Somatostatin Therapy Protects Porcine Livers in Small-for-Size Liver Transplantation

Abstract

Small-for-size (SFS) injury occurs in partial liver transplantation due to several factors, including excessive portal inflow and insufficient intragraft responses. We aim to determine the role somatostatin plays in reducing portal hyperperfusion and preventing the cascade of deleterious events produced in small grafts. A porcine model of 20% liver transplantation is performed. Perioperatively treated recipients receive somatostatin and untreated controls standard intravenous fluids. Recipients are followed for up to 5 days. In vitro studies are also performed to determine direct protective effects of somatostatin on hepatic stellate cells (HSC) and sinusoidal endothelial cells (SEC). At reperfusion, portal vein flow (PVF) per gram of tissue increased fourfold in untreated animals versus approximately threefold among treated recipients (p ¼ 0.033). Postoperatively, markers of hepatocellular, SEC and HSC injury were improved among treated animals. Hepatic regeneration occurred in a slower but more orderly fashion among treated grafts; functional recovery was also significantly better. In vitro studies revealed that somatostatin directly reduces HSC activation, though no direct effect on SEC was found. In SFS transplantation, somatostatin reduces PVF and protects SEC in the critical postreperfusion period. Somatostatin also exerts a direct cytoprotective effect on HSC, independent of changes in PVF.

Porcine models for the study of small‐for‐size syndrome and portal inflow modulation: literature review and proposal for a standardized nomenclature

“…A few studies also focused on pharmaceutical modalities of PIM, which have the advantage of being reversible and noninvasive. Hessheimer et al demonstrated that intravenous somatostatin infusion after 20% partial LT led to a decrease in postoperative portal pressure and histological liver damage, and improvement of liver function recovery and animal survival [18]. Similarly to what was studied during partial LT, we recently evaluated the impact of intraoperative infusion of somatostatin in animals undergoing left trisectionectomy or subtotal hepatectomy, and demonstrated that somatostatin decreased portal vein flow in both groups of animals and restored a normal HVPG in animals undergoing subtotal hepatectomy [38].…”

“…Besides, the cut-off value of remnant-to-initial liver volume ratio for obtaining the setting of SFS syndrome appears to be approximately 20% after partial LT [9], and the right lateral section including segment 1, which represents approximately 30% of the whole liver volume, appears to be too large for inducing a significant increase in portal vein pressure and creating the setting of SFS [7]. Therefore, the use of a right lateral section with segment 1 transplanted in a 2-3-fold larger recipient as initially described by Kelly et al without the use of venovenous bypass as described by Fondevila et al could be considered as the best possible choice for studying the SFS syndrome after partial LT in swine [13,[16][17][18].…”

Size mismatch in liver transplantation

“…Somatostatin or Octreotide also induce vasoconstriction on portal vein and splanchnic arteries and effectively reduces the portal pressure in patients with portal hypertension . Hessheimer et al found with using their small‐for‐size porcine model that Somatostatin bolus during anhepatic phase significantly suppressed the increase in portal flow before and after reperfusion in a dose‐dependent manner, hepatocyte and endothelial marker for injury were significantly reduced and markedly improve post‐transplant 5 day survival at a dose of 8 μg/kg (83% in Somatostatin treatment group vs. 26% in the control group) .…”

Stereological analysis of size and density of hepatocytes in the porcine liver

“…The use of pigs as the last step of pre-clinical research prior to designing clinical trials is done not only for newly suggested surgical procedures but also in pharmacological research on liver excretory, detoxification and synthetic functions important for liver regeneration following a partial hepatectomy (Liska et al 2012;Bruha et al 2015). Similarly, the porcine liver is used in surgical experiments regarding therapy of small-for-size injuries that occur after partial liver transplantation or extended hepatectomy (Kelly et al 2009;Hessheimer et al 2014). The porcine model has been demonstrated to be useful when examining histological alterations of the liver during carbon dioxide pneumoperitoneum (Alexakis et al 2008).…”