This thesis concentrates on nociception monitoring during general anesthesia. Nociception is the process of encoding noxious stimuli, which are potential damaging events. During general anesthesia... Show moreThis thesis concentrates on nociception monitoring during general anesthesia. Nociception is the process of encoding noxious stimuli, which are potential damaging events. During general anesthesia nociception will produce behavioral, autonomic and hormonal responses. We designed a series of studies to address the utility of nociception monitoring in clinical practice on hemodynamic stability, opioid consumption, arousal state and postoperative pain. Show less
The last decades it is increasingly recognized that acute as well as chronic postoperative pain is an important problem. Treatment and prevention of postoperative pain is a challenge, especially in... Show moreThe last decades it is increasingly recognized that acute as well as chronic postoperative pain is an important problem. Treatment and prevention of postoperative pain is a challenge, especially in special patient populations where there is only limited guidance on how to optimally use opioids. In this thesis we focused on the perioperative use of opioids in three different populations. First, the influence of the opioids remifentanil versus fentanyl on acute and chronic postoperative pain was investigated in adult cardiac surgery patients. Second, pharmacodynamic modelling methods were applied to analyze the postoperative use of morphine in children after cardiac surgery. Finally, a pharmacokinetic model was developed to investigate the influence of obesity on the pharmacokinetics of morphine and its metabolites. Pain remains a complex puzzle among biological, psychological, behavioral and social-cultural factors. The high inter-individual variation in all of these factors results in postoperative pain still being a major issue while the ultimate goal is to stay without pain after a surgical procedure. Therefore, the answer to the question: “Does it still hurt?” is: YES unfortunately. This thesis adds pieces to this complex puzzle by focusing on the use of opioids in three different patient populations. Show less
The overarching clinical aim of this thesis was to improve pharmacological pain management by characterizing the pharmacodynamics of analgesics. To achieve this aim, available advanced... Show moreThe overarching clinical aim of this thesis was to improve pharmacological pain management by characterizing the pharmacodynamics of analgesics. To achieve this aim, available advanced pharmacometric modelling approaches are used to maximize the information that can be obtained from the available clinical data. To address methodological gaps for pharmacodynamic analysis, we introduced two new model development tools, as well as two new pharmacodynamics modelling approaches for the characterization of iatrogenic withdrawal syndrome in children.In addition to expanding our pharmacodynamic knowledge, this work can increase the clinical applicability of existing pharmacokinetic models: knowing what drug concentrations will give desirable clinical outcomes, we can use pharmacokinetic models to evaluate if an analgesic dose regimen is likely to produce this concentration. The models developed in this thesis can serve as a starting point for further research into the pharmacodynamics of analgesics by extending these models to include additional patient populations or other analgesics. Moreover, the novel pharmacometric techniques that were introduced in this thesis can support future analyses in a variety of settings: repeated time-to-event data, iatrogenic withdrawal syndrome data, and composite clinical scale data. Show less
Our research group recently published a positive association between early postoperative pain and 30-day postoperative complications in a broad surgical population. To investigate whether... Show moreOur research group recently published a positive association between early postoperative pain and 30-day postoperative complications in a broad surgical population. To investigate whether heterogeneity of the population and surgical procedures influenced these results, we explored this association in a homogenous surgical population. A secondary analysis of the LEOPARD-2 (NCT02146417) and RELAX-1 study (NCT02838134) in laparoscopic donor nephrectomy patients (n = 160) was performed. Pain scores on the postanesthesia care unit and postoperative day (POD) 1 and 2 were compared between patients with infectious, noninfectious, and no complications 30 days after surgery. Patients who developed infectious complications had significantly higher pain scores on POD1 and 2 (6.7 +/- 2.1 and 6.4 +/- 2.8) than patients without complications (4.9 +/- 2.2 and 4.1 +/- 1.9), respectively (P= 0.006 andP= 0.000). Unacceptable pain (numeric rating scale [NRS] >= 6) on POD1 was reported by 72% of patients who developed infectious complications, compared to 38% with noninfectious complications and 30% without complications (P= 0.018). This difference was still present on POD2 at 67% with infectious complications, 21% with noninfectious, and 40% without complications (P= 0.000). Multiple regression analysis identified unacceptable pain (numeric rating scale >= 6) on POD2 as a significant predictor for 30-day infectious complications (odds ratio 6.09,P= 0.001). Results confirm the association between early postoperative pain and 30-day infectious complications in a separate, homogenous surgical population. Further clinical trials should focus on finetuning of postoperative analgesia to elucidate the effects on the endocrine and immune response, preserve immune homeostasis, and prevent postoperative infectious complications. Show less
