Healthcare cost attributable to bronchiolitis: A population-based cohort study.

OBJECTIVE: To determine 1-year attributable healthcare costs of bronchiolitis. METHODS: Using a population-based matched cohort and incidence-based cost analysis approach, we identified infants <12 months old diagnosed in an emergency department (ED) or hospitalized with bronchiolitis between April 1, 2003 and March 31, 2014. We propensity-score matched infants with and without bronchiolitis on sex, age, income quintile, rurality, co-morbidities, gestational weeks, small-for-gestational-age status and pre-index healthcare cost deciles. We calculated mean attributable 1-year costs using a generalized estimating equation model and stratified costs by age, sex, income quintile, rurality, co-morbidities and prematurity. RESULTS: We identified 58,375 infants with bronchiolitis (mean age 154±95 days, 61.3% males, 4.2% with comorbidities). Total 1-year mean bronchiolitis-attributable costs were $4,313 per patient (95%CI: $4,148-4,477), with $2,847 (95%CI: $2,712-2,982) spent on hospitalizations, $610 (95%CI: $594-627) on physician services, $562 (95%CI: $556-567)] on ED visits, $259 (95%CI: $222-297) on other healthcare costs and $35 ($27-42) on drugs. Attributable bronchiolitis costs were $2,765 (95%CI: $2735-2,794) vs $111 (95%CI: $102-121) in the initial 10 days post index date, $4,695 (95%CI: $4,589-4,800) vs $910 (95%CI: $847-973) in the initial 180 days and $1,158 (95%CI: $1,104-1213) vs $639 (95%CI: $599-679) during days 181-360. Mean 1-year bronchiolitis costs were higher in infants <3 months old [$5,536 (95%CI: $5,216-5,856)], those with co-morbidities [$17,530 (95%CI: $14,683-20,377)] and with low birthweight [$5,509 (95%CI: $4,927-6,091)]. CONCLUSIONS: Compared to no bronchiolitis, bronchiolitis incurs five-time and two-time higher healthcare costs within the initial and subsequent six-months, respectively. Most expenses occur in the initial 10 days and relate to hospitalization.

Assessment of primary outcome measures for a clinical trial of pediatric hemorrhagic injuries.

OBJECTIVE: We evaluated the acceptability of the Pediatric Quality of Life Inventory (PedsQL) and other outcomes as the primary outcomes for a pediatric hemorrhagic trauma trial (TIC-TOC) among clinicians. METHODS: We conducted a mixed-methods study that included an electronic questionnaire followed by teleconference discussions. Participants confirmed or rejected the PedsQL as the primary outcome for the TIC-TOC trial and evaluated and proposed alternative primary outcomes. Responses were compiled and a list of themes and representative quotes was generated. RESULTS: 73 of 91 (80%) participants completed the questionnaire. 61 (84%) participants agreed that the PedsQL is an appropriate primary outcome for children with hemorrhagic brain injuries. 32 (44%) participants agreed that the PedsQL is an acceptable primary outcome for children with hemorrhagic torso injuries, 27 (38%) participants were neutral, and 13 (18%) participants disagreed. Several themes were identified from responses, including that the PedsQL is an important and patient-centered outcome but may be affected by other factors, and that intracranial hemorrhage progression assessed by brain imaging (among patients with brain injuries) or blood product transfusion requirements (among patients with torso injuries) may be more objective outcomes than the PedsQL. CONCLUSIONS: The PedsQL was a well-accepted proposed primary outcome for children with hemorrhagic brain injuries. Traumatic intracranial hemorrhage progression was favored by a subset of clinicians. A plurality of participants also considered the PedsQL an acceptable outcome for children with hemorrhagic torso injuries. Blood product transfusion requirement was favored by fewer participants.

Multi-dose Oral Ondansetron for Pediatric Gastroenteritis: study Protocol for the multi-DOSE oral ondansetron for pediatric Acute GastroEnteritis (DOSE-AGE) pragmatic randomized controlled trial.

BACKGROUND: There are limited treatment options that clinicians can provide to children presenting to emergency departments with vomiting secondary to acute gastroenteritis. Based on evidence of effectiveness and safety, clinicians now routinely administer ondansetron in the emergency department to promote oral rehydration therapy success. However, clinicians are also increasingly providing multiple doses of ondansetron for home use, creating unquantified cost and health system resource use implications without any evidence to support this expanding practice. METHODS/DESIGN: DOSE-AGE is a randomized, placebo-controlled, double-blinded, six-center, pragmatic clinical trial being conducted in six Canadian pediatric emergency departments (EDs). In September 2019 the study began recruiting children aged 6 months to 18 years with a minimum of three episodes of vomiting in the 24 h preceding enrollment, <72 h of gastroenteritis symptoms and who were administered a dose of ondansetron during their ED visit. We are recruiting 1030 children (1:1 allocation via an internet-based, third-party, randomization service) to receive a 48-h supply (i.e., six doses) of ondansetron oral solution or placebo, administered on an as-needed basis. All participants, caregivers and outcome assessors will be blinded to group assignment. Outcome data will be collected by surveys administered to caregivers 24, 48 and 168 h following enrollment. The primary outcome is the development of moderate-to-severe gastroenteritis in the 7 days following the ED visit as measured by a validated clinical score (the Modified Vesikari Scale). Secondary outcomes include duration and frequency of vomiting and diarrhea, proportions of children experiencing unscheduled health care visits and intravenous rehydration, caregiver satisfaction with treatment and safety. A preplanned economic evaluation will be conducted alongside the trial. DISCUSSION: Definitive data are lacking to guide the clinical use of post-ED visit multidose ondansetron in children with acute gastroenteritis. Usage is increasing, despite the absence of supportive evidence. The incumbent additional costs associated with use, and potential side effects such as diarrhea and repeat visits, create an urgent need to evaluate the effect and safety of multiple doses of ondansetron in children focusing on post-emergency department visit and patient-centered outcomes. TRIAL REGISTRATION: ClinicalTrials.gov: NCT03851835. Registered on 22 February 2019.

Comparative safety and effectiveness of perinatal antiretroviral therapies for HIV-infected women and their children: Systematic review and network meta-analysis including different study designs.

BACKGROUND: Nearly all newly infected children acquire Human Immunodeficiency virus (HIV) via mother-to-child transmission (MTCT) during pregnancy, labour or breastfeeding from untreated HIV-positive mothers. Antiretroviral therapy (ART) is the standard care for pregnant women with HIV. However, evidence of ART effectiveness and harms in infants and children of HIV-positive pregnant women exposed to ART has been largely inconclusive. The aim of our systematic review and network meta-analysis (NMA) was to evaluate the comparative safety and effectiveness of ART drugs in children exposed to maternal HIV and ART (or no ART/placebo) across different study designs. METHODS: We searched MEDLINE, EMBASE, and Cochrane Central Register of Controlled Trials (inception until December 7, 2015). Primary outcomes were any congenital malformations (CMs; safety), including overall major and minor CMs, and mother-to-child transmission (MTCT; effectiveness). Random-effects Bayesian pairwise meta-analyses and NMAs were conducted. After screening 6,468 citations and 1,373 full-text articles, 90 studies of various study designs and 90,563 patients were included. RESULTS: The NMA on CMs (20 studies, 7,503 children, 16 drugs) found that none of the ART drugs examined here were associated with a significant increase in CMs. However, zidovudine administered with lamivudine and indinavir was associated with increased risk of preterm births, zidovudine administered with nevirapine was associated with increased risk of stillbirths, and lamivudine administered with stavudine and efavirenz was associated with increased risk of low birth weight. A NMA on MTCT (11 studies, 10,786 patients, 6 drugs) found that zidovudine administered once (odds ratio [OR] = 0.39, 95% credible interval [CrI]: 0.19-0.83) or twice (OR = 0.43, 95% CrI: 0.21-0.68) was associated with significantly reduced risk of MTCT. CONCLUSIONS: Our findings suggest that ART drugs are not associated with an increased risk of CMs, yet some may increase adverse birth events. Some ART drugs (e.g., zidovudine) effectively reduce MTCT.

Safety, pharmacokinetics, and preliminary assessment of efficacy of mecasermin (recombinant human IGF-1) for the treatment of Rett syndrome.

Rett syndrome (RTT) is a severe X-linked neurodevelopmental disorder mainly affecting females and is associated with mutations in MECP2, the gene encoding methyl CpG-binding protein 2. Mouse models suggest that recombinant human insulin-like growth factor 1 (IGF-1) (rhIGF1) (mecasermin) may improve many clinical features. We evaluated the safety, tolerability, and pharmacokinetic profiles of IGF-1 in 12 girls with MECP2 mutations (9 with RTT). In addition, we performed a preliminary assessment of efficacy using automated cardiorespiratory measures, EEG, a set of RTT-oriented clinical assessments, and two standardized behavioral questionnaires. This phase 1 trial included a 4-wk multiple ascending dose (MAD) (40-120 µg/kg twice daily) period and a 20-wk open-label extension (OLE) at the maximum dose. Twelve subjects completed the MAD and 10 the entire study, without evidence of hypoglycemia or serious adverse events. Mecasermin reached the CNS compartment as evidenced by the increase in cerebrospinal fluid IGF-1 levels at the end of the MAD. The drug followed nonlinear kinetics, with greater distribution in the peripheral compartment. Cardiorespiratory measures showed that apnea improved during the OLE. Some neurobehavioral parameters, specifically measures of anxiety and mood also improved during the OLE. These improvements in mood and anxiety scores were supported by reversal of right frontal alpha band asymmetry on EEG, an index of anxiety and depression. Our data indicate that IGF-1 is safe and well tolerated in girls with RTT and, as demonstrated in preclinical studies, ameliorates certain breathing and behavioral abnormalities.