End stage renal disease (ESRD) patients have an excess cardiovascular risk, above that predicted by traditional risk factor models. Despite the advances in both Cardiovascular disease (CVD) management and renal replacement therapy (RRT), there still is a major burden of cardiovascular mortality and morbidity in the chronic kidney disease (CKD) population. Declining renal function itself represents a continuum of cardiovascular risk and in those individuals who survive to reach ESRD, the risk of suffering a cardiac event is uncomfortably and unacceptably high. Pro-thrombotic status may contribute to this increased risk. Global thrombotic status assessment, including measurement of occlusion time (OT) the time taken to form an occlusive platelet rich thrombus and thrombolytic status (time taken to lyse such thrombus) as assessed by measuring Lysis Time (LT), may identify vulnerable patients. The aim of this study was to assess overall thrombotic status in ESRD and relate this to cardiovascular and peripheral thrombotic risk. Small sub studies were also planned to establish the effect of RRT modality on the thrombotic status.

L’insuffisance rénale chronique (IRC) terminale est une situation peu fréquente chez l’enfant mais a des conséquences importantes sur la survie et la qualité de vie. De nos jours, la majorité des enfants en IRC terminale en Europe vont recevoir une greffe de rein après un traitement de suppléance par dialyse ou de manière préemptive après un traitement conservateur de l’insuffisance rénale. Les objectifs de cette thèse sont de décrire l’épidémiologie de l’IRC chez l’enfant, d’évaluer les différences de pratiques et d’accès à la greffe rénale entre pays Européens, et d’investiguer le devenir clinique après transplantation, notamment la survie du greffon, la croissance, et la récidive de la maladie initiale sur le greffon. Premièrement, une revue de littérature sur l’épidémiologie de l’IRC chez l’enfant a été réalisée. Deuxièmement, nous avons mis en évidence par une enquête d’importantes variations de pratiques, de politiques d’allocation des greffons rénaux et d’accès à la greffe rénale pédiatrique à travers l’Europe. Des facteurs tels que le taux de greffe avec donneur vivant, la priorité nationale donnée aux enfants pour les donneurs décédés, ou un indicateur de richesse tel que le produit intérieur brut étaient associés à un meilleur accès à la greffe par pays. Troisièmement, l’étude du devenir après greffe par des études observationnelles a montré une amélioration de de la survie des greffons et de la taille à l’âge adulte après IRC terminale dans l’enfance. En utilisant l’oxalose comme exemple de maladie à haut risque de révidive, nous avons trouvé que le pronostic des enfants atteints d’oxalose en IRCT s’est amélioré au cours du temps. Il a été possible de déterminer quelles pratiques cliniques sont associées avec le meilleur devenir. L’ensemble de ces résultats suggère une augmentation de la prévalence et une meilleure prise en charge des enfants transplantés du rein en Europe. / Although end-stage renal disease (ESRD) is a rare condition in children, it has major consequences on their survival and quality of life. Most children with ESRD in Europe nowadays receive a renal transplant after variable periods of renal replacement therapy (RRT) with dialysis, or preemptively after conservative treatment of chronic kidney disease (CKD). The objectives of this thesis are to describe the epidemiology of CKD in children, to evaluate the differences of practices and access to transplant in Europe, and to investigate post transplant outcomes including graft survival, final height and disease recurrence. First, a literature review of the available data on pediatric CKD epidemiology was performed. Second, we analyzed the differences in transplantation practices, kidney allocation policies and access to transplantation between European countries in a survey study. Living donor transplant rate, national priority given to children, and an economic indicator like gross domestic product were found to be associated with a better access to transplantation by country. Third, we assessed post transplantation outcomes in longitudinal observational studies, including data from the European registry. We showed an improvement of graft survival and of adult height after childhood RRT over the years. Using oxalosis as an example of a rare disease with high risk of recurrence, we also found that the prognosis on RRT of children with such a disease improved over time. Some practices associated with better outcomes could be identified. Overall, our findings suggest an increasing prevalence and progress in the management of pediatric kidney transplant recipients in Europe.

Bakgrund:Dialysbehandling är en livslång behandling och kräver att patienten följer upp behandlingsrytmen för att kunna uppnå högsta möjliga livskvalitet. Olika livsförändringar uppstår i samband med uppkomsten av njurinsufficiens och påbörjad dialysbehandling. Livet med dialys innebär ofta ett helt nytt liv för patienterna. Syfte: Att beskriva upplevelser av dialysbehandling hos vuxna patienter med njurinsufficiens. Metod:En litteraturöversikt har använts som metod för att besvara arbetets syfte. Tretton vetenskapliga artiklar har analyserats med hjälp av fem olika steg framtagna av Fribergs analysmetod.  Huvudresultat:patienterna upplevde brist på information, behov av egen kontroll, förlust av aktiviteter och sociala relationer. Ibland upplevde patienterna behandlingen som påfrestande och hade svårt att anpassa livet efter det. Rädsla upplevdes också av de flesta patienterna, men däremot kunde säkerhet och trygghet upplevas när patienterna fick sin behandling av vårdpersonal som hade tillräckligt med kunskap och erfarenhet och när de hade familjen och vänner runt om sig. Slutsats:Patienterna hade både positiva och negativa upplevelser i samband med dialysbehandlingen. Vårdpersonalen och familjen spelade en viktig roll i patienterna liv och deras existens gjorde en inverkan i hur patienterna upplevde sin dialysbehandling. / Background:Dialysis treatment is a lifelong treatment and requires the patient to follow up on the treatment rhythm in order to achieve the highest possible quality of life. Different life changes occur in connection with the onset of renal insufficiency and initiated dialysis treatment. Life with dialysis often means a completely new life for patients. Aim:To describe the experiences of dialysis treatment in adult patients with renal insufficiency. Method:A literature review has been used as method for answering the purpose of this work. Thirteen scientific articles have been analyzed using five different steps developed by Friberg’s analysis method. Results:Patients experienced a lack of information, a need of own control, loss of activities and social relations. Sometimes patients experienced the treatment as stressful and had difficulty adjusting life after that. Fear was also experienced by most patients, but on the other hand, safety and security could be experienced when patients received their treatment by healthcare professionals who had enough knowledge and experience and also when they had family and friends around them.Conclusion: The patients had both positive and negative experiences in connection to the dialysis treatment. The healthcare staff and the family had an important role in the patients' lives and their existence made an impact on how the patients experienced their dialysis treatment.

L’hypertension artérielle pulmonaire (HTAP) est une maladie caractérisée par une obstruction des artères pulmonaires de petit calibre aboutissant, à terme, à une défaillance cardiaque droite. L’évolution de cette maladie est parfois émaillée d’épisodes de dégradation de l’état fonctionnel des patients, nécessitant une admission en unité de soins intensifs pour surveillance cardioscopique et administration de médicaments inotropes et/ou vasopresseurs. Peu d’éléments permettent à ce jour de guider les praticiens dans la prise en charge de ces patients et la physiopathologie de ces épisodes est assez peu connue.Dans un premier temps, nous avons retrouvé une mortalité de 41% en réanimation et testé certains facteurs pronostiques cliniques et biologiques simples issus de la pratique quotidienne dans une cohorte propective de patients avec une prise en charge standardisée. Nous avons identifié comme facteurs pronostiques la pression artérielle systémique, la natrémie, la créatininémie, la valeur de la C-reactive Proteine. Nous avons retrouvé une influence de ces épisodes sur l’évolution à moyen terme de ces épisodes. Dans un second temps nous avons testé la valeur pronostique des indices temporels de fonctionnement du ventricule gauche, suggérée par les études en imagerie par résonnance magnétique. Nous avons utilisé pour cela la tonométrie d’aplanation, outil original et non invasif. Nous avons retrouvé que la valeur de la durée d’éjection du ventricule gauche est associée au pronostic. Dans une troisième partie nous avons mesuré les conséquences et la valeur pronostique de l’épuration extra rénale en contexte d’ insuffisance rénale menaçante chez ces patients. Dans une étude rétrospective, nous avons observé 68 séances d’épuration extra-rénale continue ou discontinue. Ces séances se sont compliquées d’hypotension artérielle dans environ 50% des cas. La très haute mortalité en réanimation et à 3 mois, respectivement de 47% et 73%, soulève la question de la place de l’assistance circulatoire et de la transplantation urgente chez ces patients. Ces données soulignent la sévérité à court terme des épisodes aigus d’aggravation chez les patients porteurs d’HTAP. De plus amples données sont nécessaires pour améliorer la prise en charge de ces patients et organiser dans le meilleur délai la mise en place de thérapeutiques exceptionnelles comme l’assistance circulatoire et la transplantation pulmonaire ou cardio-pulmonaire. / Pulmonary arterial hypertension ( PAH) is a disease characterized by an obstruction of the small pulmonary arteries leading ultimately to right heart failure. The evolution of this disease is sometimes punctuated by episodes of deterioration of the functional status of patients requiring admission to intensive care unit for monitoring and administration of inotropic drugs and / or vasopressors. Few evidence to date are available to guide physicians in the care of these patients and the pathophysiology of these episodes is still elusive.In a first part, we found a mortality of 41% in the intensive care unit (ICU) and tested some simple clinical and biological prognostic factors from the daily practice in a prospective cohort of patients with a standardized management. We have identified systemic blood pressure, serum sodium, serum creatinine, serum C -reactive Protein as prognostic factors. We found an influence of these events on the medium-term evolution of the patients.In a second step we tested the prognostic value of time derived indices of left ventricular function, variables suggested by magnetic resonance imaging studies. In this purpose, we used aplanation tonometry, an original and non-invasive tool. We found that the value of the left ventricular ejection time was associated with in ICU prognosis.In the third part we measured the impact and prognostic value of renal replacement therapy in case of threatening kidney failure in these patients. In a retrospective study, we observed 68 sessions of renal replacement therapy, continuous hemofiltration and intermittent hemodialysis. These sessions were complicated by hypotension in 50 % of cases. The high in ICU mortality and three months mortilty, respectively 47% and 73%, raises the question of the role of extracorporeal life support and urgent transplantation in these patients.These data underscore the severity of acute worsening in patients with PAH. More data are needed to improve the management of these patients and determine the best timing of exceptional treatment such as circulatory support and pulmonary or cardiopulmonary transplantation.

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.

Hintergrund: Die regionale Citrat-Antikoagulation im Rahmen der Nierenersatztherapie hat bei interdisziplinären Intensivpatienten in den letzten Jahren zunehmend an Bedeutung gewonnen. Für Schwerbrandverletzte existieren bislang kaum Untersuchungen zu diesem Verfahren. Ziel dieser Arbeit war es, die kontinuierliche Nierenersatztherapie mit Citrat-Antikoagulation bei Intensivpatienten mit akutem Nierenversagen nach schwerem Verbrennungstrauma im Hinblick auf Praktikabilität, Effektivität und Komplikationshäufigkeit sowie die Stabilität von Elektrolyt- und Säure-Basen-Haushalt und Gerinnung zu untersuchen. Daneben sollten Aussagen zur Prävalenz des akuten Nierenversagens in dieser Patientengruppe und zu dessen Einfluss auf die Letalität getroffen werden. Methode: Im Rahmen einer retrospektiven Untersuchung wurden unter Verwendung von Patientenakten und Patientendatenmanagementsystem (PDMS) Daten von 27 Schwerbrandverletzten (VKOF ≥ 20% oder ABSI ≥ 8) mit akutem Nierenversagen ausgewertet, die zwischen Januar 2004 und Dezember 2009 im Verbrennungszentrum des Klinikums Sankt Georg Leipzig mit einer kontinuierlichen Nierenersatztherapie behandelt wurden. Bei allen Patienten kam ein Dialysegerät Prisma CFM (Gambro Hospal GmbH, Deutschland) mit einer Polyacrylnitril-Filtermembran (AN 69, Filterset M 100) der gleichen Firma zum Einsatz. Standardverfahren war eine kontinuierliche veno-venöse Hämodiafiltration (CVVHDF) im Prädilutionsmodus. Bei 18 Patienten wurde eine regionale Citrat-Antikoagulation als Antikoagulationsverfahren eingesetzt, bei 7 Patienten eine systemische Heparin-Antikoagulation, bei 2 Patienten kamen alternierend beide Verfahren zum Einsatz. Für die 18 Patienten unter regionaler Citrat-Antikoagulation erfolgte eine detaillierte Analyse des akuten Nierenversagens unter Einbeziehung des klinischen Verlaufes, der Laborparameter und der Behandlungsdaten des Nierenersatzverfahrens. Ergebnisse: Die Prävalenz eines akuten Nierenversagens mit Notwendigkeit zur Nierenersatztherapie bei Schwerbrandverletzten betrug 15,5%. Die Sterblichkeitsrate war in der Patientengruppe mit Nierenversagen etwa fünffach erhöht (25,9 vs. 4,8%). Die Letalitätsrate bei den Patienten unter systemischer Heparin-Antikoagulation war bei vergleichbarem Verbrennungsausmaß etwa fünfmal höher als unter regionaler Citrat-Antikoagulation (57,1 vs. 11.1%). Die Nierenersatztherapie wurde im Median nach 6 Tagen begonnen, die mediane Behandlungsdauer pro Patient betrug 7 Tage. Bei Start der CVVHDF wiesen 94,4% der Patienten einen Schockzustand mit Notwendigkeit einer Vasopressortherapie auf, 83,3% zeigten schwere Dysfunktionen in mindestens 3 Organsystemen, der SOFA-score lag im Median bei 14. Bei einer mittleren Citratkonzentration von 3,6 mmol/l Blut im Extrakorporalkreiskauf konnte eine mediane effektive Filterlaufzeit von 67 Stunden erreicht werden. Hypocalcämien (<0,9 mmol/l) fanden sich in 1,1%, Hypercalcämien (>1,3 mmol/l) in 0,4%. Hypernatriämien (<150 mmol) waren mit 0,4% ebenso selten wie metabolische Alkalosen (pH >7,50 und BE >4) mit 0,2%. Im Gesamtdialysezeitraum von 3790 Stunden gab es nur ein Blutungsereignis, die Gerinnungsparameter zeigten bis auf einen passageren Abfall der Thrombozytenzahl keine signifikanten Veränderungen. Die erzielte mittlere Dialysedosis war mit 35,1 ml/kg Körpergewicht/h ausreichend hoch. Neben einer Reduktion der Nierenretentionsparameter Serum-Creatinin und Serum-Harnstoff fanden sich unter dem Nierenersatzverfahren verbesserte Oxygenierungsindices und sinkende SOFA-scores. Keiner der überlebenden Patienten war zum Zeitpunkt der Entlassung dialysepflichtig. Zusammenfassung: Die CVVHDF unter regionaler Citrat-Antikoagulation ist bei Schwerbrandverletzten ein effektives und in Bezug auf Säure-Basen-Haushalt, Elektrolyte und Gerinnung sicheres Verfahren. Neben einer effektiven Elimination harnpflichtiger Substanzen konnten eine exzellente Stabilität von Elektrolyten und metabolischen Parametern sowie eine suffiziente Antikoagulation im Extrakorporalkreislauf mit niedrigem Blutungsrisiko und konstant langen Filterlaufzeiten nachgewiesen werden. Die Prävalenz des akuten Nierenversagens bei Schwerbrandverletzten ist hoch, die Letalität bei Vorliegen des Organversagens vier-bis fünffach erhöht.

Η τελικού σταδίου χρόνια νεφρική ανεπάρκεια (ΤΣΧΝΑ) είναι η αμετάκλητη απώλεια της νεφρικής λειτουργίας. Όταν η απώλεια της νεφρικής λειτουργίας φτάσει στο σημείο όπου οι νεφροί δεν μπορούν να συντηρήσουν τον ασθενή στην ζωή, τότε απαιτείται θεραπεία υποκατάστασης της νεφρικής λειτουργίας (ΘΥΝΛ). που είναι η αιμοκάθαρση (ΑΜΚ), η περιτοναϊκή κάθαρση, ή η μεταμόσχευση νεφρού. Η ενδονοσοκομειακή ΑΜΚ πραγματοποιείται 3 φορές την εβδομάδα και διαρκεί 3-5 ώρες. Η κατ' οίκον ΑΜΚ λαμβάνει χώρα στο σπίτι του ασθενούς, προσφέροντας ευελιξία στην επιλογή της συχνότητας (3-7 οορές εβδομάδα) και της διάρκειας της συνεδρίας ΑΜΚ (4-10 ώρες). Ειδικότερα η καθημερινή νυχτερινή κατ' οίκον ΑΜΚ, που πραγματοποιείται κατά την διάρκεια του ύπνου, προσφέρει σημαντικά κλινικά οφέλη, δυνατότητα κοινωνικής και επαγγελματικής αποκατάστασης, μείωση της φαρμακοληψίας, ελευθερία στην διατροφή και την πόση, καθώς και βελτίωση στην ποιότητα ζωής των ασθενών. Σύμφωνα με πρόσφατα στοιχεία, περισσότεροι από 10.000 Έλληνες ασθενείς υποφέρουν από ΤΣΧΝΑ και το 74% χρησιμοποιεί την ΑΜΚ ως θεραπεία υποκατάστασης, ενώ παράλληλα υπάρχει αυξανόμενη πίεση στις μονάδες ΑΜΚ, εξαιτίας της μεγάλης προσαύξησης του αριθμού των ασθενών τους. Για το 2004, η Ελλάδα παρουσίασε την μεγαλύτερη συχνότητα νεοεισαχθέντων ασθενών ανά εκατομμύριο πληθυσμού στην ΑΜΚ σε σύγκριση με 24 Ευρωπαϊκές χώρες και κατείχε την 3η θέση παγκοσμίως στην αντίστοιχη συχνότητα σε ΘΥΝΛ, μετά τις ΗΠΑ και την Ιαπωνία. Η κατάταξη της Ελλάδας στην 8η θέση, στην παγκόσμια σύγκριση του επιπολασμού σε ΘΥΝΛ, παρόλο που είναι ευνοϊκότερη, παραμένει πολύ υψηλή, υποδεικνύοντας το μέγεθος του αυξημένου αριθμού ΤΣΧΝΑ στην χώρα μας. Στους παράγοντες που συντελούν στην ύπαρξη του φαινομένου, είναι ο πολύ χαμηλός αριθμός μεταμοσχεύσεων νεφρού στην Ελλάδα, η οποία κατέχει την 20η θέση ανάμεσα σε 24 Ευρωπαϊκές χώρες, για το 2004, καθώς και η αύξηση της επιβίωσης των ασθενών σε ΘΥΝΛ. Η παρούσα διδακτορική διατριβή εστιάζεται στην αποτίμηση τεχνολογίας υγείας της κατ' οίκον αιμοκάθαρσης, στην μελέτη των παραγόντων που επιδρούν την υιοθέτηση της και στην αξιολόγηση της ποιότητας ζωής των αιμοκαθαιρομένων στην Ελλάδα. Συγκεκριμένοι στόχοι της είναι: i) Να εκτιμηθεί, πέρα από την ποιότητα ζωής, η προθυμία των Ελλήνων αιμοκαθαιρομένων να συμμετάσχουν σε πρόγραμμα κατ' οίκον ΑΜΚ και ii) Να διεξαχθεί βιβλιογραφική ανασκόπηση για να αποτιμηθεί αν η κατ' οίκον αιμοκάθαρση είναι πιο αποτελεσματική και με καλύτερο δείκτη κόστους -χρησιμότητας από την ενδονοσοκομειακή, καθώς και να συγκεντρωθούν και να αναλυθούν δεδομένα από την ερευνητική επίσκεψη σε έμπειρα κέντρα κατ' οίκον αιμοκάθαρσης του εξωτερικού. Η συγκέντρωση δεδομένων για την σχετιζόμενη με την υγεία ποιότητα ζωής 146 Ελλήνων αιμοκαθαιρομένων, πραγματοποιήθηκε σε 10 κέντρα ΑΜΚ της Ελλάδας, με ποσοστό απόκρισης 84%. Χρησιμοποιήθηκε το εξειδικευμένο στη νεφροπάθεια εργαλείο KDQOL-SF (που ενσωματώνει το εργαλείο γενικής υγείας SF-36) και ένα συμπληρωματικό ερωτηματολόγιο που συνοδευόταν από ενημερωτικό κείμενο για την* νυχτερινή κατ' οίκον ΑΜΚ, ώστε να συλλεχθούν δημογραφικά δεδομένα και να εκτιμηθεί η προθυμία συμμετοχής σε πρόγραμμα κατ' οίκον ΑΜΚ. Η συμπλήρωση των ερωτηματολογίων έγινε με επιτόπου συνέντευξη. Στην έρευνα συμμετείχαν 99 άνδρες και 47 γυναίκες, με μέση ηλικία 57 +/- 15,7 έτη. Παρόλο που το 61% των ερωτηθέντων ήταν σε παραγωγική ηλικία, μόνο το 23% είχαν παραμείνει στην εργασία τους και οι υπόλοιποι ήταν είτε άνεργοι, είτε σε άδεια ασθενείας, είτε είχαν συνταξιοδοτηθεί λόγω μερικής αναπηρίας, ενώ το 62% των ασθενών δήλωσε ετήσιο εισόδημα μικρότερο από 10.000€. Ο σακχαρώδης διαβήτης ήταν η πιο συχνά εμφανιζόμενη πρωτογενής αιτία νεφρικής ανεπάρκειας (20%) και η πλειοψηφία των ασθενών (73%) τελούν ΑΜΚ για λιγότερα από πέντε χρόνια. Τρεις ασθενείς αναγκάστηκαν να αλλάξουν τόπο διαμονής για να βρίσκονται πιο κοντά στην μονάδα ΑΜΚ, ενώ περίπου το 45% των αιμοκαθαιρομένων διανύουν συνολικά περισσότερα από 40km, 3 φορές την εβδομάδα, για κάθε συνεδρία ΑΜΚ. Από τις κλίμακες του KDQOL-SF, χαμηλότερες τιμές καταγράφηκαν στην εργασία, την σεξουαλική λειτουργία και τον φόρτο της νεοροπάθειας. Η σύγκριση των κλιμάκων SF-36 του δείγματος με τον Ελληνικό γενικό πληθυσμό παρουσίασε στατιστικά σημαντικές διαφορές (p<0,01) σε όλες τις κλίμακες, πλην του σωματικού πόνου. Επίσης, η σύνοψη συνιστωσών ψυχικής υγείας του δείγματος των αιμοκαθαιρουμένων ήταν ελαφρώς χαμηλότερη από του γενικού πληθυσμού, ενώ η σύνοψη συνιστωσών σωματικής υγείας ήταν αρκετά χαμηλότερη. Τα αποτελέσματα του δείγματος της παρούσας έρευνας (Ν=146) συγκρίθηκαν με αντίστοιχο δείγμα Ισπανών ασθενών ΤΣΧΝΑ (Ν=194) που συμπλήρωσαν το ίδιο ερωτηματολόγιο. Το γεγονός ότι και σ" αυτή την σύγκριση δεν εμφανίστηκε στατιστικά σημαντική διαφορά στην κλίμακα του σωματικού πόνου, ενδυναμώνει την εγκυρότητα της μέτρησης και υποδεικνύει ότι οι ασθενείς ΤΣΧΝΑ δεν υπέφεραν σημαντικά από σωματικό πόνο εξαιτίας της ασθένειας τους, σε σημείο τέτοιο, που να έχει αρνητική απήχηση στην αντίληψη τους για την σχετιζόμενη με την υγεία ποιότητα ζωής τους. Διάθεση συμμετοχής στην νυχτερινή κατ’ οίκον ΑΜΚ εξέφρασε το 84% των ασθενών και το 75% για την κατ΄ οίκον ΑΜΚ. Έντονη προθυμία σημειώθηκε στο 53% και το 38% των 146 ερωτηθέντων αντίστοιχα, ενώ διατεθειμένοι να δαπανήσουν κάποιο χρηματικό ποσό για να συμμετάσχουν ήταν το 38%. Στην ερευνητική επίσκεψη σε δύο μεγάλα και έμπειρα κέντρα κατ’ οίκον αιμοκάθαρσης του εξωτερικού, στο Lund και το Helsinki. συγκεντρώθηκαν πολύτιμα δεδομένα που αφορούν στην οργάνωση, την διεξαγωγή, την εμπειρία και την τεχνογνωσία τους. και τα οποία σχετίζονται με την δομή του προγράμματος, οικονομικές εκτιμήσεις, ιατρικά δεδομένα, στατιστικά αποτελέσματα, μεθόδους εκπαίδευσης και τα πιθανά ρίσκα ή προβλήματα που ενδέχεται να ανακύψουν, μαζί με τους τρόπους αποφυγής ή επίλυσης τους. Τα δημογραφικά δεδομένα σε συνδυασμό με το υψηλό κόστος, καθιστούν την ενδονοσοκομειακή αιμοκάθαρση μια από τις πιο δαπανηρές υγειονομικές παρεμβάσεις και διαπιστωμένα την πιο δαπανηρή μεταξύ των υπολοίπων μεθόδων ΘΥΝΛ. Το κόστος της στην Ελλάδα ξεπερνά το 2% των δαπανών της υγείας. Από την ανασκόπηση της παγκόσμιας βιβλιογραφίας, αλλά και από την μελέτη των κέντρων ΑΜΚ της Σκανδιναβίας, επιβεβαιώνεται ότι η κατ’ οίκον και η δορυφορική ΑΜΚ στοιχίζουν λιγότερο και έχουν καλύτερο δείκτη κόστους-αποτελεσματικότητας από την ενδονοσοκομειακή ΑΜΚ. ενώ παράλληλα εμφανίζουν αυξημένη επιβίωση και καλύτερη ποιότητα ζωής. Κατά συνέπεια, η ανάπτυξη αυτών των εναλλακτικών μεθόδων στην Ελλάδα θα μπορούσε να αμβλύνει την αύξηση του προβλεπόμενου συνολικού κόστους των μεθόδων ΘΥΝΛ στο υγειονομικό σύστημα, συμβάλλοντας και στην ανακούφιση από το πρόβλημα της αυξανόμενης πίεσης στις νοσοκομειακές μονάδες ΑΜΚ. αλλά και της έλλειψης του νοσηλευτικού προσωπικού, με την ταυτόχρονη βελτίωση της ποιότητας ζωής των αιμοκαθαιρομένων. Με την κατάλληλη οργάνωση και στελέχωση, η κατ* οίκον ΑΜΚ θα μπορούσε να γίνει εφικτή και στην Ελλάδα, αφού μεγάλη μερίδα ασθενών δηλώνουν πρόθυμοι να συμμετάσχουν, γεγονός που αποτελεί και την βασικότερη προϋπόθεση επιτυχίας ενός τέτοιου προγράμματος. Επιπρόσθετα, με δεδομένο ότι η Ελλάδα παρουσιάζει πολύ υψηλή συχνότητα νεοεισαχθέντων ασθενών ΤΣΧΝΑ, πρέπει να ενταθούν οι προσπάθειες για την συγκράτηση και τον περιορισμό αυτού του φαινομένου, μέσω προγραμμάτων ενημέρωσης και πρόληψης, που μαζί με την μεταμόσχευση παραμένουν οι αποτελεσματικότεροι τρόποι αντιμετώπισης του προβλήματος. / End stage renal failure is the irreversible loss of kidney function. When loss of kidney function reaches the point at which die kidneys fail to support life, then renal replacement therapy (RRT) is required, that is hemodialysis (HD), peritoneal dialysis or renal transplantation. Hospital hemodialysis is conducted 3 times per week and lasts 3-5 hours. Home hemodialysis takes places at patient’s home, offering flexibility in choosing the frequency (3-7 times Week) and the length of the hemodialysis session (4-10 hours). Daily nocturnal home hemodialysis in particular, which is conducted while the patient is asleep, offers significant clinical benefits, the opportunity of social and professional rehabilitation, reduction of drugs, freedom in diet and drinking intake, as well as improvement in patients' quality of life. According to recent records, more than 10.000 Greek patients suffer from end stage renal disease (ESRD) and 74% of them use hemodialysis as replacement therapy, while at die same time there is increasing pressure on hemodialysis units because of the growing number of patients who are receding hemodialysis. In 2004, Greece appeared to have the highest incidence per million population in hemodialysis, in comparison with 24 European countries and the 31 place in die world in the incidence per million population in RRT, after USA and Japan. The rating of Greece in the 8th place of global comparison in prevalence in RRT, although more propitious, remains very high suggesting die extent of the increasing number of ESRD m Greece. Among the factors that contribute to the existence of this phenomenon are the very low numbers of renal transplantation in Greece, which holds the 20th place among 24 European countries m 2004 and the increase of survival of patients on RRT. This doctoral thesis focuses on technology assessment of home HD, the study of the factors that affect its adoption and finally die evaluation of Greek hemodialysis patients' quality of life. The specific objectives are: i) To evaluate the quality of life of Greek hemodialysis patients, as well as their willingness to participate in a home HD program and ii) To conduct a review of the literature in order to assess whether home hemodialysis is more effective and with better cost-utility than hospital hemodialysis and to gather and analyze data taken from the inquiring visit in experienced home hemodialysis units of foreign countries. Data concerning die health related quality of life of 146 Greek hemodialysis patients were gathered from 10 HD units in Greece and the response rate was 84%. The renal disease specific instrument KDQOL-SF was used (which incorporates the general health instrument SF-36), accompanied with an additional questionnaire and an informative leaflet on nocturnal home hemodialysis, in order to gather demographic data and to evaluate the willingness of participation m a home hemodialysis progρam. Questionnaires were completed with on site interview. This study included 99 men and 47 women, with mean age 57 +/- 15,7 years. Although 61% of the participants were in productive age, only 23% were employed and the rest were either unemployed, on sick leave or receiving a disability pension, while 62% of the patients reported annual income less than l0.000 Euros. Diabetes mellitus was the most common primary kidney disease (20%) and the majority of patients were on hemodialysis for less than five years. Three patients were obliged to change place of residence so as to be closer to the hemodialysis unit, while almost 45% of the patients had to navel more than 40km, 3 times per week, for every HD session. The lowest scores in KDQOL-SF scales were found in work status, in sexual functioning and m the burden of kidney disease. The comparison of the SF-36 scales of die study sample with the Greek general population identified statistically significant differences (p<0.01) in all scales, except of the bodily pain scale. Moreover, the Mental Component Summary was slightly worse compared with the general population's, while the Physical Component Summary was quite lower. The results of the present study sample (N=146) were compared with an equivalent sample of Spanish ESRD patients (N=194) who completed the same questionnaire. The fact that m this comparison no statistically significant difference was found in the scale of bodily pain, strengthens the validity of the measurement and suggests that ESRD patients did not experience severe suffering from pain due to their disease that could worsen their perception of health related quality of life. Inclination to participate in nocturnal home HD was expressed by 84% of the patients and by 75% of the patients for home hemodialysis. Strong willingness was reported in 53% of the patients for nocturnal home HD and in the 38% for home HD respectively, while the 38% of the patients were also willing to contribute financially in order to participate. The inquiring visit in two experienced home hemodialysis units in Lund and Helsinki, provided valuable information concerning their organization, their waging, their experience and their know-how. which are related with the structure of the program, economical evaluations, medical data, statistical outcomes, methods of training and potential risks or problems that might emerge, together with advices on how to avoid or solve them. The demographical data in combination with the high cost renders hospital hemodialysis one of the most expensive medical interventions and certainly the most expensive among the other RRT methods. Hemodialysis cost in Greece absorbs more than 2% of total health expenditure. The review of the global literature and the study on the Scandinavian home HD units verified that both home and satellite hemodialysis are less costly and more cost-effective than hospital hemodialysis, while at the same time they present increased survival and better quality of life. Hence, the development of these alternative modalities of dialysis in Greece could mitigate the anticipated net cost increases of RRT to the health system. This could contribute to the alleviation of the increasing pressure on hospital HD units and the nursing shortage, with the simultaneous improvement of hemodialysis patients' quality of life. With the appropriate organization and staff, home hemodialysis could be feasible also in Greece, since big part of the patients are reporting willingness to participate and this fulfils the basic requirement for such a program to succeed. In addition, considering that Greece reports very high incidence, efforts must be intensified in order to restrain and reduce this phenomenon, through informing and prevention programs, which next to renal transplantation are the most effective ways to confront the problem.

Foi realizado um estudo de farmacocinética da polimixina B em pacientes críticos com desenvolvimento de um modelo populacional. Os critérios de inclusão foram pacientes internados em Unidade de Terapia Intensiva, com idade igual ou superior a 18 anos e em uso de polimixina B intravenosa por um período mínimo de 48 horas. Amostras de sangue, urina e dialisato foram coletadas durante um intervalo de doses no estado de equilíbrio. A concentração de polimixina B no plasma foi medida por meio de cromatografia líquida de alta performance associada à espectrometria de massas acoplada à espectrometria de massas, sua ligação às proteínas plasmáticas foi determinada por meio de diálise de equilíbrio rápido e a fração livre foi calculada. Foram realizadas análise farmacocinética populacional e Simulações de Monte Carlo. Foram incluídos 24 pacientes, dos quais dois estavam em hemodiálise contínua; 54,2% eram do sexo masculino e as medianas da idade, do escore APACHE e do peso corporal total foram de 61,5 anos, 21,5 e 62,5kg, respectivamente. As doses de polimixina B, conforme prescrição do médico assistente, variaram entre 0,45-3,38mg/kg/dia. O clearance estimado da creatinina nos 22 pacientes sem hemodiálise variou entre 10-143mL/min. A mediana da fração livre plasmática da polimixina B foi de 0,42 e a média (± desvio padrão) da fração livre da área sob a curva ao longo de um dia (fAUC0-24h) da polimixina B foi de 29,2±12,0mg•h/L, incluindo os pacientes em hemodiálise. A polimixina B foi excretada predominantemente por vias não renais e as medianas de sua recuperação urinária de forma inalterada foi de 4,04% e do seu clearance renal foi de 0,061L/hora. Nos pacientes 1 e 2 em hemodiálise foram identificados, respectivamente, clearance corporal total de 0,043 e 0,027L/h/kg, clearance da hemodiálise de 0,0052 e 0,0015L/h/kg; no dialisato foram recuperados 12,2% e 5,62% da dose como polimixina B não modificada. O clearance corporal total da polimixina B não mostrou nenhuma relação com o clearance da creatinina, escore APACHE II ou idade. A disposição da polimixina B no tempo foi adequadamente descrita pelo modelo de dois compartimentos com eliminação linear. O modelo farmacocinético populacional proporcionou ajustes excelentes para os perfis observados de concentração-tempo para pacientes individuais e as concentrações individuais e populacionais ajustadas foram precisas. O ajuste dos clearances e dos volumes de distribuição para o peso corporal total reduziu a variabilidade intersujeitos em 3,4% para o clearance e 41,7% para o volume de distribuição central; nos pacientes em diálise, após esse ajuste, os parâmetros estimados se assemelharam aos dos demais pacientes. As Simulações de Monte Carlo foram feitas com seis diferentes regimes de doses clinicamente relevantes escalonados pelo peso corporal total. O regime de doses de 1,5mg/kg 12/12h forneceu uma AUC0-24h de polimixina B no dia 4 de 90.4mg•hora/L para 50% dos pacientes, adequada para erradicação bacteriana em infecções graves por Pseudomonas aeruginosa ou Acinetobacter baumannii com concentração inibitória mínima para a polimixina B ≤2mg/L. Nas Simulações de Monte Carlo também foi possível identificar que uma melhor área sob a curva só foi atingida no dia 4 de tratamento. Este estudo mostrou que a dose de polimixina B intravenosa deve ser ajustada ao peso corporal total, que o melhor regime de doses é o de 1,5mg/kg 12/12h precedido de dose de ataque de 2,5mg/kg e que não há indicação de ajuste para a função renal, mesmo em pacientes em hemodiálise contínua. / A polymyxin B pharmacokinetics study in critically ill patients was conducted with the development of a population modeling. The inclusion criteria were patients from Intensive Care Unit, aged ≥18 years who received intravenous polymyxin B for ≥ 48 hours. Blood, urine and dialysate samples were collected over a dosing interval at steady state. Polymyxin B concentrations was measured by liquid chromatography- tandem mass spectrometry, its plasma protein binding was determined by rapid equilibrium dialysis and unbound fraction was calculated. Population pharmacokinetic analysis and Monte Carlo Simulations were conducted. Twenty four patients were enrolled, two of whom on continuous hemodialysis; 54.2% were male; the median of age, APACHE II score and total body weight were 61.5years, 21.5 and 62.5kg, respectively. The physician-selected dose of polymyxin B was 0.45- 3.38mg/kg/day. The creatinine clearance of the 22 patients without hemodialysis ranged from 10 to 143mL/min. The median unbound fraction in plasma of polymyxin B was 0.42 and the mean (± standard deviation) of the area under the curve over a day for unbound (fAUC0-24h) polymyxin B was 29.2±12.0mg•hour/L, including hemodialysis patients. Polymyxin B was predominantly nonrenally cleared with median unchanged urinary recovered of 4.04%; the median renal clearance was 0.061L/hour. Patients 1 and 2 in hemodialysis presented, respectively, total body clearance of 0.043 and 0.027L/h/kg, hemodialysis clearance of 0.0052 and 0.0015L/h/kg; 12.2% and 5.62% of the polymyxin dose were recovered intact in the dialysate. Polymyxin B total body clearance did not show any relationship with creatinine clearance, APACHE II score, or age. The time course of polymyxin B concentrations was well described by a 2-compartment disposition model with linear elimination. The population pharmacokinetics model provided excellent fits to the observed concentration-time profiles for individual patients and the individual-fitted and population-fitted concentrations were adequately precise. Linear scaling of clearances and volumes of distribution by total body weight reduced the between subject variability in 3.4% for clearance and 41.7% for the central volume of distribution; after this scaling, the estimated parameters in hemodialysis patients were within the range of estimates from the other patients. The population mean of the total body clearance of polymyxin B when scaled by total body weight (0.0276L/hour/kg) showed remarkably low interindividual variability. The Monte Carlo Simulations were performed for six different clinically relevant dosage regimens scaled by total body weight. The regimen of 1.5mg/kg/12 hours provided an AUC0- 24h of polymyxin B of 90.4 mg•h/L in day 4 for 50% of patients which is appropriate considering severe infections by Pseudomonas aeruginosa or Acinetobacter baumannii with minimal inhibitory concentration for polymyxin B ≤2mg/L. In Monte Carlo Simulations we also identified that the best area under the curve was attained only in the day 4 of the treatment. This study showed that doses of intravenous polymyxin B are best scaled by total body weight, that the best regimen of doses is 3mg/kg/day with a loading dose of 2.5mg/kg and that its dosage selection should not be based on renal function, even in patients in continuous hemodialysis.

Foi realizado um estudo de farmacocinética da polimixina B em pacientes críticos com desenvolvimento de um modelo populacional. Os critérios de inclusão foram pacientes internados em Unidade de Terapia Intensiva, com idade igual ou superior a 18 anos e em uso de polimixina B intravenosa por um período mínimo de 48 horas. Amostras de sangue, urina e dialisato foram coletadas durante um intervalo de doses no estado de equilíbrio. A concentração de polimixina B no plasma foi medida por meio de cromatografia líquida de alta performance associada à espectrometria de massas acoplada à espectrometria de massas, sua ligação às proteínas plasmáticas foi determinada por meio de diálise de equilíbrio rápido e a fração livre foi calculada. Foram realizadas análise farmacocinética populacional e Simulações de Monte Carlo. Foram incluídos 24 pacientes, dos quais dois estavam em hemodiálise contínua; 54,2% eram do sexo masculino e as medianas da idade, do escore APACHE e do peso corporal total foram de 61,5 anos, 21,5 e 62,5kg, respectivamente. As doses de polimixina B, conforme prescrição do médico assistente, variaram entre 0,45-3,38mg/kg/dia. O clearance estimado da creatinina nos 22 pacientes sem hemodiálise variou entre 10-143mL/min. A mediana da fração livre plasmática da polimixina B foi de 0,42 e a média (± desvio padrão) da fração livre da área sob a curva ao longo de um dia (fAUC0-24h) da polimixina B foi de 29,2±12,0mg•h/L, incluindo os pacientes em hemodiálise. A polimixina B foi excretada predominantemente por vias não renais e as medianas de sua recuperação urinária de forma inalterada foi de 4,04% e do seu clearance renal foi de 0,061L/hora. Nos pacientes 1 e 2 em hemodiálise foram identificados, respectivamente, clearance corporal total de 0,043 e 0,027L/h/kg, clearance da hemodiálise de 0,0052 e 0,0015L/h/kg; no dialisato foram recuperados 12,2% e 5,62% da dose como polimixina B não modificada. O clearance corporal total da polimixina B não mostrou nenhuma relação com o clearance da creatinina, escore APACHE II ou idade. A disposição da polimixina B no tempo foi adequadamente descrita pelo modelo de dois compartimentos com eliminação linear. O modelo farmacocinético populacional proporcionou ajustes excelentes para os perfis observados de concentração-tempo para pacientes individuais e as concentrações individuais e populacionais ajustadas foram precisas. O ajuste dos clearances e dos volumes de distribuição para o peso corporal total reduziu a variabilidade intersujeitos em 3,4% para o clearance e 41,7% para o volume de distribuição central; nos pacientes em diálise, após esse ajuste, os parâmetros estimados se assemelharam aos dos demais pacientes. As Simulações de Monte Carlo foram feitas com seis diferentes regimes de doses clinicamente relevantes escalonados pelo peso corporal total. O regime de doses de 1,5mg/kg 12/12h forneceu uma AUC0-24h de polimixina B no dia 4 de 90.4mg•hora/L para 50% dos pacientes, adequada para erradicação bacteriana em infecções graves por Pseudomonas aeruginosa ou Acinetobacter baumannii com concentração inibitória mínima para a polimixina B ≤2mg/L. Nas Simulações de Monte Carlo também foi possível identificar que uma melhor área sob a curva só foi atingida no dia 4 de tratamento. Este estudo mostrou que a dose de polimixina B intravenosa deve ser ajustada ao peso corporal total, que o melhor regime de doses é o de 1,5mg/kg 12/12h precedido de dose de ataque de 2,5mg/kg e que não há indicação de ajuste para a função renal, mesmo em pacientes em hemodiálise contínua. / A polymyxin B pharmacokinetics study in critically ill patients was conducted with the development of a population modeling. The inclusion criteria were patients from Intensive Care Unit, aged ≥18 years who received intravenous polymyxin B for ≥ 48 hours. Blood, urine and dialysate samples were collected over a dosing interval at steady state. Polymyxin B concentrations was measured by liquid chromatography- tandem mass spectrometry, its plasma protein binding was determined by rapid equilibrium dialysis and unbound fraction was calculated. Population pharmacokinetic analysis and Monte Carlo Simulations were conducted. Twenty four patients were enrolled, two of whom on continuous hemodialysis; 54.2% were male; the median of age, APACHE II score and total body weight were 61.5years, 21.5 and 62.5kg, respectively. The physician-selected dose of polymyxin B was 0.45- 3.38mg/kg/day. The creatinine clearance of the 22 patients without hemodialysis ranged from 10 to 143mL/min. The median unbound fraction in plasma of polymyxin B was 0.42 and the mean (± standard deviation) of the area under the curve over a day for unbound (fAUC0-24h) polymyxin B was 29.2±12.0mg•hour/L, including hemodialysis patients. Polymyxin B was predominantly nonrenally cleared with median unchanged urinary recovered of 4.04%; the median renal clearance was 0.061L/hour. Patients 1 and 2 in hemodialysis presented, respectively, total body clearance of 0.043 and 0.027L/h/kg, hemodialysis clearance of 0.0052 and 0.0015L/h/kg; 12.2% and 5.62% of the polymyxin dose were recovered intact in the dialysate. Polymyxin B total body clearance did not show any relationship with creatinine clearance, APACHE II score, or age. The time course of polymyxin B concentrations was well described by a 2-compartment disposition model with linear elimination. The population pharmacokinetics model provided excellent fits to the observed concentration-time profiles for individual patients and the individual-fitted and population-fitted concentrations were adequately precise. Linear scaling of clearances and volumes of distribution by total body weight reduced the between subject variability in 3.4% for clearance and 41.7% for the central volume of distribution; after this scaling, the estimated parameters in hemodialysis patients were within the range of estimates from the other patients. The population mean of the total body clearance of polymyxin B when scaled by total body weight (0.0276L/hour/kg) showed remarkably low interindividual variability. The Monte Carlo Simulations were performed for six different clinically relevant dosage regimens scaled by total body weight. The regimen of 1.5mg/kg/12 hours provided an AUC0- 24h of polymyxin B of 90.4 mg•h/L in day 4 for 50% of patients which is appropriate considering severe infections by Pseudomonas aeruginosa or Acinetobacter baumannii with minimal inhibitory concentration for polymyxin B ≤2mg/L. In Monte Carlo Simulations we also identified that the best area under the curve was attained only in the day 4 of the treatment. This study showed that doses of intravenous polymyxin B are best scaled by total body weight, that the best regimen of doses is 3mg/kg/day with a loading dose of 2.5mg/kg and that its dosage selection should not be based on renal function, even in patients in continuous hemodialysis.

Foi realizado um estudo de farmacocinética da polimixina B em pacientes críticos com desenvolvimento de um modelo populacional. Os critérios de inclusão foram pacientes internados em Unidade de Terapia Intensiva, com idade igual ou superior a 18 anos e em uso de polimixina B intravenosa por um período mínimo de 48 horas. Amostras de sangue, urina e dialisato foram coletadas durante um intervalo de doses no estado de equilíbrio. A concentração de polimixina B no plasma foi medida por meio de cromatografia líquida de alta performance associada à espectrometria de massas acoplada à espectrometria de massas, sua ligação às proteínas plasmáticas foi determinada por meio de diálise de equilíbrio rápido e a fração livre foi calculada. Foram realizadas análise farmacocinética populacional e Simulações de Monte Carlo. Foram incluídos 24 pacientes, dos quais dois estavam em hemodiálise contínua; 54,2% eram do sexo masculino e as medianas da idade, do escore APACHE e do peso corporal total foram de 61,5 anos, 21,5 e 62,5kg, respectivamente. As doses de polimixina B, conforme prescrição do médico assistente, variaram entre 0,45-3,38mg/kg/dia. O clearance estimado da creatinina nos 22 pacientes sem hemodiálise variou entre 10-143mL/min. A mediana da fração livre plasmática da polimixina B foi de 0,42 e a média (± desvio padrão) da fração livre da área sob a curva ao longo de um dia (fAUC0-24h) da polimixina B foi de 29,2±12,0mg•h/L, incluindo os pacientes em hemodiálise. A polimixina B foi excretada predominantemente por vias não renais e as medianas de sua recuperação urinária de forma inalterada foi de 4,04% e do seu clearance renal foi de 0,061L/hora. Nos pacientes 1 e 2 em hemodiálise foram identificados, respectivamente, clearance corporal total de 0,043 e 0,027L/h/kg, clearance da hemodiálise de 0,0052 e 0,0015L/h/kg; no dialisato foram recuperados 12,2% e 5,62% da dose como polimixina B não modificada. O clearance corporal total da polimixina B não mostrou nenhuma relação com o clearance da creatinina, escore APACHE II ou idade. A disposição da polimixina B no tempo foi adequadamente descrita pelo modelo de dois compartimentos com eliminação linear. O modelo farmacocinético populacional proporcionou ajustes excelentes para os perfis observados de concentração-tempo para pacientes individuais e as concentrações individuais e populacionais ajustadas foram precisas. O ajuste dos clearances e dos volumes de distribuição para o peso corporal total reduziu a variabilidade intersujeitos em 3,4% para o clearance e 41,7% para o volume de distribuição central; nos pacientes em diálise, após esse ajuste, os parâmetros estimados se assemelharam aos dos demais pacientes. As Simulações de Monte Carlo foram feitas com seis diferentes regimes de doses clinicamente relevantes escalonados pelo peso corporal total. O regime de doses de 1,5mg/kg 12/12h forneceu uma AUC0-24h de polimixina B no dia 4 de 90.4mg•hora/L para 50% dos pacientes, adequada para erradicação bacteriana em infecções graves por Pseudomonas aeruginosa ou Acinetobacter baumannii com concentração inibitória mínima para a polimixina B ≤2mg/L. Nas Simulações de Monte Carlo também foi possível identificar que uma melhor área sob a curva só foi atingida no dia 4 de tratamento. Este estudo mostrou que a dose de polimixina B intravenosa deve ser ajustada ao peso corporal total, que o melhor regime de doses é o de 1,5mg/kg 12/12h precedido de dose de ataque de 2,5mg/kg e que não há indicação de ajuste para a função renal, mesmo em pacientes em hemodiálise contínua. / A polymyxin B pharmacokinetics study in critically ill patients was conducted with the development of a population modeling. The inclusion criteria were patients from Intensive Care Unit, aged ≥18 years who received intravenous polymyxin B for ≥ 48 hours. Blood, urine and dialysate samples were collected over a dosing interval at steady state. Polymyxin B concentrations was measured by liquid chromatography- tandem mass spectrometry, its plasma protein binding was determined by rapid equilibrium dialysis and unbound fraction was calculated. Population pharmacokinetic analysis and Monte Carlo Simulations were conducted. Twenty four patients were enrolled, two of whom on continuous hemodialysis; 54.2% were male; the median of age, APACHE II score and total body weight were 61.5years, 21.5 and 62.5kg, respectively. The physician-selected dose of polymyxin B was 0.45- 3.38mg/kg/day. The creatinine clearance of the 22 patients without hemodialysis ranged from 10 to 143mL/min. The median unbound fraction in plasma of polymyxin B was 0.42 and the mean (± standard deviation) of the area under the curve over a day for unbound (fAUC0-24h) polymyxin B was 29.2±12.0mg•hour/L, including hemodialysis patients. Polymyxin B was predominantly nonrenally cleared with median unchanged urinary recovered of 4.04%; the median renal clearance was 0.061L/hour. Patients 1 and 2 in hemodialysis presented, respectively, total body clearance of 0.043 and 0.027L/h/kg, hemodialysis clearance of 0.0052 and 0.0015L/h/kg; 12.2% and 5.62% of the polymyxin dose were recovered intact in the dialysate. Polymyxin B total body clearance did not show any relationship with creatinine clearance, APACHE II score, or age. The time course of polymyxin B concentrations was well described by a 2-compartment disposition model with linear elimination. The population pharmacokinetics model provided excellent fits to the observed concentration-time profiles for individual patients and the individual-fitted and population-fitted concentrations were adequately precise. Linear scaling of clearances and volumes of distribution by total body weight reduced the between subject variability in 3.4% for clearance and 41.7% for the central volume of distribution; after this scaling, the estimated parameters in hemodialysis patients were within the range of estimates from the other patients. The population mean of the total body clearance of polymyxin B when scaled by total body weight (0.0276L/hour/kg) showed remarkably low interindividual variability. The Monte Carlo Simulations were performed for six different clinically relevant dosage regimens scaled by total body weight. The regimen of 1.5mg/kg/12 hours provided an AUC0- 24h of polymyxin B of 90.4 mg•h/L in day 4 for 50% of patients which is appropriate considering severe infections by Pseudomonas aeruginosa or Acinetobacter baumannii with minimal inhibitory concentration for polymyxin B ≤2mg/L. In Monte Carlo Simulations we also identified that the best area under the curve was attained only in the day 4 of the treatment. This study showed that doses of intravenous polymyxin B are best scaled by total body weight, that the best regimen of doses is 3mg/kg/day with a loading dose of 2.5mg/kg and that its dosage selection should not be based on renal function, even in patients in continuous hemodialysis.