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Methods to Reduce Liver Ischemia/Reperfusion Injury
Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
2014 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

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.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2014. , 136 p.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1418
National Category
Clinical Medicine Basic Medicine
Identifiers
URN: urn:nbn:se:liu:diva-110318DOI: 10.3384/diss.diva-110318ISBN: 978-91-7519-245-1 (print)OAI: oai:DiVA.org:liu-110318DiVA: diva2:744239
Public defence
2014-10-17, Aulan, Campus US, Linköpings universitet, Linköping, 09:00 (Swedish)
Opponent
Supervisors
Available from: 2014-09-08 Created: 2014-09-08 Last updated: 2014-09-08Bibliographically approved
List of papers
1. Remote or Conventional Ischemic Preconditioning -Local Liver Metabolism in Rats Studied with Microdialysis
Open this publication in new window or tab >>Remote or Conventional Ischemic Preconditioning -Local Liver Metabolism in Rats Studied with Microdialysis
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2012 (English)In: Journal of Surgical Research, ISSN 0022-4804, E-ISSN 1095-8673, Vol. 176, no 1, 55-62 p.Article in journal (Refereed) Published
Abstract [en]

Background. Ischemic preconditioning (IPC) of the liver decreases liver injury secondary to ischemia and reperfusion. An attractive alternative to IPC is remote ischemic preconditioning (R-IPC), but these two methods have not previously been compared. Material and Methods. Eighty-seven rats were randomized into four groups: sham operated (n = 15), 1 h segmental ischemia (IRI, n = 24), preceeded by IPC (n = 24), or R-IPC (n = 24) (to the left hindleg). IPC and R-IPC were performed with 10 min ischemia and 10 min of reperfusion. Analyses of liver microdialysate (MD), serum transaminase levels, and liver histology were made. Results. Rats treated with IPC and R-IPC had significantly lower AST, 71.5 (19.6) IU/L respective 96.6 (12.4) at 4 h reperfusion than those subjected to IRI alone, 155 (20.9), P = 0.0004 and P = 0.04 respectively. IPC also had lower ALT levels, 41.6 (11.3) IU/L than had IRI 107.4 (15.5), P = 0.003. The MD glycerol was significantly higher during ischemia in the R-IPC = 759 (84) mu M] and the IRI = 732 (67)] groups than in the IPC 514 (70) group, P = 0.022 and P = 0.046 respectively. The MD glucose after ischemia was lower in the IPC group 7.1 (1.2) than in the IRI group 12.7 (1.6), P = 0.005. Preconditioning to the liver caused an direct increase in lactate, glucose and glycerol in the ischemic segment compared with the control segment an effect not seen in the R-IPC and IRI groups. Conclusions. IPC affects glucose metabolism in the rat liver, observed with MD. IPC reduces liver cell injury during ischemic and reperfusion in rats. R-IPC performed over the same length of time as IPC does not have the same effect as the latter on ALT levels and MD glycerol; this may suggest that R-IPC does not offer the same protection as IPC in this setting of rat liver IRI.

Place, publisher, year, edition, pages
Elsevier, 2012
Keyword
ischemia-reperfusion injury; preconditioning; remote preconditioning; liver ischemia; liver surgery; microdialysis
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-79791 (URN)10.1016/j.jss.2011.07.038 (DOI)000305210100018 ()
Available from: 2012-08-17 Created: 2012-08-14 Last updated: 2017-12-07
2. 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
3. Conventional, but not remote ischemic preconditioning, reduces iNOS transcription in liver ischemia/reperfusion
Open this publication in new window or tab >>Conventional, but not remote ischemic preconditioning, reduces iNOS transcription in liver ischemia/reperfusion
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2014 (English)In: World Journal of Gastroenterology, ISSN 1007-9327, E-ISSN 2219-2840, Vol. 20, no 28, 9506-9512 p.Article in journal (Refereed) Published
Abstract [en]

AIM: To study the effects of preconditioning on inducible nitric oxide synthase (iNOS) and interleukin 1 (IL-1) receptor transcription in rat liver ischemia/reperfusion injury (IRI). METHODS: Seventy-two male rats were randomized into 3 groups: the one-hour segmental ischemia (IRI, n = 24) group, the ischemic preconditioning (IPC, n = 24) group or the remote ischemic preconditioning (R-IPC, n = 24) group. The IPC and R-IPC were performed as 10 min of ischemia and 10 min of reperfusion. The iNOS and the IL-1 receptor mRNA in the liver tissue was analyzed with real time PCR. The total Nitrite and Nitrate (NOx) in continuously sampled microdialysate (MD) from the liver was analyzed. In addition, the NOx levels in the serum were analyzed. RESULTS: After 4 h of reperfusion, the iNOS mRNA was significantly higher in the R-IPC (Delta Ct: 3.44 +/- 0.57) group than in the IPC (Delta Ct: 5.86 +/- 0.82) group (P = 0.025). The IL-1 receptor transcription activity was reduced in the IPC group (Delta Ct: 1.88 +/- 0.53 to 4.81 +/- 0.21), but not in the R-IPC group, during reperfusion (P = 0.027). In the MD, a significant drop in the NOx levels was noted in the R-IPC group (12.3 +/- 2.2 to 4.7 +/- 1.2 mu mol/L) at the end of ischemia compared with the levels in early ischemia (P = 0.008). A similar trend was observed in the IPC group (11.8 +/- 2.1 to 6.4 +/- 1.5 mu mol/L), although this difference was not statistically significant. The levels of NOx rose quickly during reperfusion in both groups. CONCLUSION: IPC, but not R-IPC, reduces iNOS and IL-1 receptor transcription during early reperfusion, indicating a lower inflammatory reaction. NOx is consumed in the ischemic liver lobe.

Place, publisher, year, edition, pages
Baishideng Publishing Group Co. Limited, 2014
Keyword
Ischemia-reperfusion injury; Preconditioning; Remote preconditioning; Liver ischemia; Liver surgery; Microdialysis; Nitric oxide; inducible nitric oxide synthase; interleukin-1 receptor
National Category
Gastroenterology and Hepatology
Identifiers
urn:nbn:se:liu:diva-109589 (URN)10.3748/wjg.v20.i28.9506 (DOI)000339389800032 ()25071345 (PubMedID)
Available from: 2014-08-21 Created: 2014-08-21 Last updated: 2017-12-05
4. Nitrite, a novel method to decrease ischemia/reperfusion injury in the rat liver
Open this publication in new window or tab >>Nitrite, a novel method to decrease ischemia/reperfusion injury in the rat liver
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2015 (English)In: World Journal of Gastroenterology, ISSN 1007-9327, E-ISSN 2219-2840, Vol. 21, no 6, 1775-1783 p.Article in journal (Refereed) Published
Abstract [en]

AIM: To investigate whether nitrite administered prior to ischemia/reperfusion (I/R) reduces liver injury.

METHODS: Thirty-six male Sprague-Dawley rats were randomized to 3 groups, including sham operated (n = 8), 45-min segmental ischemia of the left liver lobe (IR, n = 14) and ischemia/reperfusion (I/R) preceded by the administration of 480 nmol of nitrite (n = 14). Serum transaminases were measured after 4 h of reperfusion. Liver microdialysate (MD) was sampled in 30-min intervals and analyzed for glucose, lactate, pyruvate and glycerol as well as the total nitrite and nitrate (NOx). The NOx was measured in serum.

RESULTS: Aspartate aminotransferase (AST) at the end of reperfusion was higher in the IR group than in the nitrite group (40 ± 6.8 μkat/L vs 22 ± 2.6 μkat/L, P = 0.022). Similarly, alanine aminotransferase (ALT) was also higher in the I/R group than in the nitrite group (34 ± 6 μkat vs 14 ± 1.5 μkat, P = 0.0045). The NOx in MD was significantly higher in the nitrite group than in the I/R group (10.1 ± 2.9 μM vs 3.2 ± 0.9 μM, P = 0.031) after the administration of nitrite. During ischemia, the levels decreased in both groups and then increased again during reperfusion. At the end of reperfusion, there was a tendency towards a higher NOx in the I/R group than in the nitrite group (11.6 ± 0.7 μM vs 9.2 ± 1.1 μM, P = 0.067). Lactate in MD was significantly higher in the IR group than in the nitrite group (3.37 ± 0.18 mM vs 2.8 ± 0.12 mM, P = 0.01) during ischemia and the first 30 min of reperfusion. During the same period, glycerol was also higher in the IRI group than in the nitrite group (464 ± 38 μM vs 367 ± 31 μM, P = 0.049). With respect to histology, there were more signs of tissue damage in the I/R group than in the nitrite group, and 29% of the animals in the I/R group exhibited necrosis compared with none in the nitrite group. Inducible nitric oxide synthase (iNOS) transcription increased between early ischemia (t = 15) and the end of reperfusion in both groups.

CONCLUSION: Nitrite administered before liver ischemia in the rat liver reduces anaerobic metabolism and cell necrosis, which could be important in the clinical setting.

Place, publisher, year, edition, pages
Baishideng Publishing Group Co. Limited, 2015
Keyword
Ischemia-reperfusion injury; Nitrite; Liver ischemia; Liver surgery; Microdialysis; Nitric oxide; Inducible nitric oxide synthase
National Category
Gastroenterology and Hepatology
Identifiers
urn:nbn:se:liu:diva-110262 (URN)10.3748/wjg.v21.i6.1775 (DOI)000349666300010 ()25684942 (PubMedID)
Available from: 2014-09-05 Created: 2014-09-05 Last updated: 2017-12-05Bibliographically approved

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