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Microdialysis in Liver Ischemia and Reperfusion injury
Linköping University, Department of Clinical and Experimental Medicine, Surgery. Linköping University, Faculty of Health Sciences.
2011 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Introduction: New chemotherapy regimens and improvements in surgical technique have increased the number of patients with liver tumours eligible for curative liver resection. There is a significant risk of bleeding during liver surgery, but this risk can be reduced if the portal inflow is temporarily closed; i.e. the Pringles maneuver (PM). If the PM is used, the liver will suffer from ischemia and reperfusion injury (IRI). If the liver remnant is too small or if the patient has chronic liver disease, the IRI may inhibit the regeneration of the liver remnant. The patient may then die from postoperative liver failure. Several strategies have been tried to protect the liver from IRI. For instance can the PM be applied in short intervals or reactive oxygen species can be scavenged by antioxidants. There are no sensitive methods available for studying IRI in patients and little is known how IRI affects the metabolism in the liver. Microdialysis is a technique that allows for continuous sampling of interstitial fluid in the organ of interest

Aim: To investigate the effects of ischemia and reperfusion on glucose metabolism in the liver using the microdialysis technique.

Method: A porcine model of segmental ischemia and reperfusion was developed. The hepatic perfusion and glucose metabolism was followed for 6-8 hours by placing microdialysis catheters in the liver parenchyma (studies I-III). In study IV, 16 patients were randomized to have 10 minutes of ischemic preconditioning prior to the liver resection, which was performed with 15 minutes of ischemia and 5 minutes of reperfusion repetitively until the tumour(s) were resected.

Results: During ischemia the glucose metabolism was anaerobic in the ischemic segment, while the perfused segment had normal glucose metabolism. Urea was added in the perfusate of the microdialysis catheters and was found to be a reliable marker of liver perfusion. The antioxidant NAcetylcystein (NAC) improved the hepatic aerobic glucose metabolism in the pig during the reperfusion, shown as reduced levels of lactate and improved glycogenesis in the hepatocytes. This can be explained by the scavenging of nitric oxide by NAC as nitric oxide otherwise would inhibit mitochondrial respiration. Also IP improved aerobic glucose metabolism resulting in lower hepatic lactate levels in patients having major liver resections.

Conclusion: Microdialysis can monitor the glucose metabolism both in animal experimental models and in patients during and after hepatectomy. Both NAC and IP improves aerobic glucose metabolism, which can be of value in patients with compromised liver function postoperatively.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press , 2011. , 86 p.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1238
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-68651ISBN: 978-91-7393-190-8OAI: oai:DiVA.org:liu-68651DiVA: diva2:419267
Public defence
2011-06-10, Nils Holger, Hälsouniversitetet, Campus US. Linköpings universitet, Linköping, 09:00 (English)
Opponent
Supervisors
Available from: 2011-05-26 Created: 2011-05-26 Last updated: 2015-06-05Bibliographically approved
List of papers
1. Segmental ischemia of the liver - microdialysis in a novel porcine model.
Open this publication in new window or tab >>Segmental ischemia of the liver - microdialysis in a novel porcine model.
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2009 (English)In: European surgical research. Europäische chirurgische Forschung. Recherches chirurgicales européennes, ISSN 1421-9921, Vol. 43, no 3, 276-285 p.Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: Segmental liver ischemia is often used in rodents to study ischemia and reperfusion injuries (IRI). There are no reports of protocols using segmental ischemia in porcine models. Microdialysis (MD) provides the opportunity to study local effects of IRI in vivo. METHODS: Eight pigs received an MD catheter placed in liver segments IV and V, respectively. All circulation to segment IV was stopped for 80 min, and reperfusion was followed for 240 min. RESULTS: During ischemia the levels of lactate, glycerol and glucose increased 3-fold (p < 0.001), 40-fold (p < 0.001) and 4-fold (p < 0.01), respectively, in the ischemic segment compared to the perfused segment, whereas the levels of pyruvate fell to a tenth of the preischemic level (p < 0.001). All values returned to baseline after reperfusion. Serum levels of aspartate aminotransferase increased (p < 0.05). Polymorphonuclear cells increased in both segments, although the density was significantly higher in segment IV. CONCLUSION: Clamping of one liver segment in pigs is a simple, stable and reproducible model to study IRI with minimal systemic effects. MD revealed no signs of anaerobic metabolism in the perfused segment but still there was an increase in the number of polymorphonuclear neutrophils in this segment, although it was lower than that in the ischemic segment.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-21350 (URN)10.1159/000230675 (DOI)19641322 (PubMedID)
Available from: 2009-10-01 Created: 2009-10-01 Last updated: 2011-05-26
2. Urea Clearance: A New Technique Based on Microdialysis to Assess Liver Blood Flow Studied in a Pig Model of Ischemia/Reperfusion
Open this publication in new window or tab >>Urea Clearance: A New Technique Based on Microdialysis to Assess Liver Blood Flow Studied in a Pig Model of Ischemia/Reperfusion
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2010 (English)In: EUROPEAN SURGICAL RESEARCH, ISSN 0014-312X, Vol. 45, no 2, 105-112 p.Article in journal (Refereed) Published
Abstract [en]

Delayed detection of ischemia is one of the most feared postoperative complications. Early detection of impaired blood flow and close monitoring of the organ-specific metabolic status may therefore be critical for the surgical outcome. Urea clearance is a new technique for continuous monitoring of alterations in blood flow and metabolic markers with acceptable temporal characteristics. We compare this new microdialysis technique with the established microdialysis ethanol technique to assess hepatic blood flow. Six pigs were used in a liver ischemia/reperfusion injury model. Microdialysis catheters were placed in liver segment IV and all circulation was stopped for 80 min, followed by reperfusion for 220 min. Urea and ethanol clearance was calculated from the dialysate and correlated with metabolic changes. A laser Doppler probe was used as reference of restoration of blood flow. Both urea and ethanol clearance reproducibly depicted changes in liver blood flow in relation to metabolic changes and laser Doppler measurements. The two techniques highly correlated both overall and during the reperfusion phase (r = 0.8) and the changes were paralleled by altered perfusion as recorded by laser Doppler.

Place, publisher, year, edition, pages
S. Karger AG, 2010
Keyword
Liver perfusion, Lactate, Ethanol, Metabolism, Recovery
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-62299 (URN)10.1159/000319868 (DOI)000283851400006 ()
Available from: 2010-11-26 Created: 2010-11-26 Last updated: 2012-03-20
3. N-Acetylcysteine Improves Glycogenesis after Segmental Liver Ischemia and Reperfusion Injury in Pigs
Open this publication in new window or tab >>N-Acetylcysteine Improves Glycogenesis after Segmental Liver Ischemia and Reperfusion Injury in Pigs
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(English)Manuscript (preprint) (Other academic)
Abstract [en]

Objective: N-Acetylcysteine (NAC) is an antioxidative molecule known to protect liver tissue from oxygen radical species generated during ischemia and reperfusion. Nutritional and toxicology studies have shown that NAC also improves glucose metabolism and glycogen stores. We hypothesized that NAC improves glycogenesis and that impaired glycogenesis is a key element in ischemia-reperfusion injury.

Material and Methods: In an experimental model, 80 minutes of segmental liver ischemia was induced in 16 pigs and the reperfusion was followed for 360 minutes. Eight animals received NAC 150 mg/kg as a bolus injection followed by an infusion of NAC 50 mg/kg/h intravenously.

Results: AST and leukocyte density were lower in the NAC-treated animals, unrelated to the glutathione levels or apoptosis. Glycogen stores returned to a higher degree in the NAC treated animals and microdialysis revealed lower levels of lactate during the reperfusion phase. Nitrite/Nitrate levels in the NAC group were lower in both serum and microdialysate, indicating that NAC scavenges radical nitrosative species (RNS).

Conclusions: NAC treatment improves glycogenesis after liver ischemia and reperfusion injury and reduces the level of intraparenchymal lactate during reperfusion, possibly due to the scavenging of RNS.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-68649 (URN)
Available from: 2011-05-26 Created: 2011-05-26 Last updated: 2011-05-26Bibliographically approved
4. Ischemic Preconditioning Prior to Intermittent Pringles Maneuver in Liver Resections
Open this publication in new window or tab >>Ischemic Preconditioning Prior to Intermittent Pringles Maneuver in Liver Resections
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2012 (English)In: Journal of Hepato-Biliary-Pancreatic Sciences, ISSN 1868-6982, Vol. 19, no 2, 159-170 p.Article in journal (Refereed) Published
Abstract [en]

Background: Continuous inflow vascular occlusion during liver resections causes less severe ischemia and reperfusion injury (IRI) if it is preceded by ischemic preconditioning (IP) or if intermittent inflow occlusion is used during the resection. No previous clinical trial has studied the effects of adding IP to intermittent inflow occlusion.

Methods: Consecutive patients (n=32) with suspicion of malignant liver disease had liver resections (minimum 2 segments) performed with inflow occlusion 15/5. Half of the patients were randomized to receive IP (10/10). The patients were stratified according to volume of resection and none had chronic liver disease. The patients were followed for 5 days with microdialysis (μD).

Results: All patients completed the study and there were no deaths. No differences were seen between the groups regarding demographics or perioperative parameters (bleeding, duration of ischemia, resection volume, complications and serum lab tests). There were no differences in ALT, AST, Bilirubin or PT-INR levels, but μD revealed lower levels of lactate, pyruvate and glucose in the IP group having major liver resections (ANOVA). Nitrite and nitrate levels in μD decreased postoperatively but no differences were seen between the groups. In one patient an elevated μDglycerol curve was seen before the diagnosis of a stroke was made.

Conclusions: IP before intermittent vascular occlusion does not reduce the serum parameters used to assess IRI. IP seems to improve aerobic glucose metabolism as the levels of glucose, pyruvate and lactate locally in the liver were reduced compared to controls in patients having resected >3 segments. μD may be used to monitor metabolism locally.

Place, publisher, year, edition, pages
Springer, 2012
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-68650 (URN)10.1007/s00534-011-0402-9 (DOI)000302092500011 ()
Available from: 2011-05-26 Created: 2011-05-26 Last updated: 2014-09-08Bibliographically approved

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