Haemoxygenase modulates cytokine induced neutrophil chemoattractant in hepatic ischemia reperfusion injury.

AIM: To investigate the hepatic microcirculatory changes due to Haemoxygenase (HO), effect of HO inhibition on remote ischemic preconditioning (RIPC) and modulation of CINC. METHODS: Eight groups of animals were studied - Sham, ischemia reperfusion injury (IRI) the animals were subjected to 45 min of hepatic ischemia followed by three hours of reperfusion, RIPC (remote ischemic preconditioning) + IRI group, remote ischemic preconditioning in sham (RIPC + Sham), PDTC + IR (Pyridodithiocarbamate, HO donor), ZnPP + RIPC + IRI (Zinc protoporphyrin prior to preconditioning), IR-24 (45 min of ischemia followed by 24 h of reperfusion), RIPC + IR-24 (preconditioning prior to IR). After 3 and 24 h of reperfusion the animals were killed by exsanguination and samples were taken. RESULTS: Velocity of flow (160.83 ± 12.24 µm/s), sinusoidal flow (8.42 ± 1.19) and sinusoidal perfusion index (42.12 ± 7.28) in hepatic IR were lower (P < 0.05) in comparison to RIPC and PDTC (HO inducer). RIPC increased velocity of flow (328.04 ± 19.13 µm/s), sinusoidal flow (17.75 ± 2.59) and the sinusoidal perfusion index (67.28 ± 1.82) (P < 0.05). PDTC (HO induction) reproduced the effects of RIPC in hepatic IR. PDTC restored RBC velocity (300.88 ± 22.109 µm/s), sinusoidal flow (17.66 ± 3.71) and sinusoidal perfusion (82.33 ± 3.5) to near sham levels. ZnPP (HO inhibition) reduced velocity of flow of RBC in the RIPC group (170.74 ± 13.43 µm/s and sinusoidal flow in the RIPC group (9.46 ± 1.34). ZnPP in RIPC (60.29 ± 1.82) showed a fall in perfusion only at 180 min of reperfusion. Neutrophil adhesion in IR injury is seen in both postsinusoidal venules (769.05 ± 87.48) and sinusoids (97.4 ± 7.49). Neutrophil adhesion in RIPC + IR injury is reduced in both postsinusoidal venules (219.66 ± 93.79) and sinusoids (25.69 ± 9.08) (P < 0.05). PDTC reduced neutrophil adhesion in both postsinusoidal venules (89.58 ± 58.32) and sinusoids (17.98 ± 11.01) (P < 0.05) reproducing the effects of RIPC. ZnPP (HO inhibition) increased venular (589.04 ± 144.36) and sinusoidal neutrophil adhesion in preconditioned animals (121.39 ± 30.65) (P < 0.05). IR after 24 h of reperfusion increased venular and sinusoidal neutrophil adhesion in comparison to the early phase and was significantly reduced by RIPC. Hepatocellular cell death in IRI (80.83 ± 13.03), RIPC + IR (17.35 ± 2.47), and PTDC + IR (11.66 ± 1.17) reduced hepatocellular death. ZnPP + RIPC + IR (41.33 ± 3.07) significantly increased hepatocellular death (P < 0.05 PTDC/RIPC vs ZnPP and IR). The CINC cytokine levels in sham (101.32 ± 6.42). RIPC + sham (412.18 ± 65.24) as compared to sham (P < 0.05). CINC levels in hepatic IR were (644.08 ± 181.24). PDTC and RIPC CINC levels were significantly lower than hepatic IR (P < 0.05). HO inhibition in preconditioned animals with Zinc protoporphyrin increased serum CINC levels (521.81 ± 74.9) (P < 0.05). The serum CINC levels were high in the late phase of hepatic IR (15306 ± 1222.04). RIPC reduced CINC levels in the late phase of IR (467.46 ± 26.06), P < 0.05. CONCLUSION: RIPC protects hepatic microcirculation by induction of HO and modulation of CINC in hepatic IR.

The applicability of hepatocellular carcinoma risk prediction scores in a North American patient population with chronic hepatitis B infection.

BACKGROUND: Patients with chronic hepatitis B (CHB) infection are at an increased risk of developing hepatocellular carcinoma (HCC). Risk scores have been developed in Asian populations to predict HCC risk over time. AIM: To assess the performance of HCC risk prediction models in a heterogeneous population of patients with CHB. METHODS: Scores were calculated at baseline using CU-HCC, REACH-B, NGM1-HCC, NGM2-HCC and GAG-HCC models and the incidence of HCC was determined. The predictive ability of each score was evaluated using the area under the receiver operating characteristic curve (AUROC), Cox regression and plots of observed versus predicted HCC. The predictive value of the scores was compared between Asian and non-Asian patients and between cirrhotic versus non-cirrhotic with and without treatment. RESULTS: Of 2105 patients, 70 developed HCC. Increasing risk score was associated with HCC in all models. The CU-HCC model had the highest AUROC in Asian (0.85) and non-Asian (0.91) patients. Patients identified as low risk by any model had a very low incidence of HCC (0-0.15 per year), with the highest proportion of patients identified as low risk using CU-HCC (67%) or GAG-HCC (78%). The risk of HCC was similar to predicted for low-risk and medium-risk patients but was lower than predicted for high-risk patients. Treated patients had a lower than predicted risk of HCC, particularly in non-cirrhotic high-risk patients with longer follow-up. CONCLUSIONS: Although all models predicted the risk of HCC, models that incorporated parameters of liver function or cirrhosis (CU-HCC/GAG-HCC) were most accurate. Low-risk patients likely require reduced HCC surveillance.

Does antiviral therapy for chronic hepatitis B reduce the risk of hepatocellular carcinoma?

Chronic hepatitis B infection (CHB) is common and can lead to serious consequences including liver cirrhosis, failure, and hepatocellular carcinoma (HCC). The hepatitis B virus (HBV) has a simple genome, but a complex lifecycle that includes the production of covalently closed circular DNA (cccDNA). Currently approved antiviral treatments for CHB include interferon (IFN) and nucleos(t)ide analogues. These drugs work either by stimulating the immune system to eliminate virus-infected cells or to inhibit viral replication, respectively. The drugs do not affect the cccDNA pool in the nucleus; therefore, this molecule represents a persistent source of recurrent infection that is difficult to eradicate. With longer-term follow-up of patients treated with antiviral therapy, investigators have looked at whether treatment can prevent the development of HCC. Unfortunately, the data are fairly heterogeneous in terms of both quality and conclusions. IFN appears to reduce the risk of HCC, but the benefit seems to be restricted to cirrhotic patients who have a lasting response to therapy. Oral agents successfully suppress HBV DNA replication and slow or even reverse hepatic fibrosis. Studies suggest that long-term therapy reduces the risk of HCC in patients with active disease and again primarily in those with advanced fibrosis or cirrhosis. The mechanism by which any of the therapies reduce the risk of HCC is not clear. The authors review the lifecycle of HBV and mechanisms by which the virus may be carcinogenic followed by a review of the literature on the efficacy of therapy in reducing the risk of HCC.

Education provides significant benefits to patients with hepatitis B virus or hepatitis C virus infection: a systematic review.

BACKGROUND & AIMS: Education of individuals who are at risk for, or have been diagnosed with, chronic hepatitis B virus (HBV) or hepatitis C virus (HCV) infections can improve their participation in disease management. We performed a systematic review to evaluate the effects of educational interventions for patients with HBV or HCV infections. METHODS: We searched multiple databases for peer-reviewed studies of individuals with HBV or HCV infection, or those at risk for infection. Our final analysis included 14 studies that evaluated any educational intervention and reported the effectiveness or patient outcomes relevant to the intervention (7 patients with HCV infection, 4 patients with HBV infection, and 3 patients with either). Data extracted from studies included details on educational interventions, patient populations, comparison groups, and outcome measures. The quality of each study was appraised. RESULTS: Types of educational interventions assessed ranged from information websites and nurse-led sessions to community-wide and institutional programs. The educational interventions showed significant (P < .05) improvements to patients' knowledge about their disease, behaviors (including testing and uptake of vaccination), willingness to commence and adhere to treatment, and other outcomes such as self-efficacy and vitality or energy scores. These significant benefits were shown in 5 of 7 studies of HBV infection and 8 of 10 studies of HCV infection. On a 20-point quality scale, study scores ranged from 6 to 19. CONCLUSIONS: Simple educational interventions for patients with HBV or HCV infection significantly increase patients' knowledge about their disease. More complex, multimodal educational interventions seem to cause behavioral changes that increase rates of testing, vaccination (for HBV), and treatment.

Techniques of flushing and reperfusion for liver transplantation.

BACKGROUND: Various techniques of flushing and reperfusion have been advocated to improve outcomes after liver transplantation. There is considerable uncertainty as to which method is superior. OBJECTIVES: To compare the benefits and harms of different methods of flushing and reperfusion during liver implantation in the transplant recipients. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library, MEDLINE, EMBASE, and Science Citation Index Expanded until March 2011. SELECTION CRITERIA: We included all randomised clinical trials that were performed to compare different techniques of flushing and reperfusion during liver transplantation. DATA COLLECTION AND ANALYSIS: Two authors independently identified the trials and extracted the data. We analysed the data with both the fixed-effect model and the random-effects model using RevMan analysis. For each outcome we calculated the hazard ratio (HR), risk ratio (RR), rate ratio, mean difference (MD), or standardised mean difference (SMD) with 95% confidence intervals (CI) based on available case analysis. MAIN RESULTS: We included six trials involving 418 patients for this review. The sample size in the trials varied from 30 to 131 patients. Only one trial involving 131 patients was of low risk of bias for mortality. This trial was at high risk of bias for other outcomes. Four trials excluded patients who underwent liver transplantation for acute liver failure. All the trials included livers obtained from cadaveric donors. The remaining five trials were of high risk of bias for all outcomes. Liver transplantation was performed by the conventional method (caval replacement) in two trials and piggy-back method (caval preservation) in one trial. The method of liver transplantation was not available in the remaining three trials. The comparisons performed included an initial hepatic artery flush versus initial portal vein flush; blood venting via inferior vena cava in addition to venting of storage fluid versus no blood venting; initial hepatic artery reperfusion versus initial portal vein reperfusion; simultaneous hepatic artery and portal vein reperfusion versus initial portal vein reperfusion; and retrograde inferior vena cava reperfusion versus simultaneous hepatic artery and portal vein reperfusion. Only one or two trials could be included under each comparison. There was no significant difference in mortality, graft survival, or severe morbidity rates in any of the comparisons. Quality of life was not reported in any of the trials. AUTHORS' CONCLUSIONS: There is currently no evidence to support or refute the use of any specific technique of flushing or reperfusion during liver transplantation. Due to the paucity of data, absence of evidence should not be confused with evidence of absence of any differences. Further well designed trials with low risk of systematic error and low risk of random errors are necessary.

The hepatic soluble guanylyl cyclase-cyclic guanosine monophosphate pathway mediates the protection of remote ischemic preconditioning on the microcirculation in liver ischemia-reperfusion injury.

BACKGROUND: Remote ischemic preconditioning (RIPC) protects against liver ischemia reperfusion (IR) injury. An essential circulating mediator of this protection is nitric oxide (NO) induced by lower limb RIPC. One of the mechanisms through which NO generally acts is the soluble guanylyl cyclase-cyclic GMP (sGC-cGMP) pathway. The present study aimed to assess the role of hepatic sGC-cGMP in lower limb RIPC-induced protection against liver IR injury. METHODS: Mice were allocated to 4 groups: 1.Sham; 2.IR: 40 min of lobar hepatic ischemia and 2 hr reperfusion; 3.RIPC+IR: 6 cycles of 4x4 min IR of the lower limb followed by IR group procedure; (4) 1H-[1,2,4]oxadiazole[4,3-a]quinoxalin-1-one (ODQ)+RIPC+IR: ODQ (sGC inhibitor) was administered followed by RIPC+IR group procedure. Hepatic microcirculatory blood flow (MBF) was measured throughout the experiment. Plasma transaminases, hepatic histopathological and transmission electron microscopy studies were performed at the end of the experiment. Hepatic cGMP levels were measured in groups 1-3 in addition to an RIPC alone group. RESULTS: Compared to liver IR alone, RIPC+IR increased hepatic MBF during liver reperfusion (P<0.05), and reduced plasma transaminases (P<0.05) and ultrastructural markers of injury. In contrast compared to RIPC+IR, ODQ+RIPC+IR decreased hepatic MBF (P<0.05) and ultrastructural markers of injury. However, plasma transaminases were not significantly different in the ODQ+RIPC+IR compared to the RIPC+IR group. Hepatic cGMP levels were significantly elevated in the RIPC compared to sham group. CONCLUSIONS: The hepatic sGC-cGMP pathway is required for mediating the protective effects of lower limb RIPC on hepatic MBF in liver IR injury.

The nitric oxide pathway--evidence and mechanisms for protection against liver ischaemia reperfusion injury.

Ischaemia reperfusion (IR) injury is a clinical entity with a major contribution to the morbidity and mortality of liver surgery and transplantation. A central pathway of protection against IR injury utilizes nitric oxide (NO). Nitric oxide synthase (NOS) enzymes manufacture NO from L-arginine. NO generated by the endothelial NOS (eNOS) isoform protects against liver IR injury, whereas inducible NOS (iNOS)-derived NO may have either a protective or a deleterious effect during the early phase of IR injury, depending on the length of ischaemia, length of reperfusion and experimental model. In late phase hepatic IR injury, iNOS-derived NO plays a protective role. In addition to NOS consumption of L-arginine during NO synthesis, this amino acid may also be metabolized by arginase, an enzyme whose release is increased during prolonged ischaemia, and therefore diverts L-arginine away from NOS metabolism leading to a drop in the rate of NO synthesis. NO most commonly acts through the soluble guanylyl cyclase-cyclic GMP- protein kinase G pathway to ameliorate hepatic IR injury. Both endogenously generated and exogenously administered NO donors protect against liver IR injury. The beneficial effects of NO on liver IR are not, however, universal, and certain conditions, such as steatosis, may influence the protective effects of NO. In this review, the evidence for, and mechanisms of these protective actions of NO are discussed, and areas in need of further research are highlighted.

Modulation of microcirculatory changes in the late phase of hepatic ischaemia-reperfusion injury by remote ischaemic preconditioning.

BACKGROUND: Remote ischaemic preconditioning (RIPC) is a novel method of protecting the liver from ischaemia-reperfusion (I-R) injury. Protective effects in the early phase (4-6 h) have been demonstrated, but no studies have focused on the late phase (24 h) of hepatic I-R. This study analysed events in the late phase of I-R following RIPC and focused on the microcirculation, inflammatory cascade and the role of cytokine-induced neutrophil chemoattractant-1 (CINC-1). METHODS: A standard animal model was used. Remote preconditioning prior to I-R was induced by intermittent limb ischaemia. Ischaemia was induced in the left and median lobes of the liver (70%). The animals were recovered after 45 min of liver ischaemia. At 24 h, the animals were re-evaluated under anaesthesia. Hepatic microcirculation, sinusoidal leukocyte adherence and hepatocellular death were assessed by intravital microscopy, hepatocellular injury by standard biochemistry and serum CINC-1 by enzyme-linked immunosorbent assay (ELISA). RESULTS: At 24 h post I-R, RIPC was found to have improved sinusoidal flow by increasing the sinusoidal diameter. There was no effect of preconditioning on the velocity of red blood cells, by contrast with the early phase of hepatic I-R. Remote ischaemic preconditioning significantly reduced hepatocellular injury, neutrophil-induced endothelial injury and serum CINC-1 levels. CONCLUSIONS: Remote ischaemic preconditioning is amenable to translation into clinical practice and may improve outcomes in liver resection surgery and transplantation.

Nitric oxide is an essential mediator of the protective effects of remote ischaemic preconditioning in a mouse model of liver ischaemia/reperfusion injury.

NO (nitric oxide) may protect the liver from IR (ischaemia/reperfusion) injury. RIPC (remote ischaemic preconditioning) also protects against liver IR injury; however, the molecular mediator(s) of RIPC are currently unknown. The aim of the present study was to assess the role of NO in hindlimb RIPC-induced protection against liver IR injury. Mice were allocated to the following groups: sham group; RIPC group (six cycles of 4×4 min IR of hindlimb); IR group [40 min lobar (70%) hepatic ischaemia and 2-h reperfusion]; RIPC+IR group (RIPC followed by IR group procedures); and C-PTIO [2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide potassium salt]+RIPC+IR group [C-PTIO (a direct NO scavenger) was administered, followed by the RIPC+IR group procedure]. Hepatic MBF (microcirculatory blood flow) was measured throughout the experiment. Circulating NOx (nitrite and nitrate) levels, plasma liver transaminases, hepatic histopathological and TEM (transmission electron microscopy) studies were performed at the end of the experiment. NOx concentrations were significantly elevated (P<0.05) in the RIPC and RIPC+IR groups. Compared with liver IR alone, RIPC+IR preserved hepatic MBF during liver reperfusion (P<0.05). In contrast, C-PTIO+RIPC+IR reduced MBF compared with RIPC+IR (P<0.05). RIPC+IR reduced plasma transaminases (P<0.05), and histopathological and ultrastructural features of injury compared with IR alone. The protective effects of RIPC+IR in reducing liver IR injury were abrogated in the group that received antecedent C-PTIO (C-PTIO+RIPC+IR). In conclusion, NO is an essential mediator of the protection afforded by hindlimb RIPC against liver IR injury. The mechanisms underlying this protection involve preservation of the sinusoidal structure and maintenance of blood flow through the hepatic microcirculation.

Role of endothelial nitric oxide synthase in remote ischemic preconditioning of the mouse liver.

Hindlimb remote ischemic preconditioning (RIPC) reduces liver ischemia/reperfusion (IR) injury in wild-type mice. The underlying mechanisms of RIPC are currently unknown. In this study, we investigated the role of endothelial nitric oxide synthase (eNOS) in mediating the protective effects of RIPC. Endothelial nitric oxide synthase knockout (eNOS(-/-) ) mice were divided into 4 groups: (1) a sham surgery group, (2) an RIPC group (6 cycles of 4 minutes of hindlimb ischemia and 4 minutes of hindlimb reperfusion), (3) an IR group [40 minutes of lobar (70%) hepatic ischemia and 2 hours of reperfusion], and (4) an RIPC+IR group (RIPC followed by the IR group procedures). Plasma liver aminotransferases, hepatic histopathological injury scores, transmission electron microscopy studies, and hepatic microcirculatory blood flow (MBF) were assessed. eNOS protein expression was analyzed in the livers and hindlimb muscles of wild-type mice. Hindlimb RIPC did not protect against subsequent liver IR injury in eNOS(-/-) mice; this was demonstrated by the lack of reduction in the plasma aminotransferase levels, histopathological scores, or ultrastructural features of IR injury in the RIPC+IR group versus the IR group. Hepatic MBF did not recover during liver reperfusion in the RIPC+IR group versus the IR group. eNOS protein expression was similar among all wild-type groups. In conclusion, eNOS is essential for the protective effects of hindlimb RIPC on liver IR injury. eNOS exerts its protective effects through the preservation of hepatic MBF. At 2 hours of reperfusion, eNOS protection is likely due to the increased activation of eNOS rather than increased expression.

Effect of remote ischemic preconditioning on liver ischemia/reperfusion injury using a new mouse model.

Ischemic preconditioning of remote organs (RIPC) reduces liver ischemia/reperfusion (IR) injury in the rabbit and rat. Mice are the only species available with a large number of transgenic strains. This study describes development and validation of a mouse model of hindlimb RIPC that attenuates liver IR injury. Mice were allocated to 4 groups: (1) Sham surgery; (2) RIPC: 6 cycles of 4 × 4 minutes ischemia/reperfusion of hindlimb; (3) IR: 40 minutes lobar (70%) hepatic ischemia and 2 hours reperfusion; (4) RIPC+IR: RIPC followed by IR group procedures. Plasma liver aminotransferases and hepatic histopathological and transmission electron microscopy studies were performed at the end of the experiment. Hepatic microcirculatory blood flow was measured throughout the experiment. Postoperative complications and animal survival were evaluated. Hindlimb RIPC using a tourniquet resulted in limb paralysis. Hindlimb RIPC using direct clamping of the femoral vessels showed no side effects. Compared to liver IR alone, RIPC+IR reduced plasma aminotransferases (P < 0.05) and histopathological and ultrastructural features of injury. Hepatic microcirculatory blood flow was preserved in the RIPC+IR compared to IR group (P < 0.05). There was no mortality in any of the groups. By demonstrating a consistent improvement in these features of liver IR injury with antecedent hindlimb RIPC and by minimizing experimental confounding variables, we validated this mouse model. In conclusion, we describe a validated mouse model of hindlimb RIPC that reduces liver IR injury. With the availability of transgenic mice strains, this model should prove useful in unraveling the mechanisms of protection of hindlimb RIPC.

Liver ischemia/reperfusion injury: processes in inflammatory networks--a review.

Liver ischemia/reperfusion (IR) injury is typified by an inflammatory response. Understanding the cellular and molecular events underpinning this inflammation is fundamental to developing therapeutic strategies. Great strides have been made in this respect recently. Liver IR involves a complex web of interactions between the various cellular and humoral contributors to the inflammatory response. Kupffer cells, CD4+ lymphocytes, neutrophils, and hepatocytes are central cellular players. Various cytokines, chemokines, and complement proteins form the communication system between the cellular components. The contribution of the danger-associated molecular patterns and pattern recognition receptors to the pathophysiology of liver IR injury are slowly being elucidated. Our knowledge on the role of mitochondria in generating reactive oxygen and nitrogen species, in contributing to ionic disturbances, and in initiating the mitochondrial permeability transition with subsequent cellular death in liver IR injury is continuously being expanded. Here, we discuss recent findings pertaining to the aforementioned factors of liver IR, and we highlight areas with gaps in our knowledge, necessitating further research.

Systematic review of randomized controlled trials of pharmacological interventions to reduce ischaemia-reperfusion injury in elective liver resection with vascular occlusion.

BACKGROUND: Vascular occlusion during liver resection results in ischaemia-reperfusion (IR) injury, which can lead to liver dysfunction. We performed a systematic review and meta-analysis to assess the benefits and harms of using various pharmacological agents to decrease IR injury during liver resection with vascular occlusion. METHODS: Randomized clinical trials (RCTs) evaluating pharmacological agents in liver resections conducted under vascular occlusion were identified. Two independent reviewers extracted data on population characteristics and risk of bias in the trials, and on outcomes such as postoperative morbidity, hospital stay and liver function. RESULTS: A total of 18 RCTs evaluating 17 different pharmacological interventions were identified. There was no significant difference in perioperative mortality, liver failure or postoperative morbidity between the intervention and control groups in any of the comparisons. A significant improvement in liver function was seen with methylprednisolone use. Hospital and intensive therapy unit stay were significantly shortened with trimetazidine and vitamin E use, respectively. Markers of liver parenchymal injury were significantly lower in the methylprednisolone, trimetazidine, dextrose and ulinastatin groups compared with their respective controls (placebo or no intervention). DISCUSSION: Methylprednisolone, trimetazidine, dextrose and ulinastatin may have protective roles against IR injury in liver resection. However, based on the current evidence, they cannot be recommended for routine use and their application should be restricted to RCTs.

Pharmacological interventions versus no pharmacological intervention for ischaemia reperfusion injury in liver resection surgery performed under vascular control.

BACKGROUND: Vascular occlusion to reduce blood loss is used during elective liver resection but results in significant ischaemia reperfusion injury. This, in turn, might lead to significant postoperative liver dysfunction and morbidity. Various pharmacological drugs have been used with an intention to ameliorate the ischaemia reperfusion injury in liver resections. OBJECTIVES: To assess the benefits and harms of different pharmacological agents versus no pharmacological interventions to decrease ischaemia reperfusion injury during liver resections where vascular occlusion was performed during the surgery. SEARCH STRATEGY: We searched The Cochrane Hepato-Biliary Group Controlled Trials Register, the Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library, MEDLINE, EMBASE, and Science Citation Index Expanded until January 2009. SELECTION CRITERIA: We included randomised clinical trials, irrespective of language or publication status, comparing any pharmacological agent versus placebo or no pharmacological agent during elective liver resections with vascular occlusion. DATA COLLECTION AND ANALYSIS: Two authors independently identified trials for inclusion and independently extracted the data. We analysed the data with both the fixed-effect and the random-effects models using RevMan Analysis. We calculated the risk ratio (RR) or mean difference (MD) with 95% confidence intervals (CI) based on intention-to-treat analysis or available case analysis. MAIN RESULTS: We identified a total of 15 randomised trials evaluating 11 different pharmacological interventions (methylprednisolone, multivitamin antioxidant infusion, vitamin E infusion, amrinone, prostaglandin E1, pentoxifylline, mannitol, trimetazidine, dextrose, allopurinol, and OKY 046 (a thromboxane A2 synthetase inhibitor)). All trials had high risk of bias. There were no significant differences between the groups in mortality, liver failure, or perioperative morbidity. The trimetazidine group had a significantly shorter hospital stay than control (MD -3.00 days; 95% CI -3.57 to -2.43). There were no significant differences in any of the clinically relevant outcomes in the remaining comparisons. Methylprednisolone improved the enzyme markers of liver function and trimetazidine, methylprednisolone, and dextrose reduced the enzyme markers of liver injury compared with controls. However, there is a high risk of type I and type II errors because of the few trials included, the small sample size in each trial, and the risk of bias. AUTHORS' CONCLUSIONS: Trimetazidine, methylprednisolone, and dextrose may protect against ischaemia reperfusion injury in elective liver resections performed under vascular occlusion, but this is shown in trials with small sample sizes and high risk of bias. The use of these drugs should be restricted to well-designed randomised clinical trials before implementing them in clinical practice.

Pharmacological interventions for ischaemia reperfusion injury in liver resection surgery performed under vascular control.

BACKGROUND: Vascular occlusion used during elective liver resection to reduce blood loss results in significant ischaemia reperfusion (IR) injury. This in turn leads to significant postoperative liver dysfunction and morbidity. Various pharmacological drugs have been used in experimental settings to ameliorate the ischaemia reperfusion injury in liver resections. OBJECTIVES: To assess the relative benefits and harms of using one pharmacological intervention versus another pharmacological intervention to decrease ischaemia reperfusion injury during liver resections where vascular occlusion was performed during the surgery. SEARCH STRATEGY: We searched The Cochrane Hepato-Biliary Group Controlled Trials Register, the Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library, MEDLINE, EMBASE, and Science Citation Index Expanded until January 2009. SELECTION CRITERIA: We included randomised clinical trials, irrespective of language or publication status, comparing one pharmacological agent versus another pharmacological agent during elective liver resections with vascular occlusion. DATA COLLECTION AND ANALYSIS: Two authors independently identified trials for inclusion and independently extracted data. We analysed the data with both the fixed-effect and the random-effects models using RevMan Analysis. We planned to calculate the risk ratio (RR) or mean difference (MD) with 95% confidence intervals (CI) based on intention-to-treat analysis or available case analysis. However, all outcomes were only reported on by single trials, and meta-analysis could not be performed. Therefore, we performed Fisher's exact test on dichotomous outcomes. MAIN RESULTS: We identified a total of five randomised trials evaluating nine different pharmacological interventions (amrinone, prostaglandin E1, pentoxifylline, dopexamine, dopamine, ulinastatin, gantaile, sevoflurane, and propofol). All trials had high risk of bias. There was no significant difference between the groups in mortality, liver failure, or perioperative morbidity. The ulinastatin group had significantly lower postoperative enzyme markers of liver injury compared with the gantaile group. None of the other comparisons showed any difference in any of the other outcomes. However, there is a high risk of type I and type II errors because of the few trials included, the small sample size in each trial, and the risk of bias. AUTHORS' CONCLUSIONS: Ulinastatin may have a protective effect against ischaemia reperfusion injury relative to gantaile in elective liver resections performed under vascular occlusion. The absolute benefit of this drug agent remains unknown. None of the drugs can be recommended for routine clinical practice. Considering that none of the drugs have proven to be useful to decrease ischaemia reperfusion injury, such trials should include a group of patients who do not receive any active intervention whenever possible to determine the pharmacological drug's absolute effects on ischaemia reperfusion injury in liver resections.

Effect of remote ischemic preconditioning on hepatic microcirculation and function in a rat model of hepatic ischemia reperfusion injury.

BACKGROUND: Liver transplantation involves a period of ischemia and reperfusion to the graft which leads to primary non-function and dysfunction of the liver in 5-10% of cases. Remote ischemic preconditioning (RIPC) has been shown to reduce ischemia reperfusion injury (IRI) injury to the liver and increase hepatic blood flow. We hypothesized that RIPC may directly modulate hepatic microcirculation and have investigated this using intravital microscopy. METHODS: A rat model of liver IRI was used with 45 min of partial hepatic ischemia (70%) followed by 3 h of reperfusion. Four groups of animals (Sham, IRI, RIPC+IRI, RIPC+Sham) were studied (n= 6, each group). Intravital microscopy was used to measure red blood cell (RBC) velocity, sinusoidal perfusion, sinusoidal flow and sinusoidal diameter. Neutrophil adhesion was assessed by rhodamine labeling of neutrophils and cell death using propidium iodide. RESULTS: RIPC reduced the effects of IRI by significantly increasing red blood cell velocity, sinusoidal flow and sinusoidal perfusion along with decreased neutrophil adhesion and cell death. CONCLUSIONS: Using intravital microscopy, this study demonstrates that RIPC modulates hepatic microcirculation to reduce the effects of IRI. HO-1 may have a key role in the modulation of hepatic microcirculation and endothelial function.

Cholecystectomy for gallbladder polyp.

BACKGROUND: The management of gallbladder polyps is controversial. Cholecystectomy has been recommended for gallbladder polyps larger than 10 mm because of the association with gallbladder cancer. Cholecystectomy has also been suggested for gallbladder polyps smaller than 10 mm in patients with biliary type of symptoms. OBJECTIVES: The aim of this review is to compare the benefits (relief of symptoms, decreased incidence of gallbladder cancer) and harms (surgical morbidity) of cholecystectomy in patients with gallbladder polyp(s). SEARCH STRATEGY: We searched The Cochrane Hepato-Biliary Group Controlled Trials Register, the Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library, MEDLINE, EMBASE, and Science Citation Index Expanded until July 2008 to identify the randomised trials. SELECTION CRITERIA: Only randomised clinical trials (irrespective of language, blinding, or publication status) comparing cholecystectomy and no cholecystectomy were considered for the review. DATA COLLECTION AND ANALYSIS: We planned to collect the data on the characteristics, methodological quality, mortality, number of patients in whom symptoms were improved or cured from the one identified trial. We planned to analyse the data using the fixed-effect and the random-effects models using RevMan Analysis. For each outcome we planned to calculate the risk ratio (RR) with 95% confidence intervals based on intention-to-treat analysis. MAIN RESULTS: We were unable to identify any randomised clinical trials comparing cholecystectomy versus no cholecystectomy in patients with a gallbladder polyp. AUTHORS' CONCLUSIONS: There are no randomised trials comparing cholecystectomy versus no cholecystectomy in patients with gallbladder polyps. Randomised clinical trials with low bias -risk are necessary to address the question of whether cholecystectomy is indicated in gallbladder polyps smaller than10 mm.

Blind peritoneal access during laparoscopy: why is it still being used?

Laparoscopy is an important diagnostic and therapeutic modality. It is one of the most commonly performed surgical procedures. Gaining access into the peritoneal cavity and insufflation is the first step in any laparoscopy. This should be the safest part of the procedure. We present a case in which closed induction of the pneumoperitoneum caused a near fatality that could have been avoided had an open technique been used. Endovascular therapy was used to prevent lethal complications of the patient's injuries. In the light of this case and the available literature on this topic, we question whether continued use of closed pneumoperitoneum induction for laparoscopy is still justified.

Remote ischemic preconditioning: a novel protective method from ischemia reperfusion injury--a review.

BACKGROUND: Restoration of blood supply to an organ after a critical period of ischemia results in parenchymal injury and dysfunction of the organ referred to as reperfusion injury. Ischemia reperfusion injury is often seen in organ transplants, major organ resections and in shock. Ischemic preconditioning (IPC) is an adaptational response of briefly ischemic tissues which serves to protect against subsequent prolonged ischemic insults and reperfusion injury. Ischemic preconditioning can be mechanical or pharmacological. Direct mechanical preconditioning in which the target organ is exposed to brief ischemia prior to prolonged ischemia has the benefit of reducing ischemia-reperfusion injury (IRI) but its main disadvantage is trauma to major vessels and stress to the target organ. Remote (inter organ) preconditioning is a recent observation in which brief ischemia of one organ has been shown to confer protection on distant organs without direct stress to the organ. AIM: To discuss the evidence for remote IPC (RIPC), underlying mechanisms and possible clinical applications of RIPC. METHODS OF SEARCH: A Pubmed search with the keywords "ischemic preconditioning," "remote preconditioning," "remote ischemic preconditioning," and "ischemia reperfusion" was done. All articles on remote preconditioning up to September 2006 have been reviewed. Relevant reference articles from within these have been selected for further discussion. RESULTS: Experimental studies have demonstrated that the heart, liver, lung, intestine, brain, kidney and limbs are capable of producing remote preconditioning when subjected to brief IR. Remote intra-organ preconditioning was first described in the heart where brief ischemia in one territory led to protection in other areas. Translation of RIPC to clinical application has been demonstrated by the use of brief forearm ischemia in preconditioning the heart prior to coronary bypass and in reducing endothelial dysfunction of the contra lateral limb. Recently protection of the heart has been demonstrated by remote hind limb preconditioning in children who underwent surgery on cardiopulmonary bypass for congenital heart disease. The RIPC stimulus presumably induces release of biochemical messengers which act either by the bloodstream or by the neurogenic pathway resulting in reduced oxidative stress and preservation of mitochondrial function. Studies have demonstrated endothelial NO, Free radicals, Kinases, Opioids, Catecholamines and K(ATP) channels as the candidate mechanism in remote preconditioning. Experiments have shown suppression of proinflammatory genes, expression of antioxidant genes and modulation of gene expression by RIPC as a novel method of IRI injury prevention. CONCLUSION: There is strong evidence to support RIPC. The underlying mechanisms and pathways need further clarification. The effective use of RIPC needs to be investigated in clinical settings.