A randomized controlled trial on pharmacological preconditioning in liver surgery using a volatile anesthetic. Ischemic preconditioning improves postoperative outcome after liver resections: a randomized controlled study. Effects of Pringle manoeuvre and ischaemic preconditioning on haemodynamic stability in patients undergoing elective hepatectomy: a randomized trial. Ischemic preconditioning for major liver resection under vascular exclusion of the liver preserving the caval flow: a randomized prospective study. A prospective, randomized, controlled trial comparing intermittent portal triad clamping versus ischemic preconditioning with continuous clamping for major liver resection. Beneficial effects of ischemic preconditioning in patients undergoing hepatectomy: the role of neutrophils. Ischemic preconditioning versus intermittent vascular occlusion in liver resections performed under selective vascular exclusion: a prospective randomized study. Complete versus selective portal triad clamping for minor liver resections: a prospective randomized trial. Modified technique of hepatic vascular exclusion: effect on blood loss during complex mesohepatectomy in hepatocellular carcinoma patients with cirrhosis.
To evaluate the effects of pharmacological preconditioning with a volatile anesthetic in patients undergoing liver resection with inflow occlusion.
                In liver surgery, ischemic preconditioning and intermittent clamping are the only established protective strategies to reduce tissue damage due to ischemia during inflow occlusion. Preconditioning with volatile anesthetics has provided protection against cardiac and renal ischemic injury in several animal models through NO and HO-1 pathways. But pharmacological preconditioning has never been tested in patients undergoing liver surgery in a randomized trial.
                Sixty-four patients undergoing liver surgery with inflow occlusion were randomized intraoperatively for preconditioning with sevoflurane or not (ClinicalTrials.gov NCT00516711). Anesthesia was performed intravenously with propofol. Thirty minutes before inflow occlusion propofol was replaced by sevoflurane in the preconditioning group. Primary endpoint was postoperative liver injury assessed by peak values of liver transaminases. Postoperative complications were recorded according to an established scoring system.
                Sevoflurane preconditioning significantly limited the postoperative increase of serum transaminase levels by 261 U/L (95% CI, 65 to 458; P = 0.01) for the ALT and by 239 (95% CI, -2 to 480; P = 0.05) for the AST corresponding to decreases of baseline levels of 35% and 31%, respectively. Patients with steatosis had an even better benefit than patients without steatosis. The rates of any complication (risk ratio 0.46; 95% CI, 0.25 to 0.85; P = 0.006) and of severe complications requiring invasive procedures (risk ratio 0.25; 95% CI, 0.06 to 1.08; P = 0.05) were also lowered by preconditioning.
                This first randomized trial of pharmacological preconditioning in liver surgery in humans showed a protective effect of preconditioning with volatile anesthetics. This strategy may provide a new and easily applicable therapeutic option to protect the liver and to lower complication rates. Clamping of the portal triad (Pringle maneuver) prevents blood loss during liver resection, but leads to liver injury upon reperfusion. Ischemic preconditioning (IP) has been shown to protect the liver against prolonged ischemic injury in animal models. However, the clinical value of this procedure has not yet been established.
                61 Patients undergoing hepatic resection under inflow occlusion were randomized to either to receive (Group-A n = 30) or not to receive (Group-B n = 31) an IP (10 minutes of ischemia followed 10 minutes of reperfusion).
                Mean (+/- SD)/ Group-A vs. Group-B. Pringle time of 34 +/- 14 and 33 +/- 12 minutes and the extent of resected liver tissue (2.7 +/- 1.3 vs. 2.7 +/- 1.1 segments) were comparable in both groups. Complications, including death, severe liver dysfunction and biliary leakage occurred in 6 patients of Group-A vs. 14 patients of Group-B (p<0.05). Intraoperative blood loss was significantly lower in Group-A (1.28 +/- 0.91 l vs. 1.94 +/- 0.76 l; p<0.001) with 5 vs. 15 patients requiring transfusions (p<0.01). In a multivariate analysis the duration of the Pringle maneuver (p<0.05) and the absence of preconditioning (p<0.05) were independent predictors for the occurrence of postoperative complications.
                IP protects against reperfusion injury, reduces the incidence of complications after hepatic resection under inflow occlusion and is simple to use in clinical practice. The Pringle manoeuvre and ischaemic preconditioning are applied to prevent blood loss and ischaemia-reperfusion injury, respectively, during liver surgery. In this prospective clinical trial we report on the intraoperative haemodynamic effects of the Pringle manoeuvre alone or in combination with ischaemic preconditioning.
                Patients (n=68) were assigned randomly to three groups: (i) resection with the Pringle manoeuvre; (ii) with ischaemic preconditioning before the Pringle manoeuvre for resection; (iii) without pedicle clamping.
                Following the Pringle manoeuvre the mean arterial pressure increased transiently, but significantly decreased after unclamping as a result of peripheral vasodilation. Ischaemic preconditioning improved cardiovascular stability by lowering the need for catecholamines after liver reperfusion without affecting the blood sparing benefits of the Pringle manoeuvre. In addition, ischaemic preconditioning protected against reperfusion-induced tissue injury.
                Ischaemic preconditioning provides both better intraoperative haemodynamic stability and anti-ischaemic effects thereby allowing us to take full advantage of blood loss reduction by the Pringle manoeuvre. Two randomized prospective studies suggested that ischemic preconditioning (IP) protects the human liver against ischemia-reperfusion injury after hepatectomy performed under continuous clamping of the portal triad. The primary goal of this study was to determine whether IP protects the human liver against ischemia-reperfusion injury after hepatectomy under continuous vascular exclusion with preservation of the caval flow.
                Sixty patients were randomly divided into two groups: with (n=30; preconditioning group) and without (n=30; control group) IP (10 minutes of portal triad clamping and 10 minutes of reperfusion) before major hepatectomy under vascular exclusion of the liver preserving the caval flow. Serum concentrations of aspartate transferase, alanine transferase, glutathione-S-transferase, and bilirubin and prothrombin time were regularly determined until discharge and at 1 month. Morbidity and mortality were determined in both groups.
                Peak postoperative concentrations of aspartate transferase were similar in the groups with and without IP (851 +/- 1,733 IU/L and 427 +/- 166 IU/L respectively, p=0.2). A similar trend toward a higher peak concentration of alanine transferase and glutathione-S-transferase was indeed observed in the preconditioning group compared with the control group. Morbidity and mortality rates and lengths of ICU and hospitalization stays were similar in both groups.
                IP does not improve liver tolerance to ischemia-reperfusion after hepatectomy under vascular exclusion of the liver with preservation of the caval flow. This maneuver does not improve postoperative liver function and does not affect morbidity or mortality rates. The clinical use of IP through 10 minutes of warm ischemia in this technique of hepatectomy is not currently recommended. To evaluate whether ischemic preconditioning (IP) with continuous clamping or intermittent clamping (IC) of the portal triad confers better protection during liver surgery.
                IP and IC are distinct protective approaches against ischemic injury. Since both strategies proved to be superior in randomized controlled trials (RCTs) to continuous inflow occlusion alone, we designed a RCT to compare IP and IC in patients undergoing major liver resection.
                Noncirrhotic patients undergoing major liver resection were randomized to receive IP with inflow occlusion (n = 36) or IC (n = 37). Primary endpoints were postoperative liver injury and intraoperative blood loss. Postoperative liver injury was assessed by peak values of AST (alanine aminotransferase) and ALT (aspartate aminotransferase), as well as the area under the curve (AUC) of the postoperative transaminase course. Secondary endpoints included resection time, the need of blood transfusion, ICU, and hospital stay as well as postoperative complications and mortality.
                Both groups were comparable regarding demographics, ASA score, type of hepatectomy, duration of inflow occlusion (range, 30-75 minutes), and resection surface. The transection-related blood loss was 146 versus 250 mL (P = 0.008), and when standardized to the resection surface 1.2 versus 1.8 mL/cm (P = 0.01) for IP and IC, respectively. Although peak AST, AUCAST, and AUCALT were lower for IC, the differences did not reach statistical significance. Overall (42% vs. 38%) and major (33 vs. 27%) postoperative complications as well as median ICU (1 vs. 1 day) and hospital stay (10 vs. 11 days) were similar between both groups.
                Both IP and IC appear to be equally effective in protecting against postoperative liver injury in noncirrhotic patients undergoing major liver resection. However, IP is associated with lower blood loss and shorter transection time. Therefore, both strategies can be recommended for noncirrhotic patients undergoing liver resection. Temporary vascular clampage (Pringle maneuver) during liver surgery can cause ischemia-reperfusion injury. In this process, activation of polymorphonuclear leukocytes (PMNLs) might play a major role. Thus, we investigated the effects of hepatic ischemic preconditioning on PMNL functions.
                Prospective randomized study. Patients who underwent partial liver resection were randomly assigned to 3 groups: group 1 without Pringle maneuver; group 2 with Pringle maneuver, and group 3 with ischemic preconditioning using 10 minutes of ischemia and 10 minutes of reperfusion prior to Pringle maneuver for resection.
                University hospital, Munich, Germany.
                Seventy-five patients underwent hepatic surgery mostly owing to metastasis.
                Perioperative factors for PMNL activation, inflammation, and postoperative hepatocellular integrity.
                Ischemia-reperfusion of the human liver (mean +/- SD time to perform the Pringle maneuver, 35.5 +/- 2.6 minutes) caused (1) a decrease in the number of circulating PMNLs, (2) their intrahepatic sequestration, (3) their systemic activation, and (4) a significant correlation between the degree of their postischemic activation and the postoperative rise in liver enzyme serum levels. In parallel, cytokines with proinflammatory and chemotactic properties were released reaching the highest values when stimulation of PMNLs was most pronounced. When ischemic preconditioning preceded the Pringle maneuver, activation of PMNLs and cytokine plasma levels was reduced as evidenced by the attenuation of superoxide anion production, beta(2)-integrin up-regulation, and interleukin 8 serum concentrations, followed by a significant reduction in serum alanine aminotransferase levels on the first and second postoperative days.
                These results demonstrate in humans that ischemic preconditioning reduces activation of PMNLs elicited by the Pringle maneuver. The down-regulation of potentially cytotoxic functions of PMNLs might be one of yet unknown important pathways that altogether mediate protection by ischemic preconditioning. The aim of this study was to compare ischemic preconditioning with the intermittent vascular occlusion technique in liver resections performed under inflow and outflow occlusion.
                Fifty-four patients with resectable liver tumors assigned were randomly to undergo surgery with either ischemic preconditioning (IP group, n = 27) or with intermittent vascular occlusion (IVO group, n = 27). Both groups were compared regarding surgical parameters, aspartate transaminase levels, and apoptosis.
                For warm ischemic time less than 40 minutes, no significant difference was noticed between the 2 groups apart from caspase-3 activity, which was higher in the IVO group than in the IP group (17.2 +/- 3.4 vs. 10.3 +/- 5.2, P < .05). When warm ischemia exceeded 40 minutes, the IP group showed higher levels in blood aspartate transaminase levels on day 3 (442 +/- 178 IU/L vs. 305 +/- 104 IU/L, P < .05) and higher caspase-3 levels (26.5 +/- 5.7 count/high-power field [hpf] vs. 20.7 +/- 3.6 count/hpf, P < .05) and apoptotic activity (28.5 +/- 7.5 count/hpf vs. 20.2 +/- 4.1 count/hpf, P < .05), as compared with the IVO group.
                Although both techniques showed comparable efficacy for short ischemic times, intermittent vascular occlusion provided better cytoprotection when ischemia exceeded 40 minutes. To evaluate the feasibility, safety, efficacy, amount of hemorrhage, postoperative complications, and ischemic injury of selective clamping in patients undergoing minor liver resections.
                Inflow occlusion can reduce blood loss during hepatectomy. However, Pringle maneuver produces ischemic injury to the remaining liver. Selective hemihepatic vascular occlusion technique can reduce the severity of visceral congestion and total liver ischemia.
                Eighty patients undergoing minor hepatic resection were randomly assigned to complete clamping (CC) or selective clamping (SC). Hemodynamic parameters, including portal pressure and the hepatic venous pressure gradient (HVPG), were evaluated. The amount of blood loss, measurements of liver enzymes alanine aminotransferase (ALT), aspartate aminotransferase (AST), and postoperative evolution were also recorded.
                No differences were observed in the amount of hemorrhage (671 +/- 533 mL versus 735 +/- 397 mL; P = 0.54) or the patients that required transfusion (10% versus 15%; P = 0.55). There were no differences on postoperative morbidity between groups (38% versus 29%; P = 0.38). Cirrhotic patients with CC had significantly higher ALT (7.7 +/- 4.6 versus 4.5 +/- 2.7 mukat/L, P = 0.01) and AST (10.2 +/- 8.7 versus 4.9 +/- 2.1 mukat/L; P = 0.03) values on the first postoperative day than SC. The multivariate analysis demonstrated that high central venous pressure, HVPG >10 mm Hg, and intraoperative blood loss were independent factors related to morbidity.
                Both techniques of clamping are equally effective and feasible for patients with normal liver and undergoing minor hepatectomies. However, in cirrhotic patients selective clamping induces less ischemic injury and should be recommended. Finally, even for minor hepatic resections, central venous pressure, HVPG, and intraoperative blood loss are factors related to morbidity and should be considered. Hepatic veins remain patent during complete inflow occlusion (CIO) and bleeding from them may continue. Occlusion of the inferior vena cava (ICV) during CIO may reduce blood loss from hepatic veins. This study was designed to compare the overall outcomes after application of CIO with or without occlusion of the ICV below the liver in complex mesohepatectomy for hepatocellular carcinoma (HCC) patients with cirrhosis.
                One hundred and eighteen (118) patients were randomly assigned to CIO or a modified technique of hepatic vascular exclusion (MTHVE). Hemodynamic parameters were evaluated and the amount of blood loss, measurement of liver enzymes, and postoperative progress were recorded.
                Blood loss during liver transection in CIO groups was significantly greater than that in MTHVE group (P=0.046). Thus, incidence of blood transfusion was significantly greater in patients of the CIO group (P=0.041). There were no significant differences in liver enzyme changes, bilirubin, or morbidity in the postoperative period between the two groups.
                CIO with occlusion of the ICV below the liver is a safe, effective, and feasible technique during mesohepatectomy in HCC patients with cirrhosis. Excellent results were obtained with minimized bleeding, limited hepatic function damage, and low rate of postoperative complications.
Currently, there is no evidence to suggest a protective effect of ischaemic preconditioning in non-cirrhotic patients undergoing liver resection under continuous vascular occlusion. Ischaemic preconditioning reduces the blood transfusion requirements in patients undergoing liver resection.