The main drives of development of fast track cardiac anaesthesia are the increase burden of health care cost and the shortage of intensive care beds. Fast track (FT) is multidisciplinary process that leads to rapid patient recovery and discharge without affecting morbidity and mortality. Fast track cardiac anaesthesia (FTCA) was proved to be safe, efficient and economically effective. Leipzig FT protocol was first introduced in November 2005 for elective cardiac surgery patients in the heart center of Leipzig University. It is characterized by using intraoperative remifentanil as main opioid with treating the patients postoperatively in post-anaesthesia care unit (PACU) completely bypassing ICU admission. Remifentanil was unavailable in Germany from February to July 2017, therefore the protocol had to be modified and sufentanil was used instead. The aim of this retrospective study was to compare the effects of remifentanil and sufentanil on the well-established FT concept. The primary end points were ventilation time, LOS in PACU (LOS PACU), the visual analogue score (VAS) and the piritramide consumption on the day of operation. The secondary end points were LOS in intermediate care (LOS IMC), hospital LOS, FT failure (FTF), in-hospital mortality and postoperative complications such as postoperative nausea and vomiting (PONV), delirium and the incidence of reintubation. All cardiac surgery patients consecutively admitted to PACU during the period from February to July 2017 (n=622), received sufentanil (FT-S), were compared to patients (n=679) from the same time period of the previous year treated with continuous remifentanil infusion (FT-R) according to the standard FT protocol. To minimise selection bias and to obtain comparable groups, we used a 1:1 nearest neighbour propensity score matching approach resulted in total 1218 patients divided in 2 equal groups. In FT-R, an uninterrupted continuous infusion of remifentanil (0.2-0.3 µg/kg/min) was used for maintenance of anaesthesia throughout the whole operation. In FT-S, a continuous infusion of sufentanil was used during maintenance of anaesthesia as follows: 1 µg/kg/h until sternotomy, 0.5 µg/kg/h until cardiopulmonary bypass and 0.25 µg/kg/h until chest closure, then the infusion was stopped. Otherwise, the Leipzig FT protocol was used as previously published. Remifentanil was more effective in reducing time to extubation (by 40 minutes) and length of stay in the post anaesthetic care unit during fast track cardiac anaesthesia than sufentanil. There was an increased need of piritramide when remifentanil was used. The hospital length of stay was longer in remifentanil group. There were no differences between both groups regarding postoperative complications. Clinically, a detailed and time-directed weaning protocol is more important than the use of a specific opioid during fast track treatment in cardiac surgery patients.:TABLE OF CONTENTS 1. List of Abbreviations 3 2. Bibliographic description 5 3. Abstract 5 4. Introduction 6 4.1 Fast-track cardiac anaesthesia 6 4.1.1 Definitions 6 4.1.2 Current evidence of FTCA 7 4.1.2.1 The safety of FTCA 7 4.1.2.2 The efficiency of FTCA 7 4.1.2.3 Economic Implications of FTCA 8 4.1.3 Different FTCA pathways 8 4.1.4 Patient selection and optimization 9 4.1.5 Anaesthesia aspects of FT 11 4.1.6 Cardiopulmonary bypass aspects of FT 12 4.2 Leipzig FT Protocol 12 4.3 Opioids 16 4.3.1 Remifentanil 16 4.3.2 Sufentanil 17 5. Objective of the work 19 6. Materials and Methods 19 7. Results 21 8. Discussion 26 9. Publication manuscript: „ A comparison of sufentanil versus remifentanil in fast-track cardiac surgery patients “Anaesthesia 2019, 74, 602–608“. 30 10. Summary 37 11. Bibliography 39 12. Appendix (Anlagen): 43 12.1 Declaration of Independence (Selbstständigkeitserklärung) 43 12.2 Declaration of co-authors’ contribution 44 12.3 Publications 45 12.4 Acknowledgment 46

Univerzita Karlova 1. lékařská fakulta Studijní program: Biomedicína Studijní obor: Preventivní medicína MUDr. Karolína Hronová Polymorfismus genů účastnících se v metabolismu léčiv jako potenciální cíl prevence závažných komplikací léčby u novorozenců a dětí Polymorphism of drug metabolizing enzymes as a potential target of prevention of serious treatment complications in neonates and infants Disertační práce- ABSTRAKT V ANGLICKÉM JAZYCE Školitel: prof. MUDr. Ondřej Slanař, Ph.D. Konzultant: MUDr. Pavla Pokorná, PhD. Praha, 2018 Abstract Background and aims: The safety of analgosedative drugs includes drug interactions, adverse effects, withdrawal syndrome and drug dependence are factors that significantly affect morbidity and mortality. Its prevention is critical for quality improvement of care in paediatric patients. The aim of the thesis was to evaluate the prediction of efficacy and safety of analgosedative drugs sufentanil, midazolam, tramadol and valproic acid in neonates and children based on the occurrence of selected pharmacogenetic biomarkers. The incidence of drug interactions of phenobarbital with other analgosedative drugs has also been evaluated. Methodology: The thesis is based on two studies conducted on Intensive and Resuscitation Care Unit of the Clinic of Paediatric and Adolescent...

Backgroun and aims: Pharmacokinetic variability is of paramount importance for sucessfull pharmacotherapy. The main purpose of this work was to study variability of pharmacokinetics in clinical and non-clinical setting with the aim to predict variability in target population. Specifically, three drugs were chosen, sufentanil, with relativelly narrow therapeutic index, and nabumeton and abirateron, both with known high variability. Methods: The study of pharmacokinetic variability of sufentanil was based on clinical samples taken from patients undergoing surgical cardiac procedure, where the sufentanil was used as a part of the drug coctail used during the procedure. New analytical method was necessary to prepare and validate to measure sufentanil concentrations and obtain pharmacokinetic parameters. These were compared between determined genotype groups of MDR1 and OPRM1. Similarly, clinical study was executed with nabumetone, in which nabumetone was administered in a group of 24 subjects on two separate occassions. Plazma samples were obtained and concentrations of nabumetone and its active metabolite, 6-methoxynaphtylacetic acid (6-MNA), were determined. Obtained pharmacokinetic profiles were compared between female and male volunteers, and genotypes for MDR1 and CYP2D6. Finaly for abiraterone,...