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- Björnsson, Bergþór, 1975-
(författare)
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Methods to Reduce Liver Ischemia/Reperfusion Injury
- 2014
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Introduction: During the last two decades, liver surgery has expanded enormously, partly due to improved surgical equipment and techniques as well as new and more powerful chemotherapy agents. As the liver is a very well-vascularized organ, there is an inherent risk of bleeding during liver resection. One of the most popular methods employed to reduce this risk is to close the vascular inflow to the liver using the Pringle’s maneuver (PM). However, this procedure has been recognized to cause ischemia/reperfusion injury (IRI) to the future liver remnant (FLR). In cases of extensive resection where the FLR is small and in cases when the liver suffers from chronic diseases, such as cirrhosis, IRI can greatly increase the risk of post-operative liver failure (POLF). Ischemic preconditioning (IPC) and, more recently, remote ischemic preconditioning (R-IPC) are methods that have been employed to reduce IRI.Aim: 1) To compare the effects of IPC and R-IPC in a rat model; 2) to investigate the clinical effect of IPC during modern liver surgery; 3) to investigate the role of the nitric oxide (NO) system in IRI, IPC and R-IPC; and 4) to explore the possible protective effects of nitrite administration before IRI.Methods: A rat model of segmental ischemia followed by 4 hours of reperfusion including microdialysis (μD) was developed from earlier models. The effects of IPC and R-IPC were compared using transaminases and histology as well as continuous μD sampling for glucose, pyruvate, lactate and glycerol. The role of the NO system was examined by serum and μD measurements of NOx as well as tissue measurements of iNOS mRNA and IL-1R mRNA. In study II, patients were randomized to IPC or no IPC prior to liver resection, where intermittent PM was used to decrease bleeding.Results: IPC was more effective in protecting the liver against IRI than R-IPC, as indicated by the levels of transaminases. Lower lactate levels were detected in patients treated with IPC before major liver resections than in controls. IPC reduced iNOS mRNA transcription during reperfusion; this result may be related to the early but not sustained increases in IL-1R transcription observed in the IPC group. Nitrite administered before ischemia reduced AST and ALT levels in the level after 4 hours of reperfusion; in addition, necrosis and glycerol release from the ischemic liver were reduced as well.Conclusion: IPC is more effective than R-IPC in animal models; however, this effect is unlikely to be of clinical importance. NOx decreases in the ischemic liver and the administration of nitrite before ischemia reduces IRI in rats. This may have clinical implications in the future.
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| 2. |
- Sedigh, Amir
(författare)
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Management of Ischemia and Brain Death-Associated Injuries in Porcine Kidney Grafts
- 2014
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Organs from deceased donors after brain death (BD) remain the major source of organs for transplantation. The catastrophic event of BD and the inevitable consequences of ischemia reperfusion injury (IRI) are linked to impaired graft quality and transplantation outcome. The aim of this thesis was to create a BD model in pigs to assess early effects on IRI in kidneys preserved with an oxygenated solution and to evaluate the protective effects of coating the renal vessel walls with a heparin conjugate during hypothermic machine perfusion (HMP).Brain death was achieved by raising the intracranial pressure (ICP) through stepwise increasing the volume of an epidurally placed balloon to the point of exceeding the mean arterial pressure (MAP) creating a negative cerebral perfusion pressure (CPP). This reproducible, clinically relevant experimental model makes evaluation of potential targeted methods to protect the organs possible. Kidneys retrieved from brain-dead pigs were preserved either in an oxygenated emulsion composed of 75% histidine-tryptophan-ketoglutarate (HTK) and 25% perfluorohexyloctane F6H8 or HTK alone. After 18h of cold storage the kidneys were transplanted into allogeneic pigs. F6H8 was associated with replenishment of adenosine triphosphate and lower gene expression of hypoxia inducible factor (HIF)-1a, vascular endothelial growth factor (VEGF), interleukin (IL)-1α and tumour necrosis factor (TNF)-α. F6H8 reduced early IRI at both the cellular and molecular level.Kidneys from BD pigs were evaluated for the feasibility of coating the vessel walls with the heparin conjugate CHC (Corline Systems AB, Uppsala, Sweden) to restore glycocalyx. Porcine kidneys were preserved by HMP for 20h with 50 mg biotinylated CHC added to the perfusion solution. CHC was detected on the inner surface of the kidney vessels by immunofluorescence, and its uptake in kidneys was confirmed by reduced content in the perfusate. An ex vivo normothermic perfusion circuit was developed to assess kidney function. Perfusion with CHC during HMP was associated with lower creatinine levels, increased urine volume and reduced tubular injury. Modifying renal vessels walls using CHC during HMP improved early graft function. Preservation with the oxygenated F6H8 solution or CHC could be used to improve graft quality and ameliorate IRI in kidneys retrieved from deceased donors.
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