Mechanisms to expedite pediatric clinical trial site activation: The DOSE trial experience.

BACKGROUND: Timely trial start-up is a key determinant of trial success; however, delays during start-up are common and costly. Moreover, data on start-up metrics in pediatric clinical trials are sparse. To expedite trial start-up, the Trial Innovation Network piloted three novel mechanisms in the trial titled Dexmedetomidine Opioid Sparing Effect in Mechanically Ventilated Children (DOSE), a multi-site, randomized, double-blind, placebo-controlled trial in the pediatric intensive care setting. METHODS: The three novel start-up mechanisms included: 1) competitive activation; 2) use of trial start-up experts, called site navigators; and 3) supplemental funds earned for achieving pre-determined milestones. After sites were activated, they received a web-based survey to report perceptions of the DOSE start-up process. In addition to perceptions, metrics analyzed included milestones met, time to start-up, and subsequent enrollment of subjects. RESULTS: Twenty sites were selected for participation, with 19 sites being fully activated. Across activated sites, the median (quartile 1, quartile 3) time from receipt of regulatory documents to site activation was 82 days (68, 113). Sites reported that of the three novel mechanisms, the most motivating factor for expeditious activation was additional funding available for achieving start-up milestones, followed by site navigator assistance and then competitive site activation. CONCLUSION: Study start-up is a critical time for the success of clinical trials, and innovative methods to minimize delays during start-up are needed. Milestone-based funds and site navigators were preferred mechanisms by sites participating in the DOSE study and may have contributed to the expeditious start-up timeline achieved. CLINICALTRIALS: gov #: NCT03938857.

Outcomes of Children With Critical Bronchiolitis Meeting at Risk for Pediatric Acute Respiratory Distress Syndrome Criteria.

OBJECTIVES: New definitions of pediatric acute respiratory distress syndrome include criteria to identify a subset of children "at risk for pediatric acute respiratory distress syndrome." We hypothesized that, among PICU patients with bronchiolitis not immediately requiring invasive mechanical ventilation, those meeting at risk for pediatric acute respiratory distress syndrome criteria would have worse clinical outcomes, including higher rates of pediatric acute respiratory distress syndrome development. DESIGN: Single-center, retrospective chart review. SETTING: Mixed medical-surgical PICU within a tertiary academic children's hospital. PATIENTS: Children 24 months old or younger admitted to the PICU with a primary diagnosis of bronchiolitis from September 2013 to April 2014. Children intubated before PICU arrival were excluded. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Collected data included demographics, respiratory support, oxygen saturation, and chest radiograph interpretation by staff radiologist. Oxygen flow (calculated as FIO2 × flow rate [L/min]) was calculated when oxygen saturation was 88-97%. The median age of 115 subjects was 5 months (2-11 mo). Median PICU length of stay was 2.8 days (1.5-4.8 d), and median hospital length of stay was 5 days (3-10 d). The criteria for at risk for pediatric acute respiratory distress syndrome was met in 47 of 115 subjects (40.9%). Children who were at risk for pediatric acute respiratory distress syndrome were more likely to develop pediatric acute respiratory distress syndrome (15/47 [31.9%] vs 1/68 [1.5%]; p < 0.001), had longer PICU length of stay (4.6 d [2.8-10.2 d] vs 1.9 d [1.0-3.1 d]; p < 0.001) and hospital length of stay (8 d [5-16 d] vs 4 d [2-6 d]; p < 0.001), and increased need for invasive mechanical ventilation (16/47 [34.0%] vs 2/68 [2.9%]; p < 0.001), compared with those children who did not meet at risk for pediatric acute respiratory distress syndrome criteria. CONCLUSIONS: Our data suggest that the recent definition of at risk for pediatric acute respiratory distress syndrome can successfully identify children with critical bronchiolitis who have relatively unfavorable clinical courses.

Outcomes of Children With Critical Bronchiolitis Living in Poor Communities.

There are established associations between adverse health outcomes and poverty, but little is known regarding these associations in critically ill children. We hypothesized that living in poorer communities would be associated with unfavorable outcomes in children with critical bronchiolitis. This retrospective study included children with bronchiolitis admitted to a pediatric intensive care unit (PICU) over a 2-year period. Median household income was estimated from patient ZIP codes and 2014 US Census Bureau data. The 2014 Federal Poverty Threshold (FPT) for a family of 4 was $24 008. Patients were classified as living in ZIP codes below or above the 150% FPT (150FPT). Living <150FPT was associated with longer PICU length of stay (LOS), longer hospital LOS, higher odds of needing mechanical ventilation, and increased hospital charges. In this cohort of critically ill children with bronchiolitis, living in a poorer community was associated with more unfavorable clinical outcomes.

Pediatric Procedural Sedation Using the Combination of Ketamine and Propofol Outside of the Emergency Department: A Report From the Pediatric Sedation Research Consortium.

OBJECTIVES: Outcomes associated with a sedative regimen comprised ketamine + propofol for pediatric procedural sedation outside of both the pediatric emergency department and operating room are underreported. We used the Pediatric Sedation Research Consortium database to describe a multicenter experience with ketamine + propofol by pediatric sedation providers. DESIGN: Prospective observational study of children receiving IV ketamine + propofol for procedural sedation outside of the operating room and emergency department using data abstracted from the Pediatric Sedation Research Consortium during 2007-2015. SETTING: Procedural sedation services from academic, community, free-standing children's hospitals, and pediatric wards within general hospitals. PATIENTS: Children from birth to less than or equal to 21 years old. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: A total of 7,313 pediatric procedural sedations were performed using IV ketamine + propofol as the primary sedative regimen. Median age was 84 months (range, < 1 mo to ≤ 21 yr; interquartile range, 36-144); 80.6% were American Society of Anesthesiologists-Physical Status less than III. The majority of sedation was performed in dedicated sedation or radiology units (76.1%). Procedures were successfully completed in 99.8% of patients. Anticholinergics (glycopyrrolate and atropine) or benzodiazepines (midazolam and lorazepam) were used in 14.2% and 41.3%, respectively. The overall adverse event and serious adverse event rates were 9.79% (95% CI, 9.12-10.49%) and 3.47% (95% CI, 3.07-3.92%), respectively. No deaths occurred. Risk factors associated with an increase in odds of adverse event included ASA status greater than or equal to III, dental suite, cardiac catheterization laboratory or radiology/sedation suite location, a primary diagnosis of having a gastrointestinal illness, and the coadministration of an anticholinergic. CONCLUSIONS: Using Pediatric Sedation Research Consortium data, we describe the diverse use of IV ketamine + propofol for procedural sedation in the largest reported cohort of children to date. Data from this study may be used to design sufficiently powered prospective randomized, double-blind studies comparing outcomes of sedation between commonly administered sedative and analgesic medication regimens.

Procedural Sedation Outside of the Operating Room Using Ketamine in 22,645 Children: A Report From the Pediatric Sedation Research Consortium.

OBJECTIVE: Most studies of ketamine administered to children for procedural sedation are limited to emergency department use. The objective of this study was to describe the practice of ketamine procedural sedation outside of the operating room and identify risk factors for adverse events. DESIGN: Observational cohort review of data prospectively collected from 2007 to 2015 from the multicenter Pediatric Sedation Research Consortium. SETTING: Sedation services from academic, community, free-standing children's hospitals and pediatric wards within general hospitals. PATIENTS: Children from birth to 21 years old or younger. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Describe patient characteristics, procedure type, and location of administration of ketamine procedural sedation. Analyze sedation-related adverse events and severe adverse events. Identify risk factors for adverse events using multivariable logistic regression. A total of 22,645 sedations performed using ketamine were analyzed. Median age was 60 months (range, < 1 mo to < 22 yr); 72.0% were American Society of Anesthesiologists-Physical Status less than III. The majority of sedations were performed in dedicated sedation or radiology units (64.6%). Anticholinergics, benzodiazepines, or propofol were coadministered in 19.8%, 57.9%, and 35.4%, respectively. The overall adverse event occurrence rate was 7.26% (95% CI, 6.92-7.60%), and the frequency of severe adverse events was 1.77% (95% CI, 1.60-1.94%). Procedures were not completed in 39 of 19,747 patients (0.2%). Three patients experienced cardiac arrest without death, all associated with laryngospasm. CONCLUSIONS: This is a description of a large prospectively collected dataset of pediatric ketamine administration predominantly outside of the operating room. The overall incidence of severe adverse events was low. Risk factors associated with increased odds of adverse events were as follows: cardiac and gastrointestinal disease, lower respiratory tract infection, and the coadministration of propofol and anticholinergics.

Prevalence and Predictors of Adverse Events during Procedural Sedation Anesthesia-Outside the Operating Room for Esophagogastroduodenoscopy and Colonoscopy in Children: Age Is an Independent Predictor of Outcomes.

OBJECTIVES: Procedural sedation/anesthesia outside the operating room for a variety of procedures is well described with an overall low adverse event rate in certain settings. Adverse event associated with procedural sedation/anesthesia outside the operating room for gastrointestinal procedures have been described, albeit in small, single-center studies with wide variance in outcomes. Predictors of such outcomes are unclear. We aimed to estimate the prevalence of adverse event in children undergoing procedural sedation/anesthesia outside the operating room for esophagogastroduodenoscopy, colonoscopy, or both to identify predictors of adverse event. DESIGN/SETTING/PATIENTS: Retrospective analysis of Pediatric Sedation Research Consortium database, a large data repository of pediatric patients aged 21 years old or younger undergoing procedural sedation/anesthesia outside the operating room during September 2007 to November 2011. Twenty-two of the 40 centers provided data pertaining to the procedure of interest. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Primary outcome variable is any adverse event. Independent variables include: age (five groups), sex, American Societyof Anaesthesiologists status, procedure (esophagogastroduodenoscopy, colonoscopy, or both), provider responsible, medication used, location, and presence of coexisting medical conditions. Descriptive statistics used to summarize the data. Using multivariablelogistic regression model, odds ratio, 95% CI) were computed. A total of 12,030 procedures were performed (esophagogastroduodenoscopy, 7,970; colonoscopy, 1,378; and both, 2,682). A total of 96.9% of patients received propofol. Eighty-three percent were performed in a sedation unit. Prevalence of adverse event was 4.8%. The most common adverse event were persistent desaturations (1.5%), airway obstruction (1%), cough (0.9%), and laryngospasm (0.6%). No deaths or CPR occurred. Infants and children aged 5 years old or younger had a higher adverse event rate than older children (15.8%, 7.8% vs 4%). Regression analysis revealed age 5 years old or younger, American Society of Anaesthesiologists greater than or equal to 2, esophagogastroduodenoscopy ± colonoscopy, and coexisting medical conditions of obesity and lower airway disease were independent predictors of higher adverse event. CONCLUSIONS: Overall prevalence of any adverse event was 4.8%. Independent predictors of adverse events in procedural sedation/anesthesia outside the operating room in pediatric esophagogastroduodenoscopy/colonoscopy onoscopy were identified. Recognition of such risk factors may enable optimization of procedural sedation.