The overall goal was to develop individualized dosing guidelines for the sedatives propofol and midazolam in infants and in critically ill patients, on the basis of population pharmacokinetic... Show moreThe overall goal was to develop individualized dosing guidelines for the sedatives propofol and midazolam in infants and in critically ill patients, on the basis of population pharmacokinetic-pharmacodynamic (PK-PD) modeling. Both under- and oversedation significantly and adversely affects patient outcome. Due to the high intra- and interindividual variability in dose requirements dosing is complicated. In this thesis the interindividual variability in response has been examined by covariate analysis. In this analysis the effects of bodyweight, cardiac function, severity of illness and liver blood flow and the unexplained interindividual variability have been characterized. It was shown that infants require higher doses of propofol because of differences in pharmacokinetics rather than pharmacodynamics. When comparing the results of the PK-PD model of propofol and midazolam in infants, propofol is preferred over midazolam because of the lower interindividual variability in pharmacodynamics compared to midazolam. In critically ill patients severity of the illness was found to be a major determinant of the level of sedation, with lower propofol dosing requirements with increasing severity of illness. The PK-PD models can be used as a basis for individualized dosing of propofol and midazolam, which is essential for optimizing the quality of sedation in clinical practice and will improve patients__ outcome. Show less
Epidural neural blockade results from processes after the administration of a local anaesthetic in the epidural space until the uptake in neural tissue. The pharmacokinetics, neural blockade and... Show moreEpidural neural blockade results from processes after the administration of a local anaesthetic in the epidural space until the uptake in neural tissue. The pharmacokinetics, neural blockade and haemodynamics after epidural anaesthesia may be influenced by several factors, with age as the most important one. Using the stable-isotope-method, the pharmacokinetics of the enantiomeric-pure local anaesthetics ropivacaine and levobupivacaine were derived and the influence of age on the pharmacokinetics was investigated. These local anaesthetics showed a bi-phasic absorption pattern. The fraction absorbed during the initial absorption process for levobupivacaine was low. The initial absorption parameters decreased with increasing age for epidurally administered levobupivacaine and ropivacaine.After epidural administration the level of analgesia was higher for levobupivacaine and ropivacaine and motor blockade was increased for ropivacaine in elderly patients. Haemodynamic changes, like the decrease in mean arterial pressure (MAP), were more pronounced in elderly patients after epidural administration of ropivacaine. It was postulated that this decrease is not only the result of the higher level of analgesia in elderly patients, but also from age-related changes in the cardiovascular and autonomic nervous system. Finally, a population pharmacokinetic/ pharmacodynamic model of the lumbar epidural space was developed that was able to demonstrate the importance of age on the spread of the sensory blockade as well as on the speed of onset/offset of blockade. Show less
