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 prevalence of obesity (BMI >40 kg/m2) has increased rapidly over the recent years, not only in adults, but also in children and adolescents. Although it is well known that (patho... Show moreThe prevalence of obesity (BMI >40 kg/m2) has increased rapidly over the recent years, not only in adults, but also in children and adolescents. Although it is well known that (patho)physiological changes in obese individuals can influence drug pharmacokinetics, implying adjusted doses, there is still a need for specific dose guidelines for many classes of drugs. In this thesis, the pharmacokinetics of the renally cleared antibiotics gentamicin, tobramycin and vancomycin, drugs for which it is well known that both the efficacy and toxicity of these drugs closely relate to blood concentrations, are studied in non-obese and (morbidly) obese adults, adolescents and children. We present practical dose recommendations for the obese adult, paediatric and adolescent populations. Furthermore, some important questions are addressed regarding the pharmacokinetics of drugs in obesity: can we use the lipophilicity of a drug to predict changes in volume of distribution? Which pitfalls have to be considered when using lean body weight as basis for drug dosing? And which methods for estimating glomerular filtration can predict the clearance of renally cleared drugs in obese patients? The work in this thesis provide some important steps in filling the current knowledge gaps regarding the pharmacokinetics of drugs in obesity. Show less
Purpose The clinical diagnosis of an internal herniation (IH) after a Roux-en-Y Gastric Bypass (RYGB) remains difficult; therefore, performing a CT scan is usually part of the diagnostic process.... Show morePurpose The clinical diagnosis of an internal herniation (IH) after a Roux-en-Y Gastric Bypass (RYGB) remains difficult; therefore, performing a CT scan is usually part of the diagnostic process. The goal of this study was to assess the incidence of IH in patients with open and closed MD (mesenteric defect) and to study if the ability to diagnose an IH with a CT scan is different between these groups. Materials and Methods IH was defined as a visible intestine through the mesenteric defect underneath the jejunojejunostomy and/or in the Petersen's space. CT scan outcomes were compared with the clinical diagnosis of an IH. Until 31 June 2013, standard care was to leave mesenteric defects (MDs) open; after this date, they were always closed. Results The incidence of IH in the primarily non-closed group was 3.9%, and in the primarily closed group, this was 1.3% (p = 0.001). In group A (non-closed MD and CT), the sensitivity of the CT scan was 80%, and specificity was 0%. In group C (closed MD and CT), the sensitivity was 64.7%, and specificity was 89.5%. In group B (non-closed, no CT), an IH was visible in 58.7% of the cases and not in 41.3%. In group D (only a re-laparoscopy), an IH was visible in 34.3% of the cases and not in 65.7%. Conclusions Using the CT scan in suspected IH is not useful in if the MDs were not closed. If the MDs were closed, then a CT scan is predictive for the diagnosis IH. Show less
Despite the increasing number of obese patients, evidence-based dosing guidelines are scarce, particularly for obese children and morbidly obese adults (BMI > 40 kg/m2). For both these... Show more Despite the increasing number of obese patients, evidence-based dosing guidelines are scarce, particularly for obese children and morbidly obese adults (BMI > 40 kg/m2). For both these populations, pharmacokinetic studies are needed to provide a basis for evidence-based dosing guidelines. In this thesis, we studied the pharmacokinetics of the CYP3A substrate midazolam, the renally excreted drug metformin and acetaminophen (metabolized by glucuronidation, sulphation and CYP2E1) in obese adolescents and/or morbidly obese adults. We address several currently unanswered questions; Can doses for obese adolescents be predicted on the basis of data obtained in morbidly obese adults? How to analyse pharmacokinetic data in obese adolescents, for whom body weight is influenced by growth, age and obesity? How to achieve safe and effective acetaminophen dosing for morbidly obese patients? The studies described in this thesis contribute to the existing gaps in knowledge regarding the pharmacokinetics and evidence-based dosing of drugs in obese adolescents and morbidly obese adults. Show less
This thesis consists of three parts. Part A describes in chapter 2 the complex diagnosis of asthma in the morbidly obese, and especially focuses on underdiagnosis and overdiagnosis of asthma in... Show moreThis thesis consists of three parts. Part A describes in chapter 2 the complex diagnosis of asthma in the morbidly obese, and especially focuses on underdiagnosis and overdiagnosis of asthma in this patient group. Part B investigates bronchial and systemic inflammation. It starts in chapter 3 with a review on the association between obesity and asthma, where the metabolic syndrome __ as state of systemic inflammation - is mentioned as possible explanation for the association between obesity and asthma. In chapter 4 systemic inflammation and the metabolic syndrome and impaired lung function in morbidly obese subjects are discussed. This is followed by chapter 5, in which the presence and possible relationship between bronchial and systemic inflammation in morbidly obese asthma subjects are discussed. Part C focuses on bariatric surgery, first pulmonary function testing and complications of bariatric surgery are discussed in chapter 6. In chapter 7 the effect of bariatric surgery on asthma is described. And finally, in chapter 8, a summary and general discussion of these studies is presented. Show less
