As estratÃgias para prevenir a lesÃo de isquemia reperfusÃo durante as cirurgias hepÃticas incluem a oclusÃo intermitente do fluxo de sangue ao fÃgado ou a utilizaÃÃo de substÃncias que poderiam causar um efeito protetor ou aumento da resistÃncia do tecido hepÃtico à isquemia. O presente estudo teve o objetivo de avaliar o efeito do uso da L-Alanil-Glutamina (GLN) em Ratus novergicus submetidos à isquemia hepÃtica normotÃrmica, atravÃs de provas bioquÃmicas e imunohistoquÃmicas. Utilizou-se 30 ratos machos, da variedade Wistar, com peso mÃdio de 300 gramas, distribuÃdos em trÃs grupos de 10 ratos cada: grupo Controle, Grupo Isquemia ReperfusÃo (IR) e grupo Glutamina + Isquemia ReperfusÃo (GLN+IR). O grupo IR recebeu soluÃÃo salina 0,9% intra-peritoneal (IP), 2 horas antes de ser submetido laparotomia, e isquemia total por pinÃamento da trÃade portal por 30 minutos seguidos de reperfusÃo por 60 minutos; O grupo GLN + IR recebeu 0,75mg/Kg de glutamina IP 2 horas antes de isquemia total por 30 minutos, seguidos de reperfusÃo por 60 minutos. O grupo Controle foi submetido à punÃÃo peritoneal 2 horas antes da laparotomia, e de apenas manipulaÃÃo da trÃade portal, sem realizar pinÃamento algum. O procedimento foi realizado sob anestesia (IP) com uma soluÃÃo de cloridrato de ketamina, 80 mg/Kg + cloridrato xilazina, 10 mg/Kg. Ao final do perÃodo de reperfusÃo os animais foram relaparotomizados e colhido amostras de sangue para avaliaÃÃo dos nÃveis de ALT e DHL, e amostras de tecido hepÃtico para estudo imunohistoquÃmico com anticorpo para Caspase-3. A significÃncia estatÃstica foi calculada pelo teste ANOVA e pelo pÃs-teste de comparaÃÃo de mÃltiplas mÃdias de Tukey utilizando-se o software GraphPad Prism, versÃo 5.00. A mÃdia e erro padrÃo da dosagem de ALT, DHL, e do Ãndice de cÃlulas marcadas com Caspase-3 foi respectivamente para o grupo IR: 270,6+40,8; 2079,0+262,4 e 66,3+13,5; para o grupo GLN +IR: 127,9+31,17; 1019,0+187,9 e 36,6+12,0; para o grupo Controle: 83,3+5,5; 206,6+16,2 e 21,9+111,4. O prÃ-condicionamento com L-alanil-GLN IP reduziu significativamente os valores de ALT e DHL em Ratus novergicus, submetidos à lesÃo de IR hepÃtica, sugerindo hepatoproteÃÃo. / As estratÃgias para prevenir a lesÃo de isquemia reperfusÃo durante as cirurgias hepÃticas incluem a oclusÃo intermitente do fluxo de sangue ao fÃgado ou a utilizaÃÃo de substÃncias que poderiam causar um efeito protetor ou aumento da resistÃncia do tecido hepÃtico à isquemia. O presente estudo teve o objetivo de avaliar o efeito do uso da L-Alanil-Glutamina (GLN) em Ratus novergicus submetidos à isquemia hepÃtica normotÃrmica, atravÃs de provas bioquÃmicas e imunohistoquÃmicas. Utilizou-se 30 ratos machos, da variedade Wistar, com peso mÃdio de 300 gramas, distribuÃdos em trÃs grupos de 10 ratos cada: grupo Controle, Grupo Isquemia ReperfusÃo (IR) e grupo Glutamina + Isquemia ReperfusÃo (GLN+IR). O grupo IR recebeu soluÃÃo salina 0,9% intra-peritoneal (IP), 2 horas antes de ser submetido laparotomia, e isquemia total por pinÃamento da trÃade portal por 30 minutos seguidos de reperfusÃo por 60 minutos; O grupo GLN + IR recebeu 0,75mg/Kg de glutamina IP 2 horas antes de isquemia total por 30 minutos, seguidos de reperfusÃo por 60 minutos. O grupo Controle foi submetido à punÃÃo peritoneal 2 horas antes da laparotomia, e de apenas manipulaÃÃo da trÃade portal, sem realizar pinÃamento algum. O procedimento foi realizado sob anestesia (IP) com uma soluÃÃo de cloridrato de ketamina, 80 mg/Kg + cloridrato xilazina, 10 mg/Kg. Ao final do perÃodo de reperfusÃo os animais foram relaparotomizados e colhido amostras de sangue para avaliaÃÃo dos nÃveis de ALT e DHL, e amostras de tecido hepÃtico para estudo imunohistoquÃmico com anticorpo para Caspase-3. A significÃncia estatÃstica foi calculada pelo teste ANOVA e pelo pÃs-teste de comparaÃÃo de mÃltiplas mÃdias de Tukey utilizando-se o software GraphPad Prism, versÃo 5.00. A mÃdia e erro padrÃo da dosagem de ALT, DHL, e do Ãndice de cÃlulas marcadas com Caspase-3 foi respectivamente para o grupo IR: 270,6+40,8; 2079,0+262,4 e 66,3+13,5; para o grupo GLN +IR: 127,9+31,17; 1019,0+187,9 e 36,6+12,0; para o grupo Controle: 83,3+5,5; 206,6+16,2 e 21,9+111,4. O prÃ-condicionamento com L-alanil-GLN IP reduziu significativamente os valores de ALT e DHL em Ratus novergicus, submetidos à lesÃo de IR hepÃtica, sugerindo hepatoproteÃÃo. / The strategies to prevent the hepatic ischemia/reperfusion injury after hepatic resections or transplantation include intermittent control of blood influx to the liver or the use of a substance that could cause a protective effect or increase of the resistance of the hepatic tissue to ischemia. The present study had the objective to evaluate the effect of the use of the L-Alanil-Glutamina in Ratus novergicus submitted the normothermic hepatic ischemia on liver biochemists and imunohistochemistry, as well as evaluating apoptosis present in this experimental model. 30 male rats, with average weight of 300 grams, divided in three groups of 10 rats: Control group, Ischemia Reperfusion group and Glutamine group. Ischemia Reperfusion group received saline solution 0.9% intra-peritoneal (IP), 2 hours before being submitted to laparotomy, and total ischemia by clampping of portal triad for 30 minutes followed of reperfusion for 60 minutes; The Glutamine group received 0,75mg/Kg IP 2 hours before total ischemia for 30 minutes, followed by reperfusion for 60 minutes. Control group was submitted the peritoneal punction 2 hours before the laparotomy, and only manipulation of the biliary tree, without carrying through any clamping. The procedure was carried through under anesthesia (IP) with a solution of Ketamin chloridate , 80 mg/Kg + xilazin chloridate, 10 mg/Kg. To the end of the period of reperfusion the animals had been relaparotomized and blood collected for evaluation of the levels of ALT and DHL, and hepatic tissue samples for imunohistochemistry study with antibody for Caspase-3. The statistics significance was calculated by ANOVA and the post test of multiple comparison of Tukey, using the software GraphPad Prism, version 5.00. The average and error standard of the dosage of ALT, DHL, and of the index of cells marked with Caspase-3 was respectively for the Ischemia Reperfusion group: 270,6+40,8; 2079,0+262,4 and 66,3+13,5; for the Glutamine group: 127,9+31,17; 1019,0+187,9 and 36,6+12,0; for the Control group: 83,3+5,5; 206,6+16,2 and 21,9+111,4. The preconditioning with intraperitoneal L-alanil-glutamine significantly reduces the values of the biochemists markers, in Ratus novergicus submitted to the hepatic ischemia-reperfusion injury, suggesting hepatic protection. / The strategies to prevent the hepatic ischemia/reperfusion injury after hepatic resections or transplantation include intermittent control of blood influx to the liver or the use of a substance that could cause a protective effect or increase of the resistance of the hepatic tissue to ischemia. The present study had the objective to evaluate the effect of the use of the L-Alanil-Glutamina in Ratus novergicus submitted the normothermic hepatic ischemia on liver biochemists and imunohistochemistry, as well as evaluating apoptosis present in this experimental model. 30 male rats, with average weight of 300 grams, divided in three groups of 10 rats: Control group, Ischemia Reperfusion group and Glutamine group. Ischemia Reperfusion group received saline solution 0.9% intra-peritoneal (IP), 2 hours before being submitted to laparotomy, and total ischemia by clampping of portal triad for 30 minutes followed of reperfusion for 60 minutes; The Glutamine group received 0,75mg/Kg IP 2 hours before total ischemia for 30 minutes, followed by reperfusion for 60 minutes. Control group was submitted the peritoneal punction 2 hours before the laparotomy, and only manipulation of the biliary tree, without carrying through any clamping. The procedure was carried through under anesthesia (IP) with a solution of Ketamin chloridate , 80 mg/Kg + xilazin chloridate, 10 mg/Kg. To the end of the period of reperfusion the animals had been relaparotomized and blood collected for evaluation of the levels of ALT and DHL, and hepatic tissue samples for imunohistochemistry study with antibody for Caspase-3. The statistics significance was calculated by ANOVA and the post test of multiple comparison of Tukey, using the software GraphPad Prism, version 5.00. The average and error standard of the dosage of ALT, DHL, and of the index of cells marked with Caspase-3 was respectively for the Ischemia Reperfusion group: 270,6+40,8; 2079,0+262,4 and 66,3+13,5; for the Glutamine group: 127,9+31,17; 1019,0+187,9 and 36,6+12,0; for the Control group: 83,3+5,5; 206,6+16,2 and 21,9+111,4. The preconditioning with intraperitoneal L-alanil-glutamine significantly reduces the values of the biochemists markers, in Ratus novergicus submitted to the hepatic ischemia-reperfusion injury, suggesting hepatic protection.

Liver resection causes marked perfusion alterations in the liver remnant both on the organ scale (vascular anatomy) and on the microscale (sinusoidal blood flow on tissue level). These changes in perfusion affect hepatic functions via direct alterations in blood supply and drainage, followed by indirect changes of biomechanical tissue properties and cellular function. Changes in blood flow impose compression, tension and shear forces on the liver tissue. These forces are perceived by mechanosensors on parenchymal and non-parenchymal cells of the liver and regulate cell-cell and cell-matrix interactions as well as cellular signaling and metabolism. These interactions are key players in tissue growth and remodeling, a prerequisite to restore tissue function after PHx. Their dysregulation is associated with metabolic impairment of the liver eventually leading to liver failure, a serious post-hepatectomy complication with high morbidity and mortality. Though certain links are known, the overall functional change after liver surgery is not understood due to complex feedback loops, non-linearities, spatial heterogeneities and different time-scales of events. Computational modeling is a unique approach to gain a better understanding of complex biomedical systems. This approach allows (i) integration of heterogeneous data and knowledge on multiple scales into a consistent view of how perfusion is related to hepatic function; (ii) testing and generating hypotheses based on predictive models, which must be validated experimentally and clinically. In the long term, computational modeling will (iii) support surgical planning by predicting surgery-induced perfusion perturbations and their functional (metabolic) consequences; and thereby (iv) allow minimizing surgical risks for the individual patient. Here, we review the alterations of hepatic perfusion, biomechanical properties and function associated with hepatectomy. Specifically, we provide an overview over the clinical problem, preoperative diagnostics, functional imaging approaches, experimental approaches in animal models, mechanoperception in the liver and impact on cellular metabolism, omics approaches with a focus on transcriptomics, data integration and uncertainty analysis, and computational modeling on multiple scales. Finally, we provide a perspective on how multi-scale computational models, which couple perfusion changes to hepatic function, could become part of clinical workflows to predict and optimize patient outcome after complex liver surgery.

Small intestinal neuroendocrine tumor (SI-NET) is the most common small bowel tumor in Europe and USA, with an annual incidence of around 0.3-1.3/100000 persons. SI-NETs are the most common type of gastroenteropancreatic NETs (GEP-NETs), and they are known for their ability to produce hormones such as tachykinins and serotonin, as well as for their favorable long-term prognosis in comparison to gastrointestinal adenocarcinoma. The overall aim of the thesis was to investigate unknown or unclear aspects of SI-NET disease, in connection with prognosis, treatment and follow-up. Paper I confirmed several known negative prognostic factors and also showed, for the first time, that para-aortal lymph node metastases and peritoneal carcinomatosis were associated with worse survival by multivariable analyses. Locoregional surgery was associated with a low post-operative mortality, and a prolonged long-term survival by multivariable analysis. In Paper II we continued to investigate peritoneal carcinomatosis and found it be a risk factor not only for death, but also for emergency re-surgery. Furthermore, genetic analyses of samples from primary tumors in patients with and without peritoneal carcinomatosis showed a difference in the DNA between these two groups. In Paper III the outcome after liver surgery and/or radiofrequency ablation of liver metastases was investigated. To summarize, no difference in survival was seen in patients treated with surgery/radiofrequency ablation in comparison with matched controls. However, a superior radiological response of liver metasases and lower U-5-HIAA values were seen in patients subjected to liver surgery and/or radiofrequency ablation compared to matched controls. Paper IV compared ultrasonography, computed tomography and 11C-5HTP-PET in the follow-up after radiofrequency ablation of NET liver metastases. The study concluded that 11C-5HTP-PET depicted all residual tumors after RFA and that it, if used, should be combined with computed tomography for easier interpretation, as RFA areas are not clearly distinguishable with 11C-5HTP-PET alone. Paper V studied gallstone complications after somatostatin analog treatment in SI-NET patients, and concluded that there was a rather high risk to be subjected to a cholecystectomy due to biliary colic, cholecystitis, cholangitis or pancreatitis after primary surgery in somatostatin analog treated patients.

Le foie possède une capacité de régénération importante qui lui permet de reconstituer son volume suite à une agression. L’induction d’une régénération hépatique est réalisée en pratique courante en chirurgie hépatique afin de préparer le foie à une hépatectomie majeure. Elle est également utilisée dans de nombreux modèles animaux afin de favoriser la prise de greffe hépatocytaire au cours de la transplantation d’hépatocytes pour le traitement de maladies métaboliques héréditaires hépatiques. Les principaux objectifs de ce travail ont été d’étudier une méthode peu invasive pour induire une importante régénération hépatique : d’une part pour élargir les possibilités de prise en charge des patients nécessitant une hépatectomie, et d’autre part pour favoriser la prise de greffe des hépatocytes transplantés pour le traitement des maladies métaboliques héréditaires hépatiques.Dans un premier temps, nous avons mis au point chez le rat une technique d’embolisation portale partielle résorbable répétée (EPPRR) visant à entrainer un stimulus additionnel de régénération hépatique. Ces travaux ont validé le concept de la méthode d’EPPRR en montrant une augmentation de la prolifération hépatocytaire et une hypertrophie dans la partie du foie non embolisée.Ce protocole d’EPPRR a ensuite été appliqué dans un modèle préclinique de gros animal. Nous avons étudié chez le porc les conséquences de l’EPPRR et montré que cette technique était reproductible, bien tolérée, et qu’elle permettait une hypertrophie de la partie du foie non embolisée.Parallèlement, nous avons appliqué l’EPPRR avant transplantation d’hépatocytes chez le rat. A partir du foie de rats transgéniques exprimant la GFP (green fluorescent protein), nous avons pu isoler des hépatocytes GFP+. Ces cellules ont été transplantées dans le foie de rats receveurs GFP- en association avec une EPPRR. Nous avons montré que le stimulus de régénération répété provoqué par l’EPPRR permettait une augmentation de la prise de greffe.En conclusion, l’EPPRR est une technique peu invasive capable d’induire une régénérative hépatique efficace. Cette approche pourrait jouer un rôle dans la prise en charge des tumeurs hépatique et l’optimisation de la transplantation d’hépatocytes pour le traitement des maladies métaboliques héréditaires hépatiques. / The liver has an important regenerative capacity allowing reconstitution of the hepatic volume after an aggression. The induction of liver regeneration is used in routine clinical practice before liver surgery in order to prepare the liver for major hepatectomy. It is also used in numerous animal models in order to increase hepatocyte engraftment during hepatocyte transplantation for the treatment of inherited metabolic liver diseases. The main objective of this work was to evaluate a minimally invasive approach to induce substantial liver regeneration: firstly, to expand the therapeutic options for patients requiring an hepatectomy, and secondly to increase the engraftment of transplanted hepatocytes for the treatment of inherited metabolic liver diseases.In a first study, we developed in the rat model a technique of repeated reversible portal vein embolization (RRPVE) to induce an additional stimulus of liver regeneration. This study established the proof of concept of the RRPVE method, showing an increase in hepatocyte proliferation and hypertrophy in the non-embolized liver.This RRPVE protocol was then used in a preclinical model of large animal. We studied in swine the consequences of the RRPVE and showed that the procedure was reproducible, well tolerated, and allowed hypertrophy of the non-embolized liver.In parallel, we applied RRPVE before hepatocyte transplantation in the rat model. From the liver of transgenic rats expressing GFP (green fluorescent protein), we were able to isolate GFP+ hepatocytes. These cells were transplanted in the liver of recipient GFP- rats in association with RRPVE. We demonstrated that the repetition of the regeneration stimulus induced by RRPVE allowed increased hepatocyte engraftment.In conclusion, RRPVE is a minimally invasive technique able to induce efficient liver regeneration. This approach could play a part in the management of hepatic malignancies and the optimization of hepatocyte transplantation in the treatment of inherited metabolic liver diseases.

During laparoscopic liver resection, the limited access to the organ, the small field of view and lack of palpation can obstruct a surgeon’s workflow. Automatic navigation systems could use the images from preoperative volumetric organ scans to help the surgeons find their target (tumors) and risk-structures (vessels) more efficiently. This requires the preoperative data to be fused (or registered) with the intraoperative scene in order to display information at the correct intraoperative position. One key challenge in this setting is the automatic estimation of the organ’s current intra-operative deformation, which is required in order to predict the position of internal structures. Parameterizing the many patient-specific unknowns (tissue properties, boundary conditions, interactions with other tissues, direction of gravity) is very difficult. Instead, this work explores how to employ deep neural networks to solve the registration problem in a data-driven manner. To this end, convolutional neural networks are trained on synthetic data to estimate an organ’s intraoperative displacement field and thus its current deformation. To drive this estimation, visible surface cues from the intraoperative camera view must be supplied to the networks. Since reliable surface features are very difficult to find, the networks are adapted to also find correspondences between the pre- and intraoperative liver geometry automatically. This combines the search for correspondences with the biomechanical behavior estimation and allows the networks to tackle the full non-rigid registration problem in one single step. The result is a model which can quickly predict the volume deformation of a liver, given only sparse surface information. The model combines the advantages of a physically accurate biomechanical simulation with the speed and powerful feature extraction capabilities of deep neural networks. To test the method intraoperatively, a registration pipeline is developed which constructs a map of the liver and its surroundings from the laparoscopic video and then uses the neural networks to fuse the preoperative volume data into this map. The deformed organ volume can then be rendered as an overlay directly onto the laparoscopic video stream. The focus of this pipeline is to be applicable to real surgery, where everything should be quick and non-intrusive. To meet these requirements, a SLAM system is used to localize the laparoscopic camera (avoiding setup of an external tracking system), various neural networks are used to quickly interpret the scene and semi-automatic tools let the surgeons guide the system. Beyond the concrete advantages of the data-driven approach for intraoperative registration, this work also demonstrates general benefits of training a registration system preoperatively on synthetic data. The method lets the engineer decide which values need to be known explicitly and which should be estimated implicitly by the networks, which opens the door to many new possibilities.:1 Introduction 1.1 Motivation 1.1.1 Navigated Liver Surgery 1.1.2 Laparoscopic Liver Registration 1.2 Challenges in Laparoscopic Liver Registration 1.2.1 Preoperative Model 1.2.2 Intraoperative Data 1.2.3 Fusion/Registration 1.2.4 Data 1.3 Scope and Goals of this Work 1.3.1 Data-Driven, Biomechanical Model 1.3.2 Data-Driven Non-Rigid Registration 1.3.3 Building a Working Prototype 2 State of the Art 2.1 Rigid Registration 2.2 Non-Rigid Liver Registration 2.3 Neural Networks for Simulation and Registration 3 Theoretical Background 3.1 Liver 3.2 Laparoscopic Liver Resection 3.2.1 Staging Procedure 3.3 Biomechanical Simulation 3.3.1 Physical Balance Principles 3.3.2 Material Models 3.3.3 Numerical Solver: The Finite Element Method (FEM) 3.3.4 The Lagrangian Specification 3.4 Variables and Data in Liver Registration 3.4.1 Observable 3.4.2 Unknowns 4 Generating Simulations of Deforming Organs 4.1 Organ Volume 4.2 Forces and Boundary Conditions 4.2.1 Surface Forces 4.2.2 Zero-Displacement Boundary Conditions 4.2.3 Surrounding Tissues and Ligaments 4.2.4 Gravity 4.2.5 Pressure 4.3 Simulation 4.3.1 Static Simulation 4.3.2 Dynamic Simulation 4.4 Surface Extraction 4.4.1 Partial Surface Extraction 4.4.2 Surface Noise 4.4.3 Partial Surface Displacement 4.5 Voxelization 4.5.1 Voxelizing the Liver Geometry 4.5.2 Voxelizing the Displacement Field 4.5.3 Voxelizing Boundary Conditions 4.6 Pruning Dataset - Removing Unwanted Results 4.7 Data Augmentation 5 Deep Neural Networks for Biomechanical Simulation 5.1 Training Data 5.2 Network Architecture 5.3 Loss Functions and Training 6 Deep Neural Networks for Non-Rigid Registration 6.1 Training Data 6.2 Architecture 6.3 Loss 6.4 Training 6.5 Mesh Deformation 6.6 Example Application 7 Intraoperative Prototype 7.1 Image Acquisition 7.2 Stereo Calibration 7.3 Image Rectification, Disparity- and Depth- estimation 7.4 Liver Segmentation 7.4.1 Synthetic Image Generation 7.4.2 Automatic Segmentation 7.4.3 Manual Segmentation Modifier 7.5 SLAM 7.6 Dense Reconstruction 7.7 Rigid Registration 7.8 Non-Rigid Registration 7.9 Rendering 7.10 Robotic Operating System 8 Evaluation 8.1 Evaluation Datasets 8.1.1 In-Silico 8.1.2 Phantom Torso and Liver 8.1.3 In-Vivo, Human, Breathing Motion 8.1.4 In-Vivo, Human, Laparoscopy 8.2 Metrics 8.2.1 Mean Displacement Error 8.2.2 Target Registration Error (TRE) 8.2.3 Champfer Distance 8.2.4 Volumetric Change 8.3 Evaluation of the Synthetic Training Data 8.4 Data-Driven Biomechanical Model (DDBM) 8.4.1 Amount of Intraoperative Surface 8.4.2 Dynamic Simulation 8.5 Volume to Surface Registration Network (V2S-Net) 8.5.1 Amount of Intraoperative Surface 8.5.2 Dependency on Initial Rigid Alignment 8.5.3 Registration Accuracy in Comparison to Surface Noise 8.5.4 Registration Accuracy in Comparison to Material Stiffness 8.5.5 Champfer-Distance vs. Mean Displacement Error 8.5.6 In-vivo, Human Breathing Motion 8.6 Full Intraoperative Pipeline 8.6.1 Intraoperative Reconstruction: SLAM and Intraoperative Map 8.6.2 Full Pipeline on Laparoscopic Human Data 8.7 Timing 9 Discussion 9.1 Intraoperative Model 9.2 Physical Accuracy 9.3 Limitations in Training Data 9.4 Limitations Caused by Difference in Pre- and Intraoperative Modalities 9.5 Ambiguity 9.6 Intraoperative Prototype 10 Conclusion 11 List of Publications List of Figures Bibliography

Laparoscopic liver resection (LLR) is an increasingly relevant treatment option for patients with resectable hepatocellular carcinoma (HCC). Orthotopic liver transplantation (OLT) has been considered optimal treatment for HCC in cirrhosis, but is challenged by rising organ scarcity. While health-related quality of life (HRQoL) and mental health are well-documented after OLT, little is known about HRQoL in HCC patients after LLR. We identified all HCC patients who underwent LLR at our hospital between 2014 and 2018. HRQoL and mental health were assessed using the Short Form 36 and the Hospital Anxiety and Depression Scale, respectively. Outcomes were compared to a historic cohort of HCC patients after OLT. Ninety-eight patients received LLR for HCC. Postoperative morbidity was 25% with 17% minor complications. LLR patients showed similar overall HRQoL and mental health to OLT recipients, except for lower General Health (p = 0.029) and higher anxiety scores (p = 0.010). We conclude that LLR can be safely performed in patients with HCC, with or without liver cirrhosis. The postoperative HRQoL and mental health are comparable to that of OLT recipients in most aspects. LLR should thus always be considered an alternative to OLT, especially in times of organ shortage.

A Manobra de Pringle é tempo cirúrgico fundamental, e de uso rotineiro em cirurgia hepática, tanto no trauma, como nas ressecções eletivas e nos transplantes. Têm como principal objetivo minimizar o sangramento intraoperatório, não obstante, leve, invariavelmente, à isquemia hepática transitória, à congestão vascular, e à isquemia do território esplâncnico, promovendo distúrbios hemodinâmicos indesejáveis. Algumas drogas têm sido testadas no sentido de minimizar a lesão de isquemia e reperfusão induzida pela Manobra de Pringle. A pentoxifilina tem demonstrado efeitos benéficos contra a lesão de isquemia e reperfusão no fígado. Atua, principalmente, na microcirculação, e também tem ação imunomoduladora. Assim, os objetivos dessa pesquisa foram: comparar os efeitos do uso da pentoxifilina por via portal ou periférica sobre a hemodinâmica regional e sistêmica, bem como a eventual ação hepatoprotetora na lesão de isquemia e reperfusão induzida pela manobra de Pringle. Vinte e quatro cães adultos, machos, e sem raça definida, foram anestesiados com sevoflurano e submetidos à ventilação mecânica. Para adequada descompressão do território esplâncnico, e com o objetivo de conseguir uma isquemia hepática isolada e prolongada, utilizamos derivação venosa extra-corpórea esplenofemural com bomba ativa tipo rolete. A veia pancreatoduodenal foi canulada e posicionado cateter na veia porta para perfusão normotérmica do fígado, utilizando-se bomba de infusão contínua. As variáveis hemodinâmicas foram obtidas através de cateteres posicionados na veia porta, artéria femoral direita, e cateter de Swan-Ganz na artéria pulmonar. As avaliações de perfusão esplâncnica foram realizadas com fluxômetro ultra-sônico na artéria hepática e na veia porta e tonometria a gás. Após 45 minutos de isquemia hepática, obtida pelo clampeamento do pedículo hepático, o fluxo hepático foi restabelecido e os animais observados por mais 120 minutos. Os animais foram divididos em três grupos experimentais: controle (n=8), perfusão do fígado com 500 mL de soro fisiológico a 0,9% durante os 45 minutos de isquemia; grupo pentoxifilina intra-hepático n=8, perfusão hepática com solução de pentoxifilina 50mg/Kg diluída em 500 mL de soro fisiológico a 0,9%; e grupo pentoxifilina sistêmica n=8 perfusão hepática com 500mL de soro fisiológico 0,9% e pentoxifilina 50mg/Kg via sistêmica administrada por veia periférica dissecada no membro superior esquerdo. Foram analisadas variáveis hemodinâmicas sistêmicas e esplâncnicas, gasométricas, tonometria gástrica, metabolismo de oxigênio, enzimas hepáticas e estudo histológico. O grupo pentoxifilina sistêmica apresentou melhora significativa do débito e índice cardíaco aos 60 minutos de reperfusão, em relação ao grupo controle. O fluxo venoso portal e o índice de fluxo de veia porta apresentaram melhora significativa no grupo pentoxifilina sistêmica, em relação ao grupo controle, após 45 minutos de reperfusão, permanecendo assim até o final do experimento. O grupo pentoxifilina intra-hepático também demonstrou melhora do fluxo venoso portal, porém sem alcançar significância estatística. Nos grupos tratados com pentoxifilina, os níveis séricos das enzimas hepáticas (TGO, TGP e LDH) também foram menores do que no grupo controle, ficando próximo à significância estatística. Assim, nas condições da presente pesquisa, pode-se concluir que a administração de pentoxifilina determinou melhora do fluxo venoso portal, quer pela via sistêmica, quer pela via portal. A administração da pentoxifilina pela via sistêmica promoveu melhora estatisticamente significante do fluxo venoso portal, do débito e do índice cardíaco, em relação ao grupo controle. Finalmente, a administração da pentoxifilina na vigência da manobra de Pringle sugere efeito hepatoprotetor / Portal triad occlusion (Pringle maneuver) is currently used during most hepatic resections for trauma or malignancies in order to decrease intraoperative bleeding. However this maneuver is associated with hepatic ischemia and splanchnic congestion. In this setting, many drugs have been tested to decrease the ischemia-reperfusion injury induced by this maneuver. Pentoxifylline, a methylxanthine derivative, has been shown to have beneficial effects on intestinal microvascular blood flow as well as hepatic blood flow during shock and resuscitation. The beneficial effects of pentoxifylline can be associated to the inhibition of inflammatory cytokines, such as TNF- a and IL-6. Our objective was evaluated the potential systemic and regional benefits of intraportal or systemic infusion of pentoxifylline during an experimental model of normothermic hepatic ischemia. Twenty four dogs were evaluated in this study. They were anesthetized with sevofluorane and subjected to mechanical ventilation. During hepatic ischemia period we used an active spleno-femoral. A catheter placed, trough the pancreatoduodenal vein, was used to perform hepatic perfusion. Systemic hemodynamics were evaluated through a Swan-Ganz and arterial catheters. Gastric mucosal pCO2 (gas tonometry), portal vein and hepatic artery blood flow (ultrasonic flowprobes), systemic and regional O2-derived variables, as well as liver enzymes (ALT, AST, DHL) were evaluated throughout the protocol. The animals were subjected to 45 minutes of ischemia. Previously to the Pringle maneuver the animals were randomized in three experimental groups: control (n=8), hepatic perfusion with 500 ml of saline solution; intraportal pentoxifylline (n=8) hepatic perfusion with saline solution + 50 mg/Kg of pentoxifylline; and systemic pentoxifylline (n=8) hepatic perfusion with 500 ml of saline solution and intravenous infusion of 50 mg/Kg of pentoxifylline (brachial vein). After hepatic ischemia period the animals were followed for an additional 120 minutes. Systemic infusion of pentoxifylline improved significantly cardiac output, as well as portal vein blood flow when compared with control group. Intraportal infusion of pentoxifylline presented a partial increase of portal vein blood flow. In both groups treated with pentoxifylline, there was a significant decrease in markers of hepatic cell injury during the reperfusion period when compared with control group. We conclude that systemic or intraportal infusion of pentoxyfilline improves portal vein blood flow, after 45 minutes of hepatic ischemia. Systemic infusion of pentoxifylline promotes a significant improvement in cardiac output when compared with control group. Our findings suggested that regional or systemic infusion of pentoxifylline minimize the deleterious effects of Pringle\'s maneuver

Os resultados sobre o tempo adequado da exclusão vascular total do fígado(EVTF) para a realização de hepatectomias continuam sendo discutidos. Dados favoráveis têm sido descritos, quando se associa a EVTF com a perfusão de solução hipotérmica, porém a comparação entre estas técnicas ainda não foi descrita. Este estudo tem como objetivo comparar os resultados da ressecção hepática com EVTF, realizada sob hipotermia(solução de preservação hipotérmica in situ), com aqueles obtidos quando se realiza esta ressecção com EVTF com tempo de isquemia menor que 60 minutos, e naqueles com tempo de isquemia maior ou igual a 60 minutos. Para tanto, foram analisados, como parâmetros, a função renal e hepática, morbidade, e mortalidade pós-operatórias nos três grupos mencionados,buscando-se determinar valores preditivos para indicação das técnicas. PACIENTES E MÉTODO. Foram estudados 81 pacientes submetidos à ressecção hepática. Estes pacientes foram divididos em três grupos. Trinta e quatro pacientes com EVTF menor do que 60 minutos (EVTF < 60’), 19 pacientes com EVTF maior ou igual a 60 minutos (EVTF &#8805; 60’), e 28 pacientes nos quais a perfusão hipotérmica in situ (EVTFHIPOT) foi realizada. Os valores das transaminases hepáticas (ASAT e ALAT), Bilirrubinas totais, creatinina, e tempo de protrombina foram registrados. Também foram verificados os índices de morbidade e de mortalidade pós-operatórias nos três grupos. RESULTADOS. O valor máximo no pós-operatório das enzimas hepáticas - ASAT e ALAT foram significativamente menores (p < 0.05) no grupo EVTFHIPOT (535 + 361 U/L e 436 + 427 U/L), quando comparados aos outros grupos - EVTF<60’(988 + 798 U/L; 844 + 733 U/L), EVTF>60’ (1583 + 984 U/L; 1082 + 842 U/L). No grupo EVTFHIPOT, os valores máximos das bilirrubinas (6,5 + 2,5 mg/dl),creatinina (1,2 + 0,7 mg/dl), e o número de complicações por paciente (1,2 + 1) foram semelhantes aos do grupo EVTF<60’’ (5,5 + 7,8; 1,3 + 1; e 0,7 + 1 respectivamente), e significativamente menores que os do grupo EVTF > 60’(12,8 + 11,8; 2,3 + 2,3, e 2,3 + 1,2). A mortalidade hospitalar foi de 1/34, 2/19 e 2/28 nos grupos EVTF < 60’, EVTF > 60’, e EVTFHIPOT, respectivamente,sem diferença estatística. CONCLUSÕES. Quando comparadas as técnicas clássicas de exclusão vascular do fígado,de qualquer duração, com aquela na qual se realizou a perfusão hipotérmica do fígado, conclui-se que, nesta última, os pacientes toleraram melhor a isquemia. Deve-se enfatizar que, na EVTF com hipotermia, existe melhor preservação da função hepática, melhor preservação da função renal, e menores índices de morbidade, quando comparada com a EVTF>60’’ sem hipotermia. Os fatores preditivos de EVTF por mais de 60 minutos auxiliam na adoção da opção pelo resfriamento hepático. / OBJECTIVE. To compare the results of liver resection performed under in situ hypothermic perfusion vs standard total vascular exclusion (TVE) of the liver < 60 minutes and &#8805; 60 minutes in terms of liver tolerance, liver and renal functions, postoperative morbidity and mortality. SUMMARY BACGROUND DATA. The safe duration of TVE is still debated. Promising results have been reported following TVE associated with hypothermic perfusion of the liver with durations of up to several hours. The two techniques have not been compared so far. PATIENTS AND METHODS.The study population includes 81 consecutive liver resections under TVE < 60 minutes (group TVE < 60’ , 34 patients), &#8805; 60 minutes (group TVE &#8805; 60’, 19 patients) and in situ hypothermic perfusion (group TVEHYPOTH , 28 patients). Liver tolerance (peaks of transaminases), liver and kidney function (peak of bilirubin, minimum prothrombin time and peak of creatinine), morbidity and inhospital mortality were compared within the 3 groups. RESULTS. The postoperative peaks of ASAT and ALAT were significantly lower (p < 0.05) in group TVE HYPOTH (535 + 361 U/L and 436 + 427 U/L) compared to the groups TVE<60’ (988 + 798 U/L; 844 + 733 U/L) and TVE&#8805;60’ (1583 + 984 U/L; 1082 + 842 U/L). In the group TVE HYPOTH , the peaks of bilirubin (6,5 + 2,5 mg/dl), creatinine (1,2 + 0,7 mg/dl), and the number of complications per patient (1,2 + 1) were comparable to those of the group TVE<60’ (5,5 + 7,8; 1,3 + 1; e 0,7 + 1 respectively) and significantly lower to those of the group TVE&#8805;60’ (12,8 + 11,8; 2,3 + 2,3, e 2,3 + 1,2). In hospital mortality rates were 1/34, 2/19 and 2/28 for the groups TVE < 60’ , TVE &#8805; 60’ , and TVEHYPOTH respectively and were comparable. On multivariate analysis, the size of the tumor, portal vein embolization and a planned vascular reconstruction werem significantly predictive of TVE &#8805; 60 minutes. CONCLUSIONS. Compared to standard TVE of any duration, hypothermic perfusion of the liver is associated with a better tolerance to ischemia. In addition, compared to TVE &#8805; 60 minutes, it is associated with better postoperative liver and renal functions, and a lower morbidity. Predictive factors for TVE &#8805; 60 minutes may help to indicate hypothermic perfusion of the liver.

Os resultados sobre o tempo adequado da exclusão vascular total do fígado(EVTF) para a realização de hepatectomias continuam sendo discutidos. Dados favoráveis têm sido descritos, quando se associa a EVTF com a perfusão de solução hipotérmica, porém a comparação entre estas técnicas ainda não foi descrita. Este estudo tem como objetivo comparar os resultados da ressecção hepática com EVTF, realizada sob hipotermia(solução de preservação hipotérmica in situ), com aqueles obtidos quando se realiza esta ressecção com EVTF com tempo de isquemia menor que 60 minutos, e naqueles com tempo de isquemia maior ou igual a 60 minutos. Para tanto, foram analisados, como parâmetros, a função renal e hepática, morbidade, e mortalidade pós-operatórias nos três grupos mencionados,buscando-se determinar valores preditivos para indicação das técnicas. PACIENTES E MÉTODO. Foram estudados 81 pacientes submetidos à ressecção hepática. Estes pacientes foram divididos em três grupos. Trinta e quatro pacientes com EVTF menor do que 60 minutos (EVTF < 60’), 19 pacientes com EVTF maior ou igual a 60 minutos (EVTF &#8805; 60’), e 28 pacientes nos quais a perfusão hipotérmica in situ (EVTFHIPOT) foi realizada. Os valores das transaminases hepáticas (ASAT e ALAT), Bilirrubinas totais, creatinina, e tempo de protrombina foram registrados. Também foram verificados os índices de morbidade e de mortalidade pós-operatórias nos três grupos. RESULTADOS. O valor máximo no pós-operatório das enzimas hepáticas - ASAT e ALAT foram significativamente menores (p < 0.05) no grupo EVTFHIPOT (535 + 361 U/L e 436 + 427 U/L), quando comparados aos outros grupos - EVTF<60’(988 + 798 U/L; 844 + 733 U/L), EVTF>60’ (1583 + 984 U/L; 1082 + 842 U/L). No grupo EVTFHIPOT, os valores máximos das bilirrubinas (6,5 + 2,5 mg/dl),creatinina (1,2 + 0,7 mg/dl), e o número de complicações por paciente (1,2 + 1) foram semelhantes aos do grupo EVTF<60’’ (5,5 + 7,8; 1,3 + 1; e 0,7 + 1 respectivamente), e significativamente menores que os do grupo EVTF > 60’(12,8 + 11,8; 2,3 + 2,3, e 2,3 + 1,2). A mortalidade hospitalar foi de 1/34, 2/19 e 2/28 nos grupos EVTF < 60’, EVTF > 60’, e EVTFHIPOT, respectivamente,sem diferença estatística. CONCLUSÕES. Quando comparadas as técnicas clássicas de exclusão vascular do fígado,de qualquer duração, com aquela na qual se realizou a perfusão hipotérmica do fígado, conclui-se que, nesta última, os pacientes toleraram melhor a isquemia. Deve-se enfatizar que, na EVTF com hipotermia, existe melhor preservação da função hepática, melhor preservação da função renal, e menores índices de morbidade, quando comparada com a EVTF>60’’ sem hipotermia. Os fatores preditivos de EVTF por mais de 60 minutos auxiliam na adoção da opção pelo resfriamento hepático. / OBJECTIVE. To compare the results of liver resection performed under in situ hypothermic perfusion vs standard total vascular exclusion (TVE) of the liver < 60 minutes and &#8805; 60 minutes in terms of liver tolerance, liver and renal functions, postoperative morbidity and mortality. SUMMARY BACGROUND DATA. The safe duration of TVE is still debated. Promising results have been reported following TVE associated with hypothermic perfusion of the liver with durations of up to several hours. The two techniques have not been compared so far. PATIENTS AND METHODS.The study population includes 81 consecutive liver resections under TVE < 60 minutes (group TVE < 60’ , 34 patients), &#8805; 60 minutes (group TVE &#8805; 60’, 19 patients) and in situ hypothermic perfusion (group TVEHYPOTH , 28 patients). Liver tolerance (peaks of transaminases), liver and kidney function (peak of bilirubin, minimum prothrombin time and peak of creatinine), morbidity and inhospital mortality were compared within the 3 groups. RESULTS. The postoperative peaks of ASAT and ALAT were significantly lower (p < 0.05) in group TVE HYPOTH (535 + 361 U/L and 436 + 427 U/L) compared to the groups TVE<60’ (988 + 798 U/L; 844 + 733 U/L) and TVE&#8805;60’ (1583 + 984 U/L; 1082 + 842 U/L). In the group TVE HYPOTH , the peaks of bilirubin (6,5 + 2,5 mg/dl), creatinine (1,2 + 0,7 mg/dl), and the number of complications per patient (1,2 + 1) were comparable to those of the group TVE<60’ (5,5 + 7,8; 1,3 + 1; e 0,7 + 1 respectively) and significantly lower to those of the group TVE&#8805;60’ (12,8 + 11,8; 2,3 + 2,3, e 2,3 + 1,2). In hospital mortality rates were 1/34, 2/19 and 2/28 for the groups TVE < 60’ , TVE &#8805; 60’ , and TVEHYPOTH respectively and were comparable. On multivariate analysis, the size of the tumor, portal vein embolization and a planned vascular reconstruction werem significantly predictive of TVE &#8805; 60 minutes. CONCLUSIONS. Compared to standard TVE of any duration, hypothermic perfusion of the liver is associated with a better tolerance to ischemia. In addition, compared to TVE &#8805; 60 minutes, it is associated with better postoperative liver and renal functions, and a lower morbidity. Predictive factors for TVE &#8805; 60 minutes may help to indicate hypothermic perfusion of the liver.

A Manobra de Pringle é tempo cirúrgico fundamental, e de uso rotineiro em cirurgia hepática, tanto no trauma, como nas ressecções eletivas e nos transplantes. Têm como principal objetivo minimizar o sangramento intraoperatório, não obstante, leve, invariavelmente, à isquemia hepática transitória, à congestão vascular, e à isquemia do território esplâncnico, promovendo distúrbios hemodinâmicos indesejáveis. Algumas drogas têm sido testadas no sentido de minimizar a lesão de isquemia e reperfusão induzida pela Manobra de Pringle. A pentoxifilina tem demonstrado efeitos benéficos contra a lesão de isquemia e reperfusão no fígado. Atua, principalmente, na microcirculação, e também tem ação imunomoduladora. Assim, os objetivos dessa pesquisa foram: comparar os efeitos do uso da pentoxifilina por via portal ou periférica sobre a hemodinâmica regional e sistêmica, bem como a eventual ação hepatoprotetora na lesão de isquemia e reperfusão induzida pela manobra de Pringle. Vinte e quatro cães adultos, machos, e sem raça definida, foram anestesiados com sevoflurano e submetidos à ventilação mecânica. Para adequada descompressão do território esplâncnico, e com o objetivo de conseguir uma isquemia hepática isolada e prolongada, utilizamos derivação venosa extra-corpórea esplenofemural com bomba ativa tipo rolete. A veia pancreatoduodenal foi canulada e posicionado cateter na veia porta para perfusão normotérmica do fígado, utilizando-se bomba de infusão contínua. As variáveis hemodinâmicas foram obtidas através de cateteres posicionados na veia porta, artéria femoral direita, e cateter de Swan-Ganz na artéria pulmonar. As avaliações de perfusão esplâncnica foram realizadas com fluxômetro ultra-sônico na artéria hepática e na veia porta e tonometria a gás. Após 45 minutos de isquemia hepática, obtida pelo clampeamento do pedículo hepático, o fluxo hepático foi restabelecido e os animais observados por mais 120 minutos. Os animais foram divididos em três grupos experimentais: controle (n=8), perfusão do fígado com 500 mL de soro fisiológico a 0,9% durante os 45 minutos de isquemia; grupo pentoxifilina intra-hepático n=8, perfusão hepática com solução de pentoxifilina 50mg/Kg diluída em 500 mL de soro fisiológico a 0,9%; e grupo pentoxifilina sistêmica n=8 perfusão hepática com 500mL de soro fisiológico 0,9% e pentoxifilina 50mg/Kg via sistêmica administrada por veia periférica dissecada no membro superior esquerdo. Foram analisadas variáveis hemodinâmicas sistêmicas e esplâncnicas, gasométricas, tonometria gástrica, metabolismo de oxigênio, enzimas hepáticas e estudo histológico. O grupo pentoxifilina sistêmica apresentou melhora significativa do débito e índice cardíaco aos 60 minutos de reperfusão, em relação ao grupo controle. O fluxo venoso portal e o índice de fluxo de veia porta apresentaram melhora significativa no grupo pentoxifilina sistêmica, em relação ao grupo controle, após 45 minutos de reperfusão, permanecendo assim até o final do experimento. O grupo pentoxifilina intra-hepático também demonstrou melhora do fluxo venoso portal, porém sem alcançar significância estatística. Nos grupos tratados com pentoxifilina, os níveis séricos das enzimas hepáticas (TGO, TGP e LDH) também foram menores do que no grupo controle, ficando próximo à significância estatística. Assim, nas condições da presente pesquisa, pode-se concluir que a administração de pentoxifilina determinou melhora do fluxo venoso portal, quer pela via sistêmica, quer pela via portal. A administração da pentoxifilina pela via sistêmica promoveu melhora estatisticamente significante do fluxo venoso portal, do débito e do índice cardíaco, em relação ao grupo controle. Finalmente, a administração da pentoxifilina na vigência da manobra de Pringle sugere efeito hepatoprotetor / Portal triad occlusion (Pringle maneuver) is currently used during most hepatic resections for trauma or malignancies in order to decrease intraoperative bleeding. However this maneuver is associated with hepatic ischemia and splanchnic congestion. In this setting, many drugs have been tested to decrease the ischemia-reperfusion injury induced by this maneuver. Pentoxifylline, a methylxanthine derivative, has been shown to have beneficial effects on intestinal microvascular blood flow as well as hepatic blood flow during shock and resuscitation. The beneficial effects of pentoxifylline can be associated to the inhibition of inflammatory cytokines, such as TNF- a and IL-6. Our objective was evaluated the potential systemic and regional benefits of intraportal or systemic infusion of pentoxifylline during an experimental model of normothermic hepatic ischemia. Twenty four dogs were evaluated in this study. They were anesthetized with sevofluorane and subjected to mechanical ventilation. During hepatic ischemia period we used an active spleno-femoral. A catheter placed, trough the pancreatoduodenal vein, was used to perform hepatic perfusion. Systemic hemodynamics were evaluated through a Swan-Ganz and arterial catheters. Gastric mucosal pCO2 (gas tonometry), portal vein and hepatic artery blood flow (ultrasonic flowprobes), systemic and regional O2-derived variables, as well as liver enzymes (ALT, AST, DHL) were evaluated throughout the protocol. The animals were subjected to 45 minutes of ischemia. Previously to the Pringle maneuver the animals were randomized in three experimental groups: control (n=8), hepatic perfusion with 500 ml of saline solution; intraportal pentoxifylline (n=8) hepatic perfusion with saline solution + 50 mg/Kg of pentoxifylline; and systemic pentoxifylline (n=8) hepatic perfusion with 500 ml of saline solution and intravenous infusion of 50 mg/Kg of pentoxifylline (brachial vein). After hepatic ischemia period the animals were followed for an additional 120 minutes. Systemic infusion of pentoxifylline improved significantly cardiac output, as well as portal vein blood flow when compared with control group. Intraportal infusion of pentoxifylline presented a partial increase of portal vein blood flow. In both groups treated with pentoxifylline, there was a significant decrease in markers of hepatic cell injury during the reperfusion period when compared with control group. We conclude that systemic or intraportal infusion of pentoxyfilline improves portal vein blood flow, after 45 minutes of hepatic ischemia. Systemic infusion of pentoxifylline promotes a significant improvement in cardiac output when compared with control group. Our findings suggested that regional or systemic infusion of pentoxifylline minimize the deleterious effects of Pringle\'s maneuver