Réalisé sous la co-direction des Drs Denis Bouchard et Michel Pellerin / La sternotomie médiane est l’approche classique pour la chirurgie de la valve mitrale. Elle permet une exposition optimale, mais est associée à un traumatisme chirurgical important, car elle requiert la séparation de l’os sternal. Le présent mémoire porte sur une solution alternative à la sternotomie dans le contexte de la chirurgie mitrale : la chirurgie minimalement invasive (CMI) par minithoracotomie antérolatérale. Trois études ont été réalisées dans le cadre de ce travail. Dans un premier temps, une étude de cohorte regroupant 200 patients consécutifs a permis d’évaluer le taux de succès des réparations mitrales réalisées par minithoracotomie et d’évaluer la durabilité de ces réparations à moyen terme. Par la suite, une étude comparative a été réalisée afin d’évaluer deux méthodes de clampage aortique pour la CMI, soit l’occlusion endovasculaire avec ballon et l’occlusion transthoracique. Enfin, une étude avec analyse par score de propension (propensity score) a permis de comparer la CMI à la sternotomie en ce qui a trait à une complication fréquente en chirurgie cardiaque, l’insuffisance rénale aiguë. La première étude a permis de conclure que la CMI peut être réalisée avec un taux de réparation quasi parfait, et ce malgré la courbe d’apprentissage associée à la technique minimalement invasive. Ces réparations semblent être durables, tel que démontré par une survie sans réopération de 98.3 ± 1.2% à 5 ans. La seconde étude a permis de démontrer que l’occlusion transthoracique est plus fiable que l’occlusion endoaortique et qu’elle est associée à des temps opératoires diminués et à une plus faible incidence de complications procédurales. Enfin, la troisième étude a démontré une association significative entre la CMI et une diminution du risque d’insuffisance rénale aiguë. En conclusion, la minithoracotomie antérolatérale est une excellente alternative à la sternotomie médiane. Tout en diminuant le traumatisme chirurgical, cette approche ne compromet pas la qualité de l’acte chirurgical et présente des bénéfices cliniques. / Median sternotomy is the classic approach for mitral valve surgery. This technique allows optimal exposure but is considered invasive as it requires section of the sternal bone. This thesis discusses an alternative sternotomy : minimally invasive mitral valve surgery (MIMVS) through a right anterolateral minithoracotomy. Three studies were conducted as part of this work. First, a cohort study involving 200 consecutive patients was used to evaluate the success rate of mitral valve repairs performed by minithoracotomy and assess the midterm durability of these repairs. Second, a comparative study was conducted to evaluate two methods of aortic clamping for MIMVS, namely the endovascular balloon occlusion technique and the transthoracic occlusion approach. Finally, a propensity score analysis study was performed to compare MIMVS and sternotomy with respect to a common complication following cardiac surgery : acute renal failure. The first study demonstrated that MIMVS can be performed with a near perfect repair rate, despite the learning curve associated with the minimally invasive technique. These repairs appear to be durable, as evidenced by a freedom from reoperation rate of 98.3 ± 1.2% at 5 years. The second study demonstrated that transthoracic clamping is more reliable than endoaortic occlusion and is associated with shorter operative times and a lower incidence of procedural complications. Finally, the third study found a significant association between MIMVS and a decreased risk of postoperative acute renal failure. In conclusion, the anterolateral minithoracotomy appraoch is an excellent alternative to median sternotomy. While decreasing surgical trauma, this approach does not compromise the quality of surgery and is associated with important clinical benefits.

La circulation extracorporelle (CEC) est une technique utilisée en chirurgie cardiaque effectuée des milliers de fois chaque jour à travers le monde. L’instabilité hémodynamique associée au sevrage de la CEC difficile constitue la principale cause de mortalité en chirurgie cardiaque et l’hypertension pulmonaire (HP) a été identifiée comme un des facteurs de risque les plus importants. Récemment, une hypothèse a été émise suggérant que l'administration prophylactique (avant la CEC) de la milrinone par inhalation puisse avoir un effet préventif et faciliter le sevrage de la CEC chez les patients atteints d’HP. Toutefois, cette indication et voie d'administration pour la milrinone n'ont pas encore été approuvées par les organismes réglementaires. Jusqu'à présent, la recherche clinique sur la milrinone inhalée s’est principalement concentrée sur l’efficacité hémodynamique et l'innocuité chez les patients cardiaques, bien qu’aucun biomarqueur n’ait encore été établi. La dose la plus appropriée pour l’administration par nébulisation n'a pas été déterminée, de même que la caractérisation des profils pharmacocinétiques (PK) et pharmacodynamiques (PD) suite à l'inhalation. L'objectif de notre recherche consistait à caractériser la relation exposition-réponse de la milrinone inhalée administrée chez les patients subissant une chirurgie cardiaque sous CEC. Une méthode analytique par chromatographie liquide à haute performance couplée à un détecteur ultraviolet (HPLC-UV) a été optimisée et validée pour le dosage de la milrinone plasmatique suite à l’inhalation et s’est avérée sensible et précise. La limite de quantification (LLOQ) était de 1.25 ng/ml avec des valeurs de précision intra- et inter-dosage moyennes (CV%) <8%. Des patients souffrant d’HP pour lesquels une chirurgie cardiaque sous CEC était prévue ont d’abord été recrutés pour une étude pilote (n=12) et, par la suite, pour une étude à plus grande échelle (n=28) où la milrinone (5 mg) était administrée par inhalation pré-CEC. Dans l'étude pilote, nous avons comparé l'exposition systémique de la milrinone peu après son administration avec un nébuliseur pneumatique ou un nébuliseur à tamis vibrant. L’efficacité des nébuliseurs en termes de dose émise et dose inhalée a également été déterminée in vitro. Dans l'étude à plus grande échelle conduite en utilisant exclusivement le nébuliseur à tamis vibrant, la dose inhalée in vivo a été estimée et le profil pharmacocinétique de la milrinone inhalée a été pleinement caractérisé aux niveaux plasmatique et urinaire. Le ratio de la pression artérielle moyenne sur la pression artérielle pulmonaire moyenne (PAm/PAPm) a été choisi comme biomarqueur PD. La relation exposition-réponse de la milrinone a été caractérisée pendant la période d'inhalation en étudiant la relation entre l'aire sous la courbe de l’effet (ASCE) et l’aire sous la courbe des concentrations plasmatiques (ASC) de chacun des patients. Enfin, le ratio PAm/PAPm a été exploré comme un prédicteur potentiel de sortie de CEC difficile dans un modèle de régression logistique. Les expériences in vitro ont démontré que les doses émises étaient similaires pour les nébuliseurs pneumatique (64%) et à tamis vibrant (68%). Cependant, la dose inhalée était 2-3 fois supérieure (46% vs 17%) avec le nébuliseur à tamis vibrant, et ce, en accord avec les concentrations plasmatiques. Chez les patients, en raison des variations au niveau des facteurs liés au circuit et au ventilateur causant une plus grande dose expirée, la dose inhalée a été estimée inférieure (30%) et cela a été confirmé après récupération de la dose de milrinone dans l'urine 24 h (26%). Les concentrations plasmatiques maximales (Cmax: 41-189 ng/ml) et l'ampleur de la réponse maximale ΔRmax-R0 (0-65%) ont été observées à la fin de l'inhalation (10-30 min). Les données obtenues suite aux analyses PK sont en accord avec les données publiées pour la milrinone intraveineuse. Après la période d'inhalation, les ASCE individuelles étaient directement reliées aux ASC (P=0.045). Enfin, notre biomarqueur PD ainsi que la durée de CEC ont été identifiés comme des prédicteurs significatifs de la sortie de CEC difficile. La comparaison des ASC et ASCE correspondantes a fourni des données préliminaires supportant une preuve de concept pour l'utilisation du ratio PAm/PAPm comme biomarqueur PD prometteur et justifie de futures études PK/PD. Nous avons pu démontrer que la variation du ratio PAm/PAPm en réponse à la milrinone inhalée contribue à la prévention de la sortie de CEC difficile. / Cardiopulmonary bypass (CPB) is a technique used during cardiac surgery performed thousands of times each day worldwide. Hemodynamic complications associated with difficult separation from CPB represent a leading cause of mortality in cardiac surgery and pulmonary hypertension (PH) was identified as one of the most important predictor and risk factor. Recently, inhaled milrinone administration prior to CPB was hypothesized to have a preventive effect and facilitate separation from CPB in patients with PH. However, this indication and route of administration have not yet been approved by regulatory agencies for milrinone. So far, research efforts on inhaled milrinone have mainly focused on evidence supporting hemodynamic efficacy and safety in cardiac patients although no biomarker has been established. The most appropriate dose for nebulization has never been determined, nor have pharmacokinetic (PK) and pharmacodynamic (PD) profiles been characterized after inhalation. The objective of the current research consisted of characterizing the exposure-response relationship for milrinone administered by inhalation in patients undergoing cardiac surgery. An improved high-performance liquid chromatography (HPLC) analytical assay using UV detection was validated for the quantification of milrinone in plasma after inhalation and proved to be sensitive and accurate. The lower limit of quantification (LLOQ) was 1.25 ng/ml with mean intra-assay and inter-assay precisions (CV%) <8%. Pulmonary hypertensive patients scheduled for cardiac surgery with CPB were first recruited for a pilot (n=12) and, subsequently, a full-scale (n=28) study where milrinone (5mg) was administered by inhalation pre-CPB. In the pilot study, milrinone early systemic exposure was investigated using a jet nebulizer or a mesh nebulizer. Nebulizers performance in terms of emitted and inhaled doses were also determined in vitro. In the full-scale study, using a mesh nebulizer exclusively, in vivo inhaled dose was estimated and milrinone definite pharmacokinetics fully characterized based on blood sampling and urine collection. Mean arterial pressure to mean pulmonary arterial pressure ratio (mAP/mPAP) was selected as the PD biomarker. Milrinone exposure-response relationship was characterized during the inhalation period by studying the relationship between individual area under the effect-time curve (AUEC) and corresponding area under the plasma concentration-time curve (AUC). Finally, the mAP/mPAP ratio, among other variables, was explored as a potential predictor of difficult separation from bypass in a multiple logistic regression model. In vitro experiments demonstrated that emitted doses were similar for the jet (64%) and the mesh (68.0%) nebulizers. However, the inhaled dose was 2-3 fold higher (46% vs 17%) after mesh nebulization, which was in agreement with plasma concentrations. In patients, due to variations in circuit-related and ventilator-related factors, the inhaled dose was estimated to be lower (30%) and this was confirmed by 24-h recovery in urine (26%). Milrinone peak plasma concentrations (Cmax: 41-189 ng/ml) and magnitude of peak response ΔRmax-R0 (0-65%) were observed at the end of inhalation (10-30 min). Data obtained from PK analysis agreed with published data for intravenous milrinone. After the inhalation period, individual AUEC were directly related to AUC (P=0.045). Finally, our PD biomarker, expressed as ΔRmax-R0, as well as CPB duration, were both identified as significant predictors of DSB. The comparison of corresponding AUC and AUEC provided preliminary evidence of a proof of concept for the use of the mAP/mPAP ratio as a promising PD biomarker and warrants future PK/PD studies. Indeed, mAP/mPAP ratio variation in response to inhaled milrinone was found to contribute in the prevention of DSB.

Background: Lung dysfunction constitutes a severe complication after major cardiac surgery with cardiopulmonary bypass (CPB), substantially contributing to postoperative morbidity and mortality. The current possibilities of preventive and therapeutic interventions, however, remain insufficient. We, therefore, investigated the effects of intraoperative application of the antioxidant and anti-inflammatory green tea polyphenol epigallocatechin-3-gallate (EGCG) on CPB-associated lung injury. Materials and methods: Thirty piglets (8 - 15 kg) were divided into four groups: sham-operated and saline-treated control group (n = 7); sham-operated and EGCG-treated control group (EGCG-control group; n = 7); CPB group (n = 10); and CPB + EGCG group (n = 6). The CPB groups underwent 120 min of CPB followed by 90 min of recovery time. In the CPB + EGCG group, EGCG (10 mg/kg body weight) was administered intravenously before and after CPB. Hemodynamic monitoring, blood gas analysis, hematoxylin-eosin staining, and immunohistochemistry of lung tissue were performed. Results: Histologic examination revealed thickening of the alveolar wall and enhanced alveolar neutrophil infiltration in the CPB group (P < 0.05) compared with those in the control group, which was prevented by EGCG (P < 0.05). In the CPB group, higher formation of poly(ADP-ribose) and nuclear translocation of apoptosis-inducing factor were detected in comparison with those in the control group (P < 0.001), which were both reduced in the CPB + EGCG group (P < 0.001). Compared with the control group, the EGCG-control group showed thickening of the alveolar wall and increased neutrophil infiltration (P < 0.05). Conclusions: CPB leads to lung edema, pulmonary neutrophil infiltration, and presumably initiation of poly(ADP-ribose) polymerase-dependent cell death signaling in the lung. EGCG appears to attenuate CPB-associated lung injury, suggesting that this may provide a novel pharmacologic approach.

Durante a cirurgia de revascularização do miocárdio com circulação extracorpórea e hipotermia (CEC-H) ocorre alteração na efetividade do propofol e na sua farmacocinética realizada a partir das concentrações plasmáticas do propofol total no decurso do tempo. A ligação do propofol à proteína plasmática parece estar alterada em consequência de diversos fatores incluindo a hemodiluição e a heparinização que ocorre no início da circulação extracorpórea, uma vez que se reportou anteriormente que a concentração plasmática do propofol livre aumentou durante a realização da circulação extracorpórea normotérmica. Por outro lado, a infusão alvo controlada é recomendada para manter a concentração plasmática do propofol equivalente ao alvo de 2 &#181g/mL durante a intervenção cirúrgica com CEC-H. Se alterações significativas na hipnose do propofol ocorrem nesses pacientes, então o efeito aumentado desse agente hipnótico poderia estar relacionado à redução na extensão da ligação do fármaco as proteínas plasmáticas; entretanto, o assunto ainda permanece em discussão e necessita de investigações adicionais. Assim, o objetivo do estudo foi investigar as concentrações plasmáticas de propofol livre em pacientes durante a revascularização do miocárdio com e sem o procedimento de CEC-H através da abordagem PK-PD. Dezenove pacientes foram alocados e estratificados para realização de cirurgia de revascularização do miocárdio com circulação extracorpórea (CEC-H, n=10) ou sem circulação extracorpórea (NCEC, n=9). Os pacientes foram anestesiados com sufentanil e propofol alvo de 2 &#181g/mL. Realizou-se coleta seriada de sangue para estudo farmacocinético e o efeito foi monitorado através do índice bispectral (BIS) para medida da profundidade da hipnose no período desde a indução da anestesia até 12 horas após o término da infusão de propofol, em intervalos de tempo pré-determinados no protocolo de estudo. As concentrações plasmáticas foram determinadas através de método bioanalítico pela técnica de cromatografia líquida de alta eficiência. A farmacocinética foi investigada a partir da aplicação do modelo aberto de dois compartimentos, PK Solutions v. 2. A análise PK-PD foi realizada no Graph Pad Prisma v.5.0 após a escolha do modelo do efeito máximo (EMAX sigmóide, slope variável). Os dados foram analisados utilizando o Prisma v. 5.0, p<0,05, significância estatística. As concentrações plasmáticas de propofol total foram comparáveis nos dois grupos (CEC-H e NCEC); entretanto o grupo CEC-H evidenciou aumento na concentração do propofol livre de 2 a 5 vezes em função da redução na ligação do fármaco às proteínas plasmáticas. A farmacocinética do propofol livre mostrou diferença significativa entre os grupos no processo de distribuição pelo prolongamento da meia vida e aumento do volume aparente, e no processo de eliminação em função do aumento na depuração plasmática e redução na meia vida biológica no grupo CEC-H. A escolha do modelo EMAX sigmóide, slope variável foi adequada uma vez que se evidenciou alta correlação entre os valores do índice bispectral e as concentrações plasmáticas do propofol livre (r2>0.90, P<0.001) para os pacientes investigados. / During coronary artery bypass grafting (CABG) surgery with cardiopulmonary bypass (CPB) profound changes occur on propofol effect and on kinetic disposition related to total drug plasma measurements in these patients. It was reported that drug plasma binding could be altered as a consequence of hemodilution and heparinization before starts CPB since free propofol plasma levels was increased by twice under normothermic procedure. In addition, the target controlled infusion (TCI) is recommended to maintain propofol plasma concentration (2 &#181g/mL) during CABG CPB-H intervention. However, whether significant changes that occur in propofol hypnosis in these patients could be related to the reduction on the extension of drug plasma binding remain unclear and under discussion until now. Then, the objective of this study was to investigate propofol free plasma levels in patients undergoing CABG with and without CPB by a pharmacokinetics-pharmacodynamics (PK-PD) approach. Nineteen patients were scheduled for on-pump coronary artery bypass grafting (CABG-CPB, n=10) or off-pump coronary artery bypass grafting (OPCABG, n=9) were anesthetized with sufentanil and propofol TCI (2 &#181g/mL). Blood samples were collected for drug plasma measurements and BIS were applied to access the depth of hypnosis from the induction of anesthesia up to 12 hours after the end of propofol infusion, at predetermined intervals. Plasma drug concentrations were measured using high-performance liquid chromatography, followed by a propofol pharmacokinetic analysis based on two compartment open model, PK Solutions v.2; PK-PD analysis was performed by applying EMAX model, sigmoid shape-variable slope and data were analyzed using Prisma v. 5.0, considering p<0.05 as significant difference between groups. The total propofol plasma concentrations were comparable in both groups during CABG; however it was shown in CPB-group significant increases in propofol free plasma concentration by twice to fivefold occur as a consequence of drug plasma protein binding reduced in these patients. Pharmacokinetics of free propofol in CPB-H group compared to OPCAB group based on two compartment open model was significantly different by the prolongation of distribution half-life, increases on plasma clearance, and biological half-life shortened. In addition, the kinetic disposition of propofol changes in a different manner considering free drug levels in the CPB-H group against OPCAB group as follows: prolongation of distribution half-life and increases on volume of distribution, remaining unchanged biological half-life in spite of plasma clearance increased. BIS values showed a strong correlation with free drug levels (r2>0.90, P<0.001) in CPB-H group and also in OPCAB group by the chosen EMAX model sigmoid shape-variable slope analyzed by GraphPad Prisma v.5.0.

Das mit dem kardiopulmonalen Bypass assoziierte kapilläre Leck bei Operationen am offenen Herzen führt zu einem Anstieg des totalen Wassergehalts des Körpers, wobei es vor allem zu einer pulmonalen sowie myokardialen Ödementwicklung kommt. Mit der von Naik, Knight und Elliott (1991) hinsichtlich Filterposition und Filtrationszeitpunkt beschriebenen modifizierten Form der Ultrafiltration unmittelbar nach Abgang vom Bypass konnte eine markante Reduzierung der mit dem Bypass assoziierten Flüssigkeitsakkumulation sowie eine unmittelbare Verbesserung der hämodynamischen Parameter (Herzindex, myokardiale Kontraktilität, verminderter postoperativer Verbrauch inotroper Substanzen) nachgewiesen werden. Ziel vorliegender Studie ist deshalb die Untersuchung der Auswirkung der modifizierten Ultrafiltration auf die Lungenfunktion. Für diese Studie wurden 37 Kinder (Alter 3 Tage bis 92 Monate, Gewicht 3,1 bis 21,3 kg) beobachtet, bei denen die operative Korrektur eines angeborenen Herzfehlers unter Einsatz der Herz-Lungen-Maschine (kardiopulmonaler Bypass mit extrakorporaler Membranoxygenierung) vorgenommen wurde. Bei 27 Kindern wurde nach Abgang von der Herz-Lungen-Maschine die modifizierte Hämofiltration durchgeführt, 10 Kinder dienten als Kontrollgruppe. Bei allen Patienten wurden vor Beginn sowie nach Abschluß des Einsatzes der Herz-Lungen-Maschine, nach der ca. zehn Minuten dauernden modifizierten Ultrafiltration bzw. bei der Kontrollgruppe zu einem vergleichbaren Zeitpunkt ca. zehn Minuten nach Entwöhnung vom kardiopulmonalen Bypass und nach einem weiteren Zeitraum von ca. zehn Minuten mittels dynamischer Lungenfunktionsmessung Parameter der Lungenmechanik (dynamische Compliance und Resistance) sowie Lungenfunktion (alveoloarterielle Sauerstoffdifferenz) bestimmt. Außerdem wurden hämodynamische (arterieller und zentralvenöser Blutdruck) und rheologische Veränderungen (Hämoglobin, Hämatokrit) aufgezeichnet. Bei der modifizierten Ultrafiltration zeigte sich unmittelbar nach Filtrationsende mit dem signifikanten Anstieg der Compliance um 13,9 % ein Effekt, der sich etwa 10 Minuten nach Filtrationsende noch weiter steigerte. Weiterhin konnte ein Abfall der alveoloarteriellen Sauerstoffdifferenz um insgesamt 29,2 % gemessen werden. Es ließ sich jedoch keine proportionale Abhängigkeit zwischen der Ultrafiltratmenge und der Verbesserung der Lungenfunktion nachweisen. Die von anderen Autoren unter modifizierter Ultrafiltration festgestellten Veränderungen der Hämodynamik, wie zum Beispiel der signifikante Anstieg des arteriellen Blutdruckes, oder der rheologischen Veränderungen, wie zum Beispiel ein Anstieg des Hämatokrit-Wertes, ließen sich bestätigen. Die Ergebnisse zeigen, daß durch die modifizierte Technik der Ultrafiltration eine unmittelbare Verbesserung der postoperativen Lungenfunktion erreicht werden kann. / The capillary leak, associated with cardiopulmonary bypass in open heart surgery, causes a rise of total body water resulting in tissue, especially in pulmonary and myocardial edema. The modified ultrafiltration is a new aproach to reduce these edemas, first described by Naik, Knight and Elliot in 1991. With the modification of the postition of the ultrafilter in the bypass circuit and the time of filtration in the first minutes after the patient has been weaned from bypass a significant reduction of the bypass associated fluid accumulation could be shown as well as an improvement of hemodynamics (heart index, myocardial contractility, reduced need of inotopic drugs). To investigate the influence of the modified ultrafiltration on the lung function is the objective of this study. In this study 37 children (aging from 3 days to 92 months, weighting from 3.1 to 21.3 kg) have been examined in cardiac surgery for moderate to severe congenital heart disease with the application of the cardiopulmonary bypass. The effect of modified ultrafiltration, which immediately started after being weaned from the cardiopulmonary bypass, was studied in 27 children, 10 children formed the controll population. In all patients alterations in pulmonary mechanics (dynamic compliance and resistance), in pulmonary function (alveolar-arterial difference of oxygen), in hemodynamics (arterial and central venous blood pressure, heart rate) and in blood values (hemoglobin, hematocrit) could be recorded at frequent intervals. The measurements were done before and after being weaned from bypass, after conclusion of the modified ultrafiltration respectively after a comparable intervall in the control group and about 10 minutes later before the closure of the chest was performed. After the modified ultrafiltration a significant increase of pulmonary compliance of about 13.9 % was observed, an effect, which was further amplified in the next 10 minutes. Furthermore a decrease of alveolar-arterial difference of oxygen of 29.2 % could be shown, but no correlation between the amount of ultrafiltrat and improvement of pulmonary function could be proved. Other findings like a significant increase of arterial blood pressure or an increase of the hematocrit, which were also described by other authors in previous studies, could be confirmed. The results indicate, that by using the modified technique of ultrafiltration an improvement of pulmonary function is achievable.

Die vorliegende Arbeit setzt sich mit den funktionellen und strukturellen Veränderungen im Zentralnervensystem im Zusammenhang mit angeborenen Vitien und deren chirurgischer Behandlung mit Hilfe der extrakorporalen Zirkulation (EKZ) sowohl klinisch als auch tierexperimentell auseinander mit dem Ziel, neuroprotektive Strategien zu entwickeln. Wir haben mit den verfügbaren Methoden der Neuroüberwachung die charakteristischen Verläufe definiert und beschrieben. Zusätzlich wurden diese nicht-invasiven Methoden wie die Nahinfrarot-Spektroskopie sowohl klinisch als auch tierexperimentell validisiert. Es konnte jedoch gezeigt werden, dass diese Methoden eine zuverlässig signifikante globale Alteration in der Oxygenation und Perfusion anzeigen. Durch das Erarbeiten und die Charakterisierung des Verlaufs der Serumwerte des astroglialen Proteins S-100B wurde die klinische Wertigkeit genauer definiert. Es konnte klinisch und tierexperimentell gezeigt werden, dass die abnorm erhöhten Werte des S-100B im Serum von einem signifikanten diagnostischen Wert sind. Im Gegensatz dazu wurde die untergeordnete Rolle der Bestimmung von neuronalen Marker im Serum bestätigt. Durch die tierexperimentellen Arbeiten wurde gezeigt, dass die überwiegenden morphologischen Veränderungen nach EKZ im Gehirn in den Astrozyten und Gliazelen zu finden sind. Die neuronale Zelldegeneration war nach dem tiefhypothermen Kreislaufstillstand überwiegend in Form von hypoxischer Zellnekrose. Die apoptotische Zelldegeneration trat zellspezifisch im Gyrus Dentatus des Hippocampus auf. Vor allem konnte die bedeutende protektive Rolle der Hypothermie und der hypothermen Perfusion der EKZ demonstriert werden. Bei einer effektiven systemischen Kühlung an der EKZ könnte ein Kreislaufstillstand ohne signifikante neuronale Schädigungen überstanden werden. Die EKZ und der tiefhypotherme Kreislaufstillstand stellen an sich für das unreife Gehirn eine grobe nicht-physiologische Situation dar. Im Tiermodel könnte histologisch gezeigt werden, das die systemische Vorbehandlung mit Methylprednisolone keine protektive Wirkung hat. Obwohl eine signifikante Neuroprotektion durch Gabe von FK506 und Cyclosporin unter extremen Bedingungen der EKZ und tiefhypothermem Kreislaufstillstand erzielt wurde, bedarf es vor einer klinischen Anwendung weiterer tierexperimenteller und klinischer Überprüfungen. / The aim of our clinical and experimental studies was to evaluate functional and structural changes in the brain during corrective cardiac surgery using cardiopulmonary bypass (CPB) and deep hypothermic circulatory arrest (DHCA) in order to develop neuroprotective strategies. Using the available neurmonitoring methods such as the transcranial Doppler and near infrared spectroscopy (NIRS) characteristic changes in cerebral perfusion and oxygenation were defined and described according to the changes in hemodynamic parameters such perfusion pressure, temperature and flow rate. The diagnostic value of the astrocytic cell protein S100B was evaluated by measurement of the serum concentrations in infants and children with and without neurological complications. Additionally, the normal and abnormal release patterns were evaluated in experimental setting using an animal model of CPB and DHCA. According to the neuropathological assessment of the brain initial morphological changes were found predominantly in the astroglial cells. Systemic hypothermic perfusion on CPB before the induction of circulatory arrest period of 60 minutes was significantly protective. Ischemic neuronal injury in form of cell nekrosis was found in different brain region particularly after the prolongation of circulatory arrest time in deep hypothermia. The apoptotic cell death was found predominantly in the hippocampal region of the dentate gyrus. The routinely prophylactic systemic use steroid during cardiac surgery is not protective against ischemia and has been found to induce apoptosis in the hippocampus. In the same model the systemic pre-treatment with single high dose of Cyclosporin and FK506 decreased significantly the ischemic neuronal cell injury in different brain region. However, before clinical use further studies are necessary to optimise the dose and mode of application.

Hintergrund: Das akute Nierenversagen ist eine häufige Komplikation nach einer Herzoperation bei Neugeborenen, Säuglingen und Kleinkindern. Die Bedeutung der postoperativen Hämodynamik für eine Nierenschädigung ist gut bekannt, jedoch ist der Einfluß des kardiopulmonalen Bypasses und des tiefen hypothermen Kreislaufstillstandes weniger klar. Überdies gibt es Veränderungen der Blutviskosität während und nach der Herzoperation am kardiopulmonalen Bypass, welche die Nierenfunktion beeinflussen können. Aus diesem Grunde wurde der Einfluß der Blutviskosität am kardiopulmonalen Bypass und des tiefen hypothermen Kreislaufstillstandes auf die Nierenfunktion in dieser Patientengruppe untersucht. Methode: Untersucht wurden 44 Patienten mit einem Körpergewicht unter 10 kg, die am kardiopulmonalen Bypass operiert wurden. Von diesen erfolgte die Herzoperation bei 7 Patienten unter zusätzlicher Anwendung des tiefen hypothermen Kreislaufstillstandes. Bei allen Patienten wurden zu verschiedenen Zeitperioden Messungen zur Beschreibung der Nierenfunktion (Diurese, Kreatinin-Clearance und Gesamtprotein, Albumin, alpha-1-Mikroglobulin, Transferrin, IgG, N-Acetyl-beta-D-Glucosaminidase im Urin) und Bestimmungen der Blut- und Plasmaviskosität, der Erythrozytenaggregation und des kolloidosmotischen Druckes durchgeführt. Beide Gruppen wurden hinsichtlich des Einflusses des Kreislaufstillstandes auf die Nierenfunktion miteinander verglichen. Ergebnisse: Die während des kardiopulmonalen Bypasses im Zusammenhang mit einem erhöhten transglomerulären Filtrationsgradienten entstandene Polyurie und Proteinurie normalisierte sich innerhalb von 24 Stunden postoperativ. Die renale Ausscheidung von N-Acetyl-beta-D-Glucosaminidase und die erhöhte Natriumausscheidung zeigten zusätzlich eine tubuläre Schädigung an. Bei Hypothermie hatte die Plasmaviskosität einen deutlichen Einfluß auf die Blutviskosität, die während hypothermer Perfusion mit den im Urin gemessenen Werten von Albumin und N-Acetyl-beta-D-Glucosaminidase korrelierte. Die Patienten in der Kreislaufstillstandsgruppe hatten eine längere Bypasszeit und eine niedrigere minimale Körpertemperatur im Vergleich zu den Patienten ohne Kreislaufstillstand (p < 0,05). Diurese und Kreatinin-Clearance zeigten keine Differenzen zwischen beiden Gruppen. Während der Reperfusion wurde in der Kreislaufstillstandsgruppe signifikant mehr Albumin renal ausgeschieden als in der Vergleichsgruppe, ebenso Albumin und N-Acetyl-beta-D-Glucosaminidase nach dem kardiopulmonalen Bypass (p < 0,01). Schlußfolgerung: Die kardiopulmonale Bypassperfusion könnte eine Proteinurie und einen milden tubulären Schaden verursachen. Die Blutviskosität scheint dafür ein mitbestimmender Faktor zu sein und ist möglicherweise während hypothermer Perfusion wesentlich von der Plasmaviskosität abhängig. Es ist notwendig und wünschenswert anhand einer prospektiven Interventionsstudie den Einfluß der Blut- und Plasmaviskosität auf die postoperative Nierenfunktion zu untersuchen. Der tiefe hypotherme Kreislaufstillstand kann die Empfindlichkeit der Niere für einen Ischämie-Reperfusions-Schaden steigern. Obgleich die Befunde mild sind und keinen schweren ischämischen Nierenschaden anzeigen, sollte der durch den Kreislaufstillstand verursachte potentielle Nierenschaden für die Planung des chirurgischen Eingriffs bei Patienten mit angeborenen Herzfehlern als zusätzliches Risiko für ein akutes Nierenversagen mit in Betracht gezogen werden. / Background: Acute renal failure is a common complication after cardiopulmonary bypass in infants. Whereas it is well known that postoperative hemodynamics inflict acute renal failure, the influence of extracoporeal circulation on the kidney is less clear. Moreover, changes in blood viscosity occur during and after surgery, which may influence renal dysfunction. For this reason, the impact of blood viscosity during cardiopulmonary bypass and circulatory arrest on renal function was investigated. Methods: 44 patients weighting less than 10 kg operated on cardiopulmonary bypass were investigated, inclusive of 7 patients who additionally underwent circulatory arrest. In all patients analyses of renal function (diuresis, creatinine clearance, urinary total protein, albumin, alpha-1-microglobulin, transferrin, IgG, and N-acetyl-beta-D-glucosaminidase), blood, and plasma viscosity measurements, erythrocyte aggregation and colloid osmotic pressure were performed. Both groups were compared with regard to the impact of circulatory arrest on renal function. Results: Polyuria and proteinuria that appeared during cardiopulmonary bypass indicated an elevated transglomerular filtration gradient, which recovered within 24 hours. The appearance of N-acetyl-beta-D-glucosaminidase in the urine and elevated sodium excretion were additionally indicative of mild tubular damage. With hypothermia, plasma viscosity could had a major impact on the blood viscosity, which, during hypothermic perfusion, seemed to be related to proteinuria and N-acetyl-beta-D-glucosaminidase values. The patients of the circulatory arrest group had a longer bypass time and a lower body temperature in compare to the patients without circulatory arrest (p < 0.05). Diuresis and creatinine clearance revealed no differences between both groups. During reperfusion in the circulatory arrest group significantly more albumin were excreted as in the comparison group, likewise albumin and N-acetyl-beta-D-glucosaminidase after cardiopulmonary bypass (p < 0.01). Conclusions: Cardiopulmonary bypass perfusion could cause proteinuria and mild tubular damage. Blood viscosity may be one possible contributing factor, which in hypothermia may depend mainly on plasma viscosity. It is necessary and desirable to investigate the impact of blood, and plasma viscosity on postoperative renal function based on a prospective intervention study. The deep hypothermic circulatory arrest can increase the sensitivity of the kidney to an ischemia-reperfusion injury. Although the findings are mild and do not indicate severe ischemic renal damage, potential renal damage by deep hypothermic circulatory arrest should be taken into account for planning surgical procedures for congenital heart disease patients with additional risks of acute renal failure.

Pacientes submetidos à revascularização do miocárdio (RM), frequentemente utilizam beta-bloqueadores no pré-operatório para o controle da angina pectoris, e continuam o tratamento após a cirurgia, para a redução de mortalidade e complicações cardiovasculares perioperatórias. Entretanto, a circulação extracorpórea (CEC), empregada na maioria das cirurgias cardíacas, pode alterar as concentrações plasmáticas e a disposição cinética de muitos fármacos, e consequentemente seus efeitos terapêuticos. O atenolol é um beta-bloqueador altamente hidrossolúvel, de absorção incompleta e eliminação renal-dependente. O objetivo deste estudo foi o de investigar a influência da CEC sobre as concentrações plasmáticas do atenolol no intra-operatório de cirurgia cardíaca, além de comparar a sua farmacocinética no pré e pós-operatório de RM com CEC, em pacientes com insuficiência coronariana. Investigou-se ainda, a variabilidade das concentrações plasmáticas do atenolol no período que antecede a cirurgia cardíaca. Na primeira etapa, avaliaram-se 19 pacientes coronarianos, em terapia crônica com atenolol PO, submetidos à cirurgia cardíaca com ou sem CEC. Na segunda parte, investigaram-se os períodos pré e pós-cirúrgico de 7 pacientes submetidos à RM com CEC e tratados com atenolol PO em regime de doses múltiplas. Todos os pacientes investigados apresentavam função renal dentro da normalidade ou leve disfunção renal, decorrente da idade e da insuficiência coronariana. O monitoramento do atenolol plasmático no intra-operatório de RM e o estudo farmacocinético realizado antes e após a revascularização, exigiram coletas de amostras sangüíneas seriadas. A quantificação do atenolol em plasma foi realizada através da cromatografia líquida de alta eficiência com detector de fluorescência e consistiu num procedimento analítico rápido, simples e de baixo custo. Apenas 200 L de plasma foram utilizados em cada análise cromatográfica. O estudo de validação demonstrou que o método desenvolvido apresenta alta linearidade, sensibilidade e seletividade adequadas, alta recuperação, boa precisão e exatidão, além de estabilidade e robustez. Conclui-se que a circulação extracorpórea altera as concentrações do atenolol no intra-operatório de RM, visto que o decaimento das concentrações plasmáticas mostrou-se mais pronunciado na ausência da CEC. Entretanto, apesar das maiores concentrações obtidas ao final da cirurgia com CEC, o atenolol mostra-se seguro, em virtude do baixo acúmulo do fármaco administrado em regime de doses múltiplas. Além disso, a disposição cinética do atenolol permaneceu inalterada, quando os períodos pré e pós-operatórios foram comparados; entretanto, registrou-se uma tendência à normalização do volume de distribuição e da depuração plasmática do atenolol após a revascularização. Adicionalmente, a ausência de correlação entre meia-vida biológica e volume aparente de distribuição sugere que, tanto no pré quanto no pós-operatório, as concentrações do atenolol dependem apenas da sua depuração plasmática. Finalmente, verificou-se que o atenolol apresenta baixa variabilidade inter-pacientes nos regimes posológicos empregados no tratamento da insuficiência coronariana. / Patients submitted to coronary artery bypass grafting (CABG) surgery frequently are using beta-blockers agents for the control of angina pectoris, and continue the treatment after the surgery to reduce the mortality and cardiovascular events. However, the technique of cardiopulmonary bypass (CPB), used in most cardiac surgeries with cardioplegia, causes important changes in the plasma concentrations and pharmacokinetics of many drugs and may also alter their therapeutic effects. Atenolol is a hydrophilic beta-blocker characterized by incomplete absorption, a relatively small volume of distribution and a renal function-dependent elimination. The objective of this study was to investigate the effects of CPB on the plasma concentrations of atenolol during the intra-operative period of cardiac surgery, as well as, to compare the pharmacokinetics of atenolol in the pre and post-operative periods of revascularization with CPB, in patients with coronary insufficiency. In addition, it was investigated the variability of plasma atenolol concentrations before the cardiac surgery. In the first part of the study, it was investigated 19 coronary patients, under chronic therapy with atenolol and submitted to cardiac surgery performed with and without CPB. At the second part, it was evaluated the pre and post-operative periods from 7 patients submitted to the CABG surgery with CPB, who were chronically treated with atenolol in a multiple regimen. All enrolled patients presented normal or slightly reduced renal function as a result of age and underlying disease. A serial blood samples collection was required for monitoring of plasma atenolol concentrations at the intra-operative period and also for pharmacokinetic study at the pre and post-CABG. The quantification of plasma atenolol was performed using high-performance liquid chromatography with fluorescence detection and consisted of a relatively rapid, simple and low-cost analytical procedure. Only 200 µL of plasma was used for each chromatographic analysis. Validation of this analytical method showed high linearity, adequate sensitivity and selectivity, high recovery, good accuracy and precision, in addition to stability and a guarantee of robustness. It was concluded that the CPB changes plasma atenolol concentrations in the intra-operative period, since a marked decrease in plasma atenolol concentrations was observed in patients undergoing cardiac surgery without CPB. Thus, despite the lower decline in plasma levels observed in patients submitted to CPB, atenolol can be used safely, due to the low accumulation of the drug administrated at multiple dose regimens. In addition, pharmacokinetics of atenolol remained unaltered when pre and post-operative periods were compared; although it was observed a tendency of normalization of volume of distribution and plasma clearance of atenolol after the revascularization. Moreover, the lack of correlation between biological half-life and apparent volume of distribution suggests that, in both periods, plasma atenolol concentration only depends on its plasma clearance. Finally, it was verified a small inter-patient variability of atenolol in the dose regimens used for the control of coronary insufficiency.

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Made available in DSpace on 2016-01-26T12:51:50Z (GMT). No. of bitstreams: 1 liliangoraieb_dissert.pdf: 2524026 bytes, checksum: 35df67e734bc16baa9fa59b0adee085f (MD5) Previous issue date: 2005-12-12 / Objective: To evaluate the behavior of the pulmonary compliance and resistance of the airway passage in patients with high blood flow congenital heart disease undergoing surgical treatment with cardiopulmonary bypass. Method: The static pulmonary compliance and the airway resistance were evaluated in 35 patients during the intraoperative period, in four distinct instants: the first, before the thorax opening, with the infants being already anesthetized, under mechanical ventilation; the second, after thorax and pericardium opening, with the retractors in position; the third, five minutes after the end of cardiopulmonary bypass; the forth, after thorax closing. Pulmonary measurements were performed non-invasively by means of the airway occlusion at the end of inspiration, and the use of proper mathematical formula. In different periods, the observed and related variables with the pulmonary changes were: preoperative, the age, weight and systemic and pulmonary blood flow; intraoperative, the perfusion and the anoxia duration and the minimum body temperature; and, postoperative, duration of mechanical ventilatory support and the length of stay in the ICU. Results: At the end of the surgery, the pulmonary compliance showed a significant and immediate increase (P<0.001) in all the patients. Patients over 30-months as well as the ones with weight over 10kg showed greater increase; P=0.0004, P=0.0006, respectively. Patients with 50-minute duration of cardiopulmonary bypass delayed more to present increase of pulmonary compliance (P=0.04). The resistance of the airway passage did not present significant alteration at the end of surgical correction (P=0.393). Conclusion: All the patients presented pulmonary compliance improvement at the end of the surgery. It was influenced significantly by the age, weight and duration of cardiopulmonary bypass; however, the resistance of the airway passage has not changed. / Avaliar o comportamento da complacência pulmonar e resistência da via aérea nos pacientes portadores de cardiopatias congênitas com hiperfluxo pulmonar submetidos a tratamento cirúrgico com auxílio de circulação extracorpórea. Método: Trinta e cinco pacientes foram avaliados com medidas de complacência estática e resistência da via aérea em quatro instantes distintos durante a cirurgia: O primeiro antes da abertura do tórax, com a criança já anestesiada e sob ventilação mecânica. O segundo, após a abertura do tórax e pericárdio, com os afastadores posicionados. O terceiro, cinco minutos após a saída de circulação extracorpórea e o quarto, após o fechamento do tórax. As medidas pulmonares foram feitas de forma não invasiva com o método de oclusão da via aérea ao final da inspiração e uso de fórmulas matemáticas específicas. As variáveis observadas e relacionadas às alterações pulmonares foram: No período pré-operatório, idade, peso e a relação entre fluxo sanguíneo sistêmico e pulmonar, no intra-operatório, tempos de perfusão, de anóxia e temperatura mínima, no pós-operatório, tempo de ventilação mecânica e tempo de permanência na unidade de terapia intensiva. Resultados: A Complacência pulmonar ao final da cirurgia mostrou aumento significativo imediato (P<0,001) em todos os pacientes. Pacientes maiores de 30 meses tiveram maior aumento (P=0,0004). Os com peso superior a 10kg também apresentaram maior aumento (P=0,0006). Pacientes com tempo de circulação extracorpórea maior que 50 minutos demoraram mais para apresentar aumento da complacência pulmonar (P=0,04). A resistência da via aérea não apresentou alteração significativa ao final da correção cirúrgica (P=0,393). Conclusão: A complacência pulmonar apresentou melhora ao final da cirurgia em todos os pacientes, sendo influenciada de forma significativa pela idade, peso e tempo de circulação extracorpórea. A resistência da via aérea, entretanto, não se alterou.