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Background and aims: The Dutch Pediatric Formulary (DPF) increasingly bases its guidelines on model-based dosing simulations from pharmacokinetic studies. This resulted in nation-wide dose changes for vancomycin, gentamicin and tobramycin in 2015. We aimed to evaluate target attainment of these altered, model-based doses in critically ill neonates and children.

Methods: Retrospective cohort study in NICU and PICU patients receiving vancomycin, gentamicin or tobramycin between January 2015 and March 2017 in 2 university hospitals. The first therapeutic drug monitoring concentration for each patient was collected, as well as clinical and dosing information. Vancomycin and tobramycin target trough concentrations were 10-15 and ≤1 mg/L, respectively. Target gentamicin trough and peak concentrations were <1 and 8-12 mg/L, respectively.

Results: 482 patients were included [vancomycin (PICU) n=62, (NICU) n=102, gentamicin (NICU) n=97 and tobramycin (NICU) n=221]). Overall, median trough concentrations were within the target range for all cohorts, but showing large interindividual variability, causing non-target attainment. Trough concentrations were outside the target range in 66.1% 60.8%, 14.7% and 23.1% of patients in these 4 cohorts, respectively. Gentamicin peak concentrations were outside the range in 69% of NICU patients (term neonates 87.1%, preterm infants 57.1%). Higher creatinine concentrations were related with higher vancomycin and tobramycin trough concentrations.

Conclusion: This study illustrates the need to validate model-based dosing advices in the real-world setting as both sub- and supratherapeutic concentrations of vancomycin, gentamicin and tobramycin were very prevalent. Our data underlines the necessity for further individualization by addressing the high interindividual variability to improve target attainment.

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Objectives: Cefazolin is one of curative treatments for infections due to methicillin-sensitive Staphylococcus aureus (MSSA). Both growth and critical illness may impact the pharmacokinetics (PK) parameters. We aimed to build a population PK model for cefazolin in critically ill children, in order to optimize individual dosing regimens.

Methods: We included all children (age < 18 years, bodyweight (BW) > 2.5 Kg) receiving cefazolin for MSSA infection. Cefazolin total plasma concentrations were quantified by high-performance liquid chromatography. Data modelling process was performed with the software MONOLIX. Monte Carlo simulations were used in order to attain the PK target of 100% fT _{> 4 x MIC} .

Results: Thirty-nine patients with a median [range] age of 7 [0.1-17] years and a BW of 21 [2.8-79] kg were included. The PK was ascribed to a one-compartment model, where typical clearance and volume of distribution estimations were 1.4 L/h and 3.3 L respectively. BW, according to the allometric rules, and eGFR on clearance were the 2 influential covariates. Continuous infusion with a dose of 100 mg/kg/day to increase to 150 mg/kg/day for children with a BW < 10 kg or eGFR > 200 mL/min/1.73m² were the best schemes to reach the PK target of 100% fT _{> 4 x MIC}.

Conclusions: In critically ill children infected with MSSA, continuous infusion seems to be the most accurate scheme to reach the PK target of 100 % fT _{> 4 x MIC} in children with normal and augmented renal function.

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Aims & Objectives
To evaluate the functional outcomes in critically ill children with severe sepsis using the pediatric overall performance category scale (POPC) and pediatric cerebral performance category scale (PCPC).

Methods
In this prospective observational study, we enrolled 121 children with severe sepsis, 2 months to 17 years of age admitted to the Pediatric Intensive Care Unit (PICU) from September 2017 to October 2019. We recorded the POPC and PCPC scores at admission, PICU discharge, at and 1 year after discharge. ‘New disability’ was defined as POPC and PCPC score change from baseline score by ≥ 1 category. Risk factors for ‘worse outcomes’ (defined as ‘death’ or ‘new disability’) were evaluated by univariate and multivariate analysis.

Results
At admission, 33% (n=39) had mild to moderate ‘overall disability’ (POPC) and 26% (n=32) had mild to moderate ‘cognitive disability’ (PCPC). At PICU discharge (n=89 children), 50.5% (n=45) had ‘new disability’ in overall function and 28% (n=25) had ‘new disability’ in cognitive function
(Figure 1). At 1 year follow-up (n=84 children), only 5% (n=2/43) had residual ‘new disability’ in overall function and 14% (n=3/21) had residual ‘new disability’ in cognitive function. PICU mortality was 26% (n=32). The proportion with ‘worse outcomes’ was 64% (n=77). Day 1 p-SOFA score and patient receiving CPR during the ICU stay were associated with 'worse outcomes' on multivariate analysis.

Conclusions

Children with severe sepsis had significant ‘new onset’ mild to moderate functional disability at PICU discharge and most of them recovered within 1 year after PICU discharge.