Background The use of epidural analgesia (EA) in pancreatic surgery remains under debate. This study compares patients treated with EA versus non-EA after open pancreatectomy in a tertiary referral... Show moreBackground The use of epidural analgesia (EA) in pancreatic surgery remains under debate. This study compares patients treated with EA versus non-EA after open pancreatectomy in a tertiary referral center.Methods All patients undergoing open pancreatectomy from 2013 to 2017 were retrospectively reviewed. (Non-)EA was terminated on postoperative day (POD) 3 or earlier if required.Results In total, 190 (72.5%) patients received EA and 72 (27.5%) patients received non-EA (mostly intravenous morphine). EA was terminated prematurely in 32.6% of patients and non-EA in 10.5% of patients. Compared with non-EA patients, EA patients had significantly lower pain scores on POD 0 (1.10 (0-3.00) versus 3.00 (1.67-5.00), P < 0.001) and POD 1 (2.00 (0.50-3.41) versus 3.00 (2.00-3.80), P = 0.001), though significantly higher pain scores on POD 3 (3.00 (2.00-4.00) versus 2.33 (1.50-4.00), P < 0.001) and POD 4 (2.50 (1.50-3.67) versus 2.00 (0.50-3.00), P = 0.007). EA patients required more vasoactive medication perioperatively and had higher cumulative fluid balances on POD 1-3. Postoperative complications were similar between groups.Conclusions In our cohort, patients with EA experienced significantly lower pain scores in the first PODs compared with nonEA, yet higher pain scores after EA had been terminated. Although EA patients required more vasoactive medication and fluid therapy, the complication rate was similar. Show less
Endogenous pain modulation is a complex phenomenon involved in the perception of pain. It consists of top-down inhibitory and facilitatory pathways that originate at higher sites within the central... Show moreEndogenous pain modulation is a complex phenomenon involved in the perception of pain. It consists of top-down inhibitory and facilitatory pathways that originate at higher sites within the central nervous system and converge at dorsal horn neurons in the spinal cord, to modulate incoming afferent nociceptive information. Dysfunction of inhibitory pain pathways or a shift in the balance between pain facilitation and pain inhibition has been associated with the development of chronic pain. This thesis describes the effect of several central-acting drugs on descending control of pain in both healthy volunteers and chronic pain patients to further understand the underlying mechanism of endogenous pain control in health and disease. Show less
The maturation of UGT2B7-mediated drug glucuronidation was studied in preterm and term neonates up to infants of three years of age using a population approach. A pharmacokinetic model was... Show moreThe maturation of UGT2B7-mediated drug glucuronidation was studied in preterm and term neonates up to infants of three years of age using a population approach. A pharmacokinetic model was developed for morphine, which was used as a paradigm compound. In this model, the maturation of morphine glucuronidation is described by a bodyweight-based exponential relationship with an exponent of 1.44. The model-derived dosing algorithm was evaluated prospectively in a clinical trial and it was shown that this dosing algorithm may reduce overdosing of neonates and exposure to ineffective doses in older infants. Additionally, it was found that the bodyweight-based exponential relationship that describes the maturation of morphine glucuronidation can be directly applied to the maturation of zidovudine, which is also a UGT2B7 substrate. This expedites the development of paediatric pharmacokinetic models and evidence-based paediatric drug dosing algorithms. Based on a study using physiologically-based pharmacokinetic modeling it was concluded that the equation for maturation of morphine glucuronidation could be applicable to all small molecular drugs and to paediatric patient populations with normal hepatic function. Finally, a framework was developed to properly validate paediatric pharmacokinetic population models and the validation of paediatric pharmacokinetic models for morphine in literature were investigated. Show less
The objective of this thesis was the development of a mechanism-based pharmacokinetic-pharmacodynamic (PK-PD) model for the electro-encephalogram (EEG) effects of opioids, with emphasis on biophase... Show moreThe objective of this thesis was the development of a mechanism-based pharmacokinetic-pharmacodynamic (PK-PD) model for the electro-encephalogram (EEG) effects of opioids, with emphasis on biophase distribution and target interaction kinetics. Several in vitro and in vivo studies have been performed to characterize the transport to the site of action in the brain, the receptor interaction and EEG effects. From the transport studies it could be concluded that the efflux transporter P-glycoprotein is involved in the transport of morphine, whereas for the other opioids no interaction could be identified, which was mainly due to the high passive permeability. Population modeling showed that the predicted morphine biophase concentration-time profiles in vivo were distinctly different from the brain ECF concentration-time profiles, as estimated by intracerebral microdialysis. In addition, for morphine, a complex biophase distribution model was required to describe the hysteresis between blood concentration and EEG effect whereas for the other opioids a simple one-compartment distribution model was sufficient. Investigation of the role of target interaction showed that based on the correlation between in vitro and in vivo receptor binding characteristics, two subpopulations existed. In conclusion, for the development of a predictive PK-PD model, the underlying processes should be investigated in great detail and supportive data are essential for model validation and prediction. Show less
