Comparison of right lobe donor hepatectomy with elective right hepatectomy for other causes in New York.

INTRODUCTION: Right lobe donor hepatectomy (RLDH) is a potential source of liver allografts given the ongoing shortage of deceased donor organs available. Since there is no live donor registry in the United States, a population-based, unsolicited state-wide analysis has yet to be reported. METHODS: The New York (NY) State Inpatient Database was used to query 1,524 elective liver lobectomies performed from 2001 to 2006. RLDH were identified in this cohort (n = 195; 13%). Most common indications for elective right lobe hepatectomy (ERH) were metastatic colon cancer (50%) and hepatocellular carcinoma (HCC) (34%). Primary outcomes were mortality, perioperative resources and major postoperative complications. RESULTS: After a dramatic drop in 2002, there was a slow increase in RLDH from 2003 to 2006 in New York. Donors were younger (median age 36 vs. 60 years, P < 0.0001) and healthier (75% with no comorbidities vs. 18%, P < 0.0001) than patients undergoing ERH for other causes. Median length of hospital stay was 7 days in both groups. Donors were less likely to require blood transfusion (22.6 vs. 62.8%, P < 0.0001) and received less blood (mean 0.10 units vs. 2.4 units). Major post-operative complications based on the Clavien classification occurred in only 2.6% of donor cases compared to 13.8% in non-donors (P < 0.0001). There was one RLDH in-hospital mortality (0.5%) in New York compared to 4.3% after ERH (P = 0.003). CONCLUSIONS: This study represents one of the first unsolicited regional analyses of donor morbidity and resource utilization for RLDH and further emphasizes the need and utility of a live donor registry.

Hepatoprotection and lethality rescue by histone deacetylase inhibitor valproic acid in fatal hemorrhagic shock.

BACKGROUND: Pharmacological histone deacetylase (HDAC) inhibitors, such as known anticonvulsant valproic acid (VPA), demonstrate cytoprotective effects and increase acetylation of nuclear histones, promoting transcriptional activation of deregulated genes. Therefore, we examined protective effects of VPA administration in lethal hemorrhage and analyzed the patterns of hepatic histone acetylation. METHODS: Male Wistar Kyoto rats were pretreated with VPA (n = 10) and 2-methyl-2-pentenoic acid (2M2P), structural VPA analog with limited HDAC inhibiting activity (2M2P; n = 8), at 300 mg/kg/dose, administered subcutaneously, 24 hour and immediately before lethal, if untreated, hemorrhage was induced by removing the 60% of total blood volume. Both drugs were dissolved in normal saline (NS) and rats pretreated with corresponding volume of NS served as control group (n = 8). Time to death, the degree of histone acetylation in liver, HDAC activity and markers of cytotoxicity (alpha-glutathione S-transferase, alanine aminotransferase, aspartate aminotransferase, lactate dehydrogenase, and lactate), and apoptosis were analyzed. RESULTS: VPA-pretreated animals demonstrated five-fold increase in survival duration. At 12 hours posthemorrhage, 70% (VPA) and 12% (2M2P) pretreated rats were alive versus 0% in NS group. Hyperacetylation of histones H2A, H3, and H4 indicated the presence of active genes and correlated with survival (VPA > 2M2P > NS). Hemorrhage-induced increases in lactate, lactate dehydrogenase, aspartate aminotransferase, and alanine aminotransferase were alleviated by VPA. Moreover, alpha-glutathione S-transferase release, indicative of liver damage, was completely abolished. CONCLUSION: VPA offers considerable protection in severe hemorrhagic shock. The role of HDAC inhibition is suggested in mediating prosurvival actions of VPA.

Valproic acid prevents hemorrhage-associated lethality and affects the acetylation pattern of cardiac histones.

Pharmacological inhibitors of histone deacetylases (HDAC) demonstrate cytoprotective effects both in vitro and in vivo. In this study, we investigated whether valproic acid (VPA), a known mood stabilizer and anticonvulsant with HDAC-inhibiting activity, improves survival following otherwise lethal hemorrhage in rats. We found that preinsult injection of VPA (300 mg/kg, twice) prolonged the survival of severely hypotensive animals up to 5 times. VPA treatment increased the acetylation of nonhistone and histone proteins in the rat heart. The pattern of modifications of individual histones revealed hyperacetylation of histones H2A, H3, and H4, indicating the presence of active genes. Expression of HSP70 and superoxide dismutase, implicated in the modulation of vitality, was increased by VPA. Our results reveal that VPA offers considerable protection in the hemorrhagic shock model and suggest a role for HDAC inhibition in mediating VPA actions.