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

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

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

Insufficient serum caspofungin levels in a paediatric patient on ECMO

Caspofungin, aechinocandin, is a relatively new lipophilic antifungal drug. Little is known concerning the pharmacokinetics of caspofungin in children. Extracorporeal membrane oxygenation (ECMO) allows prolonged cardiopulmonary support in patients with life-threatening respiratory or cardiac failure. Pharmacokinetics may be altered by ECMO. We describe the case of a paediatric patient on ECMO with severe pneumonia and sepsis, who had subtherapeutic exposure of caspofungin despite normal to high dosages of caspofungin. Therapeutic drug monitoring is warranted

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

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

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