Optimization of Vancomycin Initial Dosing Regimen in Neonates Using an Externally Evaluated Population Pharmacokinetic Model.

BACKGROUND: Vancomycin therapeutic monitoring guidelines were revised in March 2020, and a population pharmacokinetics-guided Bayesian approach to estimate the 24-hour area under the concentration-time curve to the minimum inhibitory concentration ratio has since been recommended instead of trough concentrations. To comply with these latest guidelines, we evaluated published population pharmacokinetic models of vancomycin using an external dataset of neonatal patients and selected the most predictive model to develop a new initial dosing regimen. METHODS: The models were identified from the literature and tested using a retrospective dataset of Canadian neonates. Their predictive performance was assessed using prediction- and simulation-based diagnostics. Monte Carlo simulations were performed to develop the initial dosing regimen with the highest probability of therapeutic target attainment. RESULTS: A total of 144 vancomycin concentrations were derived from 63 neonates in the external population. Five of the 28 models retained for evaluation were found predictive with a bias of 15% and an imprecision of 30%. Overall, the Grimsley and Thomson model performed best, with a bias of -0.8% and an imprecision of 20.9%; therefore, it was applied in the simulations. A novel initial dosing regimen of 15 mg/kg, followed by 11 mg/kg every 8 hours should favor therapeutic target attainment. CONCLUSIONS: A predictive population pharmacokinetic model of vancomycin was identified after an external evaluation and used to recommend a novel initial dosing regimen. The implementation of these model-based tools may guide physicians in selecting the most appropriate initial vancomycin dose, leading to improved clinical outcomes.

Impact of trametinib on the neuropsychological profile of NF1 patients.

PURPOSE: The use of trametinib in the treatment of pediatric low-grade gliomas (PLGG) and plexiform neurofibroma (PN) is being investigated in an ongoing multicenter phase II trial (NCT03363217). Preliminary data shows potential benefits with significant response in the majority of PLGG and PN and an overall good tolerance. Moreover, possible benefits of MEK inhibitor therapy on cognitive functioning in neurofibromatosis type 1 (NF1) were recently shown which supports the need for further evaluation. METHODS: Thirty-six patients with NF1 (age range 3-19 years) enrolled in the phase II study of trametinib underwent a neurocognitive assessment at inclusion and at completion of the 72-week treatment. Age-appropriate Wechsler Intelligence Scales and the Trail Making Test (for children over 8 years old) were administered at each assessment. Paired t-tests and Reliable Change Index (RCI) analyses were performed to investigate change in neurocognitive outcomes. Regression analyses were used to investigate the contribution of age and baseline score in the prediction of change. RESULTS: Stable performance on neurocognitive tests was revealed at a group-level using paired t-tests. Clinically significant improvements were however found on specific indexes of the Wechsler intelligence scales and Trail Making Test, using RCI analyses. No significant impact of age on cognitive change was evidenced. However, lower initial cognitive performance was associated with increased odds of presenting clinically significant improvements on neurocognitive outcomes. CONCLUSION: These preliminary results show a potential positive effect of trametinib on cognition in patients with NF1. We observed significant improvements in processing speed, visuo-motor and verbal abilities. This study demonstrates the importance of including neuropsychological evaluations into clinical trial when using MEK inhibitors for patients with NF1.

Two months outcomes following delirium in the pediatric intensive care unit.

The lasting consequences of delirium in children are not well characterized. This study aimed to compare the two-month outcomes in pediatric intensive care unit (PICU) survivors according to the presence of delirium. Post-hoc analysis of a single-center prospective study of mechanically ventilated (invasive ventilation or non-invasive ventilation) children followed at the CHU Sainte-Justine PICU follow-up clinic two months after PICU discharge, between October 2018 and August 2022. Delirium was defined as one or more Cornell Assessment of Pediatric Delirium (CAPD) scores ≥ 9. Primary outcome was survivors' quality of life and secondary outcomes were sleep and posttraumatic stress and anxiety and depression in parents. Multivariable linear and logistic regression models assessed the independent associations between delirium and outcomes while adjusting for age, sex, comorbidity, diagnosis, severity of illness, PICU length of stay, and invasive mechanical ventilation. Of the 179 children included over a 47 month-period, 117 (65.4%) had delirium. Children with delirium were more commonly intubated (91.5% vs. 30.7%, p < 0.001) and had higher PELOD-2 scores (10 vs. 4, p < 0.001). On multivariable analysis, delirium was associated with a decreased quality of life at 2.3 months post discharge (p = 0.03). The severity of the delirium episode (higher scores of CAPD) was associated with a higher likelihood of sleep disturbances (OR 1.13, p = 0.01) and parental anxiety (OR 1.16, p = 0.01), in addition to lower quality of life (p = 0.03).Conclusions: Two months following their PICU stay, children with delirium had a lower quality of life, suggesting a lasting effect of delirium on children and their families.

Morphine versus hydromorphone in pediatrics: a narrative review of latest indications and optimal use in neonates and children.

The management of pain in pediatrics is multimodal and includes non-pharmacologic and pharmacologic approaches. Opioids, and particularly morphine and hydromorphone, are frequently used to treat moderate-to-severe pain. The goals of this review are to describe the pharmacological characteristics of both drugs, to cover the latest evidence of their respective indications, and to promote their safe use in pediatrics. Morphine is the most studied opioid in children and is known to be safe and effective. Morphine and hydromorphone can be used to manage acute pain and are usually avoided when treating chronic non-cancer pain. Current evidence suggests that both opioids have a similar efficacy and adverse effect profile. Hydromorphone has not been studied in neonates but in some centers, it has been used instead of morphine for certain patients. In palliative care, the use of opioids is often indicated and their benefits extend beyond analgesia; indications include treatment of central neuropathic pain in children with severe neurologic impairment and treatment of respiratory distress in the imminently dying patients. The longstanding belief that the use of well-titrated opioids hastens death should be abandoned as robust evidence has shown the opposite. With the current opioid crisis, a responsible use of opioids should be promoted, including limiting the opioid prescription to the patient's anticipated needs, optimizing a multimodal analgesic plan including the use of non-pharmacological measures and non-opioid medications, and providing information on safe storage and disposal to patients and families. More data is needed to better guide the use of morphine and hydromorphone in children.

Impact of Unmet Social Needs, Scarcity, and Future Discounting on Adherence to Treatment in Children With Asthma: Protocol for a Prospective Cohort Study.

BACKGROUND: Asthma is one of the most prevalent chronic diseases of childhood and disproportionately affects children with lower socioeconomic status. Controller medications such as inhaled corticosteroids significantly reduce asthma exacerbations and improve symptoms. However, a large proportion of children still have poor asthma control, in part owing to suboptimal adherence. Financial barriers contribute to hindering adherence, as do behavioral factors related to low income. For example, unmet social needs for food, lodging, and childcare may create stress and worry in parents, negatively influencing medication adherence. These needs are also cognitively taxing and force families to focus on immediate needs, leading to scarcity and heightening future discounting; thus, there is the tendency to attribute greater value to the present than to the future in making decisions. OBJECTIVE: In this project, we will investigate the relationship between unmet social needs, scarcity, and future discounting as well as their predictive power over time on medication adherence in children with asthma. METHODS: This 12-month prospective observational cohort study will recruit 200 families of children aged 2 to 17 years at the Asthma Clinic of the Centre Hospitalier Universitaire Sainte-Justine, a tertiary care pediatric hospital in Montreal, Canada. The primary outcome will be adherence to controller medication, measured using the proportion of prescribed days covered during follow-up. Exploratory outcomes will include health care use. The main independent variables will be unmet social needs, scarcity, and future discounting, measured using validated instruments. These variables will be measured at recruitment as well as at 6- and 12-month follow-ups. Covariates will include sociodemographics, disease and treatment characteristics, and parental stress. Primary analysis will compare adherence to controller medication, measured using the proportion of prescribed days covered, between families with versus those without unmet social needs during the study period using multivariate linear regression. RESULTS: The research activities of this study began in December 2021. Participant enrollment and data collection began in August 2022 and are expected to continue until September 2024. CONCLUSIONS: This project will allow the documentation of the impact of unmet social needs, scarcity, and future discounting on adherence in children with asthma using robust metrics of adherence and validated measures of scarcity and future discounting. If the relationship between unmet social needs, behavioral factors, and adherence is supported by our findings, this will suggest the potential for novel targets for integrated social care interventions to improve adherence to controller medication and reduce risk across the life course for vulnerable children with asthma. TRIAL REGISTRATION: ClinicalTrials.gov NCT05278000; https://clinicaltrials.gov/ct2/show/NCT05278000. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): PRR1-10.2196/37318.

Drug Prescriptions Requiring Compounding at a Canadian University Affiliated Pediatric Hospital: A Cross-Sectional Study.

Despite ongoing international efforts, many drugs administered to children must be compounded from dosage forms designed for adults because they remain unavailable in commercial formulations that suit their needs. Even though oral drug compounding is common in pediatrics, the extent of this practice has not been well described in recent years. This cross-sectional and retrospective study was conducted at a Canadian university-affiliated, 484-bed, tertiary care pediatric hospital and its rehabilitation centre on two randomly selected days. A total of 606 hospitalized children with 5465 prescriptions were included. Overall, compounded drugs for enteral administration (CDEA) represented 13% of all prescriptions (enteral and parenteral) and 23% of prescriptions for enteral administration. Of the 390 prescribed drugs, 122 required compounding. CDEA were mostly liquids (n = 478 [67%]) and mainly included drugs of the central nervous (35%), cardiovascular (21%), and gastro-intestinal (12%) systems. Nearly half (N = 298 [49%]) of children had at least one CDEA prescribed in their medical file. Many CDEA are available as commercial products in other jurisdictions. Collaboration is needed between all stakeholders to make these drugs available to Canadian children.

Assessment of adherence to at-home oral anti-infective therapy among paediatric patients discharged from a Quebec hospital.

OBJECTIVES: Non-adherence to anti-infective therapy contributes to treatment failure and the emergence of bacterial resistance. This study aimed to assess at-home adherence, by paediatric patients, to oral anti-infective (OAI) therapy prescribed for treatment of acute infections and to explore the factors contributing to non-adherence. METHODS: This prospective descriptive study involved French-speaking patients under 16 years of age who were discharged with one or more OAIs prescribed for home administration for a maximum of 30 days. Telephone surveys were used to assess overall adherence, which consisted of primary adherence (patient's ability to procure the medication) and secondary adherence (patient's ability to take the treatment as prescribed). RESULTS: Overall, 51.7% (30/58) of patients were adherent to OAI therapy, with 100% primary adherence (n=69/69) and 51.7% secondary adherence (n=30/58). On average, patients took 98% of the total number of doses prescribed, and non-adherence was related mostly to not following medication administration schedules (63.3% of patients followed the exact schedule). Indeed, the adherence rate for patients taking one or two doses per day was twice the rate for patients taking more than two doses per day (81.8% vs 44.7%, p=0.043). CONCLUSIONS: Half of the paediatric patients treated for acute infections were non-adherent to OAI therapy at home. Interventions are needed to improve this situation.

The Impact of Implementing a "Pain, Agitation, and Delirium Bundle" in a Pediatric Intensive Care Unit: Improved Delirium Diagnosis.

Delirium is associated with significant negative outcomes, yet it remains underdiagnosed in children. We describe the impact of implementing a pain, agitation, and delirium (PAD) bundle on the rate of delirium detection in a pediatric intensive care unit (PICU). This represents a single-center, pre-/post-intervention retrospective and prospective cohort study. The study was conducted at a PICU in a quaternary university-affiliated pediatric hospital. All patients consecutively admitted to the PICU in October and November 2017 and 2018. Purpose of the study was describe the impact of the implementation of a PAD bundle. The rate of delirium detection and the utilization of sedative and analgesics in the pre- and post-implementation phases were measured. A total of 176 and 138 patients were admitted during the pre- and post-implementation phases, respectively. Of them, 7 (4%) and 44 (31.9%) were diagnosed with delirium ( p < 0.001). Delirium was diagnosed in the first 48 hours of PICU admission and lasted for a median of 2 days (interquartile range [IQR]: 2-4). Delirium diagnosis was higher in patients receiving invasive ventilation ( p < 0.001). Compliance with the PAD bundle scoring was 79% for the delirium scale. Score results were discussed during medical rounds for 68% of the patients in the post-implementation period. The number of patients who received opioids and benzodiazepines and the cumulative doses were not statistically different between the two cohorts. More patients received dexmedetomidine and the cumulative daily dose was higher in the post-implementation period ( p < 0.001). The implementation of a PAD bundle in a PICU was associated with an increased recognition of delirium diagnosis. Further studies are needed to evaluate the impact of this increased diagnostic rate on short- and long-term outcomes.

Pharmacogenetic testing in pediatric neurology: a pragmatic study evaluating clinician and patient perceptions.

Aim: To evaluate clinicians' and patients' perceptions of pharmacogenetic testing in a clinical setting. Materials & methods: This is a pragmatic mixed-method prospective observational study. Hospital pharmacists and neurologists participated in focus groups regarding pharmacogenetic testing; patients who received pharmacogenetic testing and their community pharmacists completed surveys to assess their perception of these tests. Results: Most study participants had a positive view of pharmacogenetic testing. Three major themes were identified from the focus groups: receptiveness to pharmacogenetic testing, pharmacogenetic test characteristics and integrating pharmacogenetic tests into practice. Conclusion: The views reported are encouraging for the eventual implementation of pharmacogenetics in practice. Local integration of these tests is an essential step to improve patient care through personalized medicine.

Genetic tests can help predict patients' response to medication. This study aimed to evaluate clinicians' and patients' perceptions of these genetic tests. Pediatric patients, with epilepsy, were tested and completed a survey to assess their perception of these tests. A survey was also completed by their community pharmacists, and virtual discussion groups were held with hospital pharmacists and neurologists. Most participants had a positive view of these tests, with three major themes identified from the discussion groups: receptiveness to testing, test characteristics and integration of tests into practice. The views reported are encouraging for the eventual implementation of these tests in practice, an essential step to improve patient care through personalized medicine.

To Improve the Initial Inpatient Management of Adolescents Admitted with Severe Anorexia Nervosa: A Narrative Review and a Convenient Protocol.

Inadequate nutritional rehabilitation of severely malnourished adolescents with Anorexia Nervosa (AN) increases the risk of medical complications. There is no consensus on best practices for inpatient nutritional rehabilitation and medical stabilization for severe AN. This study aimed to elaborate an admission protocol for adolescents with severe AN based on a comprehensive narrative review of current evidence. A Pubmed search was conducted in July 2017 and updated in August 2020, using the keywords severe AN or eating disorders (ED), management guidelines and adolescent. Relevant references cited in these guidelines were retrieved. A secondary search was conducted using AN or ED and refeeding protocol, refeeding syndrome (RS), hypophosphatemia, hypoglycemia, cardiac monitoring or cardiac complications. Evidence obtained was used to develop the admission protocol. Selective blood tests were proposed during the first three days of nutritional rehabilitation. Higher initial caloric intake is supported by evidence. Continuous nasogastric tube feeding was proposed for patients with a BMI < 12 kg/m2. We monitor hypoglycemia for 72 h. Continuous cardiac monitoring for bradycardia <30 BPM and systematic phosphate supplementation should be considered. Developing protocols is necessary to improve standardization of care. We provide an example of an inpatient admission protocol for adolescents with severe AN.

Soins plus ­ mise en place d'une intervention à trois volets visant à accroître la visibilité et la disponibilité du pharmacien dans un hôpital pédiatrique : une étude randomisée contrôlée.

BACKGROUND: The pharmacist's role within the multidisciplinary team is often poorly understood. Various interventions can be put into place to promote the role of the pharmacist in the hospital setting with families, patients, and other health care professionals. Few studies have described the feasibility and assessed the impact of such interventions, particularly in pediatrics. OBJECTIVES: To describe the implementation of a 3-part intervention aimed at increasing the visibility of pharmacists and their role on the treatment team, with the goal of optimizing the pharmaceutical care of hospitalized patients in the general pediatric units of CHU Sainte-Justine, in Montréal, Quebec, and to compare the perceptions and satisfaction of patients' parents and of health care professionals with exposure to either usual pharmaceutical care or to pharmaceutical care incorporating the intervention. METHODS: This single-blind, randomized, controlled experimental study involved patients admitted to general pediatric units between March 5 and August 8, 2019. In addition to usual care, the intervention included delivery of an information brochure about pharmaceutical services and care, access to a telephone line (which allowed families and patients to contact a pharmacy resident during their stay in hospital and up to 1 month after discharge), and completion of a standardized discharge form by the pharmacist responsible for the patient. The participants and health professionals concerned were surveyed to determine their perceptions and level of satisfaction. RESULTS: A total of 641 participants were included in the study, 321 in the intervention group and 320 in the control group. The brochure was given to all parents in the intervention group. Twelve phone calls were made through the dedicated telephone line. The standardized discharge form was completed for 46.7% (150/321) of the participants in the intervention group. Most of the parents and patients who responded to the survey, in either group (81.2%, 298/367), reported satisfaction with the pharmaceutical services and care received. Of participants in the intervention group, 83.9% were satisfied with the pharmaceutical care and services received, compared with 78.5% of those in the control group (p = 0.18). In addition, 60.3% (111/184) of participants in the intervention group said that the information about medications that was provided during the hospital stay gave them new knowledge, compared with 48.1% (87/181) of those in the control group (p = 0.019). The results of the survey showed that care providers were in agreement with the intervention. CONCLUSIONS: The 3 components of the intervention were implemented in the pediatric units over a period of 5 months. The intervention was perceived as positive by the parents and care providers concerned, and the respondents were mostly satisfied with the services and pharmaceutical care offered.

Pregnancies Among the First Generation of Survivors of Perinatal HIV Infection.

OBJECTIVE: Little is known about pregnancy outcomes among women who have acquired human immunodeficiency virus (HIV) through perinatal infection and survived into adulthood. The objectives of this study were to describe pregnancy outcomes among women with perinatal HIV infection (PHIV) in Canada and to identify potential challenges in the prevention of perinatal HIV transmission in this population. METHODS: A retrospective review of all pregnancies among women with PHIV who were previously followed as children at two tertiary care centres in Montréal, Québec, was conducted. Data were extracted from pediatric and obstetrical records. RESULTS: There were 21 pregnancies among 11 women, and 18 of these pregnancies were unintentional. Mean age at first pregnancy was 19.5 years (range 15-29 years). At the first prenatal visit, 79% had a detectable viral load, 36% were immunosuppressed (CD4 T cell count <200 mm3), and only 36% were receiving antiretroviral therapy (ART). At the time of delivery, although all were prescribed ART, 50% of these women still had a detectable viral load, and 36% remained immunosuppressed. All of the women harboured mutations conferring drug resistance to zidovudine and lamivudine, and the majority (73%) were also resistant to nevirapine. None of the infants were HIV infected, although all received prophylaxis with agents to which their mother's virus was resistant. CONCLUSION: Unplanned pregnancies, difficulties with adherence to ART, and drug resistance were identified challenges in the management of pregnancies among women with PHIV. This study highlights a gap in the reproductive counselling of adolescents with PHIV and the need for close follow-up and adherence support during pregnancy in this population.

A phase 2 study of trametinib for patients with pediatric glioma or plexiform neurofibroma with refractory tumor and activation of the MAPK/ERK pathway: TRAM-01.

BACKGROUND: Pediatric low-grade gliomas (PLGG) are the most frequent brain tumors in children. Up to 50% will be refractory to conventional chemotherapy. It is now known that the majority of PLGG have activation of the MAPK/ERK pathway. The same pathway is also activated in plexiform neurofibromas (PNs) which are low-grade tumors involving peripheral nerves in patients with neurofibromatosis type 1 (NF1). These lesions are known to be refractory to chemotherapy. Specific MEK inhibitors such as trametinib are now available and have been approved for other cancers harboring mutations in the MAPK/ERK pathway such as melanoma. We have observed significant responses to trametinib in patients with refractory PLGG in our institutions and results from the phase I study are promising. The treatment appears not only efficacious but is also usually well tolerated. We hypothesize that we will observe responses in the majority of refractory PLGG and PN treated with trametinib in this phase 2 study. METHODS: The primary objective is to determine the objective response rate of trametinib as a single agent for treatment of progressing/refractory tumors with MAPK/ERK pathway activation. The TRAM-01 study is a phase II multicentric open-label basket trial including four groups. Group 1 includes NF1 patients with progressing/refractory glioma. Group 2 includes NF1 patients with plexiform neurofibroma. Group 3 includes patients with progressing/refractory glioma with KIAA1549-BRAF fusion. Group 4 includes other patients with progressing/refractory glioma with activation of the MAPK/ERK pathway. Eligible patients for a given study group will receive daily oral trametinib at full dose for a total of 18 cycles of 28 days. A total of 150 patients will be enrolled in seven Canadian centers. Secondary objectives include the assessment of progression-free survival, overall survival, safety and tolerability of trametinib, serum levels of trametinib and evaluation of quality of life during treatment. DISCUSSION: Trametinib will allow us to target directly and specifically the MAPK/ERK pathway. We expect to observe a significant response in most patients. Following our study, trametinib could be integrated into standard treatment of PLGG and PN. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03363217 December 6, 2017.

Patient access to compounded drugs in paediatrics after discharge from a tertiary centre.

OBJECTIVE: To describe the problems faced by young patients and their parents when obtaining and using compounded drugs. METHODS: This prospective observational descriptive study included patients 0 to 21 years of age who were discharged from a mother-child tertiary hospital with a prescription containing at least one compounded drug between February 2016 and July 2016. Families were called 7 to 10 business days after discharge to complete a telephone follow-up questionnaire. Retail pharmacies were contacted to obtain additional information in order to compare the dispensed compounded drug with the prescription and published master formulas. RESULTS: The parents of 71 patients with a median age of 6.9 months were surveyed regarding 99 compounded drugs corresponding to 34 different oral formulations. Out of 314 issues identified, 252 were considered as problems: 9 involved major and 243 minor problems with real or potential consequences. CONCLUSION: This study identified a significant number of compounding-related problems. It suggests that current practice standards are insufficient and action should be taken to improve the use and the dispensation of compounded drugs to ensure patients' safety.

Use of Triple Combination Antiretroviral Therapy With Raltegravir as Empiric HIV Therapy in the High-risk HIV-exposed Newborn.

The recent approval of raltegravir granules for suspension in the newborn population offers a new option for the antiretroviral prophylaxis of newborns for the prevention of perinatal transmission. However, there are little data on its use in preterm infants, nor on outcomes following its use as empiric HIV therapy for newborns subsequently found to be infected. We describe here the use of RAL granules for suspension in these cases.