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      The effects of terlipressin and direct portacaval shunting on liver hemodynamics following 80% hepatectomy in the pig

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          Abstract

          Liver failure is the major cause of death following liver resection. Post-resection portal venous pressure (PVP) predicts liver failure, is implicated in its pathogenesis, and when PVP is reduced, rates of liver dysfunction decrease. The aim of the present study was to characterize the hemodynamic, biochemical, and histological changes induced by 80% hepatectomy in non-cirrhotic pigs and determine if terlipressin or direct portacaval shunting can modulate these effects. Pigs were randomized ( n=8/group) to undergo 80% hepatectomy alone (control); terlipressin (2 mg bolus + 0.5–1 mg/h) + 80% hepatectomy; or portacaval shunt (PCS) + 80% hepatectomy, and were maintained under terminal anesthesia for 8 h. The primary outcome was changed in PVP. Secondary outcomes included portal venous flow (PVF), hepatic arterial flow (HAF), and biochemical and histological markers of liver injury. Hepatectomy increased PVP (9.3 ± 0.4 mmHg pre-hepatectomy compared with 13.0 ± 0.8 mmHg post-hepatectomy, P<0.0001) and PVF/g liver (1.2 ± 0.2 compared with 6.0 ± 0.6 ml/min/g, P<0.0001) and decreased HAF (70.8 ± 5.0 compared with 41.8 ± 5.7 ml/min, P=0.002). Terlipressin and PCS reduced PVP (terlipressin = 10.4 ± 0.8 mmHg, P=0.046 and PCS = 8.3 ± 1.2 mmHg, P=0.025) and PVF (control = 869.0 ± 36.1 ml/min compared with terlipressin = 565.6 ± 25.7 ml/min, P<0.0001 and PCS = 488.4 ± 106.4 ml/min, P=0.002) compared with control. Treatment with terlipressin increased HAF (73.2 ± 11.3 ml/min) compared with control (40.3 ± 6.3 ml/min, P=0.026). The results of the present study suggest that terlipressin and PCS may have a role in the prevention and treatment of post-resection liver failure.

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          Most cited references39

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          Liver regeneration.

          Liver regeneration after partial hepatectomy is a very complex and well-orchestrated phenomenon. It is carried out by the participation of all mature liver cell types. The process is associated with signaling cascades involving growth factors, cytokines, matrix remodeling, and several feedbacks of stimulation and inhibition of growth related signals. Liver manages to restore any lost mass and adjust its size to that of the organism, while at the same time providing full support for body homeostasis during the entire regenerative process. In situations when hepatocytes or biliary cells are blocked from regeneration, these cell types can function as facultative stem cells for each other.
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            A randomized, prospective, double-blind, placebo-controlled trial of terlipressin for type 1 hepatorenal syndrome.

            Hepatorenal syndrome (HRS) type 1 is a progressive functional renal failure in subjects with advanced liver disease. The aim of this study was to evaluate the efficacy and safety of terlipressin, a systemic arterial vasoconstrictor, for cirrhosis type 1 HRS. A prospective, randomized, double-blind, placebo-controlled clinical trial of terlipressin was performed. Subjects with type 1 HRS were randomized to terlipressin (1 mg intravenously every 6 hours) or placebo plus albumin in both groups. The dose was doubled on day 4 if the serum creatinine (SCr) level did not decrease by 30% of baseline. Treatment was continued to day 14 unless treatment success, death, dialysis, or transplantation occurred. Treatment success was defined by a decrease in SCr level to
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              Terlipressin and albumin vs albumin in patients with cirrhosis and hepatorenal syndrome: a randomized study.

              Hepatorenal syndrome is common in patients with advanced cirrhosis and constitutes a major problem in liver transplantation. There is no effective medical treatment for hepatorenal syndrome. Forty-six patients with cirrhosis and hepatorenal syndrome, hospitalized in a tertiary care center, were randomly assigned to receive either terlipressin (1-2 mg/4 hour, intravenously), a vasopressin analogue, and albumin (1 g/kg followed by 20-40 g/day) (n = 23) or albumin alone (n = 23) for a maximum of 15 days. Primary outcomes were improvement of renal function and survival at 3 months. Improvement of renal function occurred in 10 patients (43.5%) treated with terlipressin and albumin compared with 2 patients (8.7%) treated with albumin alone (P = .017). Independent predictive factors of improvement of renal function were baseline urine volume, serum creatinine and leukocyte count, and treatment with terlipressin and albumin. Survival at 3 months was not significantly different between the 2 groups (terlipressin and albumin: 27% vs albumin 19%, P = .7). Independent predictive factors of 3-month survival were baseline model for end-stage liver disease score and improvement of renal function. Cardiovascular complications occurred in 4 patients treated with albumin alone and in 10 patients treated with terlipressin and albumin, yet permanent terlipressin withdrawal was required in only 3 cases. As compared with albumin, treatment with terlipressin and albumin is effective in improving renal function in patients with cirrhosis and hepatorenal syndrome. Further studies with large sample sizes should be performed to test whether the improvement of renal function translates into a survival benefit.
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                Author and article information

                Journal
                Clin Sci (Lond)
                Clin. Sci
                ppclinsci
                CS
                Clinical Science (London, England : 1979)
                Portland Press Ltd.
                0143-5221
                1470-8736
                03 January 2019
                15 January 2019
                15 January 2019
                : 133
                : 1
                : 153-166
                Affiliations
                [1 ]Nottingham Digestive Diseases Centre and National Institute for Health Research (NIHR) Nottingham Biomedical Research Centre, Nottingham University Hospitals NHS Trust and University of Nottingham, Queen’s Medical Centre, Nottingham, U.K.
                [2 ]Department of Hepato-Pancreatico-Biliary Surgery and Transplantation, Freeman Hospital, Newcastle upon Tyne, U.K.
                [3 ]Department of Mathematics and Statistics, UiT – The Arctic University of Norway, Tromsø, Norway
                [4 ]Institute of Medical Biology, UiT – The Arctic University of Norway, Tromsø, Norway
                [5 ]Department of Clinical Pathology, The University Hospital of North Norway, Tromsø, Norway
                [6 ]Department of Pathology, Leeds Teaching Hospitals NHS Trust, Leeds, U.K.
                [7 ]Surgical Research Laboratory, Institute of Clinical Medicine, UiT – The Arctic University of Norway, Tromsø, Norway
                [8 ]Department of Gastrointestinal Surgery, The University Hospital of North Norway, Tromsø, Norway
                [9 ]MRC/ARUK Centre for Musculoskeletal Ageing Research, School of Life Sciences, University of Nottingham, Queen’s Medical Centre, Nottingham, U.K.
                Author notes
                Correspondence: Dileep N. Lobo ( Dileep.Lobo@ 123456nottingham.ac.uk )
                [*]

                These are joint senior authors.

                Author information
                http://orcid.org/0000-0003-1187-5796
                Article
                10.1042/CS20180858
                6331658
                30606815
                51645322-2751-4a7d-9732-e344b063033a
                © 2019 The Author(s).

                This is an open access article published by Portland Press Limited on behalf of the Biochemical Society and distributed under the Creative Commons Attribution License 4.0 (CC BY).

                History
                : 02 October 2018
                : 06 December 2018
                : 29 December 2018
                Page count
                Pages: 14
                Categories
                Research Articles
                Research Article
                59
                49
                44

                Medicine
                post-resection liver failure,portacaval shunt,terlipressin
                Medicine
                post-resection liver failure, portacaval shunt, terlipressin

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