Date Published: May 31, 2019
Publisher: Public Library of Science
Author(s): Eva-Maria Wittauer, Felix Oldhafer, Eva Augstein, Oliver Beetz, Moritz Kleine, Carsten Schumacher, Lion Sieg, Hendrik Eismann, Kai Johanning, André Bleich, Florian Wolfgang Rudolf Vondran, Surinder K. Batra.
Despite advances in perioperative management and surgical technique, postoperative liver failure remains a feared complication after hepatic resection. Various supportive treatment options are under current discussion, but lack of structured evaluation. We therefore established a porcine model of major liver resection to study regeneration after partial hepatectomy in a reliable and well-defined pre-clinical setting.
Major hepatectomy was performed on seven minipigs with the intention to set up a non-lethal but relevant transient impairment of liver function. For steady postoperative vascular access (e.g. for blood withdrawal, measurement of venous pressure), permanent catheters were implanted into the internal jugular and portal veins, respectively. Animals were followed up for 30 days; clinical and laboratory results were recorded in detail. Monitoring was enhanced by non-invasive determination of the maximum liver function capacity (LiMAx test).
The established porcine model appeared suitable for evaluation of postoperative liver regeneration. Clinical characteristics and progression of liver function impairment as well as subsequent recovery were comparable to courses known from surgery in humans. Laboratory parameters (e.g. liver enzymes, bilirubin, INR, coagulation factor II) showed relevant derangements during postoperative days (POD) 0 to 3 followed by normalization until POD 7. Application of the LiMAx test was feasible in minipigs, again showing values comparable to humans and kinetics in line with obtained laboratory parameters. The exteriorized portal vein catheters enabled intra- and postoperative monitoring of portal venous pressures as well as easy access for blood withdrawal without relevant risk of postoperative complications.
In the last decades, advances in perioperative management and surgical techniques improved the safety and extent of liver resections . Functional and imaging measures to predict liver remnant function as well as preventive interventions such as portal vein embolization or the Associating Liver Partition and Portal Vein Ligation for Staged Hepatectomy (ALPPS) procedure  were introduced. Nevertheless, post-hepatectomy liver failure (PHLF) remains a feared complication after liver resection with a high morbidity and mortality [2–6]. Basic treatment options of PHLF include common intensive care measures such as mechanical ventilation, dialysis, vasopressor therapy and administration of albumin and coagulation factors . Specific therapeutic approaches include plasmapheresis, for which encouraging results have been reported in acute liver failure , and portal pressure modulation via various measures like portocaval anastomosis, ligation of the splenic artery and infusion of various vasoactive drugs that have already been applied in several experimental models [8–17]. The clinical relevance of these options though remains unclear. The only potential therapy with proven benefit for PHLF is salvage liver transplantation . Nevertheless, this approach appears questionable due to possible delayed recovery of liver function, especially with current shortage of donor organs in mind. Furthermore, high post-transplantation mortality in the context of severe liver failure has been observed , and moreover transplantation often is impractical since patients with colorectal metastases, cholangiocarcinoma and hepatocellular carcinoma outside Milan criteria will not be considered. A promising alternative to bridge liver function until recovery could be hepatocyte transplantation . Small case series or single case reports have already been published in context of acute liver failure (ALF) [20, 21], whereas comparable data is still lacking for PHLF.
The liver has the unique ability for regeneration within a short time period after partial hepatectomy [34, 35]. In humans, this process starts within the first day after a major resection and has led to the development of novel strategies in liver surgery such as two-stage hepatectomy, portal vein embolization/ligation or ALPPS (Associating Liver Partition and Portal Vein Ligation for Staged Hepatectomy) . The understanding of liver regeneration is essential for many patients with liver tumors since a curative therapy is often only possible performing extended liver resection. We therefore developed a standardized partial hepatectomy model in the miniature pig to study the underlying mechanism of liver regeneration with the help of the LiMAx test as a non-invasive liver function diagnostic and a permanent portal venous catheter.