Mechanisms of regenerative preconditioning in pigs with subtotal hepatectomies.

BACKGROUND: Portal vein occlusion shortly before extended hepatic resections has hepatoprotective properties, but its molecular effects have not been elucidated. We characterized the impact of regenerative preconditioning by portal vein embolization (PVE) on hepatic energy metabolism and cytokine expression. MATERIALS AND METHODS: About 90% hepatectomies were performed in normal pigs (Control) and in pigs that underwent a PVE 24 h before the surgery (n = 10/group). Blood biochemistry and coagulation, liver damage, liver function (ICG), hepatic content of adenine nucleotides, and hepatic expression of inflammatory mediators (RT-PCR and WB) were determined before the hepatectomy, 15 min, and 24 h later. RESULTS: All PVE and hepatectomies were successfully accomplished. The 90% hepatectomy resulted in: Immediate reduction of ATP, leading to persistent decreases of energy load and ATP/ADP ratio up to the 24-h time-point; and pro-inflammatory expression profile of cytokines in the remnant liver. Prior performance of PVE attenuated the bioenergetic alterations and prevented many of the changes in hepatic cytokine expression. CONCLUSIONS: Regenerative preconditioning by PVE improved hepatic energy metabolism and modulated inflammatory mediators in the remnant liver in pigs undergoing major hepatectomies, potentially contributing to its hepatoprotective effects.

INTRODUCCIÓN: la oclusión de la vena porta precoz antes de hepatectomías extendidas tiene propiedades hepatoprotectoras, pero sus efectos moleculares no se han aclarado. Caracterizamos el impacto del preacondicionamiento regenerativo por embolización de la vena porta (PVE) sobre el metabolismo energético hepático y la expresión de citocinas. MATERIALES Y MÉTODOS: Realizamos hepatectomías del 90% en cerdos (Control) y en cerdos sometidos a PVE 24 horas antes de la cirugía (n = 10/grupo). La bioquímica y la coagulación, el daño hepático, la función hepática (ICG), los nucleótidos de adenina y la expresión de mediadores inflamatorios (RT-PCR y WB) fueron determinado antes de la hepatectomía, quince minutos y 24 horas después. RESULTADOS: Las PVE y las hepatectomías se realizaron con éxito. La hepatectomía del 90% resultó en: una reducción del ATP, lo que disminuye la carga energética y la relación ATP/ADP a las 24 horas; y en la expresión de citocinas proinflamatorias. La realización previa de PVE atenuó las alteraciones bioenergéticas y evitó muchos de los cambios en la expresión de citocinas. CONCLUSIONES: El preacondicionamiento regenerativo con PVE mejoró el metabolismo energético y moduló los mediadores inflamatorios en el hígado remanente en cerdos sometidos a hepatectomías subtotales, contribuyendo potencialmente a sus efectos hepatoprotectores.

Hepatic flow is an intraoperative predictor of early allograft dysfunction in whole-graft deceased donor liver transplantation: An observational cohort study.

BACKGROUND: Early allograft dysfunction (EAD) after liver transplantation (LT) is an important cause of morbidity and mortality. To ensure adequate graft function, a critical hepatocellular mass is required in addition to an appropriate blood supply. We hypothesized that intraoperative measurement of portal venous and hepatic arterial flow may serve as a predictor in the diagnosis of EAD. AIM: To study whether hepatic flow is an independent predictor of EAD following LT. METHODS: This is an observational cohort study in a single institution. Hepatic arterial blood flow and portal venous blood flow were measured intraoperatively by transit flow. EAD was defined using the Olthoff criteria. Univariate and multivariate analyses were used to determine the intraoperative predictors of EAD. Survival analysis and prognostic factor analysis were performed using the Kaplan-Meier and Cox regression models. RESULTS: A total of 195 liver transplant procedures were performed between January 2008 and December 2014 in 188 patients. A total of 54 (27.7%) patients developed EAD. The median follow-up was 39 mo. Portal venous flow, hepatic arterial flow (HAF) and total hepatic arterial flow were associated with EAD in both the univariate and multivariate analyses. HAF is an independent prognostic factor for 30-d patient mortality. CONCLUSION: Intraoperative measurement of blood flow after reperfusion appears to be a predictor of EAD; Moreover, HAF should be considered a predictor of 30-d patient mortality.

Comprehensive Characterization of a Porcine Model of The "Small-for-Flow" Syndrome.

INTRODUCTION: The term "Small-for-Flow" reflects the pathogenetic relevance of hepatic hemodynamics for the "Small-For-Size" syndrome and posthepatectomy liver failure. We aimed to characterize a large-animal model for studying the "Small-for-Flow" syndrome. METHODS: We performed subtotal (90%) hepatectomies in 10 female MiniPigs using a simplified transection technique with a tourniquet. Blood tests, hepatic and systemic hemodynamics, and hepatic function and histology were assessed before (Bas), 15 min (t-15 min) and 24 h (t-24 h) after the operation. Some pigs underwent computed tomography (CT) scans for hepatic volumetry (n = 4) and intracranial pressure (ICP) monitoring (n = 3). Postoperative care was performed in an intensive care unit environment. RESULTS: All hepatectomies were successfully performed, and hepatic volumetry confirmed liver remnant volumes of 9.2% [6.2-11.2]. The hepatectomy resulted in characteristic hepatic hemodynamic alterations, including portal hyperperfusion, relative decrease of hepatic arterial blood flow, and increased portal pressure (PP) and portal-systemic pressure gradient. The model reproduced major diagnostic features including the development of cholestasis, coagulopathy, encephalopathy with increased ICP, ascites, and renal failure, hyperdynamic circulation, and hyperlactatemia. Two animals (20%) died before t-24 h. Histological liver damage was observed at t-15 min and at t-24 h. The degree of histological damage at t-24 h correlated with intraoperative PP (r = 0.689, p = 0.028), hepatic arterial blood flow (r = 0.655, p = 0.040), and hepatic arterial pulsatility index (r = 0.724, p = 0.066). All animals with intraoperative PP > 20 mmHg presented liver damage at t-24 h. CONCLUSION: The present 90% hepatectomy porcine experimental model is a feasible and reproducible model for investigating the "Small-for-Flow" syndrome.

Preconditioning by portal vein embolization modulates hepatic hemodynamics and improves liver function in pigs with extended hepatectomy.

BACKGROUND: Portal vein embolization is performed weeks before extended hepatic resections to increase the future liver remnant and prevent posthepatectomy liver failure. Portal vein embolization performed closer to the operation also could be protective, but worsening of portal hyper-perfusion is a major concern. We determined the hepatic hemodynamic effects of a portal vein embolization performed 24 hours prior to hepatic operation. METHODS: An extended (90%) hepatectomy was performed in swine undergoing (portal vein embolization) or not undergoing (control) a portal vein embolization 24 hours earlier (n = 10/group). Blood tests, hepatic and systemic hemodynamics, hepatic function (plasma disappearance rate of indocyanine green), liver histology, and volumetry (computed tomographic scanning) were assessed before and after the hepatectomy. Hepatocyte proliferating cell nuclear antigen expression and hepatic gene expression also were evaluated. RESULTS: Swine in the control and portal vein embolization groups maintained stable systemic hemodynamics and developed similar increases of portal blood flow (302 ± 72% vs 486 ± 92%, P = .13). Portal pressure drastically increased in Controls (from 9.4 ± 1.3 mm Hg to 20.9 ± 1.4 mm Hg, P < .001), while being markedly attenuated in the portal vein embolization group (from 11.4 ± 1.5 mm Hg to 16.1 ± 1.3 mm Hg, P = .061). The procedure also improved the preservation of the hepatic artery blood flow, liver function, and periportal edema. These effects occurred in the absence of hepatocyte proliferation or hepatic growth and were associated with the induction of the vasoprotective gene Klf2. CONCLUSION: Portal vein embolization preconditioning represents a potential hepato-protective strategy for extended hepatic resections. Further preclinical studies should assess its medium-term effects, including survival. Our study also supports the relevance of hepatic hemodynamics as the main pathogenetic factor of post-hepatectomy liver failure.

Early Measurement of Indocyanine Green Clearance Accurately Predicts Short-Term Outcomes After Liver Transplantation.

BACKGROUND: There are no accurate tools to predict short-term mortality or the need for early retransplantation after liver transplantation (LT). A noninvasive measurement of indocyanine green clearance, the plasma disappearance rate (PDR), has been associated with initial graft function. METHODS: We evaluated the ability of PDR to predict early mortality or retransplantation after LT. In this observational prospective study, 332 LT were analyzed. Donor, recipient, and intraoperative data were investigated. The ensuing score was prospectively evaluated in a validation cohort of 77 patients. RESULTS: Thirty-three patients reached the main endpoint. By multivariate analysis, the only independent predictors of the endpoint were PDR (odds ratio [OR], 0.85; 95% confidence interval, 0.79-0.92) and international normalized ratio (OR, 1.45; 95% confidence interval, 1.17-1.82). A risk score weighted by the OR was built using cutoff values of 2.2 or greater for international normalized ratio (1 point) and less than 10%/min for PDR (2 points). Four categories (0 to 3) were possible. The risk of early death or retransplantation was associated with the score (0, 4.4%; 1, 6.5%; 2, 12%; and 3, 50%; χ for trend, P < 0.001). The score was also associated with duration of mechanical ventilation and intensive care unit stay. The score had a good diagnostic performance in the validation cohort (sensitivity, 60%; specificity, 95.5%; positive predictive value, 66.7%; negative predictive value, 94.1%). CONCLUSIONS: A simple score obtained within the first day after LT predicts short-term survival and need for retransplantation and may prove useful when selecting diagnostic and therapeutic strategies.

Positive influence of a natural product as propolis on antioxidant status and lipid peroxidation in senescent rats

Given the importance of oxidative stress associated to aging, it would be interesting to assess the effect of oral supplementation with antioxidant substances capable of diminishing oxidative aggression and free radicals generation associated to this condition. This study investigated the effects of AIN-93 M diet supplemented either with 2 % of propolis, or with 4 % of a natural product obtained from lyophilizate vegetables, selected by its antioxidant properties, in senescent healthy Wistar rats fed ad libitum over 3 months. Propolis supplementation leads to a lower level of glucose and cholesterol concentrations together with a reduction in protein oxidation. Plasma thiobarbituric acid-reactive substance levels were lower in the rats consuming the natural vegetable product and propolis possibly due to its antioxidant components, neutralizing the free radical produced, and thus preventing cellular damage. The results of the present study suggest a synergic effect of overall propolis compounds reducing the oxidative stress and glucose and cholesterol plasma levels associated with aging (AU)

Positive influence of a natural product as propolis on antioxidant status and lipid peroxidation in senescent rats.

Given the importance of oxidative stress associated to aging, it would be interesting to assess the effect of oral supplementation with antioxidant substances capable of diminishing oxidative aggression and free radicals generation associated to this condition. This study investigated the effects of AIN-93 M diet supplemented either with 2 % of propolis, or with 4 % of a natural product obtained from lyophilizate vegetables, selected by its antioxidant properties, in senescent healthy Wistar rats fed ad libitum over 3 months. Propolis supplementation leads to a lower level of glucose and cholesterol concentrations together with a reduction in protein oxidation. Plasma thiobarbituric acid-reactive substance levels were lower in the rats consuming the natural vegetable product and propolis possibly due to its antioxidant components, neutralizing the free radical produced, and thus preventing cellular damage. The results of the present study suggest a synergic effect of overall propolis compounds reducing the oxidative stress and glucose and cholesterol plasma levels associated with aging.