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Onrechtmatige daad en schadevergoeding

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Crowded trades, market clustering, and price instability

Crowded trades by similarly trading peers influence the dynamics of asset prices, possibly creating systemic risk. We propose a market clustering measure using granular trading data. For each stock the clustering measure captures the degree of trading overlap among any two investors in that stock. We investigate the effect of crowded trades on stock price stability and show that market clustering has a causal effect on the properties of the tails of the stock return distribution, particularly the positive tail, even after controlling for commonly considered risk drivers. Reduced investor pool diversity could thus negatively affect stock price stability

Pharmacokinetics and/or pharmacodynamics of propofol, atracurium and cefazolin in morbidly obese patients

In this thesis we initiated pharmacokinetic and/or pharmacodynamic studies in morbidly obese patients undergoing bariatric surgery in order to study propofol, atracurium and cefazolin in this population. The studies in this thesis show that these types of investigation in morbidly obese patients can most adequately be performed in a large teaching hospital by a multidisciplinary team working closely with a university centre. In the bariatric centre in the St. Antonius Hospital in Nieuwegein a large number of bariatric procedures (300 yearly) are carried out and all patients remain in a life-long follow-up program within a multidisciplinary team of medical specialists and nurses. While this program also allows for longterm studies, we have shown in this thesis the suitability of the infrastructure for pharmacokinetic and/or pharmacodynamic studies for different kind of drugs. The pilot study (chapter 3) on propofol for induction of anaesthesia shows that a dose based on ideal body weight (i.e. 200 mg) is an inadequate induction dose for morbidly obese patients in terms of efficacy of induction of anaesthesia measured using Bispectral Index values, haemodynamic parameters and clinical observations. While propofol 200 mg typically is an adequate dose for induction of anaesthesia in non-obese patients, it seems that the higher induction dose in morbidly obese patients (i.e. 350 mg) may be explained by the increased blood volume and cardiac output that can be expected in morbidly obese patients. Upton and co workers also showed in sheep that a higher cardiac output resulted in lower initial arterial concentrations of propofol, as upon a dose of 100 mg over two minutes, arterial concentrations of propofol were found to be inversely related to cardiac output. This implies that cardiac output may be a determinant of the induction of anaesthesia with propofol. In our pilot study, an induction dose of 350 mg seemed adequate, although temporary cardiovascular instability was observed in one patient, which was attributed to the start of the propofol maintenance infusion of 10 mg/kg/hour within five minutes after induction of anaesthesia. On the basis of these results, it was concluded that for future studies, a dose based on total body weight with or without a dose cap at 350 mg or a dose based on lean body mass in a larger sample of morbidly obese patients seems appropriate. More recently, the study of Ingrande et al. showed that lean body mass is a more appropriate weight based scalar for propofol infusion for induction of anaesthesia in morbidly obese patients compared to total body weight. These recent findings seem consistent with a report on the correlation of cardiac output with lean body mass. In the study evaluating propofol for maintenance of anaesthesia in morbidly obese patients (chapter 4), a dosing regimen of 4-6 mg/kg/hr was proposed for both the combination of propofol with remifentanil and the combination of propofol with epidural analgesia because no difference was observed in the propofol concentration __ Bispectral Index relation between the two groups. Although in this study Bispectral Index values are influenced to the same extend by adding remifentanil compared to epidural analgesia to propofol anaesthesia, the current opinion is that opioids such as remifentanil do exert a propofol-sparing effect when given in combination with propofol. Some studies did show reductions in Bispectral Index values when an opioid was given during anaesthesia with propofol, which may potentially be explained by a decrease in blood pressure, heart rate or cerebral blood flow and thus a decrease in Bispectral Index values. Guignard et al. on the other hand demonstrated that remifentanil does not affect Bispectral Index values but that the increases in Bispectral Index values associated with laryngoscopy and orotracheal intubation are prevented by remifentanil in a dose-dependent fashion. Other studies did demonstrate a deeper level of anaesthesia when an opioid was co-administered with propofol which was not reflected by lower Bispectral Index values. As the use of the Bispectral Index can be questioned as an endpoint to evaluate propofol dosing in co-administration with remifentanil, we also used haemodynamic parameters as an endpoint for propofol dosing. The predefined range of the haemodynamic parameters, however, was easier to aim for compared to the predefined range of Bispectral Index values. It seems therefore that a propofol-sparing effect by remifentanil co-administration can not be excluded and that potentially other pharmacodynamic measures are required to answer this question. From the study evaluating the population pharmacokinetics and pharmacodynamics of propofol when used in combination with remifentanil in morbidly obese patients (chapter 5) it can be concluded that body weight is the major determinant for clearance of propofol using an allometric function with an exponent of 0.72. This conclusion indicates that propofol in morbidly obese patients should be dosed in mg kg-0.72 instead of mg/kg as was reported in chapter 4. In our opinion, this different conclusion can be explained by the difference in analysis techniques. In the study described in chapter 4 dosing of propofol was based on clinical practice and dosing was thus performed in mg/kg/ hr (linear). As a result, a dosing advice in mg/kg/hr was given for maintenance of anaesthesia with propofol. In chapter 5, though, a population pharmacokinetic and pharmacodynamic analysis was performed using NONMEM allowing for a systematic covariate analysis in which the influence of different measures of body weight on pharmacokinetic and pharmacodynamic parameters can be studied. Although Lemmens et al. concluded that dosing of propofol in morbidly obese patients should be based on lean body mass, this is not confirmed by our analysis. In our study total body weight was the major determinant for clearance of propofol in morbidly obese patients, with body mass index as a good alternative, while there was no basis for the use of lean body mass. This was confirmed by repeating the analysis with the inclusion of non-obese patients. As propofol clearance is mainly influenced by hepatic blood flow, it may be speculated that in morbidly obese patients hepatic blood flow is correlated to total body weight in an allometric function with an exponent of 0.72 instead of lean body mass. Using these techniques it was also found that there was no significant influence of body weight on any of the other pharmacokinetic and pharmacodynamic parameters. A non-significant trend was identified towards an increased central volume of distribution in morbidly obese patients. This result may be explained by an increased blood volume in morbidly obese patients and thereby explain part of the results of the pilot study described in chapter 3, in which a larger dose of propofol was reported for induction of anaesthesia in morbidly obese patients compared to non-obese patients. However, another explanation for the larger dose of propofol necessary for induction in morbidly obese patients described in chapter 3 may be an increase in cardiac output in morbidly obese patients. In the pharmacokinetic and pharmacodynamic analysis of propofol described in chapter 5 patients with body weights up to 167 kg were included. The non-linear dosing regimen that is derived from this pharmacokinetic and pharmacodynamic model should therefore primarily be used in patients up to this body weight. However, it also seems of interest to evaluate the extrapolation possibilities of the model and its dosing regimen by applying this dosing regimen in patients with larger body weights. A prospective study, in this respect, is of importance to show the predictive, clinical and practical value of the model in addition to its descriptive properties in morbidly obese patients. The study of atracurium (chapter 6) showed that dosing of this muscle relaxant when used at the time of induction of anaesthesia should be based on ideal body weight, as this results in a predictable profile of muscle relaxation allowing for adequate intubation conditions and recovery of muscle strength to a train-offour- ratio > 90% within 60 minutes with lack of need for antagonism. A dose-dependent prolongation of action is shown when dosing is based on total body weight. The relative decrease in the percentage of lean body mass and total body water together with the hydrophilic characteristics of atracurium may lead to the hypothesis that less atracurium is needed per kilogram of body weight in obese patients compared to non-obese patients. This is in accordance with the findings described in chapter 6. Whether this is applicable to other muscle relaxants as rocuronium remains uncertain, as the clearance of this agent is more dependent on liver and kidney function . For rocuronium, an antagonist (sugammadex) is on the market, and it would be of interest to study the dose requirements of both drugs in morbidly obese patients. As for atracurium, in the European drug information for rocuronium a dosing advice is given in mg/kg. In our study, this proved to be incorrect for atracurium, and provokes speculations on this advice for rocuronium and sugammadex, providing a basis for future research on this topic in morbidly obese patients. The study on cefazolin in this thesis (chapter 7) shows unbound plasma cefazolin concentrations above 1 mg/L (minimal inhibitory concentration for 90% (MIC90) of methicillin sensitive isolates of S. Aureus in Europe) during four hours after a dose of two gram intravenously in morbidly obese patients. Whether these unbound plasma cefazolin concentrations are adequate in specific hospitals or countries depends on the minimal inhibitory concentration for 90% of the isolates in the local setting. As discussed in the introduction of this thesis, cefazolin is mainly albumin-bound and it is not expected that obesity influences the plasma protein binding of cefazolin. This is in accordance to our study described in chapter 7, where we conclude that plasma protein binding of cefazolin in morbidly obese patients is 79%, which is the same as in non-obese patients. The negative correlation between peak cefazolin concentration and body weight described in our study may potentially be explained by the increased volume of distribution due to the increased blood volume described in morbidly obese patients. In addition, the positive correlation between age and trough plasma cefazolin concentrations described in our study may be explained by the increase in glomerular filtration and perfusion of the kidneys described in the early stages of obesity, while in the later stages of obesity these tend to normalize and subsequently decrease. As described in the introduction of this thesis, morbidly obese patients are exposed to an increased risk of developing post-operative wound infections compared to non-obese patients due to poorly perfused excess of adipose tissue. As cefazolin is excreted via the kidneys, an increase of glomerular filtration as well as perfusion as described in obesity may result in increased cefazolin clearance, necessitating a higher dose of cefazolin in morbidly obese patients. As was shown in our study, this particularly occurred in younger individuals, even though in all cases cefazolin concentrations remained above 1 mg/L. However, it is unknown if cefazolin can penetrate into the target organ, i.e. the subcutaneous tissue. Altogether, this may explain the wound infections that occurred despite adequate plasma cefazolin concentrations in two patients in our study, even though the statistical importance of the high infection rate in our study remains uncertain due to the small patient group (n=20). A future study evaluating plasma cefazolin concentrations together with tissue concentrations of cefazolin using a microdialysis catheter is in progress. In conclusion, we initiated pharmacokinetic and/or pharmacodynamic studies in morbidly obese patients undergoing bariatric surgery by investigating propofol, atracurium and cefazolin in this population. To allow for this type of research a large (teaching) hospital with a multidisciplinary team of medical specialists and nurses is essential. Pharmacokinetic and/or pharmacodynamics studies provide the basis for dosing regimen of medication used in morbidly obese patients and give insight into the pathophysiological changes in this special population. A large amount of future research in morbidly obese patients is yet to be performed and is essential as the body weights and body mass indices in this population are still increasing.UBL - phd migration 201