Conclusies1. De complexe interactie van anesthetica en neuromusculaire blokkeringsmiddelen op perifere chemosensitiviteit is nog maar ten dele begrepen.2. Gedurende verschillende fases van het... Show moreConclusies1. De complexe interactie van anesthetica en neuromusculaire blokkeringsmiddelen op perifere chemosensitiviteit is nog maar ten dele begrepen.2. Gedurende verschillende fases van het neuromusculaire blok is er een discrepantie tussen het niveau van neuromusculaire blokkade gemeten aan de bovenarm met compressomyografie en aan de m. adductor pollicis met elektromyografie.3. De huidige zorgen ten aanzien van de veiligheid van sugammadex betreffen vooral overgevoeligheidsreacties en hartritmestoornissen. In de huidige literatuur is bradycardie de meest gemelde ritmestoornis gerelateerd aan de toediening van sugammadex. Hartritmestoornissen die verband houden met de toediening van sugammadex kunnen gepaard gaan met anafylactische symptomen en potentieel levensbedreigend zijn.4. Wanneer anesthesie wordt gehandhaafd met sevofluraan tijdens laparoscopische nierchirurgie geeft diep neuromusculaire blokkade geen voordeel met betrekking tot chirurgische werkomstandigheden ten opzichte van een moderate neuromusculaire blokkade. Show less
Thrombosis is the process of a blood clot forming inside a blood vessel, obstructing blood flow. Oral anticoagulant therapy is prescribed for treatment and prevention of thrombo-embolic diseases.... Show moreThrombosis is the process of a blood clot forming inside a blood vessel, obstructing blood flow. Oral anticoagulant therapy is prescribed for treatment and prevention of thrombo-embolic diseases. The most important side effect of anticoagulants is the occurrence of bleeding. For decades, vitamin K antagonists (VKA) were the cornerstone of treatment, which required routine monitoring of the International Normalized Ratio (INR). After the introduction of Direct Oral Anticoagulants (DOAC), which currently do not require routine concentration monitoring, patients had to decide whether to remain with VKA or switch to DOAC. The first part of this thesis focuses on the evaluation of VKA treatment and the transition of VKA to DOAC. As the incidence of major bleeding with DOAC is still 2-4% there is room for improvement in their management. The second part this thesis evaluates the variability of DOAC plasma concentrations and how DOAC therapy may be improved. Show less
Zijp, M.; Dekker, E.; Hauck, M.; Koning, A. de; Bijleveld, M.; Tokaya, J.; ... ; Posthuma, L. 2022
Background: Muscle relaxants are routinely used during anesthesia to facilitate endotracheal intubation and to optimize surgical conditions. However, controversy remains about the required depth of... Show moreBackground: Muscle relaxants are routinely used during anesthesia to facilitate endotracheal intubation and to optimize surgical conditions. However, controversy remains about the required depth of neuromuscular block (NMB) needed for optimal surgical working conditions and how this relates to other outcomes. For instance, a deep neuromuscular block yields superior surgical working conditions compared to a standard NMB in laparoscopic surgery, however, a robust association to other (safety) outcomes has not yet been established.Methods: Trial design: an international multicenter randomized controlled double-blind strategy trial. Trial population: 922 patients planned for elective, laparoscopic or robotic, abdominal surgery. Intervention: Patients will be randomized to a deep NMB (post-tetanic count 1-2 twitches) or standard care (single-dose muscle relaxant administration at induction and repeated only if warranted by surgical team). Main trial endpoints: Primary endpoint is the difference in incidence of intraoperative adverse events during laparoscopic surgery graded according to ClassIntra (R) classification (i.e., ClassIntra (R) grade >= 2) between both groups. Secondary endpoints include the surgical working conditions, 30-day postoperative complications, and patients' quality of recovery.Discussion: This trial was designed to analyze the effect of deep neuromuscular block compared to standard neuromuscular block on intra- and postoperative adverse events in patients undergoing laparoscopic surgery. Show less
Aim: To determine whether the use of a respiratory function monitor (RFM) during PPV of extremely preterm infants at birth, compared with no RFM, leads to an increase in percentage of inflations... Show moreAim: To determine whether the use of a respiratory function monitor (RFM) during PPV of extremely preterm infants at birth, compared with no RFM, leads to an increase in percentage of inflations with an expiratory tidal volume (Vte) within a predefined target range.Methods: Unmasked, randomised clinical trial conducted October 2013 - May 2019 in 7 neonatal intensive care units in 6 countries. Very preterm infants (24-27 weeks of gestation) receiving PPV at birth were randomised to have a RFM screen visible or not. The primary outcome was the median proportion of inflations during manual PPV (face mask or intubated) within the target range (Vte 4-8 mL/kg). There were 42 other prespecified monitor measurements and clinical outcomes.Results: Among 288 infants randomised (median (IQR) gestational age 26(+2) (25(+3)-27(+1)) weeks), a total number of 51,352 inflations were analysed. The median (IQR) percentage of inflations within the target range in the RFM visible group was 30.0 (18.0-42.2)% vs 30.2 (14.8-43.1)% in the RFM non-visible group (p = 0.721). There were no dierences in other respiratory function measurements, oxygen saturation, heart rate or FiO(2). There were no dierences in clinical outcomes, except for the incidence of intraventricular haemorrhage (all grades) and/or cystic periventricular leukomalacia (visible RFM: 26.7% vs non-visible RFM: 39.0%; RR 0.71 (0.68-0.97); p = 0.028).Conclusion: In very preterm infants receiving PPV at birth, the use of a RFM, compared to no RFM as guidance for tidal volume delivery, did not increase the percentage of inflations in a predefined target range. Show less
Oijen, J.C.F. van; Grit, K.J.; Bos, W.J.W.; Bal, R. 2021
The complexity of regulations governing investigator-initiated trials (IITs) places a great burden on hospitals. Consequently, many hospitals seek to alleviate regulatory pressures by seeking an... Show moreThe complexity of regulations governing investigator-initiated trials (IITs) places a great burden on hospitals. Consequently, many hospitals seek to alleviate regulatory pressures by seeking an alternative quality management system (QMS). This paper takes the Netherlands as a case. To investigate how QMSs for IITs are organized in Dutch hospitals, we adopted the theoretical concepts of mentoring and monitoring in a mixed methods study in the period 2014-2018. In clinical practice and international guidelines, monitoring is seen as the standard quality assurance for ongoing trials. However, hospitals have implemented monitoring programs that resemble mentoring. The contrast between these ideal types is less pronounced in practice as both combine elements of compliance and feedback for learning in practice. In a monitoring setting, learning is one-way, from monitor to researcher; whereas mentoring focuses on mutual support and learning. To tackle problems in each system, the authority of the Board of Directors (BoD) and the BoD's relationship with staff members are crucial. We discuss the challenges that BoD and staff face in keeping an integrated view of the various components of QMSs. Show less
This thesis assesses multiple monitoring modalities that can be used in the peri-operative period to reduce respiratory adverse events associated with the use of anesthetic drugs, particularly... Show moreThis thesis assesses multiple monitoring modalities that can be used in the peri-operative period to reduce respiratory adverse events associated with the use of anesthetic drugs, particularly opioids and neuromuscular blocking drugs. Monitors of analgesia, neuromuscular block and ventilation are studied in both healthy volunteers and surgical patient populations to assess proof of concept, efficacy, feasibility of clinical use and effect on clinical outcomes. Show less
The aim of this thesis was to optimize immunosuppressive therapy, especially everolimus therapy in renal transplantation recipients by identifying pharmacological and pharmacogenetic risk factors... Show moreThe aim of this thesis was to optimize immunosuppressive therapy, especially everolimus therapy in renal transplantation recipients by identifying pharmacological and pharmacogenetic risk factors influencing pharmacokinetics, and dynamics such as side effects and patient outcome. Therapeutic Drug Monitoring (TDM) of oral immunosuppressive agents is essential to prevent toxicity and or rejection; therefore it is very important to use a reliable and accurate bioanalytical assay. Differences between the most used analytical assays of measuring everolimus in whole blood and its effect on dosing advice were investigated. TDM is performed based on either trough or AUC monitoring and pharmacogenetics might be a valuable addition to TDM. Therefore the population pharmacokinetics of everolimus in a calcineurin free regimen was investigated and predictive factors such as pharmacogenetics were evaluated. In addition a limited sampling model was developed. MTOR inhibitors are known for a variety of side effects and high dropout rates. In this thesis a comprehensive analysis was performed aimed at identifying risk factors for discontinuation and a number of serious side effects. This thesis also describes an analysis aimed at identifying risk factor associated with delayed graft function, acute rejection and subclinical rejection in patients on a cyclosporine based immunosuppressive regimen. Show less
Geluk, C.A.M.L.; Domburgh, L. van; Doreleijers, T.A.H.; Jansen, L.M.C.; Bouwmeester, S.; Garre, F.G.; Vermeiren, R. 2014
We develop a new technique for Run-time Checking for two object-oriented languages: Java and the Abstract Behavioral Specification language ABS. In object-oriented languages, objects communicate by... Show moreWe develop a new technique for Run-time Checking for two object-oriented languages: Java and the Abstract Behavioral Specification language ABS. In object-oriented languages, objects communicate by sending each other messages. Assuming encapsulation, the behavior of objects is completely determined by the order of the messages, and their content. Traditional methods for Run-time Checking focus either exclusively on the description and testing of the order of the messages (Monitoring), or they focus on specifying and testing the content of those messages (Run-time Assertion Checking). Our method combines Monitoring with Run-time Assertion Checking.The basic idea behind our technique is that the behavior of objects can be described formally by means of an attribute grammar extended with assertions. The underlying (context-free) grammar specifies the valid orderings of the messages, the attributes define properties of the contents of the messages, and assertions specify the desired values of those properties. We develop a new Run-time Checker for attribute grammars in the form of a meta-program in the language Rascal and applied the Run-time Checker to an industrial case of the e-commerce company Fredhopper. We also investigated the efficiency of the run-time checker, and successfully discovered and solved several bugs in the Fredhopper software. Show less
Mollers, M.; Scherpenisse, M.; Klis, F.R.M. van der; King, A.J.; Rossum, T.G.J. van; Logchem, E.M. van; ... ; Melker, H.E. de 2012
Antibody-mediated rejection is increasingly recognised within the transplantation community as a cause or contributing factor in the rejection of transplanted organs. The humoral immune response... Show moreAntibody-mediated rejection is increasingly recognised within the transplantation community as a cause or contributing factor in the rejection of transplanted organs. The humoral immune response towards allografts involves B cells that, after T cell dependent activation, can differentiate into antibody producing cells. Whereas there are several therapeutic entities to treat cellular rejection, at present, no standard treatment for humoral rejection exists. The first part of this thesis describes the effects of different maintenance immunosuppressive drugs directly on B cells, as well as the effect on T cell help in vitro. The data presented in these chapters show differential effects of the drugs on B cells and T cell help. Furthermore, the effects of novel, experimental drugs on the in vitro activation of B cells are described. The second part of this thesis describes the development of a novel technique for monitoring the humoral alloimmune response. By using this technique, patients at risk for humoral rejection may be identified. The last part describes the difficulties and pitfalls of monitoring T cells that respond to alloantigen via the indirect pathway of allorecognition. In an alloimmune response, these are the T cells that provide help to B cells to become fully activated. Show less
Accurate clinical assessment of the circulatory status is particular desirable in critically ill patients in the intensive care unit (ICU) and patients undergoing cardiac, thoracic, or vascular... Show moreAccurate clinical assessment of the circulatory status is particular desirable in critically ill patients in the intensive care unit (ICU) and patients undergoing cardiac, thoracic, or vascular interventions. As the patient__s haemodynamic status may change rapidly, continuous monitoring of cardiac output will provide information allowing rapid adjustment of therapy. Aim of this thesis is an overview and evaluation with respect to less invasive cardiac output measurement and monitoring systems, especially the pulse contour technique. The introduction highlights historical and physiological aspects of cardiac output measurement and effect of respiratory changes on blood flow and pressure. Secondly it introduces methodological aspects of measurement, with attention to the reference method and analysis of agreement Show less
