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.

Adenoviral Respiratory Infection-Associated Mortality in Children: A Retrospective Case Series.

Viral respiratory infections are a leading cause of illness and hospitalization in young children worldwide. Case fatality rates in pediatric patients with adenoviral lower respiratory tract infection requiring intensive care unit (ICU) admission have been reported between 7 and 22%. We investigated the demographics and clinical characteristics in pediatric mortalities associated with adenoviral respiratory infection at 12 academic children's hospitals in the United States. There were 107 mortality cases included in our study, 73% of which had a chronic medical condition. The most common chronic medical condition was immunocompromised state in 37 cases (35%). The incidences of pediatric acute respiratory distress syndrome (78%) and multiple organ dysfunction syndrome (94%) were profound. Immunocompetent cases were more likely to receive mechanical ventilation within the first hour of ICU admission (60 vs. 14%, p < 0.001) and extracorporeal membrane oxygenation (27 vs. 5%, p = 0.009), and less likely to receive continuous renal replacement therapy (20 vs. 49%, p = 0.002) or have renal dysfunction (54 vs. 78%, p = 0.014) as compared with immunocompromised cases. Immunocompromised cases were more likely to have bacteremia (57 vs. 16%, p < 0.001) and adenoviremia (51 vs. 17%, p < 0.001) and be treated with antiviral medications (81 vs. 26%, p < 0.001). We observed a high burden of nonrespiratory organ system dysfunction in a cohort of pediatric case fatalities with adenoviral respiratory infection. The majority of cases had a chronic medical condition associated with an increased risk of complications from viral respiratory illness, most notably immunocompromised state. Important treatment differences were noted between immunocompromised and immunocompetent cases.

Current practices in pediatric hospital-acquired thromboembolism: Survey of the Children's Hospital Acquired Thrombosis (CHAT) Consortium.

Background: A rise in hospital-acquired venous thromboembolism (HA-VTE) in children has led to increased awareness regarding VTE prophylaxis and risk assessment. Despite no consensus exists regarding these practices in pediatrics. Objective: To describe common practices in VTE prophylaxis, VTE risk assessment models, and anticoagulation dosing strategies in pediatric hospitals that are members of the Children's Hospital Acquired Thrombosis (CHAT) Consortium. Methods: An electronic survey of 44 questions evaluating practices surrounding pediatric HA-VTE risk assessment and prevention was distributed between August 9, 2021, and August 30, 2021, to the primary investigators from the 32 institutions within the CHAT Consortium. Results: The survey response rate was 100% (n = 32). In total, 85% (n = 27) of the institutions assess HA-VTE, but only 63% (n = 20) have formal hospital guidelines. Within the institutions with formal guidelines, 100% (n = 20) include acute systemic inflammation or infection and presence of a central venous catheter (CVC) as risk factors for VTE. Pharmacologic prophylaxis is prescribed at 87% (28) of institutions, with enoxaparin being the most frequent (96%, n = 27). Variability in responses persisted regarding risk factors, risk assessment, thromboprophylaxis, dosing of prophylactic anticoagulation or anticoagulant drug monitoring. A majority of providers were comfortable providing thromboprophylaxis across all age groups. In addition, the global coronavirus disease 2019 increased the providers' use of prophylactic anticoagulation 78% (n = 25). Conclusion: Practices among institutions are variable in regard to use of HA-VTE prophylaxis, risk assessment, or guideline implementation, highlighting the need for further research and a validated risk assessment model through groups like the CHAT Consortium.

Evaluation of Anticoagulant Monitoring in Pediatric Patients Receiving Enoxaparin for Treatment of Venous Thrombosis.

OBJECTIVES: A venous thromboembolism (VTE) is a blood clot that occurs secondary to vessel wall injury often from a central line insertion. Enoxaparin is often considered a first-line treatment in pediatrics for VTE due to its favorable kinetic profile. Enoxaparin monitoring for pediatric patients is accomplished through anti-Xa monitoring in which monitoring practices may vary between institutions. The objective of this study is to evaluate covariates in pediatric patients to determine which variables are most likely to be associated with enoxaparin dose changes as a result of anti-Xa monitoring. METHODS: A single center, retrospective chart review was conducted in pediatric patients treated with enoxaparin for VTE over a 10-year period and who were assessed to determine covariates that lead to dose changes based on anti-Xa levels. Secondary outcomes described monitoring patterns at the University of New Mexico Children's Hospital. RESULTS: Sixty-eight patients met inclusion criteria in which results showed that patients aged 2 to 5.9 months (p = 0.026), who had critical care status (p = 0.009), and who were of Native American ethnicity (p = 0.016) were likely to have an enoxaparin dose change at least once during their treatment regimen. The mean number of levels drawn were 7.5 per patient over a 6- to 12-week period, and doses were not frequently changed based on a confirmatory lab draw. However, many doses were adjusted based on the week 1 post-therapeutic level. CONCLUSIONS: Patients of Native American ethnicity, younger than 6 months, and those admitted to the PICU were likely to have dose changes based on anti-Xa levels.

Correlation of cerebral Near-infrared spectroscopy (cNIRS) and neurological markers in critically ill children.

OBJECTIVE: To correlate regional brain saturations (RSO(2)) measured by cerebral Near-infrared spectroscopy (cNIRS) with serological markers indicative of neurological injury (neuron-specific enolase (NSE) and S100beta). METHODS: Children with at least one organ failure who were undergoing cNIRS monitoring were eligible for enrollment, while children with hyperbilirubinemia and cyanotic heart disease were excluded. Children were further analyzed based on the presence of an acute neurological injury (defined as hypoxic/ischemic injury after cardiac arrest, status epilepticus, meningitis, encephalopathy) as well as survival. RSO(2) was measured continuously (every 30 s) and averages were obtained at 6 h and 24 h epochs prior to serum collection (E6 and E24, respectively). Serum was collected for NSE and S100beta, which were both determined by ELISA. Serum from children undergoing evaluation for fever in the Emergency department served as serological controls. Correlations were determined using the Pearson Product Moment Correlations. RESULTS: A total of 26 children underwent cNIRS monitoring for a total of 47 days. Overall NSE was greater in critically ill children compared to controls, as well as in all subsets of children analyzed (acute CNS injuries, no acute CNS injuries, survivors and non-survivors). S100beta tended to be greater in critically ill children, but this did not reach statistical significance. Average RSO(2) in E6 and E24 was 68.0% +/- 1.5 and 68.6% +/- 1.6, respectively, in a total of 131,036 measurements and E6 RSO(2) was strongly, negatively correlated with S100beta in children with acute neurological injuries. CONCLUSIONS: This is the first study to correlate averaged RSO(2) measured by cNIRS with neurological injury markers in critically ill children. We believe that this data can be used to establish thresholds for RSO(2) that can be tested in future trials to determine if this technology is predictive of long-term neurological outcome.