A comparison of clinical paediatric guidelines for hypotension with population-based lower centiles: A systematic review

Background: Different definitions exist for hypotension in children. In this study, we aim to identify evidence-based reference values for low blood pressure and to compare these with existing definitions for systolic hypotension. Me

Improving Emergency Care for Febrile Children Across Europe

Fever in children is a frequent reason for visit to the Emergency Department (ED). The majority of children have viral respiratory infections that are self-limiting in nature. A small proportion of children with fever have a serious bacterial infection that requires early treatment with antibiotics to prevent morbidity and mortality in children. Emergency care of febrile children can be improved by focusing on 1) improved diagnosis by the use of host response biomarkers and 2) improvement of antibiotic prescription. The overarching aim of this thesis is to improve diagnostic strategies and antibiotic treatment of febrile children. This thesis is part of the PERFORM project (Personalised Risk assessment in febrile illness to optimise Real-life Management across the European Union)

Current Ceftriaxone Dose Recommendations are Adequate for Most Critically Ill Children

Background and Objective: Ceftriaxone is a cornerstone antibiotic for critically ill children with severe infections. Despite its widespread use, information on the pharmacokinetics of ceftriaxone is lacking in this population. We aimed to determine ceftriaxone pharmacokinetics in critically ill children and to propose ceftriaxone dosing guidelines resulting in adequate target attainment using population pharmacokinetic modeling and simulation. Methods: Critically ill children (aged 0–18 years) treated with intravenous ceftriaxone (100 mg/kg once daily, infused in 30 minutes) and a central or arterial line in place were eligible. Opportunistic blood sampling for total and unbound ceftriaxone concentrations was used. Population pharmacokinetic analysis was performed using non-linear mixed-effects modeling on NONMEM™ Version 7.4.3. Simulations were performed to select optimal doses using probability of target attainment for two pharmacokinetic targets of the minimum inhibitory concentration (MIC) reflecting the susceptibility of pathogens (f T &gt; MIC 100% and fT &gt; 4 × MIC 100%). Results: Two hundred and five samples for total and 43 time-matched samples for unbound plasma ceftriaxone concentrations were collected from 45 patients, median age 2.5 (range 0.1–16.7) years. A two-compartment model with bodyweight as the co-variate for volume of distribution and clearance, and creatinine-based estimated glomerular filtration rate as an additional covariate for clearance, best described ceftriaxone pharmacokinetics. For a typical patient (2.5 years, 14 kg) with an estimated glomerular filtration rate of 80 mL/min/1.73 m2, the current 100-mg/kg once-daily dose results in a probability of target attainment of 96.8% and 60.8% for a MIC of 0.5 mg/L and 4 × MIC (2 mg/L), respectively, when using fT &gt; MIC 100% as a target. For a 50-mg/kg twice-daily regimen, the probability of target attainment was 99.9% and 93.4%, respectively. Conclusions: The current dosing regimen of ceftriaxone provides adequate exposure for susceptible pathogens in most critically ill children. In patients with an estimated glomerular filtration rate of &gt; 80 mL/min/1.73 m2 or in areas with a high prevalence of less-susceptible pathogens (MIC ≥ 0.5 mg/L), a twice-daily dosing regimen of 50 mg/kg can be considered to improve target attainment. Clinical Trial Registration: POPSICLE study (ClinicalTrials.gov, NCT03248349, registered 14 August, 2017), PERFORM study (ClinicalTrials.gov, NCT03502993, registered 19 April, 2018).</p