Prevention for pediatric low cardiac output syndrome: results from the European survey EuLoCOS-Paed.

OBJECTIVE: Characterize current hospital practices related to preventive drug therapy for low cardiac output syndrome (LCOS) in children with open heart surgery (OHS) in Europe. METHODS: Web-based questionnaire survey of European hospitals performing OHS in children, conducted between January and August 2009. RESULTS: Responses to the questionnaire were obtained from 90 of 125 hospitals (72.0%) from 31 different countries across the geographical European regions. The majority of hospitals (77.8%) administered preventive drug therapy and primarily targeted patients at risk (63.3%). Twenty-four different drug regimens were reported, involving 17 drugs from seven therapeutic drug classes. Milrinone, dopamine, epinephrine, dobutamine, and levosimendan made up 85.9% of the total drug use. Furthermore, milrinone was reported in 70.7% of all drug regimens and significantly more often in combination with other drugs than monotherapy (Δ20%, 95% CI 4.7-34.1%). Milrinone combination therapy reports included lower bolus but higher maintenance infusion doses than monotherapy reports. The timing of drug regimen administration varied across the full perioperative period, but drug regimens were mostly initiated during surgery and continued postoperatively. CONCLUSION: Although current hospital practices related to preventive drug therapy for LCOS in children with OHS are characterized by a marked variability, only few drugs make up the bulk of prescribing practice with milrinone being most commonly used. Therefore, the survey provides information on which drugs to focus research and establish safe and effective drug use. A unified approach is urgently needed to ensure that children with OHS can benefit from evidence-based care.

Clinical pharmacy services in Germany: a national survey.

OBJECTIVES: Clinical pharmacy services in German hospitals appear to be underdeveloped compared with other European countries. However, recent developments have increased the interest in expanding these services. Detailed data about the current state of clinical pharmacy services in Germany are lacking. This survey establishes the current level of pharmacy services in Germany and the barriers to implementation. METHODS: An online survey conducted in 2017 was distributed to directors of all 389 German hospital pharmacies. The survey contained 26 questions addressing hospital and pharmacy characteristics, clinical pharmacy services provided, the number of clinical pharmacists and the frequency as well as the quality assurance of these services. RESULTS: There were 133 responses (34%). Of these, 84 (63%) pharmacies provided some form of clinical pharmacy services. Based on the 389 contacted pharmacies, a clinical pharmacy service is available in at least 22% of hospital pharmacies in Germany. On average there are 2.4 full-time equivalent (FTE) clinical pharmacists per hospital employed, although there is a wide variation in numbers (0.3-22 FTE) and service provision between hospitals. Clinical pharmacy services are generally provided on a daily or weekly basis, with a principal focus on general surgery, critical care and general medicine wards. CONCLUSIONS: This is the first survey providing a detailed picture of clinical pharmacy services in Germany. There is wide variation in clinical service provision among hospitals, with some hospitals having developed a comprehensive range of clinical services. Compared with other countries, particularly the UK where the focus has shifted to provision of 7-day clinical services, the gap in clinical pharmacy services remains large. The focus should be turned to refining clinical pharmacy services in hospital admissions and discharge planning while also improving Health IT, the opportunities for specialisation and aligning education in accordance with the EAHP common training framework.

Evaluation and optimisation of current milrinone prescribing for the treatment and prevention of low cardiac output syndrome in paediatric patients after open heart surgery using a physiology-based pharmacokinetic drug-disease model.

BACKGROUND AND OBJECTIVE: Milrinone is the drug of choice for the treatment and prevention of low cardiac output syndrome (LCOS) in paediatric patients after open heart surgery across Europe. Discrepancies, however, among prescribing guidance, clinical studies and practice pattern require clarification to ensure safe and effective prescribing. However, the clearance prediction equations derived from classical pharmacokinetic modelling provide limited support as they have recently failed a clinical practice evaluation. Therefore, the objective of this study was to evaluate current milrinone dosing using physiology-based pharmacokinetic (PBPK) modelling and simulation to complement the existing pharmacokinetic knowledge and propose optimised dosing regimens as a basis for improving the standard of care for paediatric patients. METHODS: A PBPK drug-disease model using a population approach was developed in three steps from healthy young adults to adult patients and paediatric patients with and without LCOS after open heart surgery. Pre- and postoperative organ function values from adult and paediatric patients were collected from literature and integrated into a disease model as factorial changes from the reference values in healthy adults aged 20-40 years. The disease model was combined with the PBPK drug model and evaluated against existing pharmacokinetic data. Model robustness was assessed by parametric sensitivity analysis. In the next step, virtual patient populations were created, each with 1,000 subjects reflecting the average adult and paediatric patient characteristics with regard to age, sex, bodyweight and height. They were integrated into the PBPK drug-disease model to evaluate the effectiveness of current milrinone dosing in achieving the therapeutic target range of 100-300 ng/mL milrinone in plasma. Optimised dosing regimens were subsequently developed. RESULTS: The pharmacokinetics of milrinone in healthy young adults as well as adult and paediatric patients were accurately described with an average fold error of 1.1 ± 0.1 (mean ± standard deviation) and mean relative deviation of 1.5 ± 0.3 as measures of bias and precision, respectively. Normalised maximum sensitivity coefficients for model input parameters ranged from -0.84 to 0.71, which indicated model robustness. The evaluation of milrinone dosing across different paediatric age groups showed a non-linear age dependence of total plasma clearance and exposure differences of a factor 1.4 between patients with and without LCOS for a fixed dosing regimen. None of the currently used dosing regimens for milrinone achieved the therapeutic target range across all paediatric age groups and adult patients, so optimised dosing regimens were developed that considered the age-dependent and pathophysiological differences. CONCLUSION: The PBPK drug-disease model for milrinone in paediatric patients with and without LCOS after open heart surgery highlights that age, disease and surgery differently impact the pharmacokinetics of milrinone, and that current milrinone dosing for LCOS is suboptimal to maintain the therapeutic target range across the entire paediatric age range. Thus, optimised dosing strategies are proposed to ensure safe and effective prescribing.

Treatment for paediatric low cardiac output syndrome: results from the European EuLoCOS-Paed survey.

OBJECTIVE: To characterise current hospital practice and use of prescribing resources related to drug treatment for low cardiac output syndrome (LCOS) in children with open heart surgery (OHS) in Europe. DESIGN: A web-based questionnaire survey (EuLoCOS-Paed) conducted between January and August 2009. SETTING: European hospitals performing OHS in children. RESULTS: 90 out of 125 hospitals (72%) from 31 European countries responded to the questionnaire. The initial treatment and two add-on steps reported were analysed for: (i) LCOS with elevated systemic vascular resistance (SVR), where milrinone (34% of reports), epinephrine (24%) and epinephrine/levosimendan (22%) were favoured; (ii) LCOS with low SVR, where dopamine (20%), epinephrine (29%) and norepinephrine (24%) were dominant; and (iii) LCOS with elevated pulmonary vascular resistance, where milrinone (17%), inhaled nitric oxide (20%) and prostacyclin derivatives (22%) were preferred. Overall, milrinone, epinephrine, dopamine and dobutamine were used in over 50% of the reported drug regimens for treating LCOS. The availability of drug and dosing information for prescribing was stated to be insufficient by 40% of participants, while 88% would appreciate clinical practice guidelines. CONCLUSION: Drug treatment for LCOS in children with OHS across Europe is highly variable, possibly partly reflecting the lack of evidence and prescribing standards on the use of medicines. Milrinone, epinephrine, dopamine and dobutamine are mostly used, and should be prioritised for future research on LCOS treatment. Such research should be aimed at increasing the level of evidence for clinical practice guidelines to improve the standard of care.