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

Waterbeelden : een studie naar de beelden van waternatuur onder medewerkers van Rijkswaterstaat

Het onderzoek bestaat uit vier delen: een schets van beelden van water in de Nederlandse cultuur en mogelijke veranderingen daarin; een literatuurstudie, uitmondend in een synthese, naar kennis over natuurbeelden, waar waternatuurbeelden afgeleiden van zijn; een inhoudsanalyse van documenten van Rijkswaterstaat, waarin uiteenlopende beelden van waternatuur bleken te overheersen; een gestructureerde vragenlijst onder medewerkers van Rijkswaterstaat. De gevonden waternatuurbeelden zijn het wilde, spontane, ruime, beonvloede en menselijke beeld

Verkenning kosteneffectiviteit natuur voor mensen

Het Natuurplanbureau ontwikkelt kennis om een antwoord te kunnen geven op de vraag in hoeverre verschillende fysieke maatregelen uit het natuurbeleid bijdragen aan de beoogde doelen van dit beleid in relatie tot de inzet van financiële rijksmiddelen. Dit rapport richt zich op de doelen `natuur voor mensen' uit de beleidsnota Natuur voor mensen, mensen voor natuur. Er is beschreven welke bestaande onderzoeken, methoden en modellen gebruikt kunnen worden om de in totaal 25 ¿mensendoelen¿ te operationaliseren. In totaal zijn 32 onderzoeken beschreven die met de nodige creativiteit gebruikt kunnen worden om 20 doelen te operationaliseren. Tevens blijken er 13 subsidieregelingen te zijn om de doelen te bereiken. Voor drie doelen zijn geen subsidieregelingen gevonden

Influence of Morbid Obesity on the Pharmacokinetics of Morphine, Morphine-3-Glucuronide, and Morphine-6-Glucuronide

Perioperative Medicine: Efficacy, Safety and Outcom

Head-and-neck paragangliomas are associated with sleep-related complaints, especially in the presence of carotid body tumors

Item does not contain fulltextOBJECTIVES: The carotid body functions as a chemoreceptor. We hypothesized that head-and-neck paragangliomas (HNP) may disturb the function of these peripheral chemoreceptors and play a role in sleep-disordered breathing. DESIGN: This is a case-control study. SETTING: This study was conducted in a tertiary referral center. PARTICIPANTS AND MAIN OUTCOME MEASURES: We assessed fatigue, sleep, and exercise capacity in 74 HNP patients using three questionnaires (Epworth Sleepiness Scale, St. George Respiratory Questionnaire, and a standard clinical sleep assessment questionnaire). Outcomes were compared to those of age- and sex-matched controls. RESULTS AND CONCLUSIONS: Activity, disturbance of psychosocial function, and total score were worse compared to controls (15.4 +/- 18.5 vs. 7.2 +/- 9.9, P = 0.007; 5.3 +/- 10.5 vs. 1.2 +/- 2.6, P = 0.008; and 10.4 +/- 12.9 vs. 5.0 +/- 4.8, P = 0.006, respectively). Patients reported more daytime fatigue, concentration difficulties, and depression (51% vs. 24%, P = 0.006; 31% vs. 10%, P = 0.010; and 19% vs. 2%, P = 0.012). Waking up was reported to be less refreshing in HNP patients (53% vs. 73%, P = 0.038). Dysphonia was a predictor of symptoms, activity, disturbance of psychosocial function, and total scores. Remarkably, the presence of a carotid body tumor was an independent predictor of increased daytime sleepiness (beta = 0.287, P = 0.029). In conclusion, patients with HNP have remarkable sleep-related complaints. Especially the presence of carotid body tumors appears to be associated with increased daytime somnolence.1 juni 201

Research in progress: report on the ICAIL 2017 doctoral consortium

This paper arose out of the 2017 international conference on AI and law doctoral consortium. There were five students who presented their Ph.D. work, and each of them has contributed a section to this paper. The paper offers a view of what topics are currently engaging students, and shows the diversity of their interests and influences

MVA.85A Boosting of BCG and an Attenuated, phoP Deficient M. tuberculosis Vaccine Both Show Protective Efficacy Against Tuberculosis in Rhesus Macaques

BACKGROUND: Continuous high global tuberculosis (TB) mortality rates and variable vaccine efficacy of Mycobacterium bovis Bacille Calmette-Guérin (BCG) motivate the search for better vaccine regimes. Relevant models are required to downselect the most promising vaccines entering clinical efficacy testing and to identify correlates of protection. METHODS AND FINDINGS: Here, we evaluated immunogenicity and protection against Mycobacterium tuberculosis in rhesus monkeys with two novel strategies: BCG boosted by modified vaccinia virus Ankara expressing antigen 85A (MVA.85A), and attenuated M. tuberculosis with a disrupted phoP gene (SO2) as a single-dose vaccine. Both strategies were well tolerated, and immunogenic as evidenced by induction of specific IFNgamma responses. Antigen 85A-specific IFNgamma secretion was specifically increased by MVA.85A boosting. Importantly, both MVA.85A and SO2 treatment significantly reduced pathology and chest X-ray scores upon infectious challenge with M. tuberculosis Erdman strain. MVA.85A and SO2 treatment also showed reduced average lung bacterial counts (1.0 and 1.2 log respectively, compared with 0.4 log for BCG) and significant protective effect by reduction in C-reactive protein levels, body weight loss, and decrease of erythrocyte-associated hematologic parameters (MCV, MCH, Hb, Ht) as markers of inflammatory infection, all relative to non-vaccinated controls. Lymphocyte stimulation revealed Ag85A-induced IFNgamma levels post-infection as the strongest immunocorrelate for protection (spearman's rho: -0.60). CONCLUSIONS: Both the BCG/MVA.85A prime-boost regime and the novel live attenuated, phoP deficient TB vaccine candidate SO2 showed significant protective efficacy by various parameters in rhesus macaques. Considering the phylogenetic relationship between macaque and man and the similarity in manifestations of TB disease, these data support further development of these primary and combination TB vaccine candidates

Prophylactic Cefazolin Dosing and Surgical Site Infections: Does the Dose Matter in Obese Patients?

Background Most surgical prophylaxis guidelines recommend a 3-g cefazolin intravenous dose in patients weighing ≥ 120 kg. However, this recommendation is primarily based on pharmacokinetic studies rather than robust clinical evidence. This study aimed to compare the prevalence of surgical site infections (SSIs) in obese and non-obese patients (body mass index ≥ 30 kg/m2 and < 30 kg/m2), and those weighing ≥ 120 kg and < 120 kg, who received 2- g cefazolin preoperatively. Methods A retrospective case-control study was conducted in adult elective surgical patients. Patients receiving 2- g cefazolin were grouped as obese and non-obese, and by weight (≥ 120 kg or < 120 kg). The 90-day prevalence of SSI and potential contributing factors were investigated. Results We identified 152 obese (median 134 kg) and 152 non-obese control (median 73 kg) patients. Baseline characteristics were similar between groups, except for an increased prevalence in the obese group of diabetes (35.5% vs 13.2%; p < 0.001) and an American Society of Anaesthesiologists Score of 3 (61.8% vs 17.1%; p < 0.001). While not statistically significant, the prevalence of SSI in the obese group was almost double that in the non-obese group (8.6% vs 4.6%; p = 0.25) and in patients weighing ≥ 120 kg (n = 102) compared to those weighing < 120 kg (n = 202) (9.8% vs 5.0%; p = 0.17). Conclusion The prevalence of SSI was not significantly increased in obese patients, or those weighing ≥ 120 kg, who received cefazolin 2- g prophylactically; however, trends toward an increase were evident. Large-scale randomised trials are needed to examine whether a 2-g or 3-g cefazolin is adequate to prevent SSI in obese (and ≥ 120 kg) individuals

Management of obstructive sleep apnea in Europe-A 10-year follow-up

Objective: In 2010, a questionnaire-based study on obstructive sleep apnea (OSA) management in Europe identified differences regarding reimbursement, sleep specialist qualification, and titration procedures. Now, 10 years later, a follow-up study was conducted as part of the ESADA (European Sleep Apnea Database) network to explore the development of OSA management over time.Methods: The 2010 questionnaire including questions on sleep diagnostic, reimbursement, treatment, and certification was updated with questions on telemedicine and distributed to European Sleep Centers to reflect European OSA management practice.Results: 26 countries (36 sleep centers) participated, representing 20 ESADA and 6 non-ESADA countries. All 21 countries from the 2010 survey participated. In 2010, OSA diagnostic procedures were performed mainly by specialized physicians (86%), whereas now mainly by certified sleep specialists and specialized physicians (69%). Treatment and titration procedures are currently quite homogenous, with a strong trend towards more Autotitrating Positive Airway Pressure treatment (in hospital 73%, at home 62%). From 2010 to 2020, home sleep apnea testing use increased (76%-89%) and polysomnography as sole diagnostic procedure decreased (24%-12%). Availability of a sleep specialist qualification increased (52%-65%) as well as the number of certified polysomnography scorers (certified physicians: 36%-79%; certified technicians: 20%-62%). Telemedicine, not surveyed in 2010, is now in 2020 used in diagnostics (8%), treatment (50%), and follow-up (73%). Conclusion: In the past decade, formal qualification of sleep center personnel increased, OSA diagnostic and treatment procedures shifted towards a more automatic approach, and telemedicine became more prominent.(c) 2022 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/)

Machine learning for classification of hypertension subtypes using multi-omics: a multi-centre, retrospective, data-driven study

Background: Arterial hypertension is a major cardiovascular risk factor. Identification of secondary hypertension in its various forms is key to preventing and targeting treatment of cardiovascular complications. Simplified diagnostic tests are urgently required to distinguish primary and secondary hypertension to address the current underdiagnosis of the latter. Methods: This study uses Machine Learning (ML) to classify subtypes of endocrine hypertension (EHT) in a large cohort of hypertensive patients using multidimensional omics analysis of plasma and urine samples. We measured 409 multi-omics (MOmics) features including plasma miRNAs (PmiRNA: 173), plasma catechol O-methylated metabolites (PMetas: 4), plasma steroids (PSteroids: 16), urinary steroid metabolites (USteroids: 27), and plasma small metabolites (PSmallMB: 189) in primary hypertension (PHT) patients, EHT patients with either primary aldosteronism (PA), pheochromocytoma/functional paraganglioma (PPGL) or Cushing syndrome (CS) and normotensive volunteers (NV). Biomarker discovery involved selection of disease combination, outlier handling, feature reduction, 8 ML classifiers, class balancing and consideration of different age- and sex-based scenarios. Classifications were evaluated using balanced accuracy, sensitivity, specificity, AUC, F1, and Kappa score. Findings: Complete clinical and biological datasets were generated from 307 subjects (PA=113, PPGL=88, CS=41 and PHT=112). The random forest classifier provided ∼92% balanced accuracy (∼11% improvement on the best mono-omics classifier), with 96% specificity and 0.95 AUC to distinguish one of the four conditions in multi-class ALL-ALL comparisons (PPGL vs PA vs CS vs PHT) on an unseen test set, using 57 MOmics features. For discrimination of EHT (PA + PPGL + CS) vs PHT, the simple logistic classifier achieved 0.96 AUC with 90% sensitivity, and ∼86% specificity, using 37 MOmics features. One PmiRNA (hsa-miR-15a-5p) and two PSmallMB (C9 and PC ae C38:1) features were found to be most discriminating for all disease combinations. Overall, the MOmics-based classifiers were able to provide better classification performance in comparison to mono-omics classifiers. Interpretation: We have developed a ML pipeline to distinguish different EHT subtypes from PHT using multi-omics data. This innovative approach to stratification is an advancement towards the development of a diagnostic tool for EHT patients, significantly increasing testing throughput and accelerating administration of appropriate treatment. Funding: European Union's Horizon 2020 Research and Innovation Programme under Grant Agreement No. 633983, Clinical Research Priority Program of the University of Zurich for the CRPP HYRENE (to Z.E. and F.B.), and Deutsche Forschungsgemeinschaft (CRC/Transregio 205/1)