Ausgangssituation: Die Anwendung der extrakorporalen Zirkulation im Rahmen herzchirurgischer Eingriffe wird nachteilig mit der Entstehung von akuten Nierenversagen in Verbindung gebracht. Der Beitrag der Literatur zur Thematik EKZ-induzierte Nierenschädigung ist ambivalent (Ferraris, 2018). Das Dilemma besteht darin, dass zahlreiche Arbeiten zunächst scheinbar willkürlich Prozesskenngrößen der EKZ (z.B. Transfusion von EK, HZV, Perfusionsdruck, Hämolyse, Hämatokrit, Perfusionszeit) herausgreifen, diese in den Kontext zum ANV setzen und signifikante Abhängigkeiten finden, ohne dabei eine Erklärung zu den Vorgängen an der Niere selbst zu liefern. Wahrscheinlich sind mehrere sich überlagernde oder gegenseitig bedingende Prozesse für die Nierenschädigungen verantwortlich. Die prärenale Schädigung wird jedoch als häufigste Form des ANV nach EKZ hervorgehoben. Der zentrale Vorgang besteht offenbar darin, dass es an der Niere zu einem regionalen Druckabfall kommt, das Nierenmark bei gleichbleibenden Sauerstoffextraktionsbedarf und glomerulärer Filtration ein vermindertes Sauerstoffangebot erhält und sich daraus eine Angebots-Nachfrage-Problematik entwickelt. Diese Arbeit beschäftigt sich mit dieser Sauerstoffangebotsschuld, die sich auch durch folgende Gleichung DO2 = Hb x HZV x 10 x Hüfnerzahl x SaO2 (1.4) beschreiben lässt. Darin existieren nur zwei in der EKZ beeinflussbare Größen, das Herz-Zeit-Volumen (HZV) und der Hämoglobingehalt (Hb). Eingehend genannte Prozesskenngrößen weisen zwar auch einen Zusammenhang auf, münden aber nach Auffassung der Arbeit in den zwei beeinflussbaren Parametern dieser physiologischen Gleichung. Goal directed Perfusion (GDP) gilt als eine Methodik, die sich der traditionellen Perfusion überlegen zeigt, da sie die beiden, sonst unabhängig betrachteten Parameter Hb und HZV während der EKZ in ihrem Zusammenwirken beobachtet und steuert. Studienziel: Die Hypothese bestand darin, dass sich GDP-behandelte Patienten durch das Auftreten eines ANV weniger beeinträchtigt zeigen könnten, da es durch die GDP-Methodik zu einer Gewährleistung eines postuliert ausreichenden DO2i>280 ml/(min×m²) kommen würde. Als primäre Zielgrößen wurden die Differenzen aus prä- und postoperativen Werten des SCr und eGFR, auch ΔSCr und ΔeGFR benannt. Material und Methoden: Es wurde eine unizentrische Studie am Herzzentrum Dresden durchgeführt, die aus zwei Phasen bestand. In der 1. Phase wurden Patienten retrospektiv beobachtet und in zwei Gruppen als nadirDO2i-Über- und Unterschreiter getrennt. Die Gruppe der Unterschreiter wurde als Kontrollgruppe für Phase II verwendet. Die Interventionsgruppe bildete sich aus vorher identifizierten Patienten mit einem besonderen Risiko für eine nadirDO2i-Unterschreitung. Innerhalb der Interventionsgruppe wurden zur Abwendung einer Unterschreitung verschiedene GDP-Strategien angewendet. Mit Beendigung des Krankenhausaufenthaltes der Patienten wurden die Ergebnisse für den postoperativen Verlauf der Interventionsgruppe erfasst und ausgewertet. Ergebnisse: Die gesamte Studie umfasste 137 Patienten, davon 43 Patienten in der prospektiven Interventionsgruppe. Für den Parameter SCr ergaben sich grafisch darstellbare, postoperative Verbesserungen für die Patienten der Interventionsgruppe. Signifikant waren diese aber nur an den ersten beiden Messpunkten. Für den Parameter eGFR konnte ein signifikant verbesserter Wert an allen 3 Messpunkten erzielt werden. Die abgeleitete ANV-Beurteilung zeigte stadienunabhängig einen signifikanten Vorteil der Interventionsgruppe. Weitere sekundäre Zielgrößen unterschieden sich innerhalb der Studie nicht. Unter den GDP-Strategien kristallisierte sich die Steigerung des CI-Faktors als häufigste Maßnahme heraus. Neu gegenüber den anderen Studien ist die vorherige Perfusionsplanung mit Risikoeinstufung der Patienten für ein vermindertes renales Sauerstoffangebot. Die Auswahl der Kardioplegieart entwickelte sich zu einer der wichtigsten und wirkungsvollsten präoperativen GDP-Strategien. Schlussfolgerung: Das im Rahmen der Untersuchung entwickelte GDP-Interventionskonzept ist in der Alltagsroutine praktikabel anwendbar und ermöglicht eine wirksame Steigerung des Sauerstoffangebots während der extrakorporalen Zirkulation. Die darin enthaltene Perfusionsplanung identifiziert genau jene Patienten, die von einer gezielten DO2i-Steigerung mit GDP-Strategien profitieren können. Die Ergebnisse der eigenen Studie stehen im Einklang mit den Daten der prägenden aktuellen Veröffentlichungen (Magruder et al., 2017; Ranucci et al., 2018). Die durch parametrisch SCr-Messungen erhärtete Vermutung, dass sich ein verbessertes Sauerstoffangebot positiv auf die Nierenperfusion auswirkt, sollte in weiteren Studien mit einem sensitiveren Nierenmarker als dem Serumkreatinin untermauert werden.:1 EINLEITUNG 1 1.1 Ausgangssituation 1 1.2 Akutes Nierenversagen (ANV) 3 1.2.1 Definition 3 1.2.2 Bewertung der Nierenfunktion 6 1.2.3 Klassifizierungsschemata 7 1.3 Extrakorporale Zirkulation (EKZ) 8 1.3.1 Identifizierung von modifizierbaren Einflussfaktoren auf die Nierenperfusion 8 1.3.2 Das Sauerstoffangebot 11 1.3.3 Goal Directed Perfusion (GDP) 12 1.4 Studienziel 13 2 MATERIAL UND METHODEN 15 2.1 Patientenkollektiv 15 2.1.1 Phase I - Vorstudie 15 2.1.2 Phase II - Pilotstudie 16 2.2 Versuchsdurchführung 17 2.3 Ein- und Ausschlusskriterien 19 2.4 Allgemeine Anästhesie- und Perfusionstechnik 20 2.5 Datenerfassung 22 2.5.1 Präoperative, intraoperative und postoperative Daten 22 2.5.2 Primäre Zielgröße 23 2.5.3 Sekundäre Zielgrößen 23 2.6 Statistische Verfahren 24 2.6.1 Fallzahlberechnung 24 2.6.2 Strukturähnlichkeit und allgemeine statistische Analyse 25 2.6.3 Prüfung der Normalverteilung der primären Zielgrößen 25 2.6.4 t-Test für die primären Zielgrößen 27  3 ERGEBNISSE 29 3.1 Struktureller Aufbau 29 3.2 Primäre Zielgrößen 29 3.2.1 Veränderung des Serum-Kreatininwertes (SCr) zum Basiswert 29 3.2.2 Veränderung der geschätzten glomerulären Filtrationsrate (eGFR) zum Basiswert 31 3.3 Beurteilung des akuten Nierenversagens nach KDIGO 33 3.4 GDP-Strategien zur DO2i - Anpassung 36 3.5 Analyse des Patientenkollektivs 40 3.5.1 Zusammensetzung der Patientengruppen 40 3.5.2 Präoperative Kenngrößen 40 3.5.3 Intraoperative Kenngrößen 48 3.5.4 Klinischer Verlauf 50 4 DISKUSSION 52 4.1 Das Studiendesign im Vergleich zur Literatur 52 4.2 Die primären Zielgrößen und die abgeleitete Beurteilung des ANV 55 4.3 GDP-Strategien und zukünftige Perfusionsplanung 60 4.4 Patientenauswahl - Konfliktdiskussion 62 4.5 Weitere sekundäre Zielgrößen 63 4.6 Limitationen der Studie 64 5 ZUSAMMENFASSUNG 66 6 SUMMARY 69 7 LITERATURVERZEICHNIS 71 8 ANLAGEN 80

Introduction: Venoarterial extracorporeal membrane oxygenation (VA ECMO) is widely used in the treatment of circulatory failure, but repeatedly, its negative effects on the left ventricle (LV) have been observed. The purpose of this study is to assess the influence of ex- tracorporeal blood flow (EBF) on systemic hemodynamic changes and LV performance parameters during VA ECMO therapy of decompensated heart failure. Methods: Porcine models of low-output chronic and acute heart failure were developed by long-term fast cardiac pacing and coronary hypoxemia, respectively. Profound signs of circulatory decompensation were defined by reduced cardiac output and tissue hypoperfusion. Sub- sequently, under total anesthesia and artificial ventilation, VA ECMO was introduced. LV performance and organ specific parameters were recorded at different levels of EBF using an LV pressure-volume loop analysis, arterial flow probes on carotid and subclavian arteries, and transcutaneous probes positioned to measure cerebral and forelimb regional tissue oxygen saturations. Results: Conditions of severely decompensated heart failure led to systemic hypotension, low tissue and mixed venous oxygen saturations, and increase in LV end-diastolic pressure. By increasing the EBF from minimal flow to 5 L/min, we observed a...

Diplomová práce Účinky rázové vlny v léčbě tendinopatie Achillovy šlachy 1 Abstract This thesis focuses on the observation of the effects of low-energetic focused extracorporeal shock wave therapy (ESWT) in the treatment of Achilles tendinopathy. The theoretical part summarizes the current knowledge of anatomical, histological, kinesiological and biomechanical aspects of Achilles tendon (AT), as well as pathological processes, which can be described as Achilles tendinopathy, their differential diagnosis and treatment options. Last but not least, we present up-to-date information on the physical principles and biological effects of ESWT, not only in the treatment of AT diseases. The main goal of our research was to determine the effectiveness of low-energetic focused ESWT in the treatment of Achilles tendinopathy in comparison to the placebo group. The subject of observation was not only changes in clinical manifestations, but also possible changes in the morphology of AT using ultrasonography (USG). Methods: A total of 20 patients with symptomatic Achilles tendinopathy was included in the study, while only 18 of them completed the entire program, and therefore only the results of these patients were evaluated. They were randomly divided into two groups in 1:1 ratio. Group A was treated by ESWT with...

Background: Patients with steroid-refractory intestinal acute graft-versus-host disease (aGvHD) and bronchiolitis obliterans syndrome (BOS) represent a population with a high need for alternative and effective treatment options. Methods: We report real-life data from 18 patients treated with extracorporeal photopheresis (ECP). This cohort consisted of nine patients with steroid-refractory intestinal aGvHD and nine patients with BOS. Results: We document partial or complete clinical response and reduction of symptoms in half of the patients with intestinal acute GvHD and patients with BOS treated ECP. Responding patients tended to stay on treatment longer. In patients with BOS, stabilization of lung function and forced expiratory volume was observed, whereas, less abdominal pain, less diarrhea, and a reduction of systemic corticosteroids were seen in patients with intestinal acute GvHD. Conclusions: ECP might not only abrogate symptoms but also reduce mortality caused by complications from high-dose steroid treatment. Taken together, ECP offers a serious treatment avenue for patients with steroid-refractory intestinal acute GvHD and BOS.

Introduction: Cardiogenic shock due to myocardial infarction or heart failure entails a reduction in end organ perfusion. Patients who cannot be stabilized with inotropes and who experience increasing circulatory failure are in need of an extracorporeal mechanical support system. Today, small, percutaneously implantable cardiac assist devices are available and might be a solution to reduce mortality and complications. A temporary, ventricular, continuous flow propeller pump using magnetic levitation (Impella®) has been approved for that purpose. Methods and Study Design: JenaMACS (Jena Mechanical Assist Circulatory Support) is a monocenter, proof-of-concept study to determine whether treatment with an Impella CP® leads to improvement of hemodynamic parameters in patients with cardiogenic shock requiring extracorporeal, hemodynamic support. The primary outcomes of JenaMACS are changes in hemodynamic parameters measured by pulmonary artery catheterization and changes in echocardiographic parameters of left and right heart function before and after Impella® implantation at different support levels after 24 h of support. Secondary outcome measures are hemodynamic and echocardiographic changes over time as well as clinical endpoints such as mortality or time to hemodynamic stabilization. Further, laboratory and clinical safety endpoints including severe bleeding, stroke, neurological outcome, peripheral ischemic complications and occurrence of sepsis will be assessed. JenaMACS addresses essential questions of extracorporeal, mechanical, cardiac support with an Impella CP® device in patients with cardiogenic shock. Knowledge of the acute and subacute hemodynamic and echocardiographic effects may help to optimize therapy and improve the outcome in those patients. Conclusion: The JenaMACS study will address essential questions of extracorporeal, mechanical, cardiac support with an Impella CP® assist device in patients with cardiogenic shock. Knowledge of the acute and subacute hemodynamic and echocardiographic effects may help to optimize therapy and may improve outcome in those patients. Ethics and Dissemination: The protocol was approved by the institutional review board and ethics committee of the University Hospital of Jena. Written informed consent will be obtained from all participants of the study. The results of this study will be published in a renowned international medical journal, irrespective of the outcomes of the study. Strengths and Limitations: JenaMACS is an innovative approach to characterize the effect of additional left ventricular mechanical unloading during cardiogenic shock via a minimally invasive cardiac assist system (Impella CP®) 24 h after onset and will provide valuable data for acute interventional strategies or future prospective trials. However, JenaMACS, due to its proof-of-concept design, is limited by its single center protocol, with a small sample size and without a comparison group.

Background: Extracorporeal photopheresis (ECP) induces immunological changes that lead to a reduced risk of transplant rejection. The aim of the present study was to determine optimum conditions for ECP treatment by analyzing a variety of toleranceinducing immune cells to optimize the treatment. Methods: Ten ECP treatments were applied to each of 17 heart-transplant patients from month 3 to month 9 post-HTx. Blood samples were taken at baseline, three times during treatment, and four months after the last ECP treatment. The abundance of subsets of tolerance-inducing regulatory T cells (Tregs) and dendritic cells (DCs) in the samples was determined by flow cytometry. A multivariate statistical model describing the immunological status of rejection-free heart transplanted patients was used to visualize the patient-specific immunological improvement induced by ECP. Results: All BDCA+ DC subsets (BDCA1+ DCs: p < 0.01, BDCA2+ DCs: p < 0.01, BDCA3+ DCs: p < 0.01, BDCA4+ DCs: p < 0.01) as well as total Tregs (p < 0.01) and CD39+ Tregs (p < 0.01) increased during ECP treatment, while CD62L+ Tregs decreased (p < 0.01). The cell surface expression level of BDCA1 (p < 0.01) and BDCA4 (p < 0.01) on DCs as well as of CD120b (p < 0.01) on Tregs increased during the study period, while CD62L expression on Tregs decreased significantly (p = 0.04). The cell surface expression level of BDCA2 (p = 0.47) and BDCA3 (p = 0.22) on DCs as well as of CD39 (p = 0.14) and CD147 (p = 0.08) on Tregs remained constant during the study period. A cluster analysis showed that ECP treatment led to a sustained immunological improvement. Conclusions: We developed an immune monitoring assay for ECP treatment after heart transplantation by analyzing changes in tolerance-inducing immune cells. This assay allowed differentiation of patients who did and did not show immunological improvement. Based on these results, we propose classification criteria that may allow optimization of the duration of ECP treatment.

This thesis assesses the effectiveness of shock wave therapy for dysfunctional disorders of the musculoskeletal system. While we are well aware of the physical principles and history of shock wave generators, opinion differs on the treatment effectiveness mechanisms. The theoretical part of this work explains the effects of shock waves on various types of tissue, the differentiation of the cells, and the analgetic effect of therapy. It summarizes the indications, side effects and contraindications of shock wave therapy. The research part of this thesis deals with the effectiveness of shock wave therapy at the Department of Rehabilitation and Sports Medicine at the Motol University Hospital, which specialises in various musculoskeletal disorders. This thesis evaluates the correlation between the effectiveness of shock wave therapy and length of time the patient has experienced difficulties before undergoing treatment. This thesis also reviews whether the number of treatment applications has the capability to influence the outcome of therapy. The study is controlled by a control group of 22 patients. The total effectiveness of shock wave therapy is p = 1,12*10-10 . The shock wave therapy effectiveness of patients with heel spur is p = 0,00176. The shock wave therapy effectiveness of patients with...

Introdução: A resposta inflamatória sistêmica após cirurgia cardíaca está relacionada com aumento dos marcadores de lesão cerebral e o desenvolvimento de disfunção cognitiva pós-operatória (DCPO). O objetivo deste estudo foi avaliar a potencial associação entre DCPO e os níveis séricos de proteína S100beta e enolase específica de neurônio (NSE) após cirurgia de revascularização do miocárdio (RM) com circulação extracorpórea (CEC). Métodos: Foram investigados 73 pacientes submetidos à RM com CEC. A função cognitiva foi avaliada por psicólogas no pré-operatório e nos 3º, 7º, 21º, 90º e 180º dias após a cirurgia, utilizando-se testes neurocognitivos específicos para o reconhecimento de déficits de atenção, memória, função executiva e linguagem. Os níveis séricos de proteína S100beta e NSE foram medidos no pré-operatório, após a indução da anestesia, ao final da cirurgia e seis e 24 horas após a cirurgia. Para se avaliar a associação entre DCPO e os níveis séricos de proteína S100beta e NSE, utilizou-se ANOVA e ANOVA com medidas repetidas. As diferenças encontradas foram analisadas pela comparação múltipla de Tukey. Os resultados foram significantes quando p < 0,05. Resultados: DCPO foi observada em 63,1% dos pacientes após 21 dias e em 21,7% após seis meses da cirurgia. Na primeira semana após a cirurgia, 46,6% dos pacientes apresentaram delirium pósoperatório. Os maiores níveis séricos de proteína S100beta (1,8 ng/mL) e NSE (18,2 ng/mL) foram vistos no final da cirurgia e seis horas após a cirurgia, respectivamente. No entanto, não foi observada significante associação entre DCPO e aumento dos níveis séricos dos marcadores de lesão cerebral. Conclusões: O presente estudo observou uma elevada prevalência de DCPO. Adicionalmente, detectou-se um aumento dos níveis séricos de proteína S100beta e NSE no pós-operatório. Contudo, embora RM com CEC esteja significativamente relacionada a DCPO e níveis séricos elevados de proteína S100beta e NSE, o aumento dos níveis destes marcadores de lesão cerebral não foi associado à DCPO / Background: Systemic inflammatory response after cardiac surgery is associated with increased brain injury markers and development of postoperative cognitive dysfunction (POCD). The aim of this study was to evaluate the association between POCD and serum levels S100beta protein and neuron-specific enolase (NSE) after coronary artery bypass grafting (CABG) with cardiopulmonary bypass (CPB). Methods: 73 patients undergoing CABG surgery with CPB were investigated. Cognitive function was assessed by psychologists preoperatively and at 3, 7, 21, 90 and 180 days after surgery, using neurocognitive tests for specific recognition deficits in attention, memory, executive function and language. Serum levels S100beta protein and NSE were measured preoperatively, after induction of anesthesia, in the end of surgery, and 6 and 24 hours after surgery. Association between POCD and serum levels S100beta protein and NSE was assessed with ANOVA and ANOVA with repeated measurements. Differences were analyzed by Tukey\'s multiple comparison. Results were significant at p <0.05. Results: The mean age of patients was 61.8 ± 9.1 years. POCD was observed in 63.1% of patients after 21 days and 21.7% after 6 months of surgery. Postoperative delirium was seen in 46.6% of patients in the first week after surgery. The highest serum levels of S100beta protein (1.8 ng/mL) and NSE (18.2 ng/mL) were seen at the end of surgery and 6 hours after surgery, respectively. However, this study not observed a significant association between POCD and increased serum levels brain injury markers. Conclusions: The present study observed a high prevalence of POCD. Additionally, serum levels S100beta protein and NSE increased postoperatively. However, while CABG surgery with CPB is significantly related to POCD and elevated serum levels S100beta protein and NSE, the increased levels of such brain injury markers was not associated with POCD

Fundamentos: A Síndrome da Resposta Inflamatória Sistêmica (SRIS) permanece como uma das principais causas de disfunção de órgãos associada à circulação extracorpórea (CEC) na maioria dos pacientes submetidos à cirurgia cardíaca, especialmente em neonatos submetidos à correção de cardiopatias congênitas com auxílio de CEC. A circulação extracorpórea (CEC) neonatal é uma ferramenta essencial para a correção cirúrgica de grande parte das cardiopatias congênitas. Apesar dos avanços importantes na técnica, a CEC geralmente promove uma lesão multi-órgãos, cujo mecanismo inclui a lesão de isquemia-reperfusão (IR) e a resposta inflamatória sistêmica. Na arena clínica, a complicação mais importante pós-CEC neonatal consiste na lesão pulmonar e a disfunção respiratória, com consequente congestão vascular pulmonar e aumento do liquido intersticial. No cenário fetal, a disfunção placentária representa a principal causa de morbi-mortalidade durante e após a CEC fetal. O pré-condicionamento isquêmico remoto (PCIR) tem sido aplicado como alternativa terapêutica capaz de mitigar os danos teciduais consequentes ao processo inflamatório desencadeado pela lesão de IR e proteger tecidos à distância da isquemia subsequente. No entanto, o impacto desta estratégia não foi ainda demonstrado na CEC fetal, para determinar se esta forma de intervenção terapêutica não-invasiva poderia oferecer uma proteção multi-órgãos fetais, como os pulmões e a placenta. Objetivo: Testar a hipótese de que o PCIR em fetos de ovinos submetidos a CEC reduz a inflamação sistêmica fetal e a disfunção placentária. Método: Foram estudados 18 fetos de ovinos com pesos comparáveis (p > 0,87), divididos em 3 grupos: Controle Negativo (2,68kg ± 0,2kg), CEC simples, isto é, fetos submetidos à CEC sem PCIR (2,98kg ± 0,4kg) e Grupo PCIR, que contempla fetos submetidos ao PCIR antes de serem submetidos à CEC (2,96kg ± 0,4kg). O PCIR foi realizado antes da manipulação cirúrgica fetal, com quatro ciclos de isquemia intermitente de um dos membros traseiros (cinco minutos de garroteamento do membro, alternados com dois minutos de reperfusão). Ambos os grupos de estudo foram submetidos à CEC normotérmica durante 30 minutos. O perfusato foi composto de Ringer simples (61,33 ml ± 6,57 ml) aquecido (38º C). Os fetos foram monitorizados durante 120 minutos após a CEC. Foram analisados os marcadores inflamatórios sistêmicos fetais, trocas gasosas através da placenta e alterações morfológicas da placenta e dos pulmões fetais. Resultados: Foi observada uma queda progressiva da pressão arterial sistêmica dos animais do grupo CEC simples ao longo do protocolo em relação ao grupo Controle Negativo (p=0,006). O grupo PCIR não diferiu dos demais grupos (p < 0,53). O maior fluxo sanguíneo da CEC fetal foi atingido no grupo PCIR (191,4 ± 36 ml.min-1.Kg-1), quando comparado ao grupo CEC simples (137,0 ± 16,3 ml.min-1.Kg-1; p=0,0002). Quanto à função placentária, a partir do estabelecimento da CEC, ambos os grupos de estudo (Controle Positivo e PCIR) evoluíram com uma queda significativa da saturação de oxigênio arterial em relação ao grupo Controle Negativo (p < 0,04), sendo pior no grupo CEC simples em relação ao grupo PCIR (p=0,02). Em relação à avaliação metabólica, os animais submetidos a CEC, com ou sem PCIR, desenvolveram acidose mista progressiva (p < 0,0001), níveis inferiores de bicarbonato de Sódio (p < 0,0001) e hiperlactatemia (p < 0,0003), quando comparados ao grupo Controle Negativo. A avaliação histológica dos pulmões não evidenciou diferenças significativas em relação ao edema interlobular (p=0,589), porém foi observado maior espessamento de parede das arteríolas bronquiolares no grupo da CEC simples, quando comparadas aos demais grupos (p=0,009). A avaliação imuno-histoquímica do receptor Toll-Like-4 (TLR-4) e das moléculas de adesão intercelular-1 (ICAM-1) e vascular-1 (VCAM-1) nos pulmões fetais não evidenciou diferenças significativas entre os grupos. Em relação à placenta, houve um adensamento da fração de área dos núcleos das células similar entre os três grupos (p=0,91). Entretanto, foi observado um menor percentual de área de vasculatura intersticial no grupo CEC simples, sinal indireto de maior edema placentário neste grupo (p < 0,04). A análise imunohistoquímica dos marcadores inflamatórios ICAM-1, VCAM-1 e TLR-4 no interstício placentário também não evidenciou diferenças significativas entre os grupos no momento final do protocolo, embora tenha sido observada maior expressão da molécula ICAM-1 na vasculatura placentária de ambos os grupos de estudo. Os níveis séricos dos marcadores pró-inflamatórios tromboxana A2 e Interleucina-1 do grupo PCIR foram significativamente menores que aqueles do grupo CEC simples, uma hora após a CEC (p < 0.01). Os valores séricos da Prostaglandina E2 e Interleucina-6 do grupo PCIR foram significativamente maiores que os valores do grupo CEC simples, também uma hora após a CEC (p=0,02). Os marcadores pró-inflamatórios Interleucina-10 e Fator de Necrose Tumoral Alfa não apresentaram variações significativas entre os grupos ou durante os diversos tempos do protocolo (p > 0,08). Conclusão: O PCIR preservou melhor a hemodinâmica fetal, permitindo maior fluxo sanguíneo durante a CEC fetal. A expressão dos marcadores inflamatórios nos tecidos pulmonar e placentário, após a CEC fetal, não foi modificada pelo PCIR, embora o grupo PCIR tenha apresentado menores valores séricos de marcadores próinflamatórios tromboxana A2 (TXA2) e interleucina-1 (IL-1Beta). Paradoxalmente, o PCIR não impediu a elevação dos marcadores pró-inflamatórios Interleucina-6 e Prostaglandina E2. Esta forma de terapia não invasiva, PCIR, não impediu a disfunção placentária nem a hipoperfusão tecidual em fetos de ovinos submetidos à circulação extracorpórea, embora o edema placentário e a saturação de oxigênio tenham sido melhor preservados nos fetos submetidos ao PCIR / Background: Systemic inflammatory response Syndrome (SIRS) remains one of the major causes of cardiopulmonary bypass (CPB) associated organ injury in the majority of patients undergoing cardiovascular surgery, especially in neonates submitted to surgical correction of congenital heart lesions with CPB support. Despite significant advances in the technique, CPB is still complicated by multisystem injury, the mechanisms of which include ischemia-reperfusion (IR) injury and a detrimental systemic inflammatory response. In the clinical arena, pulmonary injury and dysfunction remain important complication after CPB, with consequent pulmonary vascular congestion and increase in interstitial fluid. In the fetal scenario, placental dysfunction remains the major cause of mortality during and after fetal CPB. Remote ischemic preconditioning (RIPC) has been applied as an alternative therapy to attenuate tissue injury related to the effects of inflammatory mediators triggered by IR injury. The preconditioning stimulus has systemic effects to protect distant tissues from subsequent ischemia. At the present, the impact of this strategy has not been yet demonstrated on fetal CPB, to determine whether this non-invasive therapeutic intervention can offer fetal multi-organ protection, such as the lungs and placenta. Objective: To test the hypothesis that RIPC applied to fetal lambs under CPB reduces fetal systemic inflammation and placental dysfunction. Method: 18 fetal lambs with comparable weights (p > 0.87) were divided into 3 groups: Negative Control (2.68kg ± 0.2kg), Sham (CPB without RIPC; 2.98kg ± 0.4kg) and RIPC Group (CPB plus RIPC; 2.96kg ± 0.4kg). RIPC stimulus was applied prior to fetal surgical manipulation, with tourniquet occlusion of blood flow to one hind limb with four cycles of 5-minute occlusion followed by 2-minute reperfusion. Animals from both study groups underwent 30 minutes of normothermic CPB. Blood-free priming solution consisted of only warm Ringer Solution (61.33 ml ± 6.57 ml; 38° C). Fetuses were monitored for 120 minutes after CPB. Fetal systemic inflammatory markers, fetal gas exchange, and morphological changes of the placenta and fetal lungs were assessed. Results: There was a progressive decrease of the systemic blood pressure in the Sham group throughout the protocol, as compared to Negative Control group (p= 0.006). The RIPC group did not differ from the other groups (p < 0.53). Animals from the RIPC group reached highest blood flow during CPB (191.4 ± 36.0 ml.min-1.Kg-1), when compared to Sham group (137.0 ± 16.3 ml.min-1.Kg-1; p = 0.0002). Regarding placental function, both groups (Sham and RIPC) developed a significant decrease in arterial oxygen saturation since the very beginning of CPB, as compared to the Negative Control group (P < 0.04). That change was even worse in the Sham group, when compared to PCIR group (p=0.02). Concerning metabolic assessment, the animals from both study groups developed progressive mixed acidosis (p < 0.0001), lower levels of sodium bicarbonate (p < 0.0001) and hyperlactatemia (p < 0.0003), when compared to Negative Control group. Histological assessment of fetal lungs did not show significant differences of interlobular inflammatory edema among the three groups (p > 0,05), although the animals from Sham group presented increased thickness of the bronchiolar arterioles, when compared to the other groups (p=0.009). Fetal lung immunohistochemical assessment of Toll-Like Receptor-4 (TLR-4), as well as the intercellular adhesion molecule ICAM-1 and the vascular adhesion molecule VCAM-1 did not show significant differences among the three groups. Regarding the area fraction of the placental cellular nuclei, there was no significant differences among the three groups (p=0.91). However, Sham group presented with a smaller area fraction of interstitial vasculature, an indirect signal of increased placental edema (p < 0.04). The analysis of placental interstitial inflammatory markers ICAM-1, VCAM-1 and TLR-4 did not show significant differences among the three groups at the end of the protocol, although an increased expression of ICAM-1 was observed in the placental perivascular area of both study groups. The pro-inflammatory thromboxane A2 and interleukin-1 levels were significantly lower in the RIPC group than in Sham group, at 60-minute post-CPB (p < 0.01). Prostaglandin E2 and interleukin-6 levels were significantly higher in the RIPC group than in the Sham group at 60-minute post-CPB (p=0.02). Tumor necrosis factor-alpha and interleukin-10 did not show significant differences among the three groups nor throughout the protocol (p > 0.08). Conclusion: RIPC better preserved fetal hemodynamics, allowing for increased blood flow during fetal CPB. The expression of inflammatory markers on placenta and fetal lungs were not modified by RIPC after CPB, although the RIPC group presented with lower values of pro-inflammatory markers thromboxane A2 and Interleukin-1. Paradoxically, the RIPC did not prevent the increase of the pro-inflammatory markers interleukin-6 and Prostaglandin E2. The RIPC non-invasive therapy did not prevent placental dysfunction or tissue hypoperfusion in fetal lambs under CPB, although placental edema and oxygen saturation were better preserved in fetuses submitted to RIPC

Introdução: O estudo MASS III não mostrou diferença significativa entre a cirurgia de revascularização miocárdica (CRM) com e sem circulação extracorpórea (CEC) em relação ao desfecho composto primário de morte por todas as causas, infarto agudo do miocárdio, acidente vascular cerebral ou revascularização adicional em pacientes com doença coronariana multiarterial. No entanto, a custo-efetividade dessas estratégias permanece desconhecida. Métodos: Pacientes com doença coronariana multiarterial estável e função ventricular esquerda preservada foram randomizados para CRM com CEC (n=153) ou sem CEC (n=155). Os dois grupos eram bem semelhantes quanto às características basais. A análise dos custos foi realizada a partir da perspectiva do sistema público de saúde brasileiro, e as utilities foram avaliadas pelo questionário SF-6D. Um modelo de Markov, com base nos dados de 5 anos de seguimento, foi utilizado para extrapolar os custos e os anos de vida ajustados pela qualidade (QALY) para doença coronariana crônica. Resultados: A qualidade de vida de ambos os grupos melhorou significativamente após a cirurgia durante o seguimento, em comparação com os dados pré-cirurgia, embora os ganhos de vida adquiridos (LYG) e QALYs tenham sido semelhantes entre os grupos durante o seguimento de 5 anos. Os custos para o período total do estudo não diferiram entre os grupos sem e com CEC (R$ 19.180,65 e R$ 19.909,18, respectivamente, p=0,409). Ao longo de um horizonte de tempo ajustado para a expectativa de vida da população do estudo, a razão de custo-efetividade incremental da CRM com versus sem CEC foi R$ 45.274 por QALY ganho, que foi robusto nas simulações de Monte Carlo e nas análises de sensibilidade. Para um limiar de custo-efetividade de R$ 34.212 por QALY ganho, a CRM sem CEC tem 65% de probabilidade de ser custo-efetiva quando comparada com CRM com CEC. Conclusão: Cirurgia de revascularização miocárdica sem CEC é clinicamente tão segura e efetiva quanto a cirurgia com CEC e parece ser uma estratégia economicamente atraente em comparação com a CRM com CEC em pacientes com doença arterial coronariana estável / Background: The MASS III trial revealed that in patients with multivessel coronary disease, no significant difference was observed between on-pump and off-pump coronary artery bypass surgery (CABG) in the primary composite outcome. However, long-term cost-effectiveness of these strategies is unknown. Methods: Patients with stable multivessel coronary artery disease and preserved left ventricular function were randomized to onpump (n=153) or off-pump CABG (n=155). The 2 groups were well matched for baseline characteristics. Costs analysis was conducted from a Brazilian public healthcare system perspective, and health state utilities were assessed using the SF-6D questionnaire. A Markov\'s model based on the 5- year in-trial data was used to extrapolate costs and quality-adjusted life-years (QALY) for chronic coronary disease. Results: Both groups\' quality of life improved significantly after surgery during follow-up compared with baseline, and life-years gained (LYG) and QALY gains were similar between on-pump and off-pump CABG over the 5-year time frame of the trial. The costs for the overall period of the trial - the mean cost in U.S. dollars per patient - did not differ significantly between the off-pump group and the on-pump group ($5674.75 and $5890.29 respectively, p=0.409). Over a lifetime horizon, the incremental cost-effectiveness ratio of on-pump vs. off-pump CABG was $12,576 per QALY gained, which was robust in Monte Carlo replications and in sensitivity analyses. Using a cost-effectiveness threshold of $10,122 per QALY gained, off-pump has 65% probability of being cost-effective versus on-pump CABG. Conclusions: Off-pump CABG was clinically as safe and effective as on-pump CABG and appears to be an economically attractive strategy compared with on-pump CABG among patients with stable coronary artery disease