[Trimetazidine prevents ischemia-reperfusion injury in hepatic surgery under vascular clamping]. Treatment of liver metastases from colorectal cancer with hepatic artery occlusion, intraportal 5-fluorouracil infusion, and oral allopurinol. A randomized clinical trial. [Coronary artery disease observed in general hospitals: ETTIC study. Comparison between trimetazidine and mononitrate isosorbide for patients receiving betablockers]. A randomized controlled trial on pharmacological preconditioning in liver surgery using a volatile anesthetic. Impact of preoperative steroids administration on ischemia-reperfusion injury and systemic responses in liver surgery: a prospective randomized study. Combined-modality treatment for resectable metastatic colorectal carcinoma to the liver: surgical resection of hepatic metastases in combination with continuous infusion of chemotherapy--an intergroup study. Ischemic preconditioning improves postoperative outcome after liver resections: a randomized controlled study. The role of allopurinol in human liver ischemia/reperfusion injury: a prospective randomized clinical trial. Anti-ischaemic efficacy and tolerability of trimetazidine administered to patients with angina pectoris: results of three studies.
Clamping the hepatic pedicle (or Pringle's manoeuvre) is frequently used to reduce blood loss during liver surgery. This induces a normothermic ischaemia of the overall liver. In this study we have investigated the anti-ischaemic effect of trimetazidine during surgery on hydatid cysts of the liver requiring vascular clamping of the hepatic pedicle. Seventy-six hepatic pericystectomies were performed under a 40 min normothermic ischaemia. Two randomized groups including 38 patients each received daily either trimetazidine (80 mg/kg, group 1) or placebo (group 2) for 5 days before surgery. The effect of trimetazidine was evaluated on different parameters, the macroscopic appearance of the tissue, the ATP content in liver biopsies obtained before and after 15, 30 and 60 min reperfusion, the activity of the aminotransferase in the plasma and the plasma concentrations of reduced and oxidized gluthatione. No mortality was observed. The duration of hospital stay was reduced for patients treated with trimetazidine (8 +/- 1 days compared with 11 +/- 1.5 days for patients in group 2; p < 0.05). Morbidity rate was lower in group 1 (11 per cent) than in group 2 (18.5 per cent) but the decrease was not significant. Trimetazidine treatment reduced cytolysis (p < 0.05 on day 1, day 3, day 5), increased liver ATP content and limited the increase of reduced and oxidized gluthatione in the plasma during reperfusion. These results suggest that trimetazidine alleviates ischaemia-reperfusion injury during liver surgery and may allow extension of the ischaemic period without damage to the liver. Regional therapy for colorectal liver metastases aimed at prolonging survival has not been tested fully in a randomized trial with untreated control subjects. This study explored the efficacy of temporary hepatic artery occlusion followed by intraportal infusion of 5-fluorouracil (5-FU) and oral allopurinol as biochemical modulators in prolonging the survival of patients with nonresectable liver metastases and no extrahepatic cancer.
                Eighty-four patients were considered for randomization, of whom 24 were excluded at laparotomy because of extrahepatic cancer (n = 17) or resectable lesions (n = 5). In two patients, no cancer was identified in the liver. Thirty-two patients were allocated to receive treatment, and 28 were allocated to receive no regional or systemic treatment. Six patients were excluded after randomization because of major protocol violations.
                The median survival time for patients was 17 months (range, 0-66), and for control subjects, the median was 8 months (range, 0-31). Log rank analysis demonstrated a significant survival benefit for treatment versus no treatment (P = 0.0039). (In two patients, early death was due to toxicity from the wrong dose of 5-FU and the wrong route of administration, respectively; the mean and median survival were reduced by 1 month).
                This study identified a treatment modality that prolongs survival in patients with nonresectable liver metastases and no extrahepatic metastases from colorectal cancer, suggesting that control subjects receiving no therapy may not be necessary in future randomized trials. The extended use of interventional surgery of revascularisation has modified the prognosis and the evolution of ischaemic heart diseases. However, both coronary artery bypass graft and percutaneous transluminal coronary angioplasty failed to make the symptomatic or subclinical ischaemic manifestations of chronic coronary insufficiency disappear. The interest of using betablockers as a first-line therapy was widely demonstrated. However, their combination with another efficient molecule is often necessary. The aim of this trial has been to appreciate the efficiency of the association of a betablocker with either trimetazidine or with isosorbide monoitrate. Hundred and eighty five patients retaining a positive effort test despite 100 mg of atenolol, received in addition, either 60 mg of trimetazidine (93 cases) of 60 mg of isosorbide mononitrate (92 cases) for a two-month period and are then re-evaluated at the end of this period. The ischaemic threshold is delayed in a significant way in both groups (p < 0.0001; trimetazidine +7%, isosorbide mononitrate +10.7%). Twenty-three percent of the exercise tests under trimetzidine and 19% under isosorbide mononitrate become negative after two months of the therapeutic combination. The clinical improvement is even clearer with the disappearance of the angina crisis during the week before the second exercise test in 63% of the cases under trimetazidine and 54% of the cases under isosorbide mononitrate, among the patients who had kept it under atenolol at the inclusion. In conclusion, the combination of a second efficient molecule, trimetazidine or isosorbide mononitrate, brings a functional and objective improvement to patients with insufficient chronic coronary disease not totally controlled using a betablocker, even with high dosage. One should notice two important advantages in favour of the trimetazidine: one is practical due to a better tolerance (lack of cephalalgia), the other is conceptual (use of the complementary metabolic approach of cellular oxygenation rather than the haemodynamic approach of nitrate compounds which are already in concurrency with all other anti-ischaemic molecules). 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. Hepatic injury secondary to warm ischemia-reperfusion (I/R) injury and alterations in haemostatic parameters are often unavoidable events after major hepatic resection. The release of inflammatory mediator is believed to play a significant role in the genesis of these events. It has been suggested that preoperative steroid administration may reduce I/R injury and improve several aspects of the surgical stress response. The aim of this prospective randomized study was to investigate the clinical benefits on I/R injury and systemic responses of preoperatively administered corticosteroids. Seventy-six patients undergoing liver resection were randomized either to a steroid group or to a control group. Patients in the steroid group received preoperatively 500 mg of methylprednisolone. Serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin, coagulation parameters, and inflammatory mediators, interleukin 6 and tumor necrosis factor alpha were compared between the 2 groups. Length of stay, and type and number of complications were recorded as well. Postoperative serum levels of ALT, AST, total bilirubin, and inflammatory cytokines were significantly lower in the steroid than in the control group at postoperative days 1 and 2. Changes in hemostatic parameters were also significantly attenuated in the steroid group. In conclusion, the incidence of postoperative complications in the steroid group tended to be significantly lower than the control group. It is of clinical interest that preoperative steroids administration before major surgery may reduce I/R injury, maintain coagulant/anticoagulant homeostasis, and reduce postoperative complications by modulating the inflammatory response. Despite technical improvements that have minimized the morbidity and mortality of hepatic surgery, the long-term outcome of resection of hepatic metastases of colorectal cancer remains poor, with the majority of patients experiencing treatment failure in the liver. Because arterial chemotherapy regimens targeted to the liver have demonstrated high response rates, an intergroup trial of adjuvant therapy for patients undergoing hepatic resection of liver metastases from colorectal cancer was initiated.
                Patients with one to three potentially resectable metastases were randomized preoperatively to receive no further therapy (control arm, 56 patients) or postoperative hepatic arterial floxuridine combined with intravenous continuous-infusion fluorouracil (chemotherapy arm, 53 patients). After exclusion of patients identified as ineligible for the planned treatment at the time of surgery, there were 45 control patients and 30 on the chemotherapy arm. The study was powered to evaluate improvement in time to recurrence and hepatic disease-free survival, not overall survival.
                The 4-year recurrence-free rate was 25% for the control arm and 46% for the chemotherapy group (P =.04). The 4-year liver recurrence-free rate was 43% in the control group and 67% in the chemotherapy group (P =.03). The median survival of the 75 assessable patients was 49 months for the control arm and 63.7 months for the chemotherapy arm (P =.60). The median survival of all 109 patients was 47 months for the control arm compared with 34 months for the chemotherapy arm (P =.19)
                These data demonstrate that adjuvant intra-arterial and intravenous chemotherapy was beneficial in prolonging time to recurrence and pre-venting hepatic recurrence after hepatic resection of colorectal cancer. 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. To investigate the effect of pretreatment with allopurinol on oxidative stress during reperfusion and the role in liver tissue protection in partial liver resections for colorectal cancer metastases confined to the liver.
                Prospective, randomized, clinical trial, single center, Leiden University Medical Center, The Netherlands.
                Curative partial liver resection of colorectal metastases in 16 patients with or without allopurinol pretreatment, between June 1992 and February 1994.
                Partial liver resections with Pringle maneuver, intravenous allopurinol versus no allopurinol.
                The effect of allopurinol on liver cell damage caused by ischemia/reperfusion studied by measuring malondialdehyde, glutathione, glutathione disulfide, vitamin C, liver enzymes and blood clotting factors in blood samples. Morbidity and mortality were also evaluated.
                Pretreatment with allopurinol had no significant effect on any of our study parameters.
                Because ischemia/reperfusion damage is little in our study, pretreatment with allopurinol is of no value. Several clinical studies have compared the anti-ischaemic properties of trimetazidine used as monotherapy with those of standard anti-anginal therapy. In the treatment of uncontrolled angina pectoris, the addition of a metabolic agent such as trimetazidine to existing therapy with a haemodynamic agent would appear to confer advantages over the addition of a second haemodynamic agent. Here we report the results of three studies conducted in Poland, the Czech Republic and Hungary that provide additional evidence for the beneficial effects of combining trimetazidine with a conventional haemodynamic agent such as beta-blockers, long-acting nitrate or calcium channel blockers. This combination provided significant benefits in terms of improved exercise capacity and decreased number of angina attacks along with a good tolerability profile.
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.