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

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.

[1]  J. Kim,et al.  Effects of splanchnic vasoconstrictors on liver regeneration and survival after 90% rat hepatectomy , 2018, Annals of surgical treatment and research.

[2]  U. Neumann,et al.  Comparative study of the effects of terlipressin versus splenectomy on liver regeneration after partial hepatectomy in rats. , 2017, Hepatobiliary & pancreatic diseases international : HBPD INT.

[3]  I. Vignon-Clementel,et al.  Modulating Portal Hemodynamics With Vascular Ring Allows Efficient Regeneration After Partial Hepatectomy in a Porcine Model , 2017, Annals of surgery.

[4]  Ezio Fornasiere,et al.  Terlipressin plus albumin versus midodrine and octreotide plus albumin in the treatment of hepatorenal syndrome: A randomized trial , 2015, Hepatology.

[5]  C. Ripoll,et al.  Characteristic haemodynamic changes of cirrhosis may influence the diagnosis of portopulmonary hypertension , 2015, Liver international : official journal of the International Association for the Study of the Liver.

[6]  F. Carrilho,et al.  Terlipressin versus Norepinephrine in the Treatment of Hepatorenal Syndrome: A Systematic Review and Meta-Analysis , 2014, PloS one.

[7]  D. Candinas,et al.  Elevated Liver Regeneration in Response to Pharmacological Reduction of Elevated Portal Venous Pressure by Terlipressin After Partial Hepatectomy , 2014, Transplantation.

[8]  Xian-qiang Wang,et al.  Portal inflow preservation during portal diversion in small-for-size syndrome. , 2014, World journal of gastroenterology.

[9]  H. Bismuth,et al.  Posthepatectomy Portal Vein Pressure Predicts Liver Failure and Mortality after Major Liver Resection on Noncirrhotic Liver , 2013, Annals of surgery.

[10]  E. Refaat,et al.  Effect of perioperative terlipressin infusion on systemic, hepatic, and renal hemodynamics during living donor liver transplantation. , 2013, Journal of critical care.

[11]  Xuan Wang,et al.  Impact of mesocaval shunt on safe minimal liver remnant: porcine model. , 2013, World journal of gastroenterology.

[12]  G. Franck.  Open access , 2012, Cell cycle.

[13]  D. Lobo,et al.  Prediction, prevention and management of postresection liver failure , 2011, The British journal of surgery.

[14]  Brigitte Vollmar,et al.  Splenectomy improves survival by increasing arterial blood supply in a rat model of reduced‐size liver , 2010, Transplant international : official journal of the European Society for Organ Transplantation.

[15]  E. Christensen,et al.  Systematic review of randomized trials on vasoconstrictor drugs for hepatorenal syndrome , 2010, Hepatology.

[16]  L. Conley,et al.  Increased sinusoidal flow is not the primary stimulus to liver regeneration , 2010, Comparative hepatology.

[17]  T. Reinhold,et al.  The costs of postoperative liver failure and the economic impact of liver function capacity after extended liver resection—a single-center experience , 2009, Langenbeck's Archives of Surgery.

[18]  Jian-jun Zhang,et al.  Extended hepatectomy with segments I and VII as resection remnant: a simple model for small-for-size injuries in pigs. , 2008, Hepatobiliary & pancreatic diseases international : HBPD INT.

[19]  A. Sanyal,et al.  A randomized, prospective, double-blind, placebo-controlled trial of terlipressin for type 1 hepatorenal syndrome. , 2008, Gastroenterology.

[20]  V. Arroyo,et al.  Terlipressin and albumin vs albumin in patients with cirrhosis and hepatorenal syndrome: a randomized study. , 2008, Gastroenterology.

[21]  J. Hedegaard,et al.  Regenerative response in the pig liver remnant varies with the degree of resection and rise in portal pressure. , 2008, American Journal of Physiology - Gastrointestinal and Liver Physiology.

[22]  S. Yagi,et al.  Improvement of morphological changes after 70% hepatectomy with portocaval shunt: preclinical study in porcine model. , 2007, The Journal of surgical research.

[23]  Fred Godtliebsen,et al.  Scale-space analysis of time series in circulatory research. , 2006, American journal of physiology. Heart and circulatory physiology.

[24]  N. Ohkohchi,et al.  Effect of Portocaval Shunt on Residual Extreme Small Liver after Extended Hepatectomy in Porcine , 2006, World Journal of Surgery.

[25]  A. Demetris,et al.  Pathophysiologic Observations and Histopathologic Recognition of the Portal Hyperperfusion or Small-for-Size Syndrome , 2006, The American journal of surgical pathology.

[26]  S J Wigmore,et al.  The value of residual liver volume as a predictor of hepatic dysfunction and infection after major liver resection , 2005, Gut.

[27]  Y. Maehara,et al.  The impact of splenectomy or splenic artery ligation on the outcome of a living donor adult liver transplantation using a left lobe graft. , 2004, Hepato-gastroenterology.

[28]  Yoshinobu Sato,et al.  Splenectomy for reduction of excessive portal hypertension after adult living-related donor liver transplantation. , 2002, Hepato-gastroenterology.

[29]  K. Hatakeyama,et al.  Splenic arterial ligation prevents liver injury after a major hepatectomy by a reduction of surplus portal hypertension in hepatocellular carcinoma patients with cirrhosis. , 2001, Hepato-gastroenterology.

[30]  D. Pateron,et al.  Multicenter Randomized Controlled Trial of Terlipressin Versus Sclerotherapy in the Treatment of Acute Variceal Bleeding: The TEST Study , 2000, Hepatology.

[31]  T. Myrmel,et al.  Myocardial substrate metabolism influences left ventricular energetics in vivo. , 2000, American journal of physiology. Heart and circulatory physiology.

[32]  T. Schroeder,et al.  Splanchnic haemodynamics after intravenous terlipressin in anaesthetised healthy pigs. , 1999, Journal of hepatology.

[33]  H. Figulla,et al.  Portosystemic hepatic encephalopathy after transjugular intrahepatic portosystemic shunt in patients with cirrhosis: Clinical, laboratory, psychometric, and electroencephalographic investigations , 1998, Hepatology.

[34]  W. Lautt,et al.  Shear-induced modulation of vasoconstriction in the hepatic artery and portal vein by nitric oxide. , 1998, American journal of physiology. Gastrointestinal and liver physiology.

[35]  G. Michalopoulos,et al.  Liver Regeneration , 1997, Journal of cellular physiology.

[36]  J. Bruix,et al.  Surgical resection of hepatocellular carcinoma in cirrhotic patients: prognostic value of preoperative portal pressure. , 1996, Gastroenterology.

[37]  Division on Earth.  Guide for the Care and Use of Laboratory Animals , 1996 .

[38]  D. Pateron,et al.  Early administration of terlipressin plus glyceryl trinitrate to control active upper gastrointestinal bleeding in cirrhotic patients , 1995, The Lancet.

[39]  W W Lautt,et al.  Mechanism and role of intrinsic regulation of hepatic arterial blood flow: hepatic arterial buffer response. , 1985, The American journal of physiology.

[40]  P. Richardson,et al.  The Effects of Intra‐arterial and Intraportal Injections of Vasopressin on the Simultaneously Perfused Hepatic Arterial and Portal Venous Vascular Beds of the Dog , 1978, Circulation research.

[41]  P. Richardson,et al.  Pressure‐flow relationships and effects of noradrenaline and isoprenaline on the hepatic arterial and portal venous vascular beds of the dog. , 1978, The Journal of physiology.

[42]  T. Chalmers,et al.  A CONTROLLED TRIAL OF PROPHYLACTIC PORTACAVAL-SHUNT SURGERY. , 1964, The New England journal of medicine.

[43]  Lloyd H. Michael,et al.  The Guide for the Care and Use of Laboratory Animals. , 2016, ILAR journal.

[44]  P. A. Nunes,et al.  LIVER REGENERATION AFTER PARTIAL HEPATECTOMY IN RATS SUBMITTED TO POST-HEPATIC PORTAL HYPERTENSION , 2011 .

[45]  Gyeong a Kim,et al.  Terlipressin and Albumin vs Albumin in Patients with Cirrhosis and Hepatorenal Syndrome: A Randomized Study , 2008 .

[46]  G. Maddern,et al.  Subtotal hepatectomy: a porcine model for the study of liver regeneration. , 2004, The Journal of surgical research.

[47]  Hartmut Jaeschke,et al.  Molecular mechanisms of hepatic ischemia-reperfusion injury and preconditioning. , 2003, American journal of physiology. Gastrointestinal and liver physiology.