Rebecca Ronsley

Importance: Acute kidney injury (AKI) in children is associated with poor short-term and long-term health outcomes; however, the frequency of AKI in children hospitalized for diabetic ketoacidosis (DKA) has not been previously examined. Objectives: To determine the proportion of children hospitalized for DKA who develop AKI and to identify the associated clinical and biochemical markers of AKI. Design, Setting, and Participants: This medical record review of all DKA admissions from September 1, 2008, through December 31, 2013, was conducted at British Columbia Children's Hospital, the tertiary pediatric hospital in British Columbia, Canada. Children aged 18 years or younger with type 1 diabetes and DKA and with complete medical records available for data analysis were included (n = 165). All data collection occurred between September 8, 2014, and June 26, 2015. Data analysis took place from August 25, 2015, to June 8, 2016. Main Outcomes and Measures: Acute kidney injury was defined using Kidney Disease/Improving Global Outcomes serum creatinine criteria. Multinomial logistic regression was used to identify potential factors associated with AKI. Results: Of the 165 children hospitalized for DKA, 106 (64.2%) developed AKI (AKI stage 1, 37 [34.9%]; AKI stage 2, 48 [45.3%]; and AKI stage 3, 21 [19.8%]). Two children required hemodialysis. In the adjusted multinomial logistic regression model, a serum bicarbonate level less than 10 mEq/L (compared with ≥10 mEq/L) was associated with a 5-fold increase in the odds of severe (stage 2 or 3) AKI (adjusted odds ratio [aOR], 5.22; 95% CI, 1.35-20.22). Each increase of 5 beats/min in initial heart rate was associated with a 22% increase in the odds of severe AKI (aOR, 1.22; 95% CI, 1.07-1.39). Initial corrected sodium level of 145 mEq/L or greater (compared with 135-144 mEq/L) was associated with a 3-fold increase in the odds of mild (stage 1) AKI (aOR, 3.29; 95% CI, 1.25-8.66). There were no cases of mortality in patients with or without AKI. Conclusions and Relevance: This study is the first to date to document that a high proportion of children hospitalized for DKA develop AKI. Acute kidney injury was associated with markers of volume depletion and severe acidosis. Acute kidney injury is concerning because it is associated with increased morbidity and mortality as well as increased risk of chronic renal disease, a finding that is especially relevant among children who are already at risk for diabetic nephropathy. Strategies are needed to improve the diagnosis, management, and follow-up of AKI in children with type 1 diabetes.

Abstract Diffuse intrinsic pontine glioma (DIPG) is a fatal central nervous system (CNS) tumor that confers a median survival of 11 months. As B7-H3 is expressed on pediatric CNS tumors, we conducted BrainChild-03, a single-center, dose-escalation phase 1 clinical trial of repetitive intracerebroventricular (ICV) dosing of B7-H3-targeting chimeric antigen receptor T cells (B7-H3 CAR T cells) for children with recurrent or refractory CNS tumors and DIPG. Here we report results from Arm C, restricted to patients with DIPG. The primary objectives were to assess feasibility and tolerability, which were both met. Secondary objectives included assessments of CAR T cell distribution and survival. A total of 23 patients with DIPG enrolled, and 21 were treated with repeated doses of ICV B7-H3 CAR T cells using intra-patient dose-escalation regimens without previous lymphodepletion. Concurrent tumor-directed therapy, including re-irradiation, was not allowed while on protocol therapy. We delivered a total of 253 ICV doses and established the highest planned dose regimen, DR4, which escalated up to 10 × 10 7 cells per dose, as the maximally tolerated dose regimen. Common adverse events included headache, fatigue and fever. There was one dose-limiting toxicity (intratumoral hemorrhage) during DR2. For all treated patients ( n = 21), the median survival from their initial CAR T cell infusion was 10.7 months and the median survival from diagnosis was 19.8 months with 3 patients still alive at 44, 45 and 52 months from diagnosis. Ultimately, this completed first-in-human trial shows that repetitive ICV dosing of B7-H3 CAR T cells in pediatric and young adult patients with DIPG is tolerable, including multiyear repeated dosing, and may have clinical efficacy that warrants further investigation on a multisite phase 2 trial. ClinicalTrials.gov registration: NCT04185038 .

OBJECTIVES: To establish prevalence rates of antipsychotic (AP) prescriptions for children 18 years of age or younger in British Columbia (BC) from 1996 to 2011 by age, sex, AP type, and primary diagnosis; and to identify the predominant AP prescribers for children by specialty training. METHODS: BC Ministry of Health administrative data were used to describe AP prescriptions for youth aged 18 years or younger. Comparisons were made using population prevalence based on sex; age group; AP; International Classification of Diseases, Ninth Revision, diagnosis; and prescriber specialty. RESULTS: From 1996 to 2011, overall AP (both first and second generation) prescription prevalence rate increased 3.8-fold (1.66 to 6.37 per 1000 population); second-generation AP (SGA) prescriptions increased 18.1-fold (0.33 to 5.98 per 1000 population). The highest increase in all AP prescriptions occurred in males aged 13 to 18 years (3.3 to 14.4 per 1000 population; 4.4-fold), followed by similar increases in males aged 6 to 12 years (2.3 to 8.6 per 1000 population; 3.7-fold) and in females aged 13 to 18 years (2.8 to 10.7 per 1000 population; 3.8-fold). Overall, the 3 most common diagnoses associated with all AP prescriptions were depressive disorders (12.8%), hyperkinetic syndrome of childhood (11.7%), and neurotic disorders (11.1%); however, variation was observed by prescriber specialty training. Among all new AP prescriptions in 2010/11, 38.6%, 34.3%, and 15.6% were provided by psychiatrists, family physicians, and pediatricians, respectively. CONCLUSIONS: There has been an exponential rise in SGA prescriptions in BC secondary to extensive off-label use, not only by psychiatrists but also by family physicians and pediatricians. Knowledge translation initiatives promoting evidence-based prescribing and monitoring practices related to SGA treatment need to target all 3 prescriber groups and be tailored for age subgroups.

OBJECTIVES: To review the evidence for efficacy and metabolic effects of atypical antipsychotics (AAPs), and to propose a metabolic monitoring protocol for AAP use in children and adolescents. METHODS: A PubMed search was performed to obtain all studies related to efficacy, metabolic side-effects, and monitoring in those less than 18 years of age. RESULTS: There are no approved indications for AAP use in children and adolescents in Canada. Based on US Food and Drug Administration approvals and a review of randomized controlled trials, we identified 7 indications for AAP use that target specific symptoms in youth including schizophrenia, bipolar I disorder, autism, pervasive developmental disorder, disruptive behaviour disorders (including conduct disorder and ADHD), developmental disabilities and Tourette Syndrome. A wide range of metabolic effects including weight gain, increased waist circumference, dysglycemia, dyslipidemia, hypertension, elevated hepatic transaminases and prolactin levels have been reported. We have developed a proposal for metabolic monitoring that includes anthropometric measurements and laboratory testing at baseline and appropriate intervals thereafter. CONCLUSION: There is an urgent need for national clinical practice guidelines that provide, not only appropriate treatment algorithms for AAP-use based on evidence, but also address metabolic monitoring and subsequent management of complications in this vulnerable population.

OBJECTIVE: To compare the rates of obesity, impaired fasting glucose (IFG), and type 2 diabetes between second-generation antipsychotic (SGA)-treated and -naive youth. METHODS: A retrospective chart review was conducted for all child and adolescent psychiatry emergency admissions over 2.5 years. Data collected included age, sex, psychiatric diagnosis, medications, height, weight, fasting glucose, and lipid profile. Body mass index (BMI) was standardized for age and sex and converted to a z score. Overweight was defined as a BMI between the 85th and 95th percentile and obese as a BMI at the 95th percentile or greater for age and sex. The 2007 American Diabetes Association criteria for IFG and type 2 diabetes were used. RESULTS: Among the 432 admissions, 167 (39%) had both height and weight measured, and 145 (34%) had fasting glucose measured. The mean zBMI was higher in the SGA-treated (n = 68), compared with the SGA-naive group (n = 99) (mean difference 0.81; 95% CI 0.46 to 1.16). In the SGA-treated group, 31% were obese and 26% were overweight, compared with 15% and 8%, respectively, in the SGA-naive group (P < 0.01). In the SGA-treated group (n = 65), 21.5% had IFG or type 2 diabetes, compared with 7.5% in the SGA-naive group (n = 80) (P = 0.01). CONCLUSIONS: Youth treated with SGAs have significantly higher rates of obesity and glucose intolerance than SGA-naive youth. These data emphasize the need for consistent metabolic monitoring of youth with psychiatric disorders who are prescribed SGAs.