Drug therapies in neonates and children during extracorporeal membrane oxygenation (ECMO)

__Abstract__ Extracorporeal life support (ECLS) or extra corporeal membrane oxygenation (ECMO) is a technique for providing life support in severe but potentially reversible cardiorespiratory failure in patients with an expected mortality greater than 80%. First pioneered in cardiopulmonary bypass during cardiac surgery, ECLS has been used as prolonged cardiopulmonary support in neonates since 1976. It has been shown to have a survival benefit in neonates and adults. Increasingly ECMO support is used in older children and adults. (ELSO registry report 2010) ECMO provides extracorporeal gas exchange and circulatory support by pumping blood from the patient through an artificial circuit comprising of tubing, a pump, an oxygenator and a heater. The oxygenator is used to oxygenate the blood and extract carbon dioxide. Blood is drawn from a venous access site, preferably a central catheter positioned in the right atrium, and returned either in the right atrium via a double lumen catheter (venovenous ECMO) for respiratory support or via the carotid artery (venoarterial ECMO) for cardiopulmonary support

Application to Add Midazolam to the Model List of Essential Medicines

Summary statement of the proposal for inclusion The benzodiazepine midazolam has proven sedative, anxiolytic and amnesic properties. It is extensively used for premedication and procedural sedation in both adults and children. In comparison to other benzodiazepine and non-benzodiazepine drugs, midazolam is equally or more effective for premedication/preoperative sedation. No evidence exists that premedication with midazolam prolongs discharge time from hospital. Its efficacy and safety have been extensively studied in both adults and children. This contrasts its comparator drug, diazepam for which data in children and elderly are scarce or lacking. Midazolam is also effective for procedural sedation as a single drug or in combination with an opioid. As a single drug, adequate sedation for procedures in the emergency room, is achieved in over 90% of all procedures. Comparative efficacy was shown for propofol. Data are insufficient to determine comparative efficacy for procedural sedation for other drugs. When administered with the appropriate precautions, e.g. titration to effect, adequate monitoring and personnel to support ventilation, midazolam is very safe. No major adverse events were seen in 847 adults who received midazolam for procedural sedation. Also, adverse effects can be antagonized with an effective antagonist, flumazenil. As midazolam is off-patent, drug costs are relatively low. Drug costs per procedure range from approximately 0.15 US$to 2.6 US$ in an adult, depending on dose and country, with significantly lower costs in developing countries

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

An exploratory study with an adaptive continuous intravenous furosemide regimen in neonates treated with extracorporeal membrane oxygenation

Introduction: The objective of the present study was to explore a continuous intravenous furosemide regimen that adapts to urine output in neonates treated with extracorporeal membrane oxygenation (ECMO). Methods: Seven neonates admitted to a paediatric surgical intensive care unit for ECMO therapy were treated with a furosemide regimen consisting of a loading bolus (1-2 mg/kg) followed by a continuous infusion at 0.2 mg/kg per hour, which was adjusted according to the target urine production of 6 ml/kg per hour. Therapeutic drug monitoring for furosemide concentrations in blood was performed. Results: The mean ± standard deviation furosemide dose was 0.17 ± 0.06 mg/kg per hour, 0.08 ± 0.04 mg/kg per hour and 0.12 ± 0.07 mg/kg per hour

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

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

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