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Roehl AB, Andert A, Junge K, Neumann UP, Hein M, Kork F. Effect of Aprotinin on Liver Injury after Transplantation of Extended Criteria Donor Grafts in Humans: A Retrospective Propensity Score Matched Cohort Analysis. J Clin Med 2021; 10:jcm10225232. [PMID: 34830514 PMCID: PMC8623344 DOI: 10.3390/jcm10225232] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2021] [Revised: 10/29/2021] [Accepted: 11/08/2021] [Indexed: 11/16/2022] Open
Abstract
The number of patients awaiting liver transplantation still widely exceeds the number of donated organs available. Patients receiving extended criteria donor (ECD) organs are especially prone to an aggravated ischemia reperfusion syndrome during liver transplantation leading to massive hemodynamic stress and possible impairment in organ function. Previous studies have demonstrated aprotinin to ameliorate reperfusion injury and early graft survival. In this single center retrospective analysis of 84 propensity score matched patients out of 274 liver transplantation patients between 2010 and 2014 (OLT), we describe the association of aprotinin with postreperfusion syndrome (PRS), early allograft dysfunction (EAD: INR 1,6, AST/ALT > 2000 within 7–10 days) and recipient survival. The incidence of PRS (52.4% vs. 47.6%) and 30-day mortality did not differ (4.8 vs. 0%; p = 0.152) but patients treated with aprotinin suffered more often from EAD (64.3% vs. 40.5%, p = 0.029) compared to controls. Acceptable or poor (OR = 3.3, p = 0.035; OR = 9.5, p = 0.003) organ quality were independent predictors of EAD. Our data do not support the notion that aprotinin prevents nor attenuates PRS, EAD or mortality.
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Affiliation(s)
- Anna B. Roehl
- Department of Anesthesiology, Faculty of Medicine, RWTH Aachen University, 52074 Aachen, Germany; (M.H.); (F.K.)
- Correspondence: ; Tel.: +49-241-808-0179
| | - Anne Andert
- Department of General, Visceral and Transplantation Surgery, Faculty of Medicine, RWTH Aachen University, 52074 Aachen, Germany; (A.A.); (U.P.N.)
| | - Karsten Junge
- Department of General and Visceral Surgery, Rhein-Maas Hospital, 52146 Würselen, Germany;
| | - Ulf P. Neumann
- Department of General, Visceral and Transplantation Surgery, Faculty of Medicine, RWTH Aachen University, 52074 Aachen, Germany; (A.A.); (U.P.N.)
| | - Marc Hein
- Department of Anesthesiology, Faculty of Medicine, RWTH Aachen University, 52074 Aachen, Germany; (M.H.); (F.K.)
| | - Felix Kork
- Department of Anesthesiology, Faculty of Medicine, RWTH Aachen University, 52074 Aachen, Germany; (M.H.); (F.K.)
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Abstract
Objective: Impairment of liver blood flow and, therefore, potentially liver function, has important short-term consequences because of the liver’s key metabolic importance and role in drug metabolism. The objective of this study was to quantify the effect of cardiac surgery on liver blood flow from before the induction of anaesthesia to 24 hours postoperatively. Method: Ten patients with no history of liver impairment, moderate or good left ventricular function, and undergoing routine hypothermic coronary artery bypass graft surgery, were entered into the study. Liver blood flow was determined by the clearance of indocyanine green (ICG), expressed as a percentage disappearance rate (PDR). Results: The mean baseline percentage disappearence rate (PDR) of indocyanine green (ICG) was 19.849-4.47%/min. This increased marginally to 20.429-6.67%/min following the induction of anaesthesia, but after 15 min of cardiopulmonary bypass, the PDR fell to 13.519-3.69%/min; this was significantly lower than all other PDRs measured throughout the study. Prior to extubation, the PDR increased again to 20.019-3.72%-min, and this level was maintained at 12 hours (PDR 20.329-3.53%min) and 24 hours (PDR 20.519-2.27%/min). Conclusion: The induction of anaesthesia and positive pressure ventilation do not affect liver blood flow. Cardiopulmonary bypass at 308C is associated with a significant reduction in liver blood flow, which returns to normal within 4 / 6 hours of surgery and remains normal for up to 24 hours after surgery.
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Affiliation(s)
- Govind Chetty
- Department of Cardiothoracic Surgery, Blackpool Victoria Hospital, Blackpool, UK
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Cámara-Lemarroy CR, Guzmán-de la Garza FJ, Alarcón-Galván G, Cordero-Pérez P, Muñoz-Espinosa L, Torres-González L, Fernández-Garza NE. Hepatic ischemia/reperfusion injury is diminished by atorvastatin in Wistar rats. Arch Med Res 2014; 45:210-6. [PMID: 24726586 DOI: 10.1016/j.arcmed.2014.02.001] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2013] [Accepted: 01/30/2014] [Indexed: 01/09/2023]
Abstract
BACKGROUND AND AIMS Temporal occlusion of the hepatoduodenal ligament (HDL) is often used during liver surgeries in order to reduce blood loss, resulting in ischemia/reperfusion injury (I/R). The aim of the study was to investigate the effects of atorvastatin (ATOR) on hepatic I/R injury and on serum levels of tumor necrosis factor-alpha (TNF-α), endothelin-1 (ET-1), antithrombin III (ATIII) and intracellular adhesion molecule-1 (ICAM-1). METHODS Liver ischemia was induced in Wistar rats by clamping the HDL for 60 min, followed by either 60 or 180 min reperfusion. Rats received either vehicle or 10 mg/kg ATOR before hepatic I/R. Control group received sham surgery. Livers were examined for histological damage and serum AST, ALT, TNF-α, ET-1, ATIII and ICAM-1 concentrations were measured. RESULTS After I/R, AST and ALT were significantly elevated, ATIII levels were significantly depleted, both TNF-α and ICAM-1 levels increased and ET-1 was significantly elevated (at 180 min). ATOR pretreatment attenuated these alterations and diminished histological injury scores. CONCLUSIONS Our results show that ATOR protects the liver from I/R injury.
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Affiliation(s)
| | | | - Gabriela Alarcón-Galván
- Servicio de Anatomía Patológica y Citopatología, Hospital Universitario "José Eleuterio González," Monterrey, Nuevo León, Mexico
| | - Paula Cordero-Pérez
- Unidad de Hígado, Departamento de Medicina Interna, Universidad Autónoma de Nuevo León, School of Medicine, Monterrey, Nuevo León, Mexico
| | - Linda Muñoz-Espinosa
- Unidad de Hígado, Departamento de Medicina Interna, Universidad Autónoma de Nuevo León, School of Medicine, Monterrey, Nuevo León, Mexico
| | - Liliana Torres-González
- Unidad de Hígado, Departamento de Medicina Interna, Universidad Autónoma de Nuevo León, School of Medicine, Monterrey, Nuevo León, Mexico
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Kloek JJ, Levi M, Heger M, van der Loos CM, Gouma DJ, van Gulik TM. Cholestasis enhances liver ischemia/reperfusion-induced coagulation activation in rats. Hepatol Res 2010; 40:204-15. [PMID: 19737317 DOI: 10.1111/j.1872-034x.2009.00579.x] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
AIM Cholestasis is associated with increased morbidity and mortality in patients undergoing major liver surgery. An additional risk is induced when vascular inflow occlusion is applied giving rise to liver ischemia/reperfusion (I/R) injury. The role of the coagulation system in this type of injury is elusive. The aim of the current study was to assess activation of coagulation following hepatic I/R injury in cholestatic rats. METHODS Male Wistar rats were randomized into two groups and subjected to bile duct ligation (BDL) or sham laparotomy. After 7 days, both groups underwent 30 min partial liver ischemia. Animals were sacrificed before ischemia or after 6 h, 24 h, and 48 h reperfusion. RESULTS Plasma AST and ALT levels were higher after I/R in cholestatic rats (P < 0.05). Hepatic necrosis, liver wet/dry ratio and neutrophil influx were increased in the BDL group up to 48 h reperfusion (P < 0.05). Liver synthetic function was decreased in the BDL group as reflected by prolonged prothrombin time after 6 h and 24 h reperfusion (P < 0.05). I/R in cholestatic rats resulted in a 12-fold vs. 7-fold (P < 0.01) increase in markers for thrombin generation and a 6-fold vs. 2-fold (P < 0.01) increase in fibrin degradation products (BDL vs. control, respectively). In addition, the cholestatic rats exhibited significantly decreased levels of antithrombin (AT) III and increased levels of the fibrinolytic inhibitor plasminogen activator inhibitor (PAI-1) during reperfusion. CONCLUSIONS Cholestasis significantly enhances I/R-induced hepatic damage and inflammation that concurs with an increased activation of coagulation and fibrinolysis.
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Affiliation(s)
- Jaap J Kloek
- Departments of Surgery, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands
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Vollmar B, Menger MD. The hepatic microcirculation: mechanistic contributions and therapeutic targets in liver injury and repair. Physiol Rev 2009; 89:1269-339. [PMID: 19789382 DOI: 10.1152/physrev.00027.2008] [Citation(s) in RCA: 368] [Impact Index Per Article: 23.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023] Open
Abstract
The complex functions of the liver in biosynthesis, metabolism, clearance, and host defense are tightly dependent on an adequate microcirculation. To guarantee hepatic homeostasis, this requires not only a sufficient nutritive perfusion and oxygen supply, but also a balanced vasomotor control and an appropriate cell-cell communication. Deteriorations of the hepatic homeostasis, as observed in ischemia/reperfusion, cold preservation and transplantation, septic organ failure, and hepatic resection-induced hyperperfusion, are associated with a high morbidity and mortality. During the last two decades, experimental studies have demonstrated that microcirculatory disorders are determinants for organ failure in these disease states. Disorders include 1) a dysregulation of the vasomotor control with a deterioration of the endothelin-nitric oxide balance, an arterial and sinusoidal constriction, and a shutdown of the microcirculation as well as 2) an overwhelming inflammatory response with microvascular leukocyte accumulation, platelet adherence, and Kupffer cell activation. Within the sequelae of events, proinflammatory mediators, such as reactive oxygen species and tumor necrosis factor-alpha, are the key players, causing the microvascular dysfunction and perfusion failure. This review covers the morphological and functional characterization of the hepatic microcirculation, the mechanistic contributions in surgical disease states, and the therapeutic targets to attenuate tissue injury and organ dysfunction. It also indicates future directions to translate the knowledge achieved from experimental studies into clinical practice. By this, the use of the recently introduced techniques to monitor the hepatic microcirculation in humans, such as near-infrared spectroscopy or orthogonal polarized spectral imaging, may allow an early initiation of treatment, which should benefit the final outcome of these critically ill patients.
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Affiliation(s)
- Brigitte Vollmar
- Institute for Experimental Surgery, University of Rostock, Rostock, Germany.
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Polat KY, Aydinli B, Polat O, Aydin U, Yazici P, Ozturk G, Gundogdu C, Kiziltunc A. The protective effect of aprotinin and alpha-tocopherol on ischemia-reperfusion injury of the rat liver. Transplant Proc 2008; 40:63-8. [PMID: 18261548 DOI: 10.1016/j.transproceed.2007.11.047] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023]
Abstract
BACKGROUND Liver injury caused by ischemia-reperfusion (I/R) processes is a complication of hepatic resection surgery and transplantation, particularly using grafts from marginal donors. Despite improvements in organ preservation and advances in surgical techniques, I/R injury remains a significant clinical problem. In this study, we investigated whether aprotinin provided protection against the adverse effects of I/R injury in liver tissue. METHODS Forty rats were randomized into four groups (n = 10): group I: (control group) I/R + no medication; group II: sham-operated group + no medication or I/R; group III: I/R + aprotinin; group IV: I/R + alpha-tocopherol. Malondialdehyde (MDA) was measured in the liver tissue and superoxide dismutase (SOD), catalase (CAT), aspartate aminotransferase (AST), alanine aminotransferase (ALT), as well as lactate dehydrogenase (LDH) in rat serum. RESULTS Administration of aprotinin and alpha-tocopherol before I/R resulted in significant reductions of MDA levels compared to the I/R alone group (group I; P = .01 and P < .01, respectively). Administration of aprotinin or alpha-tocopherol prior to I/R resulted in significant increases in SOD and CAT levels compared with the I/R group (P < .05 each). Compared to the I/R group, significant decreases in plasma AST, ALT, and LDH levels were observed both in the aprotinin and in the alpha-tocopherol group (P < .05). Histological evaluation revealed the injury grade to be relatively lower among groups III and IV compared to group I. DISCUSSION In conclusion, rat hepatic structures in aprotinin and alpha-tocopherol administered groups were well protected. Therefore, aprotinin may provide protection against the adverse effects of I/R injury in liver transplantation.
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Affiliation(s)
- K Y Polat
- Department of General Surgery, Ataturk University, Erzurum, Turkey
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Ischemia-Reperfusion Injury. Eur J Trauma Emerg Surg 2007; 33:600-12. [DOI: 10.1007/s00068-007-7152-z] [Citation(s) in RCA: 69] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2007] [Accepted: 10/30/2007] [Indexed: 12/21/2022]
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Maksan SM, Ulger Z, Gebhard MM, Schmidt J. Impact of antithrombin III on hepatic and intestinal microcirculation in experimental liver cirrhosis and bowel inflammation: An in vivo analysis. World J Gastroenterol 2005; 11:4997-5001. [PMID: 16124052 PMCID: PMC4321916 DOI: 10.3748/wjg.v11.i32.4997] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To analyze the hepatic and intestinal microcirculation in an animal model of liver cirrhosis and inflammatory bowel disease (IBD) and to characterize the anti-inflammatory action of antithrombin III (ATIII) on leukocyte kinetics and liver damage.
METHODS: Hepatic and intestinal microcirculation was investigated by intravital videomicroscopy. Standardized models of experimental chronic liver cirrhosis and bowel inflammation were employed. Animals were divided into four groups (n = 6/group): controls, animals with cirrhosis, animals with cirrhosis and IBD, animals with cirrhosis and IBD treated with ATIII.
RESULTS: Cirrhosis facilitated leukocyte rolling and sticking in hepatic sinusoids (1.91±0.28 sticker/µm vs 0.5±0.5 sticker/µm in controls, P<0.05). The effect enhanced in animals with cirrhosis and IBD (5.4±1.65 sticker/µm), but reversed after ATIII application (3.97±1.04 sticker/µm, P<0.05). Mucosal blood flow showed no differences in cirrhotic animals and controls (5.3±0.31 nL/min vs 5.4±0.25 nL/min) and was attenuated in animals with cirrhosis and IBD significantly (3.49±0.6 nL/min). This effect was normalized in the treatment group (5.13±0.4 nL/min, P<0.05). Enzyme values rose during development of cirrhosis and bowel inflammation, and reduced after ATIII application (P<0.05).
CONCLUSION: Liver cirrhosis in the presence of IBD leads to a significant reduction in mucosal blood flow and an increase in hepatic leukocyte adherence with consecutive liver injury, which can be prevented by administration of ATIII.
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Maksan SM, Ryschich E, Ulger Z, Gebhard MM, Schmidt J. Disturbance of hepatic and intestinal microcirculation in experimental liver cirrhosis. World J Gastroenterol 2005; 11:846-9. [PMID: 15682478 PMCID: PMC4250594 DOI: 10.3748/wjg.v11.i6.846] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To analyze hepatic, mesenteric and mucosal microcirculation and leukocyte-endothelium interaction (LEI) in a rat model with liver cirrhosis.
METHODS: Hepatic cirrhosis was induced in Wistar rats by gavage with carbon tetrachloride, and intravital videomicroscopy was performed in liver, mesentery and small intestine mucosa. Special emphasis is given on microcirculatory and morphometric changes during cirrhotic portal hypertension.
RESULTS: LEI was influenced significantly in the cirrhotic liver but not in the gut. Blood flow measurement showed significant differences among liver, main mesenteric vessels and the mucosa. The results of our study indicate that liver cirrhosis leads to alterations in hepatic and mesenteric blood flow but not in mucosal blood flow.
CONCLUSION: The enhanced inflammatory response in hepatic microvessels may be caused by a decrease of antithrombin III levels and could be responsible for disturbances of organ pathology.
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Affiliation(s)
- Sasa-Marcel Maksan
- Department of Surgery, University of Mainz, Langenbeckstrasse 1, D-55131 Mainz, Germany.
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