Doctor of Philosophy

dissertationFollowing liver transplantation, patients require lifelong immunosuppressive care and monitoring to prevent organ rejection, drug toxicity, and death. Traditionally, transplant centers use paper-based processes that are not scalable and can lead to inefficiencies and deficiencies in information management. Clinical decision support (CDS) tools may help to overcome information management challenges, and a system-agnostic approach may help to disseminate these tools nationwide. We sought to inform the development of new transplant information systems by analyzing existing information systems. To meet this overall objective, we administered a survey and found that all liver transplant programs used manual, paper-based processes and nearly all used electronic health record (EHR) systems. Programs also had immunosuppression guidelines with similar logic patterns. Then we analyzed long-term use of a computerized notification system at one transplant center and found that a system designed specifically for the posttransplant workflow can meet long-term information management needs. Next, we assessed the clinical outcomes associated with computerized notifications for laboratory monitoring of immunosuppressive care and found that a system designed specifically for the posttransplant workflow was associated with improved clinical outcomes. Following this, we described workflow processes at two transplant centers and found that a transplant-specific notification system was associated with changes in workflow process iv measures and the satisfaction of performing laboratory monitoring tasks compared to a general EHR notification system. Finally, we administered a questionnaire to coordinators using a transplant-specific notification system and identified the usage of specific data elements in computerized notifications for posttransplant laboratory monitoring. Our findings show that near universal use of EHRs provides an infrastructure for implementing CDS tools, and logic patterns for posttransplant laboratory monitoring can be generalized to other U.S. transplant centers. Transplant-specific computerized notifications may be part of a system of processes that improve the scalability, quality, and satisfaction of patient management by postliver transplant coordinators. However, these systems must be flexible enough to accommodate new immunosuppressants and changing or additional parameters used in computerized logic as clinical practice or needs of the patient population evolve. Proactive notifications sent directly to patients regarding upcoming due dates via patient portals may also improve patient outcomes

Immunosuppression and Tolerance in Adult Liver Transplantation. A literature review on the immunosuppression-drugs after a liver transplantation; how to best provide safe treatment and good quality of life.

Background: There is increasing interest in long-term management issues in liver transplantation recipients; quality of life, complications related to extended immunosuppressants, natural development of co-morbidities and recurrent disease. IS agents are used in induction of the liver transplantation, maintenance of the organ, and reversal of organ rejection. Aim: A systematic literature search with the purpose of summaries the existing clinical research on this specific topic; immunosuppressive medications post-liver transplantation. Material and methods: Search method in PubMed; Medical Subject Headings, with the terms: ("Liver Transplantation"[Mesh]) AND "Immunosuppression" [Mesh]. The selected studies were assessed for scientific quality and relevance for the thesis. Results: Steroid-based IS are responsible for a substantial post-LTx morbidity and mortality, hence, minimization of its use is of utmost importance to improve patient’s quality of life. Because of systemic steroids impact on all organs in the human body and all its side effects that increases risk factors of morbidity. It is important to comprehend the hepatic disease and the patient, as well as understanding the efficacies and side effects/interactions of IS medication. This way the doctor and the patient can strike a balance between suppression of rejection and minimization of side effects. The patient group are very complex, and this have been shown to be a challenge when it comes to comparing the result on the effect of different studies with different immunosuppression’s as the reason for liver failure have a lot to say for graft rejection and patient survival, especially for complication accruing with lifelong IS. Conclusion: LTx recipients are an inherently complex population, with diverse and serious underlying medical concerns that have the potential to adversely affect posttransplant outcomes, thus would a general IS therapy lead to a greater rejection rate. There is a need for more clinical studies, random control trails, that can help us finding the best immunosuppressive treatment for liver transplanted patients

La adherencia a la terapia inmunosupresora tras un trasplante de hígado: una revisión integradora

Objetivo: investigar la evidencia disponible en la literatura sobre la falta de adherencia a la terapia inmunosupresora en los pacientes sometidos a trasplante hepático. Método: revisión integradora de la literatura, que incluye investigaciones cuya muestra estaba constituida por pacientes mayores de 18 años sometidos a trasplante hepático. Se excluyeron aquellos que tenían pacientes sometidos a trasplantes de varios órganos. Para la selección de los artículos fueron consultadas las bases Medline / Pubmed, CINAHL, LILACS, Scopus y Embase. El período de búsqueda determinado correspondió a la fecha inicial de indexación de las diferentes bases, con fecha límite de 10 de febrero de 2015, usándose descriptores controlados y no controlados: liver transplantation, hepatic transplantation, liver orthotopic transplantation, medication adherence, medication non-adherence, medication compliance e patient compliance. Resultados: se localizaron 191 investigaciones, de los cuales 10 cumplieron con los objetivos del estudio y se agruparon en cuatro categorías, a saber: proceso educativo y ocurrencia de no adhesión; falta de adhesión relacionada con el número de dosis diarias de medicamentos inmunosupresores; métodos de detección de la falta de adhesión y los efectos secundarios de la terapia. Conclusión: se verificaron factores de riesgo relacionados con el servicio de salud, tales como el control y la reducción del número de dosis; inherentes a la persona, como ser hombre, divorciado, usuario de alcohol u otras sustancias, expuestos a un menor apoyo social y portadores de enfermedades mentales.Objective: to investigate the evidence available in the literature on non-adherence to immunosuppressive therapy among patients undergoing liver transplantation. Method: integrative literature review, including research whose sample consisted of patients aged over 18 years undergoing liver transplantation. It excluded those containing patients undergoing multiple organ transplants. For the selection of articles, Medline / Pubmed, CINAHL, LILACS, Scopus and Embase were searched. The search period corresponded to the initial date of indexation of different bases, up to the deadline of February 10, 2015, using controlled and uncontrolled descriptors: liver transplantation, hepatic transplantation, liver orthotopic transplantation, medication adherence, medication non-adherence, medication compliance and patient compliance. Results: were located 191 investigations, 10 of which met the objectives of the study and were grouped into four categories, namely: educational process and non-adherence; non-adherence related to the number of daily doses of immunosuppressive medications; detection methods for non-adherence and side effects of therapy. Conclusion: there were risk factors related to the health service, such as control and reduction of the number of doses; related to the individual, such as being male, divorced, alcohol or other substances user, exposed to low social support and being mentally ill.Objetivo: investigar as evidências disponíveis na literatura sobre a não adesão à terapêutica imunossupressora entre pacientes submetidos ao transplante de fígado. Método: revisão integrativa da literatura, que incluiu investigações cuja amostra era composta por pacientes com idade igual ou superior a 18 anos, submetidos a transplante de fígado. Excluíram-se as que continham pacientes submetidos a transplantes de múltiplos órgãos. Para a seleção dos artigos foram consultadas as bases Medline/Pubmed, CINAHL, LILACS, Scopus e Embase. O período de busca determinado correspondeu à data inicial de indexação das diferentes bases, até a data limite de 10 de fevereiro de 2015, empregando-se os descritores controlados e não controlados: liver transplantation, hepatic transplantation, liver orthotopic transplantation, medication adherence, medication non-adherence, medication compliance e patient compliance. Resultados: foram localizadas 191 investigações, das quais 10 atenderam aos objetivos do estudo e foram agrupadas em quatro categorias, a saber: processo educativo e ocorrência de não adesão; não adesão relacionada ao número de doses diárias dos medicamentos imunossupressores; métodos de detecção da não adesão e efeitos colaterais da terapêutica. Conclusão: verificou-se a existência de fatores de risco relacionados ao serviço de saúde, como controle e redução do número de doses; relacionados ao indivíduo, como ser do sexo masculino, divorciado, usuário de álcool ou outras substâncias, expostos a menor suporte social e portadores de transtorno mental

Role of therapeutic drug monitoring in pulmonary infections : use and potential for expanded use of dried blood spot samples

Respiratory tract infections are among the most common infections in men. We reviewed literature to document their pharmacological treatments, and the extent to which therapeutic drug monitoring (TDM) is needed during treatment. We subsequently examined potential use of dried blood spots as sample procedure for TDM. TDM was found to be an important component of clinical care for many (but not all) pulmonary infections. For gentamicin, linezolid, voriconazole and posaconazole dried blood spot methods and their use in TDM were already evident in literature. For glycopeptides, beta-lactam antibiotics and fluoroquinolones it was determined that development of a dried blood spot (DBS) method could be useful. This review identifies specific antibiotics for which development of DBS methods could support the optimization of treatment of pulmonary infections

Optimizing drug therapy in liver transplantation:For better patient outcomes

In this thesis we showed that adapting immunosuppressive agents based on patients’ comorbidities and side effects is essential in order to modify and minimize immunosuppressive related toxicity (i.e. renal insufficiency, hypertension, post-transplant diabetes mellitus). We showed that 1) once-daily low-dose SRL combined with low-dose extended-release tacrolimus does ultimately not provide less chronic kidney disease grade ≥3 at 36 months compared to normal-dose extended release tacrolimus (LOL study) and 2) LCP-tacrolimus provides better results compared to ER-tacrolimus (MOTTO study). Based on findings in this thesis we suggested that low-dose ribavirin for at least 180 days has a positive effect on hepatitis E virus clearance in solid organ transplant recipients. Next, immunosuppressive agents affecting the B lymphocytes reduce the immunogenicity of vaccination in LT recipients. This should be considered when vaccinating LT recipients. Finally, until the start of this thesis, in the Netherlands clinical pharmacists were solely involved in therapeutic drug monitoring of immunosuppressive agents and computerized medication monitoring. In this thesis, we showed that clinical pharmacists can have an added value in the clinical and outpatient transplant care and increase the medication safety and efficacy for these patients. Overall, we added new insights to the field of optimizing drug therapy for LT recipients to improve patient outcomes.<br/

Optimizing drug therapy in liver transplantation:For better patient outcomes

In this thesis we showed that adapting immunosuppressive agents based on patients’ comorbidities and side effects is essential in order to modify and minimize immunosuppressive related toxicity (i.e. renal insufficiency, hypertension, post-transplant diabetes mellitus). We showed that 1) once-daily low-dose SRL combined with low-dose extended-release tacrolimus does ultimately not provide less chronic kidney disease grade ≥3 at 36 months compared to normal-dose extended release tacrolimus (LOL study) and 2) LCP-tacrolimus provides better results compared to ER-tacrolimus (MOTTO study). Based on findings in this thesis we suggested that low-dose ribavirin for at least 180 days has a positive effect on hepatitis E virus clearance in solid organ transplant recipients. Next, immunosuppressive agents affecting the B lymphocytes reduce the immunogenicity of vaccination in LT recipients. This should be considered when vaccinating LT recipients. Finally, until the start of this thesis, in the Netherlands clinical pharmacists were solely involved in therapeutic drug monitoring of immunosuppressive agents and computerized medication monitoring. In this thesis, we showed that clinical pharmacists can have an added value in the clinical and outpatient transplant care and increase the medication safety and efficacy for these patients. Overall, we added new insights to the field of optimizing drug therapy for LT recipients to improve patient outcomes.<br/

Studies in Advanced Chronic Liver Disease

In patients with severely advanced liver disease, clinical, diagnostic and therapeutic aspects of frequent complications, including spontaneous bacterial peritonitis, bacterascites, other infections, (ectopic) variceal bleeding, hepatic encephalopathy and malnutrition were studied, with the general aim to evaluate current and new diagnostic and therapeutic strategies and with the ultimate aim to optimize patient management