Does a Dose Calculator as an Add-On to a Web-Based Paediatric Formulary Reduce Calculation Errors in Paediatric Dosing? A Non-Randomized Controlled Study

OBJECTIVES: The structured digital dosing guidelines of the web-based Dutch Paediatric Formulary provided the opportunity to develop an integrated paediatric dose calculator. In a simulated setting, we tested the ability of this calculator to reduce calculation errors. METHODS: Volunteer healthcare professionals were allocated to one of two groups, manual calculation versus the use of the dose calculator. Professionals in both groups were given access to a web-based questionnaire with 14 patient cases for which doses had to be calculated. The effect of group allocation on the probability of making a calculation error was determined using generalized estimated equations (GEE) logistic regression analysis. The causes of all the erroneous calculations were evaluated. RESULTS: Seventy-seven healthcare professionals completed the web-based questionnaire: thirty-seven were allocated to the manual group and 40 to the calculator group. Use of the dose calculator resulted in an estimated mean probability of a calculation error of 24.4% (95% CI 16.3-34.8) versus 39.0% (95% CI 32.4-46.1) with use of manual calculation. The mean difference of probability of calculation error between groups was 14.6% (95% CI 3.1-26.2; p =

Chloroquine dosing recommendations for pediatric COVID-19 supported by modeling and simulation

As chloroquine (CHQ) is part of the Dutch Centre for Infectious Disease Control COVID-19 experimental treatment guideline, pediatric dosing guidelines are needed. Recent pediatric data suggest that existing WHO dosing guidelines for children with malaria are suboptimal. The aim of our study was to establish best-evidence to inform pediatric CHQ doses for children infected with COVID-19. A previously developed physiologically-based pharmacokinetic (PBPK) model for CHQ was used to simulate exposure in adults and children and verified against published pharmacokinetic data. The COVID-19 recommended adult dosage regimen of 44mg/kg total was tested in adults and children to evaluate the extent of variation in exposure. Based on differences in AUC0-70h the optimal CHQ dose was determined in children of different ages compared to adults. Revised doses were re-introduced into the model to verify that overall CHQ exposure in each age band was within 5% of the predicted adult value. Simulations showed differences in drug exposure in children of different ages and adults when the same body-weight based dose is given. As such, we propose the following total cumulative doses: 35 mg/kg (CHQ base) for children 0-1 month, 47 mg/kg for 1-6 months, 55 mg/kg for 6 months-12 years and 44 mg/kg for adolescents and adults, not to exceed 3300 mg in any patient. Our study supports age-adjusted CHQ dosing in children with COVID-19 in order to avoid suboptimal or toxic doses. The knowledge-driven, model-informed dose selection paradigm can serve as a science-

Diagnosis and Treatment of Chronic Neuropathic and Mixed Pain in Children and Adolescents: Results of a Survey Study amongst Practitioners

Валідовані діагностичні засоби для діагностики хронічного невропатичного та змішаного болю у дітей відсутні. Терапевтичні варіанти часто походять від терапевтичних засобів для дорослих. Щоб дослідити міжнародну практику серед практикуючих лікарів з діагностики та лікування хронічного невропатичного болю у дітей та підлітків, ми провели опитування серед членів наукових товариств або груп, члени яких залучені до лікування дитячого болю. Опитування включало питання стосовно практиків та характеристик практики, оцінки та діагностики, лікування та прийому ліків. Ми проаналізували 117 повернутих анкет, з яких 41 (35%) була повністю заповнена, а 76 (65%) заповнені частково. Більшість респондентів базували діагноз невропатичного болю на фізичному обстеженні (68 (58,1%)), анамнезі пацієнтів (67 (57,3%)) та основному захворюванні (59 (50,4%)). Габапентин, амітриптилін та прегабалін були першим вибором засобів для лікування помірного невропатичного болю. Трамадол, ібупрофен, амітриптилін і парацетамол були першочерговими методами лікування помірного змішаного болю. Консенсусу щодо діагностичного процесу невропатичного болю у дітей та підлітків бракує. Медикаментозне лікування широко варіюється у разі помірного, сильного невропатичного та змішаного болю. Отже, діагностичні засоби та терапію необхідно узгодити та перевірити для використання у дітей.Утвержденные диагностические инструменты для диагностики хронической невропатической и смешанной боли у детей отсутствуют. Варианты лечения часто основываются на терапии для взрослых. Чтобы изучить международную практику среди практикующих врачей по диагностике и лечению хронической нейропатической боли у детей и подростков, мы провели исследование среди членов научных обществ или групп, члены которых принимают участие в лечении педиатрической боли. Опрос включал вопросы, касающиеся практикующих врачей и характеристик практики, оценки и диагноза, лечения и приема медикаментов. Мы проанализировали 117 возвращенных анкет, из которых 41 (35%) были заполнены полностью, а 76 (65%) - частично. Большинство респондентов ставили диагноз невропатической боли на основании медицинского осмотра (68 (58,1%)), истории болезни (67 (57,3%)) и основного заболевания (59 (50,4%)). Габапентин, амитриптилин и прегабалин были препаратами первого выбора при умеренной невропатической боли. Трамадол, ибупрофен, амитриптилин и парацетамол были препаратами первого выбора при умеренной смешанной боли. Единого мнения о диагностическом процессе невропатической боли у детей и подростков нет. Медикаментозное лечение умеренной, тяжелой невропатической и смешанной боли широко варьируется. Следовательно, диагностические инструменты и терапия должны быть согласованы и утверждены для использования у детей.Validated diagnostic tools to diagnose chronic neuropathic and mixed pain in children are missing. Therapeutic options are often derived from therapeutics for adults. To investigate the international practice amongst practitioners for the diagnosis and treatment of chronic, neuropathic pain in children and adolescents, we performed a survey study among members of learned societies or groups whose members are known to treat pediatric pain. The survey included questions concerning practitioners and practice characteristics, assessment and diagnosis, treatment and medication. We analyzed 117 returned questionnaires, of which 41 (35%) were fully completed and 76 (65%) were partially completed. Most respondents based the diagnosis of neuropathic pain on physical examination (68 (58.1%)), patient history (67 (57.3%)), and underlying disease (59 (50.4%)) combined. Gabapentin, amitriptyline, and pregabalin were the first-choice treatments for moderate neuropathic pain. Tramadol, ibuprofen, amitriptyline, and paracetamol were the first-choice treatments for moderate mixed pain. Consensus on the diagnostic process of neuropathic pain in children and adolescents is lacking. Drug treatment varies widely for moderate, severe neuropathic, and mixed pain. Hence, diagnostic tools and therapy need to be harmonized and validated for use in children

Gabapentin as add-on to morphine for severe neuropathic or mixed pain in children from age 3 months to 18 years - evaluation of the safety, pharmacokinetics, and efficacy of a new gabapentin liquid formulation: study protocol for a randomized controlled trial

Габапентин показав ефективність у лікуванні хронічного нейропатичного або змішаного болю у дорослих. Хоча фахівці з терапії дитячого болю мають великий досвід роботи з габапентином для лікування невропатичного болю, він практично не використовується за призначенням. Його ефективність та безпека в цьому контексті ніколи не були показані. Метою цього випробування є порівняння габапентину з плацебо як доповнення до морфіну для лікування сильного хронічного змішаного або невропатичного болю у дітей. Це випробування є частиною проекту сьомої рамкової програми Європейського Союзу «Габапентин при педіатричному болю» (GAPP) для розробки дозволу на продаж нової суспензії габапентину для дітей.Габапентин показал эффективность в лечении хронической невропатической или смешанной боли у взрослых. Хотя специалисты по детской боли имеют большой опыт применения габапентина для лечения невропатической боли, он практически не используется по назначению. Его эффективность и безопасность в этом контексте никогда не были показаны. Целью данного исследования является сравнение габапентина с плацебо в качестве дополнения к морфину для лечения тяжелой хронической смешанной или невропатической боли у детей. Это исследование является частью проекта Седьмой рамочной программы Европейского союза «Габапентин в детской боли» (GAPP), направленного на разработку разрешения на использование в педиатрии новой суспензии габапентина.Gabapentin has shown efficacy in the treatment of chronic neuropathic or mixed pain in adults. Although pediatric pain specialists have extensive experience with gabapentin for the treatment of neuropathic pain, its use is off-label. Its efficacy and safety in this context have never been shown. The aim of this trial is to compare gabapentin with placebo as add-on to morphine for the treatment of severe chronic mixed or neuropathic pain in children. This trial is part of the European Union Seventh Framework Programme project Gabapentin in Paediatric Pain (GAPP) to develop a pediatric use marketing authorization for a new gabapentin suspension.Project Gabapentin in Paediatric Pain (GAPP), Grant Agreement №60204

Diagnosis and Treatment of Chronic Neuropathic and Mixed Pain in Children and Adolescents: Results of a Survey Study amongst Practitioners

Validated diagnostic tools to diagnose chronic neuropathic and mixed pain in children are missing. Therapeutic options are often derived from therapeutics for adults. To investigate the international practice amongst practitioners for the diagnosis and treatment of chronic, neuropathic pain in children and adolescents, we performed a survey study among members of learned societies or groups whose members are known to treat pediatric pain. The survey included questions concerning practitioners and practice characteristics, assessment and diagnosis, treatment and medication. We analyzed 117 returned questionnaires, of which 41 (35%) were fully completed and 76 (65%) were partially completed. Most respondents based the diagnosis of neuropathic pain on physical examination (68 (58.1%)), patient history (67 (57.3%)), and underlying disease (59 (50.4%)) combined. Gabapentin, amitriptyline, and pregabalin were the first-choice treatments for moderate neuropathic pain. Tramadol, ibuprofen, amitriptyline, and paracetamol were the first-choice treatments for moderate mixed pain. Consensus on the diagnostic process of neuropathic pain in children and adolescents is lacking. Drug treatment varies widely for moderate, severe neuropathic, and mixed pain. Hence, diagnostic tools and therapy need to be harmonized and validated for use in children

A New Framework to Implement Model-Informed Dosing in Clinical Guidelines: Piperacillin and Amikacin as Proof of Concept

Background: Modeling and simulation is increasingly used to study pediatric pharmacokinetics, but clinical implementation of age-appropriate doses lags behind. Therefore, we aimed to develop model-informed doses using published pharmacokinetic data and a decision framework to adjust dosing guidelines based on these doses, using piperacillin and amikacin in critically ill children as proof of concept. Methods: Piperacillin and amikacin pharmacokinetic models in critically ill children were extracted from literature. Concentration-time profiles were simulated for various dosing regimens for a virtual PICU patient dataset, including the current DPF dose and doses proposed in the studied publications. Probability of target attainment (PTA) was compared between the different dosing regimens. Next, updated dosing recommendations for the DPF were proposed, and evaluated using a new framework based on PK study quality and benefit-risk analysis of clinical implementation. Results: Three studies for piperacillin (