-17 years). Speech perception ability in background noise was evaluated in device-active and inactive conditions using the CNC-word test. Participants were then randomized to one of two treatment sequences: (1) inactive device for two weeks (placebo), followed by active device use for two weeks, or (2) active device for 2 weeks, followed by inactive device for 2 weeks. Listening and communication ratings (LIFE-R Questionnaire) were obtained at baseline and at the end of each treatment phase. RESULTS: Each participant demonstrated functional hearing benefits with remote-microphone use. All showed a speech perception in noise increase when the device was activated with a mean phoneme-score difference of 16.4% (p < 0.001) and reported improved listening/communication abilities in the school classroom (mean difference: 23.4%; p = 0.017). DISCUSSION: Conventional hearing aids are typically ineffective as a treatment for auditory neural dysfunction, making sounds louder, but not clearer for affected individuals. In this study, we demonstrate that remote-microphone technologies are acceptable/tolerable in pediatric patients with NF1 and can ameliorate their hearing deficits. CONCLUSION: Remote-microphone listening systems offer a viable treatment option for children with auditory deficits associated with NF1.

Sustainability of evidence-based practices in the management of infants with bronchiolitis in hospital settings - a PREDICT study protocol.

BACKGROUND: Understanding how and why de-implementation of low-value practices is sustained remains unclear. The Paediatric Research in Emergency Departments International CollaboraTive (PREDICT) Bronchiolitis Knowledge Translation (KT) Study was a cluster randomised controlled trial conducted in 26 Australian and New Zealand hospitals (May-November 2017). Results showed targeted, theory-informed interventions (clinical leads, stakeholder meetings, train-the-trainer workshop, targeted educational package, audit/feedback) were effective at reducing use of five low-value practices for bronchiolitis (salbutamol, glucocorticoids, antibiotics, adrenaline and chest x-ray) by 14.1% in acute care settings. The primary aim of this study is to determine the sustainability (continued receipt of benefits) of these outcomes at intervention hospitals two-years after the removal of study supports. Secondary aims are to determine sustainability at one-year after removal of study support at intervention hospitals; improvements one-and-two years at control hospitals; and explore factors that influence sustainability at intervention hospitals and contribute to improvements at control hospitals. METHODS: A mixed-methods study design. The quantitative component is a retrospective medical record audit of bronchiolitis management within 24 hours of emergency department (ED) presentations at 26 Australian (n = 20) and New Zealand (n = 6) hospitals, which participated in the PREDICT Bronchiolitis KT Study. Data for a total of 1800 infants from intervention and control sites (up to 150 per site) will be collected to determine if improvements (i.e., no use of all five low-value practices) were sustained two- years (2019) post-trial (primary outcome; composite score); and a further 1800 infants from intervention and control sites will be collected to determine sustained improvements one- year (2018) post-trial (secondary outcome). An a priori definition of sustainability will be used. The qualitative component will consist of semi-structured interviews with three to five key emergency department and paediatric inpatient medical and nursing staff per site (total n = 78-130). Factors that may have contributed to sustaining outcomes and/or interventions will be explored and mapped to an established sustainability framework. DISCUSSION: This study will improve our understanding of the sustainability of evidence-based bronchiolitis management in infants. Results will also advance implementation science research by informing future de-implementation strategies to reduce low-value practices and sustain practice change in paediatric acute care. TRIAL REGISTRATION: Australian and New Zealand Clinical Trials Registry No: ACTRN12621001287820.

A pilot feasibility study of gabapentin for managing pain in children with dystonic cerebral palsy.

BACKGROUND: Gabapentin is often used to manage pain in children with dystonic cerebral palsy, however the evidence for its effectiveness in this population is limited. The primary objective of this feasibility pilot study was to assess the factors which might impact on a future randomised controlled trial including the ability to recruit and retain participants, assess adherence/compliance to the prescribed intervention, and ability to complete all outcome assessments. The secondary objective was to gather preliminary evidence for the effectiveness of gabapentin at reducing pain, improving comfort and reducing dystonia in children with dystonic cerebral palsy. METHODS: This open label pilot study recruited children aged 5-18 years with dystonic cerebral palsy and accompanying pain affecting daily activities from four centres around Australia. Children were prescribed gabapentin for 12 weeks and were assessed at baseline, 6 weeks and 12 weeks. The primary outcome was feasibility of the protocol. Secondary outcomes were pain behaviour, pain intensity, care and comfort, individualised goal setting and dystonia severity. RESULTS: Thirteen children (mean age 10.4 years (SD 2.4yrs), 9 females) were recruited from 71 screened over 15 months. Two children withdrew while eight children experienced side effects. There were issues with adherence to medication dosage regimens and data collection. Improvements were seen in pain behaviour, comfort and pain related goals at 12 weeks. Dystonia was not significantly changed. CONCLUSIONS: Whilst gabapentin has potential to improve pain and comfort in children with dystonic CP, the feasibility of implementing a definitive randomised controlled trial is low. Alternative trials designs are required to further examine the effectiveness of gabapentin in this heterogeneous population. TRIAL REGISTRATION: The trial was registered with the Australian Clinical Trial Registry ( ACTRN12616000366459 ) on 22/03/2016 and the Therapeutic Goods Administration (CT-2016-CTN-00500-1) on 22/06/2016.

Minimising Immunisation Pain of childhood vaccines: The MIP pilot study.

AIM: Pain associated with immunisations can result in distress and/or anxiety for children and parents. We assessed the feasibility and acceptability of two novel devices; Coolsense (cold) and Buzzy (vibration ± cooling pads) versus standard care to minimise pain during immunisations. We also evaluated compliance to the devices and parent's perception of the effectiveness of the devices/standard care for minimising pain during immunisation. DESIGN: Open label, pilot, randomised controlled trial (RCT). METHODS: Forty children aged 3.5 to 6 years attending an Immunisation Centre at The Royal Children's Hospital in Melbourne, Australia, were randomised (1:1:1:1) into four groups: (i) Coolsense plus standard care; (ii) Buzzy with cold plus standard care; (iii) Buzzy without cold plus standard care; and (iv) Standard care alone (distraction with bubbles). RESULTS AND ANALYSIS: Recruitment was completed in 12 days. Seventy percent were compliant with Buzzy (±cold), 82% with Coolsense, and 60% with standard care. Buzzy (with cold) was identified as effective by 70% of parents, Coolsense by 64%, Buzzy without cold by 50% and standard care by 60%. CONCLUSIONS: This pilot study demonstrated feasibility. A larger RCT is needed to provide definitive evidence to inform best practice for minimising immunisation pain in young children.

Process evaluation of a cluster randomised controlled trial to improve bronchiolitis management - a PREDICT mixed-methods study.

BACKGROUND: Bronchiolitis is the most common reason for hospitalisation in infants. All international bronchiolitis guidelines recommend supportive care, yet considerable variation in practice continues with infants receiving non-evidence based therapies. We developed six targeted, theory-informed interventions; clinical leads, stakeholder meeting, train-the-trainer, education delivery, other educational materials, and audit and feedback. A cluster randomised controlled trial (cRCT) found the interventions to be effective in reducing use of five non-evidence based therapies in infants with bronchiolitis. This process evaluation paper aims to determine whether the interventions were implemented as planned (fidelity), explore end-users' perceptions of the interventions and evaluate cRCT outcome data with intervention fidelity data. METHODS: A pre-specified mixed-methods process evaluation was conducted alongside the cRCT, guided by frameworks for process evaluation of cRCTs and complex interventions. Quantitative data on the fidelity, dose and reach of interventions were collected from the 13 intervention hospitals during the study and analysed using descriptive statistics. Qualitative data identifying perception and acceptability of interventions were collected from 42 intervention hospital clinical leads on study completion and analysed using thematic analysis. RESULTS: The cRCT found targeted, theory-informed interventions improved bronchiolitis management by 14.1%. The process evaluation data found variability in how the intervention was delivered at the cluster and individual level. Total fidelity scores ranged from 55 to 98% across intervention hospitals (mean = 78%; SD = 13%). Fidelity scores were highest for use of clinical leads (mean = 98%; SD = 7%), and lowest for use of other educational materials (mean = 65%; SD = 19%) and audit and feedback (mean = 65%; SD = 20%). Clinical leads reflected positively about the interventions, with time constraints being the greatest barrier to their use. CONCLUSION: Our targeted, theory-informed interventions were delivered with moderate fidelity, and were well received by clinical leads. Despite clinical leads experiencing challenges of time constraints, the level of fidelity had a positive effect on successfully de-implementing non-evidence-based care in infants with bronchiolitis. These findings will inform widespread rollout of our bronchiolitis interventions, and guide future practice change in acute care settings. TRIAL REGISTRATION: Australian and New Zealand Clinical Trials Registry: ACTRN12616001567415 .

Effect of Minimally Invasive Surfactant Therapy vs Sham Treatment on Death or Bronchopulmonary Dysplasia in Preterm Infants With Respiratory Distress Syndrome: The OPTIMIST-A Randomized Clinical Trial.

Importance: The benefits of surfactant administration via a thin catheter (minimally invasive surfactant therapy [MIST]) in preterm infants with respiratory distress syndrome are uncertain. Objective: To examine the effect of selective application of MIST at a low fraction of inspired oxygen threshold on survival without bronchopulmonary dysplasia (BPD). Design, Setting, and Participants: Randomized clinical trial including 485 preterm infants with a gestational age of 25 to 28 weeks who were supported with continuous positive airway pressure (CPAP) and required a fraction of inspired oxygen of 0.30 or greater within 6 hours of birth. The trial was conducted at 33 tertiary-level neonatal intensive care units around the world, with blinding of the clinicians and outcome assessors. Enrollment took place between December 16, 2011, and March 26, 2020; follow-up was completed on December 2, 2020. Interventions: Infants were randomized to the MIST group (n = 241) and received exogenous surfactant (200 mg/kg of poractant alfa) via a thin catheter or to the control group (n = 244) and received a sham (control) treatment; CPAP was continued thereafter in both groups unless specified intubation criteria were met. Main Outcomes and Measures: The primary outcome was the composite of death or physiological BPD assessed at 36 weeks' postmenstrual age. The components of the primary outcome (death prior to 36 weeks' postmenstrual age and BPD at 36 weeks' postmenstrual age) also were considered separately. Results: Among the 485 infants randomized (median gestational age, 27.3 weeks; 241 [49.7%] female), all completed follow-up. Death or BPD occurred in 105 infants (43.6%) in the MIST group and 121 (49.6%) in the control group (risk difference [RD], -6.3% [95% CI, -14.2% to 1.6%]; relative risk [RR], 0.87 [95% CI, 0.74 to 1.03]; P = .10). Incidence of death before 36 weeks' postmenstrual age did not differ significantly between groups (24 [10.0%] in MIST vs 19 [7.8%] in control; RD, 2.1% [95% CI, -3.6% to 7.8%]; RR, 1.27 [95% CI, 0.63 to 2.57]; P = .51), but incidence of BPD in survivors to 36 weeks' postmenstrual age was lower in the MIST group (81/217 [37.3%] vs 102/225 [45.3%] in the control group; RD, -7.8% [95% CI, -14.9% to -0.7%]; RR, 0.83 [95% CI, 0.70 to 0.98]; P = .03). Serious adverse events occurred in 10.3% of infants in the MIST group and 11.1% in the control group. Conclusions and Relevance: Among preterm infants with respiratory distress syndrome supported with CPAP, minimally invasive surfactant therapy compared with sham (control) treatment did not significantly reduce the incidence of the composite outcome of death or bronchopulmonary dysplasia at 36 weeks' postmenstrual age. However, given the statistical uncertainty reflected in the 95% CI, a clinically important effect cannot be excluded. Trial Registration: anzctr.org.au Identifier: ACTRN12611000916943.

Integrating trials into a whole-population cohort of children and parents: statement of intent (trials) for the Generation Victoria (GenV) cohort.

BACKGROUND: Very large cohorts that span an entire population raise new prospects for the conduct of multiple trials that speed up advances in prevention or treatment while reducing participant, financial and regulatory burden. However, a review of literature reveals no blueprint to guide this systematically in practice. This Statement of Intent proposes how diverse trials may be integrated within or alongside Generation Victoria (GenV), a whole-of-state Australian birth cohort in planning, and delineates potential processes and opportunities. METHODS: Parents of all newborns (estimated 160,000) in the state of Victoria, Australia, will be approached for two full years from 2021. The cohort design comprises four elements: (1) consent soon after birth to follow the child and parent/s until study end or withdrawal; retrospective and prospective (2) linkage to clinical and administrative datasets and (3) banking of universal and clinical biosamples; and (4) GenV-collected biosamples and data. GenV-collected data will focus on overarching outcome and phenotypic measures using low-burden, universal-capable electronic interfaces, with funding-dependent face-to-face assessments tailored to universal settings during the early childhood, school and/or adult years. RESULTS: For population or registry-type trials within GenV, GenV will provide all outcomes data and consent via traditional, waiver, or Trials Within Cohorts models. Trials alongside GenV consent their own participants born within the GenV window; GenV may help identify potential participants via opt-in or opt-out expression of interest. Data sharing enriches trials with outcomes, prior data, and/or access to linked data contingent on custodian's agreements, and supports modeling of causal effects to the population and between-trials comparisons of costs, benefits and utility. Data access will operate under the Findability, Accessibility, Interoperability, and Reusability (FAIR) and Care and Five Safes Principles. We consider governance, ethical and shared trial oversight, and expectations that trials will adhere to the best practice of the day. CONCLUSIONS: Children and younger adults can access fewer trials than older adults. Integrating trials into mega-cohorts should improve health and well-being by generating faster, larger-scale evidence on a longer and/or broader horizon than previously possible. GenV will explore the limits and details of this approach over the coming years.

Association of Center-Specific Patient Volumes and Early Respiratory Management Practices with Death and Bronchopulmonary Dysplasia in Preterm Infants.

OBJECTIVES: To describe variability in admission volumes and approach to early respiratory support between neonatal intensive care units in the Australian and New Zealand Neonatal Network and to evaluate whether these center-specific factors are associated with death and bronchopulmonary dysplasia. STUDY DESIGN: This retrospective cohort study included 19 099 neonates born between 25 and 32 weeks' gestation and admitted to 1 of 25 NICUs from 2007 to 2013. Center-specific factors evaluated were annual admission volume and rate of using continuous positive airway pressure (CPAP) rather than intubation as the first mode of respiratory support. Logistic regression was used to examine any association of these center-specific factors with death, BPD, and death or survival with BPD (death/BPD). Analysis was performed separately for 2 gestation groups (25-28 weeks and 29-32 weeks inclusive). RESULTS: Admission volumes and rates of early CPAP use varied widely across centers. Higher admission volumes were associated with lower odds of death or survival with BPD in the 25-28 week group (aOR 0.93, 99% CI 0.88-0.99 per increase of 10 babies per center annually). Centers with higher early CPAP use did not have lower odds of death or BPD than centers that intubated more frequently. CONCLUSIONS: Higher admission volumes are associated with more favorable outcomes for the more preterm infants in the Australian and New Zealand Neonatal Network. Further investigation is required to explore why the individual benefits of early CPAP do not translate to better outcomes for centers that use this approach most frequently.

Effect of Fluoxetine on Obsessive-Compulsive Behaviors in Children and Adolescents With Autism Spectrum Disorders: A Randomized Clinical Trial.

Importance: Selective serotonin receptor inhibitors are prescribed to reduce the severity of core behaviors of autism spectrum disorders, but their efficacy remains uncertain. Objective: To determine the efficacy of fluoxetine for reducing the frequency and severity of obsessive-compulsive behaviors in autism spectrum disorders. Design, Setting, and Participants: Multicenter, randomized, placebo-controlled clinical trial. Participants aged 7.5-18 years with autism spectrum disorders and a total score of 6 or higher on the Children's Yale-Brown Obsessive Compulsive Scale, modified for pervasive developmental disorder (CYBOCS-PDD) were recruited from 3 tertiary health centers across Australia. Enrollment began November 2010 and ended April 2017. Follow-up ended August 2017. Interventions: Participants were randomized to receive fluoxetine (n = 75) or placebo (n = 71). Study medication was commenced at 4 or 8 mg/d for the first week, depending on weight, and then titrated to a maximum dose of 20 or 30 mg/d over 4 weeks. Treatment duration was 16 weeks. Main Outcomes and Measures: The primary outcome was the total score on the CYBOCS-PDD (scores range from 0-20; higher scores indicate higher levels of maladaptive behaviors; minimal clinically important difference, 2 points) at 16 weeks postrandomization, analyzed with a linear regression model adjusted for stratification factors (site, age at baseline, and intellectual disability), with an additional prespecified model that included additional adjustment for baseline score, sex, communication level, and imbalanced baseline and demographic variables. Results: Among the 146 participants who were randomized (85% males; mean age, 11.2 years), 109 completed the trial; 31 in the fluoxetine group and 21 in the placebo group dropped out or did not complete treatment. The mean CYBOCS-PDD score from baseline to 16 weeks decreased in the fluoxetine group from 12.80 to 9.02 points (3.72-point decrease; 95% CI, -4.85 to -2.60) and in the placebo group from 13.13 to 10.89 points (2.53-point decrease; 95% CI, -3.86 to -1.19). The between-group mean difference at 16 weeks was -2.01 (95% CI, -3.77 to -0.25; P = .03) (adjusted for stratification factors), and in the prespecified model with further adjustment, it was -1.17 (95% CI, -3.01 to 0.67; P = .21). Conclusions and Relevance: In this preliminary study of children and adolescents with autism spectrum disorders, treatment with fluoxetine compared with placebo resulted in significantly lower scores for obsessive-compulsive behaviors at 16 weeks. Interpretation is limited by the high dropout rate, null findings of prespecified analyses that accounted for potentially confounding factors and baseline imbalances, and CIs for the treatment effect that included the minimal clinically important difference. Trial Registration: anzctr.org.au Identifier: ACTRN12608000173392.

Implementing evidence-based practices in the care of infants with bronchiolitis in Australasian acute care settings: study protocol for a cluster randomised controlled study.

BACKGROUND: Bronchiolitis is the most common reason for admission to hospital for infants less than one year of age. Although management is well defined, there is substantial variation in practice, with infants receiving ineffective therapies or management. This study will test the effectiveness of tailored, theory informed knowledge translation (KT) interventions to decrease the use of five clinical therapies or management processes known to be of no benefit, compared to usual dissemination practices in infants with bronchiolitis. The primary objective is to establish whether the KT interventions are effective in increasing compliance to five evidence based recommendations in the first 24 h following presentation to hospital. The five recommendations are that infants do not receive; salbutamol, antibiotics, glucocorticoids, adrenaline, or a chest x-ray. METHODS/DESIGN: This study is designed as a cluster randomised controlled trial. We will recruit 24 hospitals in Australia and New Zealand, stratified by country and provision of tertiary or secondary paediatric care. Hospitals will be randomised to either control or intervention groups. Control hospitals will receive a copy of the recent Australasian Bronchiolitis Guideline. Intervention hospitals will receive KT interventions informed by a qualitative analysis of factors influencing clinician care of infants with bronchiolitis. Key interventions include, local stakeholder meetings, identifying medical and nursing clinical leads in both emergency departments and paediatric inpatient areas who will attend a single education train-the-trainer day to then deliver standardised staff education with the training materials provided and coordinate audit and feedback reports locally over the study period. Data will be extracted retrospectively for three years prior to the study intervention year, and for seven months of the study intervention year bronchiolitis season following intervention delivery to determine compliance with the five evidence-based recommendations. Data will be collected to assess fidelity to the implementation strategies and to facilitate an economic evaluation. DISCUSSION: This study will contribute to the body of knowledge to determine the effectiveness of tailored, theory informed interventions in acute care paediatric settings, with the aim of reducing the evidence to practice gaps in the care of infants with bronchiolitis. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry ACTRN12616001567415 (retrospectively registered on 14 November 2016).

What do Clinicians Perceive as a Successful "Trial of Fluids"?: A Secondary Assessment of a Randomized Controlled Trial.

OBJECTIVE: The aim of the study was to explore physician perceptions of the amount of fluid that demonstrates a successful "trial of fluids" (adequate fluid intake) in the emergency department in children who have had insufficient fluid intake at home. METHODS: This is a secondary analysis of a randomized placebo-controlled trial of viscous lidocaine versus placebo in children aged 6 months to 8 years with acute infectious ulcerative mouth conditions (gingivostomatitis, ulcerative pharyngitis, or hand foot and mouth disease) and poor oral fluid intake. We measured the amount of fluid ingested in 60 minutes after administration of the intervention and related physician perception of adequate intake to measured intake. Given that there was little difference in oral intake between the treatment groups, the 2 arms were pooled for this analysis. RESULTS: One hundred participants were recruited (50 per treatment group), all of whom completed the 60-minute trial period. At baseline, 72% were mildly dehydrated, 21% were not dehydrated, and 5% were moderately dehydrated. The participants drank a median of 8.6 mL/kg (interquartile range [IQR], 3.7-14). Clinicians perceived 58% of the participants to have an adequate intake within the first hour after intervention. The median consumption of those whose oral intake was deemed as adequate was 12.6 mL/kg (IQR, 9.4-18.4); for those whose oral intake was not deemed adequate, the median consumption was 2.7 mL/kg (IQR, 0.7-5.3) (rank sum, P < 0.001). CONCLUSIONS: In children undergoing trial of fluids, we found that most clinicians perceived a fluid intake greater than 9 mL/kg as adequate and lower than 5 mL/kg as inadequate.

Comparison of lumbar epidural bupivacaine with fentanyl or clonidine for postoperative analgesia in children with cerebral palsy after single-event multilevel surgery.

AIM: To compare diazepam use, muscle spasm, analgesia, and side effects when clonidine or fentanyl are added to epidural bupivacaine in children with cerebral palsy after multilevel orthopaedic surgery. METHOD: Fifty children were prospectively randomized to receive clonidine (n=24, mean age 10y 10mo [SD 2y 11mo]) or fentanyl (n=26, mean age 10y 11mo [SD 2y 10mo]). RESULTS: There was no difference in primary outcome measures: median diazepam use (fentanyl 0, interquartile range [IQR] 0-0; clonidine 0, IQR 0-0; p=0.46), any muscle spasm (no muscle spasms in: fentanyl, 36%; clonidine, 62%; p=0.11), painful muscle spasm (fentanyl 40%; clonidine 25%; p=0.46), or pain score ≥6 (none: fentanyl 44%; clonidine 42%; p=0.29). There were differences in secondary outcome measures: no vomiting (clonidine 63%; fentanyl 20%); vomiting occurred more frequently with fentanyl (32% vomited more than three times; clonidine none; p=0.001). Fentanyl resulted in more oxygen desaturation (at least two episodes: fentanyl 20%; clonidine 0; p<0.001). Clonidine resulted in lower mean (SD) area under the curve for systolic blood pressure (fentanyl 106.5 [11.0]; clonidine 95.7mmHg [7.9]) and heart rate (fentanyl 104.9 beats per minute [13.6]; clonidine 85.3 [11.5]; p<0.001). INTERPRETATION: Clonidine and fentanyl provide adequate analgesia with low rates of muscle spasm, resulting in low diazepam use. The choice of epidural additive should be based upon the most tolerable side-effect profile.

"Did you ever drink more?" A detailed description of pregnant women's drinking patterns.

BACKGROUND: This paper presents drinking patterns in a prospective study of a population-based cohort of 1570 pregnant women using a combination of dose and timing to give best estimates of prenatal alcohol exposure (PAE). Novel assessments include women's special occasion drinking and alcohol use prior to pregnancy recognition. METHODS: Information on up to nine types of alcoholic drink, with separate frequencies and volumes, including drinking on special occasions outside a 'usual' pattern, was collected for the periconceptional period and at four pregnancy time points. Weekly total and maximum alcohol consumption on any one occasion was calculated and categorised. Drinking patterns are described in the context of predictive maternal characteristics. RESULTS: 41.3 % of women did not drink during pregnancy, 27 % drank in first trimester only; most of whom stopped once they realised they were pregnant (87 %). When compared to women who abstained from alcohol when pregnant, those who drank in the first trimester only were more likely to have an unplanned pregnancy and not feel the effects of alcohol quickly. Almost a third of women continued to drink alcohol at some level throughout pregnancy (27 %), around half of whom never drank more than at low or moderate levels. When compared with abstainers and to women who only drank in trimester one, those who drank throughout pregnancy tended to be in their early to mid-thirties, smoke, have a higher income and educational attainment. Overall, almost one in five women (18.5 %) binge drank prior to pregnancy recognition, a third of whom were identified with a question about 'special occasion' drinking. Women whose age at first intoxication was less than 18 years (the legal drinking age in Australia), were significantly more likely to drink in pregnancy and at binge levels prior to pregnancy recognition. CONCLUSIONS: We have identified characteristics of pregnant women who either abstain, drink until pregnancy awareness or drink throughout pregnancy. These may assist in targeting strategies to enhance adherence to an abstinence policy and ultimately allow for appropriate follow-up and interpretation of adverse child outcomes. Our methodology also produced important information to reduce misclassification of occasional binge drinking episodes and ensure clearly defined comparison groups.

Minimising impairment: Protocol for a multicentre randomised controlled trial of upper limb orthoses for children with cerebral palsy.

BACKGROUND: Upper limb orthoses are frequently prescribed for children with cerebral palsy (CP) who have muscle overactivity predominantly due to spasticity, with little evidence of long-term effectiveness. Clinical consensus is that orthoses help to preserve range of movement: nevertheless, they can be complex to construct, expensive, uncomfortable and require commitment from parents and children to wear. This protocol paper describes a randomised controlled trial to evaluate whether long-term use of rigid wrist/hand orthoses (WHO) in children with CP, combined with usual multidisciplinary care, can prevent or reduce musculoskeletal impairments, including muscle stiffness/tone and loss of movement range, compared to usual multidisciplinary care alone. METHODS/DESIGN: This pragmatic, multicentre, assessor-blinded randomised controlled trial with economic analysis will recruit 194 children with CP, aged 5-15 years, who present with flexor muscle stiffness of the wrist and/or fingers/thumb (Modified Ashworth Scale score ≥1). Children, recruited from treatment centres in Victoria, New South Wales and Western Australia, will be randomised to groups (1:1 allocation) using concealed procedures. All children will receive care typically provided by their treating organisation. The treatment group will receive a custom-made serially adjustable rigid WHO, prescribed for 6 h nightly (or daily) to wear for 3 years. An application developed for mobile devices will monitor WHO wearing time and adverse events. The control group will not receive a WHO, and will cease wearing one if previously prescribed. Outcomes will be measured 6 monthly over a period of 3 years. The primary outcome is passive range of wrist extension, measured with fingers extended using a goniometer at 3 years. Secondary outcomes include muscle stiffness, spasticity, pain, grip strength and hand deformity. Activity, participation, quality of life, cost and cost-effectiveness will also be assessed. DISCUSSION: This study will provide evidence to inform clinicians, services, funding agencies and parents/carers of children with CP whether the provision of a rigid WHO to reduce upper limb impairment, in combination with usual multidisciplinary care, is worth the effort and costs. TRIAL REGISTRATION: ANZ Clinical Trials Registry: U1111-1164-0572 .

Administration of a probiotic with peanut oral immunotherapy: A randomized trial.

BACKGROUND: Coadministration of a bacterial adjuvant with oral immunotherapy (OIT) has been suggested as a potential treatment for food allergy. OBJECTIVE: To evaluate a combined therapy comprising a probiotic together with peanut OIT. METHODS: We performed a double-blind, placebo-controlled randomized trial of the probiotic Lactobacillus rhamnosus CGMCC 1.3724 and peanut OIT (probiotic and peanut oral immunotherapy [PPOIT]) in children (1-10 years) with peanut allergy. The primary outcome was induction of sustained unresponsiveness 2 to 5 weeks after discontinuation of treatment (referred to as possible sustained unresponsiveness). Secondary outcomes were desensitization, peanut skin prick test, and specific IgE and specific IgG4 measurements. RESULTS: Sixty-two children were randomized and stratified by age (≤5 and >5 years) and peanut skin test wheal size (≤10 and >10 mm); 56 reached the trial's end. Baseline demographics were similar across groups. Possible sustained unresponsiveness was achieved in 82.1% receiving PPOIT and 3.6% receiving placebo (P < .001). Nine children need to be treated for 7 to achieve sustained unresponsiveness (number needed to treat, 1.27; 95% CI, 1.06-1.59). Of the subjects, 89.7% receiving PPOIT and 7.1% receiving placebo were desensitized (P < .001). PPOIT was associated with reduced peanut skin prick test responses and peanut-specific IgE levels and increased peanut-specific IgG4 levels (all P < .001). PPOIT-treated participants reported a greater number of adverse events, mostly with maintenance home dosing. CONCLUSION: This is the first randomized placebo-controlled trial evaluating the novel coadministration of a probiotic and peanut OIT and assessing sustained unresponsiveness in children with peanut allergy. PPOIT was effective in inducing possible sustained unresponsiveness and immune changes that suggest modulation of the peanut-specific immune response. Further work is required to confirm sustained unresponsiveness after a longer period of secondary peanut elimination and to clarify the relative contributions of probiotics versus OIT.

The OPTIMIST-A trial: evaluation of minimally-invasive surfactant therapy in preterm infants 25-28 weeks gestation.

BACKGROUND: It is now recognized that preterm infants ≤28 weeks gestation can be effectively supported from the outset with nasal continuous positive airway pressure. However, this form of respiratory therapy may fail to adequately support those infants with significant surfactant deficiency, with the result that intubation and delayed surfactant therapy are then required. Infants following this path are known to have a higher risk of adverse outcomes, including death, bronchopulmonary dysplasia and other morbidities. In an effort to circumvent this problem, techniques of minimally-invasive surfactant therapy have been developed, in which exogenous surfactant is administered to a spontaneously breathing infant who can then remain on continuous positive airway pressure. A method of surfactant delivery using a semi-rigid surfactant instillation catheter briefly passed into the trachea (the "Hobart method") has been shown to be feasible and potentially effective, and now requires evaluation in a randomised controlled trial. METHODS/DESIGN: This is a multicentre, randomised, masked, controlled trial in preterm infants 25-28 weeks gestation. Infants are eligible if managed on continuous positive airway pressure without prior intubation, and requiring FiO2 ≥ 0.30 at an age ≤6 hours. Randomisation will be to receive exogenous surfactant (200 mg/kg poractant alfa) via the Hobart method, or sham treatment. Infants in both groups will thereafter remain on continuous positive airway pressure unless intubation criteria are reached (FiO2 ≥ 0.45, unremitting apnoea or persistent acidosis). Primary outcome is the composite of death or physiological bronchopulmonary dysplasia, with secondary outcomes including incidence of death; major neonatal morbidities; durations of all modes of respiratory support and hospitalisation; safety of the Hobart method; and outcome at 2 years. A total of 606 infants will be enrolled. The trial will be conducted in >30 centres worldwide, and is expected to be completed by end-2017. DISCUSSION: Minimally-invasive surfactant therapy has the potential to ease the burden of respiratory morbidity in preterm infants. The trial will provide definitive evidence on the effectiveness of this approach in the care of preterm infants born at 25-28 weeks gestation. TRIAL REGISTRATION: Australia and New Zealand Clinical Trial Registry: ACTRN12611000916943; ClinicalTrials.gov: NCT02140580.

The addition of tramadol to the standard of i.v. acetaminophen and morphine infusion for postoperative analgesia in neonates offers no clinical benefit: a randomized placebo-controlled trial.

BACKGROUND: Tramadol is used following neonatal cardiac and general surgery. However, its ability to opioid-spare or facilitate earlier extubation in postoperative neonates is unquantified. OBJECTIVE: This randomized placebo-controlled trial aimed to assess whether tramadol's addition to standard analgesia resulted in earlier extubation or reduced analgesic/sedative requirements in postsurgical neonates. METHODS: Neonates born ≥32 weeks postmenstrual age received either tramadol [T] 2 mg·kg(-1) or placebo [P] 6-hourly for up to 5 days postthoracoabdominal surgery in addition to morphine (commenced at 20 mcg·kg(-1) ·h(-1)) and 6-hourly i.v. acetaminophen. Time to extubation, morphine and midazolam amounts, hourly pain scores, and seizure activity were compared using an intention-to-treat and per-protocol analysis. RESULTS: Seventy-one neonates participated. Median survival time to extubation was similar between the groups (T 67 h [95% CI 51, 84] vs P 52 h [95%CI 43, 65]; P = 0.4), and similar numbers were extubated by 96 h (T 69% vs P 77%; difference -8%, 95%CI -28, 13%). Morphine and midazolam exposure was similar, with low pain scores in both groups (mean percentage of time with a pain score >5/20 during the 5 days: T 13% vs P 11%, difference in means 2.8 [95% CI -1.8, 7.6], P = 0.20). Most participants had normal cranial ultrasounds (T 86% vs P 86%); no seizures occurred clinically or electroencephalographically. CONCLUSION: Tramadol's addition to standard analgesia in this small group of postsurgical neonates did not appear to have any positive effect on time to extubation, morphine or midazolam exposure, or pain scores. This questions the benefit of tramadol for postsurgical neonates. Importantly, no seizures occurred in these ill neonates who may potentially be at greater risk of tramadol toxicity compared with adults.