The Pharmacokinetics of Beta-Lactam Antibiotics Using Scavenged Samples in Pediatric Intensive Care Patients:The EXPAT Kids Study Protocol

Background: Emerging evidence supports the importance of optimized antibiotic exposure in pediatric intensive care unit (PICU) patients. Traditional antibiotic dosing is not designed for PICU patients, as the extreme pharmacokinetic (PK) behavior of drugs threatens the achievement of optimal antibiotic treatment outcomes. Scavenged sampling is a sampling strategy which may have positive implications for routine TDM and PK research, as well as monitoring other biomarkers. EXPAT Kids study was designed to analyze whether current empiric dosing regimens of frequently used beta-lactam antibiotics achieve defined therapeutic target concentrations in PICU patients. Methods: A mono-centre, exploratory pharmacokinetic and pharmacodynamic study was designed to assess target attainment of beta-lactam antibiotics. One hundred forty patients will be included within 24 months after start of inclusion. At various time points serum concentration of the study antibiotic (cefotaxime, ceftazidime, ceftriaxone, cefuroxime, flucloxacillin, and meropenem) are determined. In parallel with these sampling moments, residual material is collected to validate the use of blood of scavenged heparinized astrup syringes for the quantification of antibiotic exposure. The primary outcome is the time that the free (unbound) concentration of the study antibiotic remains above one to four the minimal inhibitory concentration during a dosing interval (100%ƒT > MIC and 100%ƒT>4xMIC). Other included outcomes are disease severity, safety, length of stay, and inflammatory biomarkers. Discussion: Potentially, scavenged sampling may enrich the EXPAT Kids dataset, and reduce additional blood sampling and workload for clinical personnel. The findings from the EXPAT Kids study will lead to new insights in the PK parameters of beta-lactams and consecutive effects on target attainment and clinical outcomes. Is there a need for more precision in dosing? Netherlands Trial Register Number: Trial NL9326

Haemofiltration in newborns treated with extracorporeal membrane oxygenation: a case-comparison study

Introduction: Extracorporeal membrane oxygenation is a supportive cardiopulmonary bypass technique for patients with acute reversible cardiovascular or respiratory failure. Favourable effects of haemofiltration during cardiopulmonary bypass instigated the use of this technique in infants on extracorporeal membrane oxygenation. The current study aimed at comparing clinical outcomes of newborns on extracorporeal membrane oxygenation with and without continuous haemofiltration. Methods: Demographic data of newborns treated with haemofiltration during extracorporeal membrane oxygenation were compared with those of patients treated without haemofiltration in a retrospective 1:3 case-comparison study. Primary outcome parameters were time on extracorporeal membrane oxygenation, time until extubation after decannulation, mortality and potential cost reduction. Secondary outcome parameters were total and mean fluid balance, urine output in mL/kg/day, dose of vasopressors, blood products and fluid bolus infusions, serum creatinin, urea and albumin levels. Results: Fifteen patients with haemof

Sequestration of Voriconazole and Vancomycin Into Contemporary Extracorporeal Membrane Oxygenation Circuits: Anin vitroStudy

Background: Bacterial and fungal infections are common and often contribute to death in patients undergoing extracorporeal membrane oxygenation (ECMO). Drug disposition is altered during ECMO, and adsorption in the circuit is an established causative factor. Vancomycin and voriconazole are widely used, despite the lack of evidence-based prescription guidelines. Objective: The objective of this study was to determine the extraction of voriconazole and vancomycin by the Xenios/Novalung ECMO circuits. Methods: We have set up nine closed-loop ECMO circuits, consisting of four different iLAActivve® kits for neonatal, pediatric, and adult support: three iLA-ActivveMiniLung® petite kits, two iLA-ActivveMiniLung® kits, two iLA-ActivveiLA® kits, and two iLA-Activve X-lung® kits. The circuits were primed with whole blood and maintained at physiologic conditions for 24 h. Voriconazole and vancomycin were injected as a single-bolus age-related dose into the circuits. Pre-membrane (P2) blood samples were obtained at baseline and after drug injection at 2, 10, 30, 180, 360 min, and 24 h. A control sample at 2 min was collected for spontaneous drug degradation testing at 24 h. Results: Seventy-two samples were analyzed in triplicate. The mean percentage of drug recovery at 24 h was 20% for voriconazole and 62% for vancomycin. Conclusions: The extraction of voriconazole and vancomycin by contemporary ECMO circuits is clinically relevant across all age-related circuit sizes and may result in reduced drug exposure in vivo

An international survey of management of pain and sedation after paediatric cardiac surgery

Objective The mainstay of pain treatment after paediatric cardiac surgery is the use of opioids. Current guidelines for its optimal use are based on small, non-randomised clinical trials, and data on the pharmacokinetics (PK) and pharmacodynamics (PD) of opioids are lacking. This study aims at providing an overview of international hospital practices on the treatment of pain and sedation after paediatric cardiac surgery. Design A multicentre survey study assessed the management of pain and sedation in children aged 0–18 years after cardiac surgery. setting Pediatric intensive care units (PICU)of 19 tertiary children’s hospitals worldwide were invited to participate. The focus of the survey was on type and dose of analgesic and sedative drugs and the tools used for their pharmacodynamic assessment. results Fifteen hospitals (response rate 79%) filled out the survey. Morphine was the primary analgesic in most hospitals, and its doses for continuous infusion ranged from 10 to 60 mcg kg-1 h-1 in children aged 0–36 months. Benzodiazepines were the first choice for sedation, with midazolam used in all study hospitals. Eight hospitals (53%) reported routine use of sedatives with pain treatment. Overall, type and dosing of analgesic and sedative drugs differed substantially between hospitals. All participating hospitals used validated pain and sedation assessment tools. conclusion There was a large variation in the type and dosing of drugs employed in the treatment of pain and sedation after paediatric cardiac surgery. As a consequence, there is a need to rationalise pain and sedation management for this vulnerable patient group.</p

Analgosedation in paediatric severe traumatic brain injury (TBI): practice, pitfalls and possibilities

Analgosedation is a fundamental part of traumatic brain injury (TBI) treatment guidelines, encompassing both first and second tier supportive strategies. Worldwide analgosedation practices continue to be heterogeneous due to the low level of evidence in treatment guidelines (level III) and the choice of analgosedative drugs is made by the treating clinician. Current practice is thus empirical and may result in unfavourable (often hemodynamic) side effects. This article presents an overview of current analgosedation practices in the paediatric intensive care unit (PICU) and addresses pitfalls both in the short and long term. We discuss innovative (pre-)clinical research that can provide the framework for initiatives to improve our pharmacological understanding of analgesic and sedative drugs used in paediatric severe TBI and ultimately facilitate steps towards evidence-based and precision pharmacotherapy in this vulnerable patient group

Risk factors of impaired neuropsychological outcome in school-aged survivors of neonatal critical illness

__Objective__ Until now, long-term outcome studies have focused on general cognitive functioning and its risk factors following neonatal extracorporeal membrane oxygenation (ECMO) and/or congenital diaphragmatic hernia (CDH). However, it is currently unknown which neuropsychological domains are most affected in these patients, and which clinical variables can be used to predict specific neuropsychological problems. This study aimed to identify affected neuropsychological domains and its clinical determinants in survivors of neonatal ECMO and/or CDH. __Design__ Prospective follow-up study. __Setting__ Tertiary university hospital. __Patients__ Sixty-five eight-year-old survivors of neonatal ECMO and/or CDH. __Interventions__ None. __Measurements and Main Results__ Intelligence, attention, memory, executive functioning and visuospatial processing were evaluated

Hyperoxia in pediatric severe traumatic brain injury (TBI): a comparison of patient classification by cutoff versus cumulative (area-under-the-curve) analysis

Objective: Hyperoxia is associated with adverse outcome in severe traumatic brain injury (TBI). This study explored differences in patient classification of oxygen exposure by PaO2 cutoff and cumulative areaunder-the-curve (AUC) analysis. Methods: Retrospective, explorative study including children (<18 years) with accidental severe TBI (2002–2015). Oxygen exposure analysis used three PaO2 cutoff values and four PaO2 AUC categories during the first 24 hours of Pediatric Intensive Care Unit (PICU) admission. Results: Seventy-one patients were included (median age 8.9 years [IQR 4.6–12.9]), mortality 18.3% (n = 13). Patient hyperoxia classification differed depending on PaO2 cutoff vs AUC analysis: 52% vs. 26%, respectively, were classified in the highest hyperoxia category. Eleven patients (17%) classified as ‘intermediate oxygen exposure’ based on cumulative PaO2 analysis whereby they did not exceed the 200 mmHg PaO2 cutoff threshold. Patient classification variability was reflected by Pearson correlation coefficient of 0.40 (p-value 0.001). Conclusions: Hyperoxia classification in pediatric severe TBI during the first 24 hours of PICU admission differed depending on PaO2 cutoff or cumulative AUC analysis. We consider PaO2 cumulative (AUC) better approximates (patho-)physiological circumstances due to its time- and dose-dependent approach. Prospective studies exploring the association between cumulative PaO2, physiological parameters (e.g. ICP, PbtO2) and outcome are warranted as different patient classifications of oxygen exposure influences how its relationship to outcome is interpreted

The sublingual microcirculation throughout neonatal and pediatric extracorporeal membrane oxygenation treatment: Is it altered by systemic extracorporeal support?

Background: Extracorporeal membrane oxygenation (ECMO) treatment alleviates systemic cardiorespiratory failure. However, it is unclear whether ECMO also improves microcirculatory function, as the microcirculation can be disturbed despite normal systemic hemodynamics. We therefore aimed to study the sublingual microcirculation (SMC) throughout neonatal and pediatric ECMO treatment. We hypothesized that the SMC improves after starting ECMO, that the SMC differs between venovenous (VV) and venoarterial (VA) ECMO, and that insufficient recovery of microcirculatory disturbances during ECMO predicts mortality. Methods: This single-center prospective longitudinal observational study included 34 consecutive children (April 2016-September 2018). The SMC was assessed daily with a handheld vital microscope (integrated with incident dark field illumination) before, during, and after ECMO. Validated parameters of vessel density, perfusion, and flow quality were assessed for all vessels (diameter 2.6) increased with higher MAP (OR: 1.050, 95%CI: 1.008-1.094). Microcirculatory parameters did not significantly differ between VV and VA ECMO or between survivors and non-survivors. None of the microcirculatory parameters could predict mortality on ECMO or overall mortality. Conclusion: In this heterogeneous study population, we were not able to demonstrate an effect of ECMO on the sublingual microcirculation. Microcirculatory parameters did not change throughout ECMO treatment and did not differ between VV and VA ECMO or between survivors and non-survivors. Future research should focus on determining which neonatal and pediatric ECMO patients wou

Recovery of cefazolin and clindamycin in in vitro pediatric CPB systems

Cardiopulmonary bypass (CPB) is often necessary for congenital cardiac surgery, but CPB can alter drug pharmacokinetic parameters resulting in underdosing. Inadequate plasma levels of antibiotics could lead to postoperative infections with increased morbidity. The influence of pediatric CPB systems on cefazolin and clindamycin plasma levels is not kn

Coagulation complications after conversion from roller to centrifugal pump in neonatal and pediatric extracorporeal membrane oxygenation

Background/purpose: Coagulation complications are frequent, unwanted occurrences in extracorporeal membrane oxygenation (ECMO) treatment, possibly influenced by the pump in the ECMO-circuit. We hypothesized that fewer complications would occur with a smaller, heparin-coated ECMO system with a centrifugal pump (CP) than with one with a roller pump (RP) and that after conversion, complication rates would decrease over time. Methods: This single-center, retrospective chart study included all first neonatal and pediatric ECMO runs between 2009 and 2015. Differences between groups were assessed with Mann–Whitney U tests and Kruskal–Wallis tests. Determinants of complication rates were evaluated through Poisson regression models. The CP group was divided into three consecutive groups to assess whether complication rates decreased over time. Results: The RP group comprised 90 ECMO runs and the CP group 82. Hemorrhagic complication rates were significantly higher with the CP than with the RP, without serious therapeutic consequences, while thrombotic complications rates were unaffected. Intracranial hemorrhage rates and coagulation-related mortality rates were similar. Gained experience with the CP did not improve complication rates or su