Background In the Netherlands, in 2002, euthanasia became a legitimate medical act, only allowed when the due care criteria and procedural requirements are met. Legally, an Advanced Euthanasia Directive (AED) can replace direct communication if a patient can no longer express his own wishes. In the past decade, an exponential number of persons with dementia (PWDs) share a euthanasia request with their physician. The impact this on physicians, and the consequent support needs, remained unknown. Our objective was to gain more insight into the experiences and needs of Dutch general practitioners and elderly care physicians when handling a euthanasia request from a person with dementia (PWD). Methods We performed a qualitative interview study. Participants were recruited via purposive sampling. The interviews were transcribed verbatim, and analyzed using the conventional thematic content analysis. Results Eleven general practitioners (GPs) and elderly care physicians with a variety of experience and different attitudes towards euthanasia for PWD were included. Euthanasia requests appeared to have a major impact on physicians. Difficulties they experienced were related to timing, workload, pressure from and expectations of relatives, society’s negative view of dementia in combination with the ‘right to die’ view, the interpretation of the law and AEDs, ethical considerations, and communication with PWD and relatives. To deal with these difficulties, participants need support from colleagues and other professionals. Although elderly care physicians appreciated moral deliberation and support by chaplains, this was hardly mentioned by GPs. Conclusions Euthanasia requests in dementia seem to place an ethically and emotionally heavy burden on Dutch GPs and elderly care physicians. The awareness of, and access to, existing and new support mechanisms needs further exploration.

Background Eculizumab is a lifesaving yet expensive drug for atypical hemolytic uremic syndrome. Current guidelines advise a fixed-dosing schedule, which can be suboptimal and inflexible in the individual patient. Methods We evaluated pharmacokinetics (PK) and pharmacodynamics (PD) (classical pathway (CP) activity levels) of eculizumab in 48 patients, consisting of 849 time-concentration data and 569 CP activity levels. PK-PD modeling was performed with non-linear mixed effects modeling. The final model was used to develop improved dosing strategies. Results A PK-model with parallel linear and non-linear elimination rates best described the data with the parameter estimates: clearance 0.163L/day, Volume of distribution 6.42L, maximal rate 29.6mg/day, concentration for 50% of maximum rate 37.9mg/L. The PK-PD relation between eculizumab concentration and CP activity was described using an inhibitory Emax model with the parameter estimates: baseline 101%, maximal inhibitory effect 95.9%, concentration for 50% inhibition 22.0mg/L, Hill coefficient 5.42. A weight-based loading dose, followed by pharmacokinetically-guided dosing was found to improve treatment. On day 7, we predict 99.95% of the patients to reach the efficacy target (CP activity <10%), compared to 94.75% with standard dosing. Comparable efficacy was predicted during the maintenance phase, while the dosing interval could be prolonged in ∼33% of the population by means of individualized dosing. With a fixed-dose four-week dosing interval to allow holidays, treatment costs will increase with 7.1% and we predict 91% of the patients to reach the efficacy target. Conclusions A patient-friendly individualized dosing strategy of eculizumab has the potential to improve treatment response at reduced costs.

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BackgroundWith the introduction of eculizumab, a C5-inhibitor, morbidity and mortality improved significantly for patients with atypical hemolytic uremic syndrome (aHUS). In view of the high costs, actual needs of the drug, and increasing evidence in literature, aHUS patients can be treated according to a restrictive eculizumab regimen. We retrospectively analyzed the pharmacokinetic and dynamic parameters of eculizumab in one patient in time, emphasizing various factors which could be taken into account during tapering of treatment.Case PresentationA nowadays 18-year-old male with a severe, frequently relapsing form of atypical HUS due to a hybrid CFH/CFHR1 gene in combination with the homozygous factor H haplotype, required chronic plasma therapy (PT), including periods with plasma infusion, from the age of onset at 5 months until initiation of eculizumab at the age of 11 years. A mild but stable chronic kidney disease (CKD) and 9 years of disease remission enabled prolongation of eculizumab interval. At the age of 15 years, a sudden yet multifactorial progression of chronic kidney disease (CKD) was observed, without any signs of disease recurrence. However, an acquired glomerulocystic disease, a reduced left kidney function, and abnormal abdominal venous system of unknown etiology were found. In addition, after an aHUS relapse, an unexpected increase in intra-patient variability of eculizumab concentrations was seen. Retrospective pharmacokinetic analysis revealed a change in eculizumab clearance, associated with a simultaneous increase in proteinuria.ConclusionHigh intra-patient variability of eculizumab pharmacokinetics were observed over time, emphasizing the necessity for adequate and continuous therapeutic drug monitoring in aHUS patients. Eculizumab serum trough levels together with complement activation markers (CH50) should be frequently assessed, especially during tapering of drug therapy and/or changing clinical conditions in the patient. In addition, an increase in proteinuria could result in urinary eculizumab loss, indicating that urinary monitoring of eculizumab may be important in aHUS patients with an unexplained decline in serum concentrations.

ObjectiveTo determine the validity, reliability, feasibility and applicability of a neonatal intubation scoring instrument.DesignProspective observational study.SettingSimulation-based research and training centre (Center for Advanced Pediatric and Perinatal Education), California, USA.SubjectsForty clinicians qualified for neonatal intubation.InterventionsVideotaped elective intubations on a neonatal patient simulator were scored by two independent raters. One rater scored the intubations twice. We scored the preparation of equipment and premedication, intubation performance, tube position/fixation, communication, number of attempts, duration and successfulness of the procedure.Main outcome measuresIntraclass correlation coefficients (ICC) were calculated for intrarater and inter-rater reliability. Kappa coefficients for individual items and mean kappa coefficients for all items combined were calculated. Construct validity was assessed with one-way analysis of variance using the hypothesis that experienced clinicians score higher than less experienced clinicians. The approximate time to score one intubation and the instrument’s applicability in another setting were evaluated.ResultsICCs for intrarater and inter-rater reliability were 0.99 (95% CI 0.98 to 0.99) and 0.89 (95% CI 0.35 to 0.96), and mean kappa coefficients were 0.93 (95% CI 0.85 to 1.01) and 0.71 (95% CI 0.56 to 0.92), respectively. There were no differences between the more and less experienced clinicians regarding preparation, performance, communication and total scores. The experienced group scored higher only on tube position/fixation (p=0.02). Scoring one intubation took approximately 15 min. Our instrument, developed in The Netherlands, could be readily applied in the USA.ConclusionsOur scoring instrument for simulated neonatal intubations appears to be reliable, feasible and applicable in another centre. Construct validity could not be established.