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Liver ischemia/reperfusion injury may significantly compromise hepatic postoperative function. Various hepatoprotective methods have been improvised, aiming at attenuating IR injury. With ischemic preconditioning (IPC), the liver is conditioned with a brief ischemic period followed by reperfusion, prior to sustained ischemia. Ischemic postconditioning (IPostC), consisting of intermittent sequential interruptions of blood flow in the early phase of reperfusion, seems to be a more feasible alternative than IPC, since the onset of reperfusion is more predictable. Regarding the potential mechanisms involved, it has been postulated that the slow intermittent oxygenation through controlled reperfusion decreases the burst production of oxygen free radicals, increases antioxidant activity, suppresses neutrophil accumulation, and modulates the apoptotic cascade. Additionally, favorable effects on mitochondrial ultrastructure and function, and upregulation of the cytoprotective properties of nitric oxide, leading to preservation of sinusoidal structure and maintenance of blood flow through the hepatic circulation could also underlie the protection afforded by postconditioning. Clinical studies are required to show whether biochemical and histological improvements afforded by the reperfusion/reocclusion cycles of postconditioning during early reperfusion can be translated to a substantial clinical benefit in liver resection and transplantation settings or to highlight more aspects of its molecular mechanisms.

Purpose: Increased intra-abdominal pressure, as used in laparoscopic surgery or seen in intraabdominal hypertension (IAH), is associated with tissue ischemia and oxidative stress. Ischemic preconditioning (IP) is a method successfully used in liver and transplant surgery, in order to attenuate the detrimental effects of ischemia and reperfusion. In this experimental study, we tested the ability of IP to modify oxidative stress induced by extremely high intraabdominal pressures., Methods: Twenty-five female pigs were studied and divided in three groups: a control group, a pneumoperitoneum group (with pressure of 30 mmHg), and an ischemic preconditioning group (initially subjected to preconditioning with pressure of 25 mmHg for 15 min and desufflation for 15 min and then to pneumoperitoneum as in pneumoperitoneum group). Blood samples were obtained at identical time intervals in the three groups. Total oxidative capacity, total antioxidative capacity and total nitric oxide (NO), nitrite and nitrate concentrations were measured and compared between groups., Results: IP increased total antioxidative capacity (p = .045) and protective mediators like nitrite (p = .022). It was also associated with a trend toward lower levels of total oxidative capacity at the end of the abdominal desufflation period but statistical significance was not met., Conclusions: IP attenuated oxidative stress induced by IAH, mainly by increasing antioxidative capacity and the levels of protective mediators. The fact that IP was effective, even when used at extremely high levels of intraabdominal pressure, reinforces the interest on this method but further studies are needed to clarify its mechanism of action and potential clinical applications.

Background: Ischemia-reperfusion (I/R) injury is one of the main factors affecting the function and structure of small bowel transplantation (SBT), by generation of proinflammatory mediators such as reactive oxygen species, reactive nitrogen species, cytokines, and endotoxin. Experimental data have demonstrated that N-acetylcysteine (NAC) attenuates intestinal I/R injury. The objective of this study was to determine the effect of NAC preconditioning on the SBT-I/R induced inflammatory cascade, with particular focus on TNF, IL-8, hyaluronic acid, and NO., Methods: Fifteen domestic pigs were used as donors. Fifteen recipient animals were randomly assigned into two groups. Group 1: SBTx (n=7) served as controls and Group 2: SBTx (n=8) served as the experimental group (NAC administration)., Results: NAC administration at a continuous 4 h intravenous bolus dose of 200 mg/kg of body weight, starting before initiation of bowel transplantation, resulted in statistically significant (P<0.05) higher plasma levels of NO, and lower plasma levels of hyaluronic acid, TNF-α, IL-8, and LDH compared with those of the control group, at the 360 min time point., Conclusions: NAC confers a protective role in small bowel transplantation associated, partly, with NO generation and hyaluronic acid, TNF-α and IL-8 amelioration., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Ischemic preconditioning is one of the therapeutic interventions aiming at preventing ischemia/reperfusion-related injury. Numerous experimental studies and a few clinical series have shown that during liver resections, ischemic preconditioning is a promising strategy for optimizing the postoperative outcome. Moreover, various types of pharmacological intervention as well as different types of preconditioning, such as remote preconditioning, the use of heat shock, and hyperbaric oxygen, have been developed to attenuate the functional impairment accompanying ischemia/reperfusion injury. This review summarizes the various forms of preconditioning, thus suggesting that close cooperation between surgeons and anesthesiologists paves the way to apply novel strategies to improve the outcome of liver resection.

Background: We have previously demonstrated lactate release by the liver itself in hepatectomies performed under selective hepatic vascular exclusion. We hypothesized that ischemic preconditioning applied in this setting might lead to a reduction of hepatic lactate production., Methods: Twenty-one patients underwent hepatectomy under inflow and outflow occlusion combined with ischemic preconditioning (IP group, n = 21). These patients were matched 1:1 with patients subjected to the same technique of hepatectomy under vascular occlusion without ischemic preconditioning (control group, n = 21). The transhepatic lactate gradient (hepatic vein-portal vein) was calculated before liver dissection and 60 min post-reperfusion., Results: In the control group, the transhepatic lactate gradient before liver resection was negative indicating consumption by the liver. After 60 min post-reperfusion, this gradient became positive, indicating net lactate production by the liver (0.2 ± 0.3 vs. -0.3 ± 0.2 mmol/L, P < 0.001). In the IP group, the liver consumed lactate both before resection and 60 min post-reperfusion (gradients -0.2 ± 1.1 and -0.1 ± 0.6 mmol/L, respectively). The magnitude of lactate release by the liver correlated with systemic hyperlactatemia post-reperfusion and 24 h postoperatively (r(2) = 0.54, P < 0.001 and r(2) = 0.67, P < 0.001, respectively). Significant correlations between the transhepatic lactate gradient post-reperfusion and peak postoperative AST as well as the apoptotic response of the liver remnant were also demonstrated (r(2) = 0.72, P < 0.001 and r(2) = 0.66, P < 0.001, respectively)., Conclusion: The microcirculatory derangement and cellular aerobic metabolism breakdown elicited by ischemia-reperfusion insults can be prevented with hepatoprotective measures such as ischemic preconditioning. The transhepatic lactate gradient could act as a monitoring and prognostic tool of the efficacy of ischemic preconditioning.

Background: Extensive experimental studies and a few clinical series have shown that ischemic preconditioning (IPC) attenuates oxidative ischemia/reperfusion (I/R) injuries in liver resections performed under inflow vascular control. Selective hepatic vascular exclusion (SHVE) employed during hepatectomies completely deprives the liver of blood flow, as it entails simultaneous clamping of the portal triad and the main hepatic veins. The aim of the present study was to identify whether IPC can also protect hepatocytes during liver resections performed under SHVE., Methods: Patients undergoing major liver resection were randomly assigned to have either only SHVE (control group, n = 43) or SHVE combined with IPC--10 min of ischemia followed by 15 min of reperfusion before SHVE was applied (IPC group, n = 41)., Results: The two groups were comparable with regard to age, liver resection volume, blood loss and transfusions, warm ischemic time, and total operative time. In liver remnant biopsies obtained 60 min post-reperfusion, IPC patients had significantly fewer cells stained positive by TUNEL compared to controls (19% +/- 8% versus 45% +/- 12%; p < 0.05). Also IPC patients had attenuated hepatocyte necrosis, systemic inflammatory response, and oxidative stress as manifested by lower postoperative peak values of aspartate transaminase, interleukin-6, interleukin-8, and malondialdehyde compared to controls. Morbidity was similar for the two groups, as were duration of intensive care unit stay and extent of total hospital stay., Conclusions: In major hepatectomies performed under SHVE, ischemic preconditioning appears to attenuate apoptotic response of the liver remnant, possibly through alteration of inflammatory and oxidative pathways.

Background: 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., Methods: 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., Results: 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., Conclusions: Although both techniques showed comparable efficacy for short ischemic times, intermittent vascular occlusion provided better cytoprotection when ischemia exceeded 40 minutes.

Background: Numerous previous studies have established the hepatoprotective properties of N-acetylcysteine (NAC). The present study was designed to investigate the effects of NAC on a warm hepatic ischemia-reperfusion rat model with a focus on the role of cAMP., Materials and Methods: Fifty-six male Wistar rats were allocated randomly into the control group (n = 28) or the study group (group NAC, n = 28). Group NAC animals received an intravenous bolus dose of 0.3 mg/g NAC, whereas control animals were given an equal volume of normal saline. Subsequently, 60-min partial liver ischemia was induced by occlusion of blood inflow to the left and middle liver lobes. Aspartate aminotransferase, alanine aminotransferase, and alpha-glutathione S-transferase levels, platelet aggregation, and ischemic tissue cyclic adenosine 5-monophosphate (cAMP) levels were examined at 30, 60, and 120 min after reperfusion. Parts of the ischemic liver were sampled at the same time-points. Measurements were obtained from seven animals at each time point., Results: The administration of NAC resulted in lower levels of aspartate aminotransferase, alanine aminotransferase, and alpha-glutathione S-transferase, decreased platelet aggregation, and increased levels of ischemic tissue cAMP at all time points after reperfusion. Histologically, fewer necrotic changes were observed in the NAC group at 60 and 120 min after reperfusion. All differences were statistically significant (P < 0.05)., Conclusions: In the present study, NAC seems to attenuate hepatic ischemia-reperfusion damage, as demonstrated by liver function tests and liver histology. The effects of NAC appear to be mediated by the decrease in platelet aggregation and increase in the levels of cAMP observed in ischemic liver tissue.

Ischemic preconditioning (IPC) and intermittent vascular control (IVC) have been shown to reduce the number of ischemia/reperfusion injuries during liver resections with the Pringle maneuver. Our study aimed to compare the beneficial effect of these two modalities in relation to the duration of normothermic liver ischemia. A group of 24 Landrace pigs with a mean body weight of 25 to 30 kg were subjected to extended liver resection of more than 65%. Although, 12 animals underwent IPC (10 minutes of ischemia and 10 minutes of reperfusion), and subsequently the Pringle maneuver was applied for 90 minutes (n= 6) or 120 minutes (n= 6). Another 12 animals underwent liver resection by IVC (20 minutes of ischemia alternated with 5 minutes of reperfusion) for 60 minutes (n = 6) or 120 minutes (n = 6) of inflow vascular control. At 90 minutes of liver ischemia, the IPC group demonstrated lower levels of asportate aminotransferase (AST) (173 +/- 53 vs. 265 +/- 106 IU; p =0.089) and malondialdehyde (MDA) (2.60 +/- 1.03 vs. 5.33 +/- 2.25 micromol/L; p =0.022) and higher liver tissue cAMP (200 +/- 42 vs. 146 +/- 40 pmol/g wet wt, p = 0.04) compared to the IVC group. However, no pathologic differences were observed between the two groups. By contrast, at 120 minutes of liver ischemia, IVC proved to be more beneficial, reflected by lower levels of AST (448 +/- 135 vs. 857 +/- 268 IU; p = 0.006) and MDA (8.33 +/- 1.75 vs. 12.7 +/- 4.31 micromol/L; (p = 0.045), a higher cAMP level (127 +/- 10 vs. 97 +/- 31 pmol/g wet wt p = 0.045), and eventually less cellular necrosis (necrosis score 1.66 +/- 0.51 vs. 2.85 +/- 1.16; p = 0.04) compared to the IPC group. It appears that IPC should be employed when liver ischemia is anticipated to last less than 90 minutes, followed by IVC when the liver ischemia is expected to last 120 minutes.