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.

Introdução: a revascularização miocárdica (RM) sem circulação extracorpórea (CEC) tem sido associada a menores complicações quando comparadas à com CEC. Objetivos: determinar os efeitos da CEC em marcadores de hemostasia, fibrinólise, inflamação e correlacionar com eventos clínicos. Método: os pacientes foram incluídos de forma prospectiva e randomizada para cirurgia de RM com (n=41) ou sem CEC (n=51). As concentrações de proteína C reativa (PCR), fibrinogênio, dímero-D e inibidor do ativador do plasminogênio tipo 1 (PAI1) foram quantificadas antes e após (1 e 24 horas) a RM. As técnicas cirúrgicas e anestésicas foram padronizadas para ambos os grupos. Eventos clínicos foram avaliados durante a hospitalização inicial e após 1 ano de seguimento. Resultados: as concentrações de PAI1 e dímeros-d foram maiores quando comparados os valores pré-operatórios com os de 1 e 24 h, após a RM em ambos os grupos, porém as concentrações de PAI1 aumentadas estenderam-se por 24 h após a RM com CEC (p<0,01). A concentração de PCR teve um aumento de pequena magnitude imediatamente após a cirurgia em ambos os grupos e aumentou de modo similar 24h após a RM (p<0,01). A RM com CEC foi associada com maior perda sanguínea durante a cirurgia e mais sangramento pós-operatório (p<0,01). A incidência de todas as outras complicações foi similar nos dois grupos. Conclusão: a RM com CEC apresentou evidências bioquímicas de um estado pró-trombótico precoce após a cirurgia, porém, sem evidências no aumento no número de eventos trombóticos. O estado pró-trombótico pode ser consequência do circuito extracorpóreo, resposta compensatória ao sangramento, ou a ambos em pacientes submetidos à cirurgia com CEC. / Objective: To delineate the effects of extracorporeal bypass on biomarkers of hemostasis, fibrinolysis, and inflammation and clinical sequelae. Methods: Patients were assigned prospectively and randomly to either on-pump (n=41) or off-pump (n=51) coronary bypass surgery. The concentrations of C-reactive protein (CRP), fibrinogen, D-dimer, and plasminogen activator inhibitor type 1 (PAI-1) in blood were quantified before and after (1 hour and 24 hours) surgery. Similar surgical and anesthetic procedures were used for both groups. Clinical events were assessed during initial hospitalization and at the end of 1 year. Results: The concentrations of PAI-1 and d-dimer were greater compared with preoperative values 1 hour and 24 hours after surgery in both groups, but their concentrations increased to a greater extent 24 hours after surgery in the on-pump group (p<0.01). The concentration of CRP did not change appreciably immediately after surgery in either group but increased in a parallel fashion 24 hours after either on-pump or off-pump surgery (p<0.01). Bypass surgery in the on-pump group was associated with greater blood loss during surgery and more bleeding after surgery (p0.01). The incidence of all other complications was similar in the 2 groups. Conclusion: On-pump surgery was associated with biochemical evidence of a pro-thrombotic state early after surgery but no greater incidence of thrombotic events. The pro-thrombotic state may have been a consequence of extracorporeal bypass, compensation in response to more bleeding, or both in patients undergoing on-pump surgery.

No description available.

La fibrillation auriculaire (FA) est une arythmie touchant les oreillettes. En FA, la contraction auriculaire est rapide et irrégulière. Le remplissage des ventricules devient incomplet, ce qui réduit le débit cardiaque. La FA peut entraîner des palpitations, des évanouissements, des douleurs thoraciques ou l’insuffisance cardiaque. Elle augmente aussi le risque d'accident vasculaire. Le pontage coronarien est une intervention chirurgicale réalisée pour restaurer le flux sanguin dans les cas de maladie coronarienne sévère. 10% à 65% des patients qui n'ont jamais subi de FA, en sont victime le plus souvent lors du deuxième ou troisième jour postopératoire. La FA est particulièrement fréquente après une chirurgie de la valve mitrale, survenant alors dans environ 64% des patients. L'apparition de la FA postopératoire est associée à une augmentation de la morbidité, de la durée et des coûts d'hospitalisation. Les mécanismes responsables de la FA postopératoire ne sont pas bien compris. L'identification des patients à haut risque de FA après un pontage coronarien serait utile pour sa prévention. Le présent projet est basé sur l'analyse d’électrogrammes cardiaques enregistrées chez les patients après pontage un aorte-coronaire. Le premier objectif de la recherche est d'étudier si les enregistrements affichent des changements typiques avant l'apparition de la FA. Le deuxième objectif est d'identifier des facteurs prédictifs permettant d’identifier les patients qui vont développer une FA. Les enregistrements ont été réalisés par l'équipe du Dr Pierre Pagé sur 137 patients traités par pontage coronarien. Trois électrodes unipolaires ont été suturées sur l'épicarde des oreillettes pour enregistrer en continu pendant les 4 premiers jours postopératoires. La première tâche était de développer un algorithme pour détecter et distinguer les activations auriculaires et ventriculaires sur chaque canal, et pour combiner les activations des trois canaux appartenant à un même événement cardiaque. L'algorithme a été développé et optimisé sur un premier ensemble de marqueurs, et sa performance évaluée sur un second ensemble. Un logiciel de validation a été développé pour préparer ces deux ensembles et pour corriger les détections sur tous les enregistrements qui ont été utilisés plus tard dans les analyses. Il a été complété par des outils pour former, étiqueter et valider les battements sinusaux normaux, les activations auriculaires et ventriculaires prématurées (PAA, PVA), ainsi que les épisodes d'arythmie. Les données cliniques préopératoires ont ensuite été analysées pour établir le risque préopératoire de FA. L’âge, le niveau de créatinine sérique et un diagnostic d'infarctus du myocarde se sont révélés être les plus importants facteurs de prédiction. Bien que le niveau du risque préopératoire puisse dans une certaine mesure prédire qui développera la FA, il n'était pas corrélé avec le temps de l'apparition de la FA postopératoire. Pour l'ensemble des patients ayant eu au moins un épisode de FA d’une durée de 10 minutes ou plus, les deux heures précédant la première FA prolongée ont été analysées. Cette première FA prolongée était toujours déclenchée par un PAA dont l’origine était le plus souvent sur l'oreillette gauche. Cependant, au cours des deux heures pré-FA, la distribution des PAA et de la fraction de ceux-ci provenant de l'oreillette gauche était large et inhomogène parmi les patients. Le nombre de PAA, la durée des arythmies transitoires, le rythme cardiaque sinusal, la portion basse fréquence de la variabilité du rythme cardiaque (LF portion) montraient des changements significatifs dans la dernière heure avant le début de la FA. La dernière étape consistait à comparer les patients avec et sans FA prolongée pour trouver des facteurs permettant de discriminer les deux groupes. Cinq types de modèles de régression logistique ont été comparés. Ils avaient une sensibilité, une spécificité et une courbe opérateur-receveur similaires, et tous avaient un niveau de prédiction des patients sans FA très faible. Une méthode de moyenne glissante a été proposée pour améliorer la discrimination, surtout pour les patients sans FA. Deux modèles ont été retenus, sélectionnés sur les critères de robustesse, de précision, et d’applicabilité. Autour 70% patients sans FA et 75% de patients avec FA ont été correctement identifiés dans la dernière heure avant la FA. Le taux de PAA, la fraction des PAA initiés dans l'oreillette gauche, le pNN50, le temps de conduction auriculo-ventriculaire, et la corrélation entre ce dernier et le rythme cardiaque étaient les variables de prédiction communes à ces deux modèles. / Atrial fibrillation (AF) is an abnormal heart rhythm (cardiac arrhythmia). In AF, the atrial contraction is rapid and irregular, and the filling of the ventricles becomes incomplete, leading to reduce cardiac output. Atrial fibrillation may result in symptoms of palpitations, fainting, chest pain, or even heart failure. AF is an also an important risk factor for stroke. Coronary artery bypass graft surgery (CABG) is a surgical procedure to restore the perfusion of the cardiac tissue in case of severe coronary heart disease. 10% to 65% of patients who never had a history of AF develop AF on the second or third post CABG surgery day. The occurrence of postoperative AF is associated with worse morbidity and longer and more expensive intensive-care hospitalization. The fundamental mechanism responsible of AF, especially for post-surgery patients, is not well understood. Identification of patients at high risk of AF after CABG would be helpful in prevention of postoperative AF. The present project is based on the analysis of cardiac electrograms recorded in patients after CABG surgery. The first aim of the research is to investigate whether the recordings display typical changes prior to the onset of AF. A second aim is to identify predictors that can discriminate the patients that will develop AF. Recordings were made by the team of Dr. Pierre Pagé on 137 patients treated with CABG surgery. Three unipolar electrodes were sutured on the epicardium of the atria to record continuously during the first 4 post-surgery days. As a first stage of the research, an automatic and unsupervised algorithm was developed to detect and distinguish atrial and ventricular activations on each channel, and join together the activation of the different channels belonging to the same cardiac event. The algorithm was developed and optimized on a training set, and its performance assessed on a test set. Validation software was developed to prepare these two sets and to correct the detections over all recordings that were later used in the analyses. It was complemented with tools to detect, label and validate normal sinus beats, atrial and ventricular premature activations (PAA, PVC) as well as episodes of arrhythmia. Pre-CABG clinical data were then analyzed to establish the preoperative risk of AF. Age, serum creatinine and prior myocardial infarct were found to be the most important predictors. While the preoperative risk score could to a certain extent predict who will develop AF, it was not correlated with the post-operative time of AF onset. Then the set of AF patients was analyzed, considering the last two hours before the onset of the first AF lasting for more than 10 minutes. This prolonged AF was found to be usually triggered by a premature atrial PAA most often originating from the left atrium. However, along the two pre-AF hours, the distribution of PAA and of the fraction of these coming from the left atrium was wide and inhomogeneous among the patients. PAA rate, duration of transient atrial arrhythmia, sinus heart rate, and low frequency portion of heart rate variability (LF portion) showed significant changes in last hour before the onset of AF. Comparing all other PAA, the triggering PAA were characterized by their prematurity, the small value of the maximum derivative of the electrogram nearest to the site of origin, as well as the presence of transient arrhythmia and increase LF portion of the sinus heart rate variation prior to the onset of the arrhythmia. The final step was to compare AF and Non-AF patients to find predictors to discriminate the two groups. Five types of logistic regression models were compared, achieving similar sensitivity, specificity, and ROC curve area, but very low prediction accuracy for Non-AF patients. A weighted moving average method was proposed to design to improve the accuracy for Non-AF patient. Two models were favoured, selected on the criteria of robustness, accuracy, and practicability. Around 70% Non-AF patients were correctly classified, and around 75% of AF patients in the last hour before AF. The PAA rate, the fraction of PAA initiated in the left atrium, pNN50, the atrio-ventricular conduction time, and the correlation between the latter and the heart rhythm were common predictors of these two models.

A quantitative research design for a descriptive and contextual study to determine the critical care nurses knowledge and data preferences regarding the central venous and pulmonary artery catheters management and decision making after coronary arte.y bypass graft operations and the utmzation period of the pulmonary artery catheter after coronary artery bypass graft operations. The data was collected through a questionnaire completed by critical care nurses and retrospective analysis of patient records through a structured checklist. Data analysis indicated the following: critical care nurses have a knowledge deficit in the management of the central venous and pulmonary artery catheters and felt more competent and confident in the central venous measurements. The utilization period of the pulmonary artery catheter was 48% compared to the 100% of the central venous catheter. / Advanced Nursing Science / M.A. (Advanced Nursing Science)

Made available in DSpace on 2016-12-06T17:07:23Z (GMT). No. of bitstreams: 1 Kelly.pdf: 1033318 bytes, checksum: b10b8be25b6a3230a6d02542f0cf28a7 (MD5) Previous issue date: 2010-03-08 / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior / Introduction: The coronary artery bypass graft is associated with deleterious effects on lung function and functional capacity in the immediate postoperative. Objective: To analyse the effects of a preoperative inspiratory muscle training (IMT) program on functional and pulmonary capacities in pre-and post-operative coronary artery bypass graft. Material and Methods: The study is a controlled clinical trial. The sample of this research was composed of 32 individuals admitted to the Imperial Hospital de Caridade (Florianópolis) undergoing elective coronary artery bypass grafting with cardiopulmonary bypass through a median thoracotomy (sternotomy). The study included individuals at high risk for developing pulmonary complications after surgery. The subjects were divided into control and intervention groups. The intervention group received inspiratory muscle training (IMT) with Threshold-loading device. The patients started breathing at a resistence equal of 30% of their maximal inspiratory mouth pressure. The patients trained 7 days a week, 2 times a day (3 sets, 10 repetitions) at least 2 weeks before surgery. Data collection was obtained by: individual assessments records, information about surgical procedures, spirometry, maximal mouth pressures, 6-minute walk test and pulmonary complications after surgery range. The data were analyzed using descriptive statistic and compared by specific statistical tests. Results: The demographic, clinical and surgical procedures were similar in both groups. In the assessment of lung volumes and flows was found that the FVC (p = 0.783), FEV1 (p = 0.668), PEF (p = 0.94) and FEV1/FVC (p =0.745) did not differ significantly between the intervention and control groups in different conditions before and after surgery, however, both showed a significant decrease after surgery. The maximal inspiratory pressure (MIP) differed significantly between groups (p <0.001). Before surgery, it was observed that there was a significant increase in MIP in the intervention group of 70.0 ± 19.7 cmH2O to 92.7 ± 26.8 cmH2O. In contrast, the control group showed a significant reduction in MIP from 75.9 ± 25.6 cmH2O to 66.6 ± 23.6 cmH2O. MIP in the intervention group had a better recovery, returning to baseline (57.5 ± 11.5 and 64.1 ± 14.1 cmH2O, respectively), but the control group remained decreased (43.4 ± 14.1 and 47.1 ± 15.0 cmH2O, respectively), after surgery. The MEP did not obtain significant difference between control and intervention group (p = 0.286), both groups showed a decrease after surgery. There was a significant increase in functional capacity in the intervention group (361.9 ± 92.6 to 434.4 ± 89.5) preoperatively, with smaller drop after surgery. The control group had a decrease in distance walked in 6 minutes (361.9 ±92.6 to 434.4 ±89.5m) in the preoperative period, not returning to baseline in the postoperative period. The length of stay in ICU (p = 0.564) and hospital stay (p = 0.892) did not differ between the two groups. The intervention group had a lower incidence of pulmonary complications (p = 0.046). Conclusion: An inspiratory muscle training program before surgery was able to increase the functional and pulmonary capacities in preoperative, and improve clinical outcomes in patients at high risk for developing pulmonary complications undergoing surgery coronary artery bypass graft. / Introdução: A realização da cirurgia de revascularização do miocárdio está associada com efeitos deletérios sobre a função pulmonar e capacidade funcional no pós-peratório imediato. Objetivo: Analisar os efeitos de um programa de treinamento muscular inspiratório (TMI) pré-operatório sobre a capacidade funcional e pulmonar pré e pós-operatória de cirurgia de Revascularização do Miocárdio (RM). Material e Métodos: O estudo caracteriza-se por ser um ensaio clínico controlado. A amostra desta pesquisa foi constituída por 32 indivíduos internados no Imperial Hospital de Caridade de Florianópolis que foram submetidos à cirurgia eletiva de revascularização do miocárdio com circulação extracorpórea através de toracotomia mediana (esternotomia). Foram incluídos no estudo, indivíduos de alto risco para o desenvolvimento de complicações pulmonares pós-operatórias. Os indivíduos foram alocados em grupo controle e intervenção. O grupo intervenção foi submetido a um treinamento muscular respiratório com auxílio do aparelho Threshold IMT. A carga utilizada para o fortalecimento respiratório foi de 30% do valor registrado na PIMáx. Os pacientes realizaram o treinamento 7 dias por semana, 2 vezes ao dia (3 séries de 10 repetições), pelo menos 2 semanas que antecedem a cirurgia. Foram utilizados como instrumentos de coleta de dados: fichas de avaliações do indivíduo, ficha de procedimentos cirúrgicos, espirometria, manovacuometria, teste de caminhada de 6 minutos e escala de complicações pulmonares pós-operatórias. Os dados foram analisados através da estatística descritiva e comparados por meio de testes estatísticos específicos. Resultados: Os dados demográficos, clínicos e cirúrgicos foram similares nos dois grupos. Na avaliação dos volumes e fluxos pulmonares foi verificado que a CVF (p=0.783), o VEF1 (p= 0.668), o PFE (p= 0.94) e o VEF1/CVF (p=0.745) não se diferenciaram significativamente entre os grupos controle e intervenção, nas diferentes condições pré e pós-operatórias, ambos apresentaram uma queda significativa após a cirurgia. A força muscular inspiratória diferenciou-se significativamente entre os grupos (p<0.001). No pré-operatório, observou-se que ocorreu um aumento significativo de força muscular inspiratória no grupo intervenção de 70.0 ±19.7cmH2O para 92.7 ±26.8 cmH2O. Em contrapartida, o grupo controle apresentou uma redução significativa da PImáx de 75.9 ±25.6 cmH2O para 66.6 ±23.6 cmH2O. A PIMáx do grupo intervenção teve uma melhor recuperação no pós-operatório, retornando ao valor basal (57.5 ±11.5 e 64.1 ±14.1 cmH2O, respectivamente), porém, a do grupo controle continuou diminuída (43.4 ±14.1 e 47.1 ±15.0 cmH2O, respectivamente), após a cirurgia. A PEMáx não obteve diferença significativa entre o grupo controle e intervenção (p=0.286), apresentando uma redução após a cirurgia. Houve um aumento significativo da capacidade funcional no grupo intervenção (361.9 ±92.6 para 434.4 ±89.5m) no pré-operatório, com menor queda após a cirurgia. O grupo controle teve uma diminuição da distância percorrida (384.8 ±136.3 para 333.7 ±116.3 m) no pré-operatório, não retornando aos valores basais, no pós-operatório. O tempo de internação em UTI (p=0.564) e permanência hospitalar (p=0.892) não apresentou diferença entre os dois grupos. O grupo intervenção teve menor incidência de complicações pulmonares (p=0.046). Conclusão: A realização de um programa de treinamento muscular inspiratório no pré-operatório foi capaz de incrementar a capacidade funcional e pulmonar pré-operatória, e melhorar os desfechos clínicos, em indivíduos com alto risco para o desenvolvimento de complicações pulmonares pós-operatórias submetidos à cirurgia de revascularização do miocárdio.

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.

Introdução: a revascularização miocárdica (RM) sem circulação extracorpórea (CEC) tem sido associada a menores complicações quando comparadas à com CEC. Objetivos: determinar os efeitos da CEC em marcadores de hemostasia, fibrinólise, inflamação e correlacionar com eventos clínicos. Método: os pacientes foram incluídos de forma prospectiva e randomizada para cirurgia de RM com (n=41) ou sem CEC (n=51). As concentrações de proteína C reativa (PCR), fibrinogênio, dímero-D e inibidor do ativador do plasminogênio tipo 1 (PAI1) foram quantificadas antes e após (1 e 24 horas) a RM. As técnicas cirúrgicas e anestésicas foram padronizadas para ambos os grupos. Eventos clínicos foram avaliados durante a hospitalização inicial e após 1 ano de seguimento. Resultados: as concentrações de PAI1 e dímeros-d foram maiores quando comparados os valores pré-operatórios com os de 1 e 24 h, após a RM em ambos os grupos, porém as concentrações de PAI1 aumentadas estenderam-se por 24 h após a RM com CEC (p<0,01). A concentração de PCR teve um aumento de pequena magnitude imediatamente após a cirurgia em ambos os grupos e aumentou de modo similar 24h após a RM (p<0,01). A RM com CEC foi associada com maior perda sanguínea durante a cirurgia e mais sangramento pós-operatório (p<0,01). A incidência de todas as outras complicações foi similar nos dois grupos. Conclusão: a RM com CEC apresentou evidências bioquímicas de um estado pró-trombótico precoce após a cirurgia, porém, sem evidências no aumento no número de eventos trombóticos. O estado pró-trombótico pode ser consequência do circuito extracorpóreo, resposta compensatória ao sangramento, ou a ambos em pacientes submetidos à cirurgia com CEC. / Objective: To delineate the effects of extracorporeal bypass on biomarkers of hemostasis, fibrinolysis, and inflammation and clinical sequelae. Methods: Patients were assigned prospectively and randomly to either on-pump (n=41) or off-pump (n=51) coronary bypass surgery. The concentrations of C-reactive protein (CRP), fibrinogen, D-dimer, and plasminogen activator inhibitor type 1 (PAI-1) in blood were quantified before and after (1 hour and 24 hours) surgery. Similar surgical and anesthetic procedures were used for both groups. Clinical events were assessed during initial hospitalization and at the end of 1 year. Results: The concentrations of PAI-1 and d-dimer were greater compared with preoperative values 1 hour and 24 hours after surgery in both groups, but their concentrations increased to a greater extent 24 hours after surgery in the on-pump group (p<0.01). The concentration of CRP did not change appreciably immediately after surgery in either group but increased in a parallel fashion 24 hours after either on-pump or off-pump surgery (p<0.01). Bypass surgery in the on-pump group was associated with greater blood loss during surgery and more bleeding after surgery (p0.01). The incidence of all other complications was similar in the 2 groups. Conclusion: On-pump surgery was associated with biochemical evidence of a pro-thrombotic state early after surgery but no greater incidence of thrombotic events. The pro-thrombotic state may have been a consequence of extracorporeal bypass, compensation in response to more bleeding, or both in patients undergoing on-pump surgery.

La maladie coronaire stable est une maladie chronique pour laquelle de nombreuses stratégies thérapeutiques sont disponibles, dont le traitement par médicaments seuls et les traitements invasifs par angioplastie avec stent ou par pontage aortocoronaire. Face aux résultats de plusieurs méta-analyses mettant en évidence un taux de mortalité comparable entre ces traitements, nous avons décidé d’effectuer un travail de recherche comparant leurs coûts. Dans la première partie de mon travail, nous avons comparé, après une période de un an et une autre de 3 ans de suivi des patients, les données cliniques et économiques publiées pour 5 traitements de l’angor stable : les médicaments seuls, le pontage aortocoronaire, l’angioplastie sans stent, l’angioplastie avec stent nu et l’angioplastie avec stent actif. La mortalité et le taux d’IDM étaient nos critères de jugement clinique. Les coûts directs, liés au traitement effectué et liés à la prise en charge des éventuelles complications, ont été uniformisés via la parité de pouvoir d’achat et exprimés en US $ 2008. Il s’agissait de notre critère de jugement économique. Un total de 19 études cliniques a été retenu dans notre méta-analyse en réseau. Nos résultats mettent en évidence une absence de différence significative sur le critère clinique. En revanche, nous avons observé une différence concernant le coût moyen de chaque traitement après un an et 3 ans de suivi. Le traitement le moins onéreux était le traitement par médicaments seuls, après un an et 3 ans de suivi, avec respectivement un coût moyen par patient de 3 069 US $ et 13 854 US $. Le coût moyen le plus élevé a toujours été obtenu avec le traitement par pontage aortocoronaire : 27 003 US $ après un an et 28 670 US $ après 3 ans de suivi. Cependant, nos conclusions sont limitées d’une part, par la variabilité des méthodes économiques utilisées dans les études sélectionnées dans notre méta-analyse et, d’autre part, par l’évolution des traitements dans le temps. Dans la seconde partie de mon travail de recherche, nous avons calculé le coût de prise en charge d’un patient angoreux stable traité par l’une des 4 stratégies thérapeutiques suivantes : médicaments seuls, pontage aortocoronaire, angioplastie avec stent nu et angioplastie avec stent actif. Pour se faire, nous avons défini d’une part 6 situations cliniques correspondant aux possibles états cliniques du patient un an après l’instauration du traitement étudié et, d’autre part, déterminé les quantités de soins consommés pour chacune de ces situations cliniques. La perspective retenue était celle de l’Assurance Maladie. Les coûts calculés étaient liés aux hospitalisations, aux soins ambulatoires et aux moyens de transport utilisés pour accéder à l’hôpital. La stratégie médicamenteuse était la moins onéreuse avec un coût moyen annuel de 1 518 € ; ce coût prenant en compte les probabilités de survenue des 6 états cliniques. Le traitement par pontage aortocoronaire était le plus onéreux des 4 traitements étudiés, avec un coût moyen annuel de 15 237 €. La perspective de mes travaux est de modéliser la prise en charge d’un patient angoreux stable en envisageant un second traitement si le premier traitement effectué conduit à une situation d’échec thérapeutique. Les arbres que nous avons construits nous permettront ensuite d’effectuer une analyse coût-efficacité de deux stratégies thérapeutiques avec une durée totale de suivi des patients de 2 ans. Enfin, si nos travaux mettent en avant l’intérêt économique du traitement par médicaments, nous soulignons que ces résultats sont obtenus après avoir suivi les patients sur une courte durée (études à un an et à 3 ans), alors que l’angor stable est une maladie chronique où les stratégies thérapeutiques peuvent se succéder en cas d’échec à l’un des traitements... / Stable coronary artery disease is a chronic disease for which many treatment strategies are available, treatment with drugs alone and invasive treatment by stenting or coronary artery bypass graft. With the results of several meta-analyzes showing a mortality rate comparable between treatments, we decided to conduct a research comparing costs. In the first part of my work, we compared, after a period of one year and of 3 years of patient follow-up, clinical and economic data for five treatment of stable angina: medication alone, coronary artery bypass graft, angioplasty without stent, angioplasty with bare metal stent and angioplasty with drug-eluting stent. Mortality and MI rates were our clinical end point. Direct costs related to the treatment performed and related to the management of complications, have been standardized using the purchasing power parity and expressed in U.S. $ 2008. It was our criterion for economic analysis. A total of 19 clinical studies have been selected in our network meta-analysis. Our results show there is no significant difference in clinical end point. In contrast, we observed a difference in the average cost of each treatment after one year and three year follow-up. The least expensive treatment was the only treatment with drugs, after a year and 3 years of follow-up, each with an average cost per patient of U.S. $ 3,069 and U.S. $ 13,854. The highest average cost has been obtained with the treatment coronary artery bypass graft: U.S. $ 27,003 after one year and U.S. $ 28,670 after 3 years of follow-up. However, our conclusions are limited due to the high variability of the economic methods used in the selected studies and because of the evolution of revascularization techniques. In the second part of my research work, we calculated the cost of management of stable angina pectoris patients treated with one of the following four treatment strategies: medication alone, coronary artery bypass graft, angioplasty with bare metal stent and angioplasty with stent active. We defined a part 6 clinical situations corresponding to the possible clinical conditions of the patient one year after the treatment. We have defined the quantities of care consumed for each of these clinical situations. The perspective selected was the statutory health insurance in 2011. The calculated costs were related to hospitalization, ambulatory care and medical transport used to reach the hospital. The drug strategy was the least expensive with an average annual cost of € 1,518, the cost taking into account the probability of occurrence of 6 clinical conditions. Treatment with coronary artery bypass graft was the most expensive of the four treatments studied, with an average annual cost of € 15,237. The prospect of my work is to model the management of stable angina pectoris patient considering a second treatment if the first treatment led to a situation of treatment failure. The trees we built then allow us to perform a cost-effectiveness analysis of two strategies with a total duration of patient follow-up of 2 years. Finally, if our work highlights the economic benefits of drug treatment, we emphasize that these results are obtained after following patients over a short period (1 year and 3 years), while stable angina is a chronic disease where therapeutic strategies may succeed in case of failure to one of the treatments. In addition, we keep in mind that the choice of treatment, whether conservative or by drugs, by invasive myocardial revascularization should be done individually, i.e. taking into account the individual characteristics of each patient.

Introduction: Cardiovascular surgery is a relatively young but progressively evolving field in medicine. More specifically, in the past decades, cardiac surgery achieved significant advances in understanding the causes, progression and treatments of ischemic heart disease (IHD). The IHD is the most common coronary disease, and it ranks first in morbidity and mortality in the developed world. It justifies the need for significant fundamental research as well as its study in clinical practice. It now includes specialized cardiovascular centres with the complex specialized treatments. A group of interventional cardiologists capable of performing routine examinations of the coronary veins using selective angiography has been established. They can eventually also perform percutaneous coronary interventions with direct stent implants. Thus the advances have been made in comprehensive indication of the patients towards their optimal treatments under the regime of a cardio-team. Such team comprises of a cardio-surgeon, interventional cardiologist, echocardiography specialist and the attending physician who is usually the cardiologist. The IHD treatments involve preventive cardiology with the regime measures and checks, pharmacotherapy, interventional cardiology and cardiac surgery to spa treatment and...