Thesis (doctoral)--Katholieke Universiteit te Leuven. / Includes bibliographical references (p. 141-152).

Introdução: O uso de membranas de alto fluxo tornou-se comum na prática de hemodiálise convencional (HDC), hemodiafiltração (HDF) e hemofiltração (HF) devido ao elevado coeficiente de ultrafiltração e à maior permeabilidade do poro. A produção de fluido de reposição online proporciona maior facilidade na execução de HDF e HF. Estas modalidades aumentam a depuração de solutos maiores por convecção. O objetivo do estudo é comparar a eficácia de três métodos dialíticos: HDC, HDF online (HDF-OL) pós-diluição e HF online (HF-OL) pré-diluição, por meio da quantificação direta da dose de diálise pela extração de solutos. Método: Trata-se de um ensaio clínico, envolvendo 14 pacientes em hemodiálise. Os pacientes iniciaram no estudo na modalidade de HDC com prescrição de quatro horas, fluxo de sangue de 350ml/min e fluxo de dialisato de 800ml/min com dialisador novo de alto fluxo e alta eficiência. Posteriormente, os mesmos pacientes foram submetidos à uma sessão de HDF-OL pós-diluição de quatro horas, fluxo de sangue de 350ml/min, fluxo de reposição de 100ml/min e fluxo de dialisato de 700ml/min. Por último, fizeram uma sessão de HF-OL pré-diluição com mesma duração, fluxo de sangue de 350ml/min e fluxo de reposição de 100% do fluxo de sangue. Foram realizadas 42 sessões de tratamento. A extração de solutos foi avaliada por meio de dosagens plasmáticas e quantificação do efluente. Resultados: As concentrações séricas dos solutos pré-diálise não foram diferentes entre as sessões do estudo. O volume de substituição em HDF-OL foi de 20,6 ± 0,8L/sessão e em HF-OL foi de 81,8 ± 7,1L/sessão. A HDF-OL quando comparada com a HDC não apresentou diferença na extração de moléculas pequenas. Da mesma forma, a extração de ?2-microglobulina foi semelhante nas 3 modalidades: 121,1 ± 46,4 mg em HDC, 130,1 ± 46,5 mg em HDF-OL e 106,0 ± 45,0 mg em HF-OL. A perda de albumina foi significativamente maior em HDF-OL (1360,2 ± 425,0 mg) e HF-OL (1310,3 ± 201,4 mg) Vs. HDC (269,6 ± 15,3 mg) (p<0,0001). A depuração de pequenos solutos foi superior em HDF-OL. A depuração de ?2-microglobulina foi maior em HDF- OL (114,0 ± 15,7 ml/min) e HF-OL (116,1 ± 19,5 ml/min) Vs. HDC (86,5 ± 16,1 ml/min) (p<0,0001). A dose de diálise avaliada pelo singlepool, equilibrated, standard Kt/V e pela quantificação direta da diálise (DDQKt/V) não foi diferente entre HDF-OL e HDC. Na HF-OL a ausência de difusão contribuiu para menor extração e menor Kt/V de solutos pequenos (p<0,0001). Conclusão: A dose de diálise avaliada pela extração de solutos foi semelhante entre HDC e HDF-OL sendo a HF-OL menos favorável na extração de solutos pequenos / Introduction: The use of high-flux membranes became common practice in conventional hemodialysis (CHD), hemodiafiltration (HDF) and hemofiltration (HF) due to the high pore permeability and ultrafiltration coefficient. The online production of substitution volume can make easier HDF and HF execution. These modalities can increase the clearance of larger solutes by convection. The aim of this study is to compare the dialysis efficacy among three methods: CHD, online post-dilution HDF (OL-HDF), and online pre- dilution HF (OL-HF) through the direct quantification of dialysis dose by the solutes extraction. Method: This is a clinical trial involving 14 patients on hemodialysis. The patients began the study in CHD modality with a four-hour prescription, blood flow of 350ml/min and dialysate flow of 800ml/min with new high-flux and high efficiency dialyzer. Subsequently, these patients were submitted to a four-hour post-dilution OL-HDF session, with flow replacement of 100ml/min, blood flow of 350ml/min and dialysate flow of 700ml/min. Finally, patients underwent a pre-dilution OL-HF with the same duration, blood flow of 350ml/min and flow replacement of 100% of the blood flow. Forty-two sessions of treatments were performed. The solutes extraction was assessed by plasma measurements and effluent quantification Results: Pre-treatment serum concentrations of different solutes showed no statistical difference among the modalities. The substitution volume in OL- HDF was 20.6 ± 0.8L/session and in OL-HF was 81.8 ± 7.1 L/session. The OL-HDF compared to CHD showed no difference in the small solutes extraction. Similarly, ?2-microglobulin extraction was similar among the three modalities: 121.1 ± 46.4 mg in CHD, 130.1 ± 46.5 mg in OL-HDF and 106.0 ± 45.0 mg in OL-HF. Albumin loss was significantly higher in OL-HDF (1360.2 ± 425.0 mg) and OL-HF (1310.3 ± 201.4 mg) Vs. CHD (269.6 ± 15.3 mg) (p<0.0001). The small solutes clearance was greater in OL-HDF. ?2- microglobulin clearance was higher in OL-HDF (114.0 ± 15.7 ml/min) and OL- HF (116.1 ± 19.5 ml/min) Vs. CHD (86.5 ± 16.1 ml/min) (p<0.0001). The dialysis dose measured by singlepool, equilibrated, standard Kt/V and by direct dialysis quantification (DDQ Kt/V) was not different between CHD and OL-HDF. In OL-HF the absence of diffusion contributed to lower extraction and lower Kt/V of small solutes. Conclusion: The dialysis dose evaluated by extraction of solutes was similar between CHD and OL-HDF being a OL-HF less favorable in small solutes extraction

Thesis--University of Oklahoma. / Includes bibliographical references (leaves 65-69).

Introdução: O uso de membranas de alto fluxo tornou-se comum na prática de hemodiálise convencional (HDC), hemodiafiltração (HDF) e hemofiltração (HF) devido ao elevado coeficiente de ultrafiltração e à maior permeabilidade do poro. A produção de fluido de reposição online proporciona maior facilidade na execução de HDF e HF. Estas modalidades aumentam a depuração de solutos maiores por convecção. O objetivo do estudo é comparar a eficácia de três métodos dialíticos: HDC, HDF online (HDF-OL) pós-diluição e HF online (HF-OL) pré-diluição, por meio da quantificação direta da dose de diálise pela extração de solutos. Método: Trata-se de um ensaio clínico, envolvendo 14 pacientes em hemodiálise. Os pacientes iniciaram no estudo na modalidade de HDC com prescrição de quatro horas, fluxo de sangue de 350ml/min e fluxo de dialisato de 800ml/min com dialisador novo de alto fluxo e alta eficiência. Posteriormente, os mesmos pacientes foram submetidos à uma sessão de HDF-OL pós-diluição de quatro horas, fluxo de sangue de 350ml/min, fluxo de reposição de 100ml/min e fluxo de dialisato de 700ml/min. Por último, fizeram uma sessão de HF-OL pré-diluição com mesma duração, fluxo de sangue de 350ml/min e fluxo de reposição de 100% do fluxo de sangue. Foram realizadas 42 sessões de tratamento. A extração de solutos foi avaliada por meio de dosagens plasmáticas e quantificação do efluente. Resultados: As concentrações séricas dos solutos pré-diálise não foram diferentes entre as sessões do estudo. O volume de substituição em HDF-OL foi de 20,6 ± 0,8L/sessão e em HF-OL foi de 81,8 ± 7,1L/sessão. A HDF-OL quando comparada com a HDC não apresentou diferença na extração de moléculas pequenas. Da mesma forma, a extração de ?2-microglobulina foi semelhante nas 3 modalidades: 121,1 ± 46,4 mg em HDC, 130,1 ± 46,5 mg em HDF-OL e 106,0 ± 45,0 mg em HF-OL. A perda de albumina foi significativamente maior em HDF-OL (1360,2 ± 425,0 mg) e HF-OL (1310,3 ± 201,4 mg) Vs. HDC (269,6 ± 15,3 mg) (p<0,0001). A depuração de pequenos solutos foi superior em HDF-OL. A depuração de ?2-microglobulina foi maior em HDF- OL (114,0 ± 15,7 ml/min) e HF-OL (116,1 ± 19,5 ml/min) Vs. HDC (86,5 ± 16,1 ml/min) (p<0,0001). A dose de diálise avaliada pelo singlepool, equilibrated, standard Kt/V e pela quantificação direta da diálise (DDQKt/V) não foi diferente entre HDF-OL e HDC. Na HF-OL a ausência de difusão contribuiu para menor extração e menor Kt/V de solutos pequenos (p<0,0001). Conclusão: A dose de diálise avaliada pela extração de solutos foi semelhante entre HDC e HDF-OL sendo a HF-OL menos favorável na extração de solutos pequenos / Introduction: The use of high-flux membranes became common practice in conventional hemodialysis (CHD), hemodiafiltration (HDF) and hemofiltration (HF) due to the high pore permeability and ultrafiltration coefficient. The online production of substitution volume can make easier HDF and HF execution. These modalities can increase the clearance of larger solutes by convection. The aim of this study is to compare the dialysis efficacy among three methods: CHD, online post-dilution HDF (OL-HDF), and online pre- dilution HF (OL-HF) through the direct quantification of dialysis dose by the solutes extraction. Method: This is a clinical trial involving 14 patients on hemodialysis. The patients began the study in CHD modality with a four-hour prescription, blood flow of 350ml/min and dialysate flow of 800ml/min with new high-flux and high efficiency dialyzer. Subsequently, these patients were submitted to a four-hour post-dilution OL-HDF session, with flow replacement of 100ml/min, blood flow of 350ml/min and dialysate flow of 700ml/min. Finally, patients underwent a pre-dilution OL-HF with the same duration, blood flow of 350ml/min and flow replacement of 100% of the blood flow. Forty-two sessions of treatments were performed. The solutes extraction was assessed by plasma measurements and effluent quantification Results: Pre-treatment serum concentrations of different solutes showed no statistical difference among the modalities. The substitution volume in OL- HDF was 20.6 ± 0.8L/session and in OL-HF was 81.8 ± 7.1 L/session. The OL-HDF compared to CHD showed no difference in the small solutes extraction. Similarly, ?2-microglobulin extraction was similar among the three modalities: 121.1 ± 46.4 mg in CHD, 130.1 ± 46.5 mg in OL-HDF and 106.0 ± 45.0 mg in OL-HF. Albumin loss was significantly higher in OL-HDF (1360.2 ± 425.0 mg) and OL-HF (1310.3 ± 201.4 mg) Vs. CHD (269.6 ± 15.3 mg) (p<0.0001). The small solutes clearance was greater in OL-HDF. ?2- microglobulin clearance was higher in OL-HDF (114.0 ± 15.7 ml/min) and OL- HF (116.1 ± 19.5 ml/min) Vs. CHD (86.5 ± 16.1 ml/min) (p<0.0001). The dialysis dose measured by singlepool, equilibrated, standard Kt/V and by direct dialysis quantification (DDQ Kt/V) was not different between CHD and OL-HDF. In OL-HF the absence of diffusion contributed to lower extraction and lower Kt/V of small solutes. Conclusion: The dialysis dose evaluated by extraction of solutes was similar between CHD and OL-HDF being a OL-HF less favorable in small solutes extraction

Le choc septique est la première cause de mortalité en réanimation. Des techniques extracorporelles de purification sanguine sont aujourd’hui proposées pour améliorer le pronostic de cette pathologie. Leur mode d’action est basé sur l’immunomodulation de la réponse inflammatoire systémique de l’hôte, obtenue principalement par épuration nonsélective des médiateurs de l’inflammation. Nous rapportons les résultats de différentes études in vitro, animales et cliniques ayant évalué les techniques de purification sanguine suivantes :hémofiltration à haut débit, hémofiltration en cascade, hémofiltration hautement adsorbante,filtration et adsorption couplée, hémoadsorption, et hémodialyse à haute perméabilité.Ce travail de recherche translationnelle montre que les techniques de purification sanguine sont non seulement capables d’épurer les médiateurs de l’inflammation mais aussi l’endotoxine pour l’hémofiltration hautement adsorbante et l’hémoadsorption. Nous démontrons par ailleurs la faisabilité technique, la sécurité d’application et les intérêts del’hémofiltration en cascade et de l’hémodialyse continue à haute perméabilité. Les effets hémodynamiques bénéfiques des techniques de purification sanguine sont également retrouvés. Pour les années à venir, il conviendra d’optimiser les techniques les plus performantes en tenant compte de leurs avantages et inconvénients respectifs. Sur le planphysiopathologique, l’effet plus direct de ces thérapies sur les leucocytes sera à approfondir. Il semble maintenant admis que convection, diffusion et adsorption ne doivent plus être opposés mais plutôt être considérés comme des mécanismes complémentaires / Septic shock is the main cause of death in the intensive care unit. Extracorporeal blood purification therapies are now being proposed in order to improve septic shock outcomes. These therapies work based on immunomodulation of the host inflammatory response, obtained by non selectively removing inflammatory mediators. We report data from several different studies performed in vitro, in animals and in human beings, assessing various blood purification therapies which include high-volume hemofiltration, cascade hemofiltration, high-adsorption hemofiltration, coupled plasma filtration adsorption, hemoadsorption and high-permeability hemodialysis. This translational research work shows that blood purification therapies are capable of removing not only the inflammatory mediators but also the endotoxins as far as highadsorptionhemofiltration and hemoadsorption are concerned. We demonstrate technical feasibility, safety and advantages of cascade hemofiltration and continuous high-permeability hemodialysis. The beneficial hemodynamic effects related to these blood purification techniques are also highlighted. For future research, optimization of the most efficient techniques is warranted, takinginto account of their respective advantages and drawbacks. Regarding pathophysiology, the direct effect of these therapies on leukocyte function is subject to further investigation. To date, convection, diffusion and adsorption should not be viewed in opposition but rather, seen as complementary mechanisms.

A high-performance liquid chromatography was developed to assay levofloxacin and vancomycin. Fluorescence polarization immunoassay was to assay amikacin. The oseltamivir carboxylate and telavancin concentrations were assayed by high-performance liquid chromatography coupled with tandem mass spectrometry. / An in vitro model was utilized to examine adsorption of antibiotics onto haemofilters. In order to test antibiotics from a range of classes, levofloxacin, amikacin, vancomycin, telavancin, and oseltamivir carboxylate were studied. / In summary, the antibiotic adsorption by haemofilters is a complex process. Both characteristics of antibiotics and haemofilters may determine adsorption. Among the studied antibiotics, in vitro adsorption of amikacin by PAN filters may have clinical significance, thus the routine monitoring of amikacin peak concentration in vivo during CRRT is recommended. / In the in vitro model, blood was pumped from an agitated, glass mixing chamber (heated using an automatic water bath), around a circuit and returned to the mixing chamber using a haemofiltration machine. Ultrafiltrate was also returned to the mixing chamber to constitute a closed circuit. As a result any decrease in drug concentration could only be due to adsorption to the filter and extracorporeal circuit, spontaneous degradation or metabolism by red cells. / The main findings were: (1) low adsorption of levofloxacin and vancomycin by haemofilters at clinically relevant concentrations; (2) significant absolute adsorption of amikacin by polyacrylonitrile haemofilters; (3) the adsorption of antibiotics was membrane-material dependent with greater adsorption by polyacrylonitrile filters; (4) lack of relationship between membrane surface area and amikacin adsorption; (5) the adsorption of levofloxacin is reversible, contrary to irreversibility of vancomycin and amikacin; (6) sieving coefficient of oseltamivir is very near to 1.0. / This thesis investigated: (1) the extent of antibiotic adsorption (levofloxacin, vancomycin, amikacin, telavancin and oseltamivir carboxylate) by haemofilters; (2) the time course of antibiotic adsorption by haemofilters; (3) the effects of plasma albumin concentration, initial dosage, pH, filter membrane material, filter membrane surface area and repeated dosing on adsorption; (4) the reversibility or irreversibility of adsorption; (5) clearance of oseltamivir carboxylate and telavancin by ultrafiltration. / Up to 25% of critically ill patients develop acute renal failure with sepsis being the most common cause. Outside of North and South America, these patients usually receive continuous renal replacement therapy (CRRT) which utilizes high flux haemofilter membranes. Thus it is common for these patients to be concurrently receiving antibiotics and CRRT. However, information about the adsorptive capacity of various haemofilters for most drugs is lacking. / "September 2007." / Advisers: Charles Gomersall; Tony Gin. / Source: Dissertation Abstracts International, Volume: 69-08, Section: B, page: 4659. / Thesis (Ph.D.)--Chinese University of Hong Kong, 2007. / Includes bibliographical references (p. 147-164). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Electronic reproduction. [Ann Arbor, MI] : ProQuest Information and Learning, [200-] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Abstract in English and Chinese. / School code: 1307.

Zirkulierende inflammatorische Mediatoren spielen eine zentrale Rolle in der Induktion und Unterhaltung eines septischen Multiorganversagens (MOV). Tritt im Rahmen eines septischen MOV ein akutes Nierenversagen auf, so wird der Einsatz einer Nierenersatztherapie notwendig. Kontinuierliche Nierenersatztherapieverfahren (CRRT) haben sich hier bewährt. Der Einsatz von CRRT zur adjuvanten Therapie des septischen MOV ist in den neunziger Jahren aufgekommen. Grundlage bildet die Hypothese, dass durch die Reduktion von Spitzenpegeln pro- and anti-inflammatorischer Mediatoren im Blutplasma die Homöostase der Immunabwehr wiederhergestellt werden kann. Kommerziell erhältlichen Hämofilter weisen aufgrund ihrer Konstruktion nur eine geringe Clearanceleistung für inflammatorische Mediatoren auf. In Kooperation mit der Industrie (Gambro, Medical Research, Hechingen, Germany) entwickelten wir einen neuartigen, großporigen Hämofilter für den klinischen Einsatz. Der Hämofilter wurde konzipiert, um Moleküle in einer Größe von bis zu 60 kD aus dem Blut septischer Patienten zu eliminieren. In einer ersten Pilotstudie wurde der Hämofilter auf seine klinische Verwendbarkeit untersucht. Untersucht wurde die hämodynamische Verträglichkeit, der Verlust an Bluteiweißen und Gerinnungsfaktoren sowie die Effektivität der Mediatorelimination am Beispiel von Interleukin-6 (IL-6) und Tumornekrosefaktor-alpha (TNF-alpha). Wir konnten zeigen, dass die großporige Hämofiltrationstherapie ein sicheres und effizientes Nierenersatzverfahren darstellt. Es erwies sich als hämodynamisch verträglich. Der kumulative Eiweißverlust lag bei 8 g/Tag. Signifikante Verluste an essentiellen Gerinnungsfaktoren wurden nicht beobachtet. Es zeigte sich zudem eine signifikante Filtration von im Blut zirkulierendem IL-6. Die Clearancekapazität für TNF-alpha war jedoch gering. In Folgestudien konnten wir zeigen, dass die großporige Hämofiltration immunmodulatorische Eigenschaften ausübt. Sowohl die Phagozytose-Aktivität zirkulierender polymorphkerniger Leukozyten und Monozyten, als auch die Proliferationseigenschaften von T-Lymphozyten wurden günstig beeinflusst. Um den Verlust an Bluteiweißen durch den großporigen Hämofilter zu reduzieren, wurden verschiedene Nierenersatzstrategien experimentiert. Der diffusive Stofftransport scheint dem konvektiven Verfahren hinsichtlich der Mediatorelimination, bei deutlich günstigerem Effekt auf den Proteinhaushalt, gleichwertig zu sein. In wieweit die großporige Hämofiltration den Krankheitsverlauf septischer Patienten beeinflussen kann, ist Gegenstand aktueller Studien. / Inflammatory mediators play a pivotal role in the induction and maintenance of a septic syndrome. In the course of a septic multiorgan dysfunction syndrome, acute renal failure (ARF) often necessitates the use of renal replacement therapy. Continuous renal replacement therapy (CRRT) is the treatment of choice in this regard, and convection (hemofiltration) has become the most common used purification technique. Apart from representing a valuable renal replacement modality, CRRT also allows the elimination of inflammatory mediators. Since the early nineties CRRT has been used as an adjuvant treatment strategy in the septic multiorgan failure syndrome. It has been hypothesized that CRRT may re-institute the immunologic and hemostasilogic homeostasis by reducing the peak cytokine concentration in circulating blood. Commercially available hemofilters do not allow for a substantial elimination of inflammatory mediators. Their clearance capacity for septic mediators is poor. In cooperation with an industry company (Gambro, Medical Research, Hechingen, Germany), we developed a high cut-off hemofilter for clinical use in septic patients. The hemofilter was developed in order to allow the elimination of septic mediators in the molecular weight range up to 60 kilodaltons (kD). In a first pilot study the newly developed hemofilter was analyzed for clinical feasibility. We studied the hemodynamic impact, the transmembrane loss of plasma proteins and coagulation parameters as well as the efficacy in regard to mediator elimination. For mediator elimination Interleukin-6 (IL-6) and tumor-necrosis-factor-alpha (TNF-alpha) were chosen. We were able to show, that high cut-off hemofiltration is a safe and effective renal replacement procedure. Hemodynamically high cut-off hemofiltration was well tolerated. The cumulative transmembrane total plasma protein loss was around 8g/day. Coagulation parameters were not effected. We further demonstrated, that high cut-off hemofiltration is able to significantly eliminate substantial amounts of circulating IL-6. However, the elimination capacity for TNF-alpha was poor. We were also able to show, that high cut-off hemofiltration exerts immunomodulatory properties. The phagocytotic activity of polymorphnuclear leukocytes and monocytes as well as proliferative capacity of lymphocytes were positively influenced. In order to reduced transmembrane protein losses through the high cut-off hemofilter, a variety of different renal replacement strategies were tested. Diffusive purification techniques were comparable to convective techniques in regard to the mediator elimination capacity, but were associated with significantly lower transmembrane protein losses. Whether high cut-off hemofiltration can positively influence the course of critically ill septic patients is still under investigation.