Chaque année, environ 1 à 1,25 million d’individus subiront une chirurgie cardiaque. [1] Environ 36 000 chirurgies cardiaques sont effectuées au Canada et 8000 procédures au Québec (http://www.ccs.ca). Le vieillissement de la population aura pour conséquence que la chirurgie cardiaque sera offerte à des patients de plus en plus à risque de complications, principalement en raison d’une co-morbidité plus importante, d’un risque de maladie coronarienne plus élevée, [2] d’une réserve physiologique réduite et par conséquent un risque plus élevé de mortalité à la suite d’une chirurgie cardiaque. L’une des complications significatives à la suite d’une chirurgie cardiaque est le sevrage difficile de la circulation extracorporelle. Ce dernier inclut la période au début du sevrage de la circulation extracorporelle et s’étend jusqu’au départ du patient de la salle d’opération. Lorsque le sevrage de la circulation extracorporelle est associé à une défaillance ventriculaire droite, la mortalité sera de 44 % à 86 %. [3-7] Par conséquent le diagnostic, l’identification des facteurs de risque, la compréhension du mécanisme, la prévention et le traitement du sevrage difficile de la circulation extracorporelle seront d’une importance majeure dans la sélection et la prise en charge des patients devant subir une chirurgie cardiaque. Les hypothèses de cette thèse sont les suivantes : 1) le sevrage difficile de la circulation extracorporelle est un facteur indépendant de mortalité et de morbidité, 2) le mécanisme du sevrage difficile de la circulation extracorporelle peut être approché d’une façon systématique, 3) la milrinone administrée par inhalation représente une alternative préventive et thérapeutique chez le patient à risque d’un sevrage difficile de la circulation extracorporelle après la chirurgie cardiaque. / Every year, 1 million to 1.25 million patients worldwide undergo cardiac surgery. [1] Up to 36,000 cardiac surgeries are performed each year in Canada and close to 8000 in Quebec (http://www.ccs.ca). Because of the aging of the population, cardiac surgery will increasingly be offered to patients at a higher risk of complications. Indeed, elderly patients have increased co-morbidities, and aging is also a significant risk factor in the prevalence of coronary artery disease. [2] The consequence is a reduced physiologic reserve, hence an increased risk of mortality. These issues will have a significant impact on future healthcare costs, because our population undergoing cardiac surgery will be older and more likely to develop postoperative complications. One of the most dreaded complications in cardiac surgery is difficult separation from cardiopulmonary bypass (CPB). The definition of difficult separation from CPB includes the time period from when CPB is initiated and until the patient leaves the operating room. When separation from CPB is associated with right ventricular failure, the mortality rate will range from 44% to 86%. [3-7] Therefore the diagnosis, the preoperative prediction, the mechanism, prevention and treatment of difficult separation from CPB will be crucial in order to improve the selection and care of patients and to prevent complications for this high-risk patient population. The hypotheses of this thesis are the following: 1) difficult separation from CPB is an independent factor of morbidity and mortality, 2) the mechanism of difficult separation from CPB can be understood through a systematic approach, 3) inhaled milrinone is a preventive and therapeutic approach in the patient at risk for difficult weaning from CPB after cardiac surgery.

Im Rahmen dieser Dissertation wurden anhand eines Ferkelmodells (8-15kg Schweine, 5 Gruppen: „nicht pulsatile HLM“: n=9, „Minozyklin+HLM“: n= 6, „pulsatile HLM“: n=7, „Minozyklin-Kontrolle: n=6, „Kontrolle“: n=8) während einer 120-minütigen extrakorporaler Zirkulation (EKZ) und einer darauffolgenden 90-minütigen Rekonvaleszenzzeit der physikalische Einflussfaktor des pulsatilen Flusses sowie der pharmakologische Effekt von Minozyklin auf die Niere jeweils unabhängig voneinander untersucht. In allen Gruppen wurden HE-Färbungen sowie immunhistochemische Färbungen (HIF-1-α, 3-Nitrotyrosin, PAR, AIF) durchgeführt um pathologische Veränderungen auf zellulärer Ebene zu detektieren. Zusätzlich wurden energiereiche Phosphate und ihre Abbauprodukte mittels High Pressure/Performance Liquid Chromatography (HPLC) bestimmt. Zur Beurteilung der klinischen Funktion der Niere wurden nierenspezifische Blutwerte (Serumkreatinin, Serumharnstoff) und Laktat im arteriellen Blut bestimmt. Mit der pulsatilen Perfusion konnte ein Abfall des O2-Partialdruckes nicht verhindert werden (HIF-1-α), allerdings konnte die ATP-Konzentration aufrecht erhalten werden. Dies spricht dafür, dass die pulsatile Perfusion im Gegensatz zu der nicht pulsatilen Perfusion keinen relevanten O2-Mangel verursachte. Auch die Ergebnisse der Nitrotyrosin-3-Auswertung zeigen, dass die Bildung von Peroxynitrit reduziert und somit der nitrosative Stress auf die Zellen begrenzt wurde. Die DNA wurde jedoch unabhängig vom gewählten Blutflussprofil geschädigt (PAR). Auch anhand der nierenspezifischen Blutparameter (Serumkreatinin, Serumharnstoff) ließ sich eine postoperative Beeinträchtigung der Nierenfunktion feststellen. Im Vergleich zu der nicht pulsatilen EKZ war hier jedoch eine geringfügige Verbesserung zu erkennen (Serumkreatinin). Zusammenfassend kann gesagt werden, dass durch die pulsatile EKZ der Grad der Ischämie beeinflusst werden konnte, allerdings waren insgesamt keine wesentlich positiven Auswirkungen auf zellulärer Ebene und auf die postoperative Nierenfunktion festzustellen. Der Einsatz des technisch anspruchsvollen pulsatilen Perfusionssystems scheint daher in Bezug auf die Niere in der routinemäßigen Herzchirurgie nicht unbedingt erforderlich zu sein. Durch die Gabe von Minozyklin wurde zwar der Grad der Ischämie (HIF-1-α, ATP) nicht beeinflusst, allerdings konnte Minozyklin durch seine antioxidativen bzw. antinitrosativen (3-Nitrotyrosin), PARP-1-hemmenden (PAR) sowie antiapoptotischen (AIF) Wirkmechanismen die Niere offenbar vor den Folgen einer Ischämie schützen. Anhand der nierenspezifischen Blutwerte (Serumkreatinin, Serumharnstoff) wurde erkenntlich, dass Minozyklin die Nierenfunktion positiv beeinflusst, was wiederum die histologischen Befunde bestätigt. Für die Humanmedizin ist somit der Einsatz von Minozyklin während der EKZ eine Möglichkeit die Auswirkungen des Ischämie/Reperfusionsschadens und deren klinische Folgen hinsichtlich der Niere zu begrenzen. Allerdings muss berücksichtigt werden, dass der einmalige Einsatz eines Antibiotikums auch negativen Einfluss auf den Körper ausübt (Resistenzentwicklung, Nebenwirkungen), sodass Minozyklin aufgrund der in dieser Versuchsreihe gezeigten positiven Eigenschaften, insbesondere die PARP-1-Inhibition, lediglich als Modellsubstanz für Weiterentwicklungen genutzt werden kann.

Introduction: Coronary artery disease (CAD) has been associated with depressive symptoms and deficits in cognitive performance, both of which have been associated with poorer medical prognoses and poorer psychosocial outcomes. Physical activity can improve cognitive and depressive symptoms, and, for those with CAD, improve medical prognoses. It was hypothesized that depressive symptoms and poorer cognitive performance would be associated with poorer cardiopulmonary fitness in patients with CAD, and that these sequelae would be associated prospectively with noncompletion of cardiac rehabilitation (CR). The benefits of physical activity are thought to result, in part, from decreased inflammatory activity and increased adaptive neural plasticity, to which the ratio of kynurenine to tryptophan (K/T) and brain derived neurotrophic factor (BDNF), respectively, in peripheral blood may pertain. Methods and Results: In a cohort study of patients entering CR, depressive symptoms (Center for Epidemiological Studies Depression scale; CES-D scores) were associated with cardiopulmonary fitness (peak volume of oxygen uptake; VO2Peak) during an exercise stress test (B=-.404, p=.001, n=366). The VO2Peak was also associated with performance across multiple cognitive domains, but most strongly with performance on tests involving executive function, attention and psychomotor processing speed (β=.322, p=.002 for composite score, n=81) in a cohort of patients entering CR. In prospective cohort studies, Major Depressive Disorder (adjusted hazard ratio [HR] 2.5, 95% confidence interval [CI] 1.3–4.7, n=195) and poorer performance on a verbal memory test (HR 0.86, 95% CI 0.77-0.96, p=.009, n=131) predicted non-completion of CR. In patients undertaking CR, higher serum K/T ratios were associated with CES-D scores (β=.322, p=.002, n=95) and with VO2Peak (β=-.391, p<.001, n=95), and in a cohort of patients entering CR (n=88), serum concentrations of BDNF were associated with psychomotor processing speed (F1,87=9.620, p=.003), overall cognitive status (Mini Mental Status Exam) scores (F1,87=15.406, p<.0005) and VO2Peak (β=.305, p=.013). Conclusions: Depressive symptoms and poorer cognitive performance are clinically important in patients with CAD entering CR and they are both associated with poorer cardiopulmonary fitness. Poorer cardiopulmonary fitness was also associated with higher K/T ratios and with lower BDNF concentrations in serum, which predicted depressive symptoms and poorer cognitive performance, respectively.

Introduction: Coronary artery disease (CAD) has been associated with depressive symptoms and deficits in cognitive performance, both of which have been associated with poorer medical prognoses and poorer psychosocial outcomes. Physical activity can improve cognitive and depressive symptoms, and, for those with CAD, improve medical prognoses. It was hypothesized that depressive symptoms and poorer cognitive performance would be associated with poorer cardiopulmonary fitness in patients with CAD, and that these sequelae would be associated prospectively with noncompletion of cardiac rehabilitation (CR). The benefits of physical activity are thought to result, in part, from decreased inflammatory activity and increased adaptive neural plasticity, to which the ratio of kynurenine to tryptophan (K/T) and brain derived neurotrophic factor (BDNF), respectively, in peripheral blood may pertain. Methods and Results: In a cohort study of patients entering CR, depressive symptoms (Center for Epidemiological Studies Depression scale; CES-D scores) were associated with cardiopulmonary fitness (peak volume of oxygen uptake; VO2Peak) during an exercise stress test (B=-.404, p=.001, n=366). The VO2Peak was also associated with performance across multiple cognitive domains, but most strongly with performance on tests involving executive function, attention and psychomotor processing speed (β=.322, p=.002 for composite score, n=81) in a cohort of patients entering CR. In prospective cohort studies, Major Depressive Disorder (adjusted hazard ratio [HR] 2.5, 95% confidence interval [CI] 1.3–4.7, n=195) and poorer performance on a verbal memory test (HR 0.86, 95% CI 0.77-0.96, p=.009, n=131) predicted non-completion of CR. In patients undertaking CR, higher serum K/T ratios were associated with CES-D scores (β=.322, p=.002, n=95) and with VO2Peak (β=-.391, p<.001, n=95), and in a cohort of patients entering CR (n=88), serum concentrations of BDNF were associated with psychomotor processing speed (F1,87=9.620, p=.003), overall cognitive status (Mini Mental Status Exam) scores (F1,87=15.406, p<.0005) and VO2Peak (β=.305, p=.013). Conclusions: Depressive symptoms and poorer cognitive performance are clinically important in patients with CAD entering CR and they are both associated with poorer cardiopulmonary fitness. Poorer cardiopulmonary fitness was also associated with higher K/T ratios and with lower BDNF concentrations in serum, which predicted depressive symptoms and poorer cognitive performance, respectively.

Made available in DSpace on 2016-06-02T20:18:24Z (GMT). No. of bitstreams: 1 6556.pdf: 2232464 bytes, checksum: d84f3d538456b42ad0ec52f81c1f7771 (MD5) Previous issue date: 2015-02-11 / Financiadora de Estudos e Projetos / This thesis consisted of two studies described below. The Study 1 aimed to investigate if expiratory flow limitation (EFL) present at moderate intensity exercise in subjects following myocardial infarction (MI) (as shown in a previous study conducted in our laboratory) already manifests in those with stable coronary artery disease (CAD). Forty-one men aged 40-65 years were allocated into four different groups: 1) stable coronary artery disease (SCADG) (n=9), 2) recent myocardial infarction (RMIG) (n=8), 3) late myocardial infarction group (LMIG) (n=12), and 4) health control group (CG) (n=12). Two cardiopulmonary exercise testing (CPX) at constant workload (moderate and high intensity) were applied and EFL was evaluated by exercise flow-volume loops. We observed that during moderate intensity exercise the RMIG and LMIG presented with a significantly higher number of subjects with EFL compared to the CG, while no significant difference was observed among groups at high intensity exercise. Regarding the degree of expiratory flow limitation, the RMIG and LMIG showed significantly higher values at moderate intensity exercise when compared to the CG. At high intensity exercise, significantly higher values for the degree of expiratory flow limitation were observed only in the LMIG compared to the CG. We concluded that an EFL was only present in MI groups (recent and late) during moderate intensity exercise; whereas at high intensity exercise all groups presented EFL. Thus, EFL observed at moderate intensity exercise in both MI groups may be linked to the consequences of event and not to CAD. Following, the Study II aimed to investigate the indexes of circulatory (CP) and ventilatory power (VP) in CAD patients. Eighty-seven men were studied aged 40-65 years, being 42 subjects in the CAD group and 45 in the CG. CPX was performed on a treadmill and the following measures were obtained: 1) peak oxygen consumption (VO2), 2) peak heart rate (HR), 3) peak blood pressure (BP), 4) peak rate-pressure product (peak systolic BP x peak HR), 5) peak oxygen pulse = (peak VO2/peak HR), 6) the oxygen uptake efficiency (OUES), 7) the carbon dioxide production efficiency (VE/VCO2 slope), 8) CP (peak VO2 x peak systolic BP) and 9) VP (peak systolic BP/VE/VCO2 slope). The CAD group had significantly lower values for peak VO2, peak HR, peak systolic BP, peak rate-pressure product, peak oxygen pulse, the OUES, CP and VP and significantly higher values for peak diastolic BP and the VE/VCO2 slope compared to the CG. Furthermore, a stepwise regression analysis showed that CP was influenced by the group and VP was influenced both by group and by number of vessels with stenosis after treatment. Given the findings, we concluded that the indices of CP and VP were lower in men with CAD compared to CG. Thus, both studies brought important findings related to the responses of the cardiovascular, pulmonary and musculoskeletal systems of patients with CAD during physical exercise, bringing many contributions to clinical practice and assisting in the prescription of exercise training. / Esta tese constou de 2 estudos descritos a seguir. O Estudo I teve como objetivo verificar se a limitação ao fluxo expiratório (LFE) presente na moderada intensidade do exercício em sujeitos com infarto do miocárdio (IM) (conforme mostrado em estudo prévio realizado em nosso laboratório) já está presente naqueles com doença arterial coronariana (DAC) estável. Quarenta e um homens com idade entre 40 e 65 anos foram alocados em quatro diferentes grupos: 1) DAC estável (GDAC) (n=9), 2) IM recente (GIMR) (n=8), 3) IM tardio (GIMT) (n=12) e, 4) grupo controle saudável (GC) (n=12). Dois testes de exercício cardiopulmonar (TECP) em carga constante (moderada e alta intensidade) foram aplicados e a LFE foi avaliada por meio da alça fluxo-volume corrente durante o exercício. Nós observamos que durante a moderada intensidade do exercício somente os GIMR e GIMT apresentaram número significativamente maior de sujeitos com LFE comparados ao GC, enquanto nenhuma diferença significativa foi observada entre os grupos na alta intensidade do exercício. Em relação ao grau de LFE, tanto o GIMR como o GIMT apresentaram significativamente maiores valores de LFE na moderada intensidade do exercício comparado ao GC, e na alta intensidade do exercício foi observado maior grau de LFE somente para o GIMT em relação ao GC. Concluímos que a LFE esteve presente somente nos grupos com IM (recente e tardio) durante a moderada intensidade do exercício; já na alta intensidade do exercício todos os grupos apresentaram LFE. Diante do exposto, a LFE observada na moderada intensidade do exercício em ambos os grupos com IM pode estar relacionada às consequências do evento e não à DAC. Na sequência, o Estudo II objetivou investigar os índices da potência circulatória (PC) e ventilatória (PV) em pacientes com DAC comparados a indivíduos saudáveis. Para isso foram estudados oitenta e sete homens com idade entre 45 a 65 anos, sendo 42 sujeitos no grupo DAC e 45 no GC. Um TECP foi realizado em esteira e as seguintes variáveis foram obtidas: 1) consumo de oxigênio (VO2) pico, 2) frequência cardíaca (FC) pico, pressão arterial (PA) pico, duplo produto pico (PA sistólica pico x FC pico), 5) pulso de oxigênio pico (VO2 pico dividido pela FC pico), 6) eficiência ventilatória para o consumo de oxigênio (OUES), 7) eficiência ventilatória para a produção de dióxido de carbono (VE/VCO2 slope), 8) PC (VO2 pico x PA sistólica pico) e 9) PV (PA sistólica pico dividido pelo VE/VCO2 slope). O grupo DAC apresentou significativamente menores valores no pico do exercício de VO2, FC, PA sistólica, duplo produto, pulso de oxigênio, OUES, PC e PV e, significativamente maiores valores de PA diastólica e VE/VCO2 slope em relação ao GC. Além disso, uma análise de regressão pelo método stepwise mostrou que a PC foi influenciada pelo grupo e a PV tanto pelo grupo quanto pelo número de vasos com estenose pós tratamento. Diante dos achados, nós concluímos que os índices da PC e PV foram menores em homens com DAC comparados ao GC. Desta forma, ambos os estudos trouxeram importantes achados relacionados às respostas dos sistemas cardiovascular, pulmonar e musculoesquelético de pacientes com DAC durante o exercício físico, trazendo contribuições para a prática clínica e auxiliando na prescrição do treinamento físico.

Made available in DSpace on 2016-06-02T20:19:26Z (GMT). No. of bitstreams: 1 6645.pdf: 2027088 bytes, checksum: 18fe5648e0835cf1cfcbef303f079520 (MD5) Previous issue date: 2015-02-27 / Universidade Federal de Sao Carlos / In chronic obstructive pulmonary disease (COPD), functional and structural impairment of lung function can negatively impact heart rate variability (HRV); in addition, a reduced exercise capacity is an important independent prognostic marker in COPD patients. However, 1) if the degree of lung impairment negatively impacts HRV responses and 2) whether the injury of the autonomic control may be associated with reduced exercise capacity in patients with COPD remain unclear. Thus, two studies were conducted in order to verify if functional status at rest and during exercise would be related to autonomic impairment in COPD patients. In the first study, entitled "Relationship between linear and nonlinear dynamics of heart rate and impairment of lung function in COPD patients," we investigated whether the impairment static lung volumes and lung diffusion capacity (DL) would be related to HRV indices in moderate-to-severe COPD. Sixteen patients with COPD underwent pulmonary function tests (spirometry, plethysmography and lung diffusion capacity for carbon monoxide - DLCO). The RR interval was registered in the supine, standing and seated positions and during a respiratory sinus arrhythmia maneuver (M-RSA). Our results suggest that responses of HRV indices were more prominent during M-RSA in moderate-to-severe COPD. Moreover, greater lung function impairment was related to poorer heart rate dynamics. Finally, impaired DLCO is related to an altered parasympathetic response in these patients. The second study, entitled "Are linear and nonlinear heart rate dynamics in submaximal exercise related to cardiorespiratory responses during maximal exercise in patients with COPD?", we inquired whether there is a relationship between HRV responses and exercise capacity in patients with COPD. Fifteen patients underwent incremental cardiopulmonary exercise testing and six-minute walk test (6MWT). The RR interval was registered at rest (standing position) and during 6MWT. Our results showed that HRV responses at rest and during simple field tests may reflect functional impairment of COPD patients, providing important information about both ventilatory and hemodynamic inefficiency in these patients. / Em pacientes com doença pulmonar obstrutiva crônica (DPOC), as alterações funcionais e estruturais do pulmão podem impactar negativamente na variabilidade da frequência cardíaca (VFC). Além disso, a reduzida capacidade de exercício se traduz como um marcador prognóstico nesses pacientes. No entanto, ainda não estão esclarecidos 1) se o grau de comprometimento pulmonar tem impacto negativo sobre as respostas da VFC, frente a diferentes estímulos autonômicos, e 2) se o prejuízo no controle autonômico pode estar relacionado à reduzida capacidade de exercício nos pacientes com DPOC. Sendo assim, dois estudos foram realizados com o intuito de relacionar as alterações funcionais, no repouso e no exercício, com o grau de prejuízo autonômico em pacientes com DPOC. O primeiro estudo, cujo título é Correlação entre as dinâmicas linear e não linear da frequência cardíaca e o comprometimento da função pulmonar em pacientes com DPOC , teve como objetivo investigar se o comprometimento nos volumes pulmonares estáticos e na difusão pulmonar estaria relacionado aos índices da VFC em repouso e em resposta às mudanças posturais. Dezesseis pacientes com diagnóstico de DPOC foram submetidos à prova de função pulmonar (espirometria, pletismografia e capacidade de difusão pulmonar ao monóxido de carbono DCO) e à coleta da VFC nas posturas supino, ortostatismo e sentado e durante a manobra de arritmia sinusal respiratória (M-ASR). Nossos resultados sugerem que as respostas da VFC frente a um estímulo vagal (M-ASR) são mais evidentes. Ainda, quanto maior o comprometimento da função pulmonar pior a dinâmica da frequência cardíaca. Por fim, a redução da DCO está relacionada à alterada resposta vagal nos pacientes com DPOC. O segundo estudo, intitulado Os índices da dinâmica linear e não linear na frequência cardíaca no exercício submáximo estão relacionados com as respostas cardiorrespiratórias ao exercício máximo em pacientes com DPOC? teve por objetivo avaliar se existe relação entre as respostas da VFC e a capacidade de exercício em pacientes com DPOC. Quinze pacientes foram submetidos aos testes de exercício cardiopulmonar incremental e de caminhada de seis minutos (TC6). A coleta da VFC feita em repouso (ortostatismo) e durante o TC6. Os resultados mostraram que as respostas da VFC no repouso e em testes simples de campo podem inferir o prejuízo funcional de pacientes com DPOC, fornecendo informações importantes acerca das limitações ventilatória e hemodinâmica destes pacientes.

The thesis is devoted to the issue of non-professional first aid provision. Everyone should have knowledge of first aid procedures, because in the Czech Republic there is a statutory duty to provide first aid. It is therefore necessary to start training as soon as possible, already in school-aged children. The thesis is focused on pupils of 8th grade of primary schools in České Budějovice and their knowledge of first aid. The thesis is divided into two parts, theoretical and practical. In the theoretical part basic information on first aid is given. News and changes brought about by global directive in resuscitation Guidelines 2005. It also gives and account of individual diseases with brief descriptions, causes and emergency procedures. The last two chapters are focused on the Red Cross activities and first aid training in schools. The practical part examines the attitude of pupils to first-aid provision and their first aid knowledge. In this section, the following two objectives and hypotheses were stated: The first objective is to determine the pupils´ interest to get involved in first aid training. The other objective is to monitor the first aid knowledge and skills of primary school pupils before and after the training implementation. Hypothesis 1 assumes that primary school pupils are interested in obtaining information relating to first aid. The second hypothesis determines if the pupils´ awareness got improved after the training. To meet the goals of the thesis quantitative research was used. To pupils interested in the issue, professional instruction in first aid, led by a worker of the Red Cross in České Budějovice, was provided. Based on the pre and post test, a questionnaire survey was carried out when the pupils responded in writing to questions in two questionnaires. The first questionnaire contained 19 and the second 21 questions. Total 122 questionnaires were distributed. The goals of the thesis were met and after the questionnaires evaluation, both my hypothesis were confirmed. The research has shown the pupils' interest in the issue and a better understanding after the training. In order to improve basic first aid knowledge in primary school pupils it would certainly be beneficial to put emphasis on first aid training in schools.

Introdução: Apesar do desenvolvimento tecnológico, permanece baixa a sobrevida hospitalar das vítimas de parada cardiorrespiratória extra-hospitalar. Há importante dúvida na literatura quanto à retenção de habilidades de ressuscitação cardiopulmonar (RCP) e a periodicidade adequada de treinamento para manutenção dessas habilidades. O presente estudo investigou a retenção, em alunos a partir de treinamento no primeiro semestre de ingresso no curso médico, das habilidades práticas de RCP até 42 meses após o referido treinamento. Métodos: Estudo de corte transversal, realizado com 298 alunos de graduação de uma faculdade de Medicina, treinados com base nas diretrizes de ressuscitação de 2010 da American Heart Association. Foram avaliados 205 alunos sem retreinamento das habilidades, divididos em quatro grupos conforme o tempo decorrido desde o treinamento de ingresso: 73 alunos após 1 mês, 55 após 18 meses, 41 após 30 meses e 36 após 42 meses. A análise da retenção das habilidades foi comparada com 93 alunos que referiram ter realizado retreinamento em RCP. Dezenove habilidades de RCP e nove potenciais erros de técnica na execução das ventilações pulmonares e compressões torácicas foram avaliados por meio de simulação realística e revisados com utilização de filmagem e avaliadores independentes. Resultados: A média de retenção das dezenove habilidades nos alunos sem retreinamento foi: 90% após 1 mês, 74% após 18 meses, 62% após 30 meses e 61% após 42 meses (p < 0,001). Nos alunos que referiram retreinamento, a retenção foi de 74% após 18 meses, 70% após 30 meses e 66% após 42 meses do treinamento inicial. Realizada curva de predição da retenção de habilidades, com estimativa de 80% das habilidades mantidas após 10 meses, 70% após 21 meses e 60% após 42 meses. A profundidade das compressões torácicas foi a habilidade com maior retenção ao longo do tempo (87,8%), sem diferença estatística entre os quatro grupos. Houve aumento da prevalência de compressões realizadas com menos de 5 cm de profundidade quando realizadas em frequência maior que 120 por minuto. A média da frequência de compressões torácicas obtidas nos grupos após 1, 18, 30 e 42 meses foi, respectivamente, 114, 114, 104 e 108 compressões por minuto; 104 (50,7%) alunos mantiveram frequência média entre 100-120 por minuto. As ventilações pulmonares apresentaram diminuição progressiva de retenção, de 93% após 1 mês até 19% após 42 meses (p < 0,001). Todos os alunos efetivaram o choque com o desfibrilador externo automático, porém com o grupo após 1 mês do treinamento com menor tempo para efetivação do choque e maior prevalência de posicionamento adequado das pás do desfibrilador. Conclusões: O presente estudo demonstrou diferentes níveis de retenção para as habilidades de RCP e diferentes níveis de decréscimo de tais habilidades ao longo de 42 meses. A profundidade das compressões torácicas e o uso do desfibrilador externo automático foram as habilidades com maior retenção ao longo do tempo. Treinamentos adicionais ao longo do curso de Medicina atenuaram a perda de habilidades, mas sem retorno ao desempenho observado após 1 mês do treinamento. Sugerimos que o intervalo mínimo de retreinamento para manutenção de pelo menos 70% das habilidades deva ser de 18 a 24 meses / Introduction: Despite technological development, the survival of victims of out-ofhospital cardiac arrest remains low. There are important questions in the literature regarding the retention of cardiopulmonary resuscitation (CPR) skills and the ideal frequency of retraining required to enhance retention of skills. This study investigated the retention of practical CPR skills by medical students over 42 months after training in the first semester of admission to the medical course. Methods: A cross-sectional study was conducted with 298 undergraduate medical students who were trained based on the 2010 American Heart Association resuscitation guidelines. A total of 205 students divided into four groups according to the time elapsed since the entrance training were evaluated without retraining (73 students after 1 month, 55 students after 18 months, 41 students after 30 months and 36 students after 42 months). The analysis of the retention of skills was compared to 93 students who reported having performed retraining in CPR. Nineteen CPR skills and nine potential technical errors in ventilations and chest compressions were evaluated by realistic simulation and reviewed using filming by independent examiners. Results: The mean retention of the nineteen skills in not retrained students was: 90% after 1 month, 74% after 18 months, 62% after 30 months and 61% after 42 months (p < 0.001). In retraining students, retention was 74% after 18 months, 70% after 30 months, and 66% after 42 months of initial training, with statistical difference between the students with and without retraining in the 30-month group (p=0.005). The estimation of mean skill retention was 80% after 10 months, 70% after 21 months and 60% after 42 months. The depth of chest compressions was the skill with greater retention over time (87.8%), with no statistical difference among groups. There was an increase in the prevalence of compressions performed with less than 5 cm depth when performed at a frequency greater than 120 per minute. The mean chest compressions rate obtained in the groups after 1, 18, 30 and 42 months were 114, 114, 104 and 108 per minute, respectively, and 104 (50.7%) students maintained a mean frequency of 100-120 per minute. Pulmonary ventilation showed a progressive decrease in retention from 93% after 1 month to 19% after 42 months (p < 0.001). All students delivered the shock with the automated external defibrillator; however, for the group one month post-training, the time for the application of the shock was lower, and the prevalence of adequate positioning of the defibrillator pads was greater. Conclusion: This study showed different retention levels for CPR skills and different decrease levels of these skills over 42 months. Depth of chest compressions and use of automated external defibrillator were the skills with the highest retention over time. Additional training throughout the medical course attenuated the loss of skills, but no return to the initial performance achieved after 1 month. We suggest that the minimum retraining interval for maintenance of at least 70% of skills should be 18 to 24 months

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.

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.