Safe upper limit of intermittent hepatic inflow occlusion for liver resection in cirrhotic rats

AIM To evaluate the effects of varying ischemicdurations on cirrhotic liver and to determine the safeupper limit of repeated intermittent hepatic inflowocclusion.METHODS Hepatic ischemia in cirrhotic rats was inducedby clamping the common pedicle of left and median lobesafter non-ischemic lobes resection.The cirrhotic ratswere divided into six groups according to the duration andform of vascular clamping:sham occlusion(SO),intermittent occlusion for 10(IO-10),15(IO-15),20(IO-20)and 30(IO-30)minutes with 5 minutes of reflow andcontinuous occlusion for 60 minutes(CO-60).All animalsreceived a total duration of 60 minutes of hepatic inflowocclusion.Liver viability was investigated in relation ofhepatic adenylate energy charge(EC).Triphenyltetrazollum chloride(TTC)reduction activitieswere assayed to qualitatively evaluate the degree ofirreversible hepatocellular injury.The biochemical andmorphological changes were also assessed and a 7-daymortality was observed.RESULTS At 60 minutes after reperfusion following atotal of 60 minutes of hepatic inflow occlusion,EC valuesin IO-10(0.749±0.012)and IO-15(0.699±0.002)groupswere rapidly restored to that in SO group(0.748±0.016),TTC reduction activities remained in high levels(0.144±0.002mg/mg protein,0.139±0.003mg/mg protein and0.121±0.003mg/mg protein in SO,IO-10 and IO-15groups,respectively).But in IO-20 and IO-30 groups,EClevels were partly restored(0.457±0.023 and 0.534±0.027)accompanying with a significantly decreased TTCreduction activities(0.070±0.005mg/mg protein and0.061±0.003mg/mg protein).No recovery in EC values(0.228±0.004)and a progressive decrease in TTCreduction activities(0.033±0.002mg/mg protein)wereshown in CO-60 group.Although not significantlydifferent,the activities of the serum aspartateaminotransferase(AST)on the third postoperative day(POD_3)and POD_7 and of the serum alanineaminotransferase(ALT)on POD_3 in CO-60 group remained higher than that in intermittent occlusion groups.Moreover,a 60% animal mortality rate and more severemorphological alterations were also shown in CO-60group.CONCLUSION Hepatic inflow occlusion during 60 minutesfor liver resection in cirrhotic rats resulted in lesshepatocellular injury when occlusion was intermittentrather than continuous.Each period of 15 minutes was thesafe upper limit of repeated intermittent vascularocclusion that the cirrhotic liver could tolerate withoutundergoing irreversible hepatocellular injury.     

Hypothermia during reperfusion limits 'no-reflow' injury in a rabbit model of acute myocardial infarction

OBJECTIVE: Reflow following coronary artery occlusion is an important predictor of clinical outcome. This study tests the effects of regional hypothermia, initiated late during ischemia and maintained for 2 h of reperfusion, on the no-reflow phenomenon. METHODS: Anesthetized, open-chest New Zealand White rabbits received 30 min of coronary artery occlusion and 3 h reperfusion. Regional myocardial hypothermia (H, n=14), starting 10 min before reperfusion and continuing for 2 h of reperfusion, was compared with normothermia (N, n=14). Regional myocardial blood flow (microspheres) was measured during occlusion and at the end of reperfusion. The anatomic zone of no-reflow (thioflavin S in vivo injection) and infarct size were measured in the ischemic risk region at the end of the study. RESULTS: Myocardial temperature in H rabbits was decreased by 5.0+/-0.4 degrees C from baseline (37.1+/-0.2 degrees C) and remained about 32 degrees C during the cooling phase, returning to 36.0+/-0.3 degrees C at 3 h. N hearts remained within 0.2 degrees C of baseline (37.3+/-0.1 degrees C) throughout. Both groups were equally ischemic during occlusion, but at the end of reperfusion reflow to the previously ischemic zone was significantly higher in H, 77+/-5% of normal blood flow versus 36+/-4% in N (P=0.0001). The zone of anatomic no-reflow was significantly smaller in H, 11+/-3% of the ischemic risk zone versus 37+/-3% in N (P=0.0001), and was proportionally smaller when represented as a percent of the necrotic zone 36+/-6% compared with 75+/-5% in N. Infarct size, expressed as a percent of the ischemic risk zone was significantly smaller in H vs. N hearts (27+/-4 and 51+/-5%, P=0.0000). CONCLUSION: This study shows that hypothermic therapy initiated late during ischemia and continuing for several hours of reperfusion significantly improves reflow and reduces macroscopic zones of no-reflow and necrosis in this model. The improvement in reflow was greater than would be expected in the H group compared with N, based on the extent of necrosis. As reflow is a predictor of outcome, this intervention may have clinical implications.     

Mild hypothermia reduces the inflammatory response and hepatic ischemia/reperfusion injury in rats.

BACKGROUND/AIMS: Hypothermia is known to protect against ischemia/reperfusion (I/R) injury. The mechanisms of protection are incompletely understood and a temperature threshold for protection has not been established. METHODS: In anesthetized Wistar rats, partial (70%) hepatic ischemia was applied for 45 min. Three study groups were used. Group T31 (n = 6) spontaneously cooled to 31.3 +/- 0.8 degrees C, while group T34 (n = 6) spontaneously cooled to 34 degrees C and was then maintained at 34.0 +/- 0.1 degrees C using a heat lamp. The normothermic group (T37, n = 6) was maintained at 37.1 +/- 0.3 degrees C. Hepatic injury, inflammation, lipid peroxidation and metabolic function (using quantitative 1H-NMR) were assessed 24 h after reperfusion. RESULTS: At 24 h following reperfusion, alanine aminotransferase and aspartate aminotransferase increased to 5101 +/- 2378 and 6409 +/- 4202 U/l in the normothermic T37 group (P < 0.05 vs. T34 and T31), whereas transaminases in hypothermic groups (T31 and T34) were significantly lower. Severe liver necrosis was only noted with T37. Myeloperoxidase activity was increased in the T37 group when compared with hypothermic groups (223 +/- 161 (T37) vs. 16 +/- 10 (T31) and 8 +/- 5 (T34) mU/min/mg of tissue, P<0.05 vs. T31 and T34). 1H-NMR analysis of the blood of normothermic animals revealed metabolic changes consistent with increased ischemic injury, which was almost completely ameliorated in T34 and T31 groups. CONCLUSIONS: Mild hypothermia of 34 degrees C is sufficient to reduce I/R injury by inhibiting the inflammatory response. Further spontaneous cooling to 31 degrees C did not demonstrate any additional protective effect.     

Catheter-based transcoronary myocardial hypothermia attenuates arrhythmia and myocardial necrosis in pigs with acute myocardial infarction.

OBJECTIVES: This study evaluated the efficacy of catheter-based transcoronary myocardial hypothermia (CTMH) in pigs with acute myocardial ischemia. BACKGROUND: Although it has been suggested that hypothermia therapy can attenuate myocardial necrosis, few applications have been accepted for clinical use. METHODS: This study comprises 2 substudies. In both studies, pigs underwent 60 min of coronary occlusion and 180 min of reperfusion. In study 1, after 15 min of coronary occlusion with an over-the-wire-type balloon (OTWB), pigs in the hypothermia group (H) (n = 13) were directly infused with 4 degrees C saline into the coronary artery through the OTWB wire lumen (2.5 ml/min) for 60 min. Pigs in the normothermia group (N) (n = 15) received the same amount of 36.5 degrees C saline. In study 2, pigs in the hypothermia-reperfusion group (HR) (n = 5) were infused with 4 degrees C saline through the infusion catheter (8 ml/min) for 30 min with a later start (60 min after coronary occlusion), whereas simple reperfusion was used for the reperfusion group (R) (n = 6). RESULTS: Catheter-based transcoronary myocardial hypothermia was successful in both studies. In study 1, CTMH significantly decreased ventricular arrhythmia and the ratio of necrosis to ischemic risk area (H: 9 +/- 2%; N: 36 +/- 4%; p < 0.0001) with a significant reduction of enzyme leaks. In study 2, CTMH tended to reduce the ratio of necrosis (HR: 33 +/- 2%; R: 45 +/- 5%; p = 0.08). In both studies, CTMH significantly suppressed the increase of 8-iso-prostaglandin F(2alpha) while preserving the coronary flow reserve. CONCLUSIONS: Catheter-based transcoronary myocardial hypothermia reduced myocardial necrosis while preserving coronary flow reserve, due, in part, to attenuation of oxidative stress.     

Myocardial temperature reduction attenuates necrosis after prolonged ischemia in rabbits

OBJECTIVE: Previously we observed that a large reduction in infarct size was attained by cooling the risk region of the heart, either before or early after the onset of a 30-min coronary artery occlusion. While this is a standard duration of ischemia used in the rabbit model of infarction, it may not reflect the situation of patients who are reperfused late. The effects of regional hypothermia with a longer duration of ischemia, and when the intervention is applied later, are unknown. This study tests the hypothesis that a local reduction in cardiac temperature protects myocardium during prolonged ischemia (2 h) even if begun well after coronary artery occlusion. METHODS: Anesthetized rabbits received 2 h of coronary artery occlusion and 3 h of reperfusion. Rabbits were randomly assigned to a treated group: topical myocardial cooling starting 30 min after coronary occlusion (n = 14), or control group, no intervention (n = 12). Myocardial temperature in the risk zone, hemodynamics and regional myocardial blood flow were measured. RESULTS: Ischemic zone temperature was similar in both groups at 30 min post occlusion, but the cooling maneuver produced a reduction in temperature in the risk region of the treated group such that myocardial temperature was reduced an average of 10 degrees C between 30 and 60 min of coronary artery occlusion. Myocardial temperature in the control group remained within 0.3 degree C of baseline during coronary artery occlusion and into reperfusion. Core temperatures were similar in both groups. Hemodynamic parameters and collateral blood flow during occlusion were also equivalent in both groups. After 120 min of coronary occlusion, necrosis in the control group comprised 72 +/- 3% of the ischemic risk region. However, in cooled hearts, infarct size, expressed as a fraction of the risk region was significantly lower. Infarct size in this group averaged 59 +/- 3% of the risk region (p < 0.004 vs. controls), and thus cooling resulted in a salvage of approximately 18% of the risk region. CONCLUSION: These results show that reducing myocardial temperature protects ischemic myocardium during a long duration of ischemia even if initiated after coronary artery occlusion.     

Protective effect of platelet-activating factor antagonist on hepatic energy metabolism following transient hepatic inflow occlusion in rabbits.

To investigate whether or not platelet-activating factor (PAF) is a mediator of the liver injury resulting from transient hepatic inflow occlusion (Pringle's maneuver), the effect of pretreatment with a potent PAF antagonist (CV6209) on hepatic energy metabolism was evaluated following 30 min of inflow occlusion in rabbits. At 60 min after declamping, the arterial ketone body ratio (AKBR; acetoacetate/3-hydroxybutyrate), reflecting hepatic mitochondrial redox state (NAD+/NADH), increased to 1.10 +/- 0.05 (mean +/- SEM) in the CV6209 (5 mg/kg)-pretreated group (group 1, n = 5) compared with 0.72 +/- 0.06 (P less than 0.01) in the untreated group (group 2, n = 5). Hepatic energy charge at 60 min after declamping was significantly higher in group 1 than in group 2 (0.871 +/- 0.010 vs. 0.800 +/- 0.023; P less than 0.05). Pretreatment with CV6209 had no significant influence on these parameters in sham-operated animals. The present study demonstrates that pretreatment with CV6209 has a protective effect against the impairment of hepatic energy metabolism following transient hepatic inflow occlusion.     

Mild Hypothermia reduces infarct size in the beating rabbit heart: A practical intervention for acute myocardial infarction?

The present study describes a method for rapidly cooling the whole body via its blood pool and tests whether cooling instituted after ischemia has begun can sill limit infarction. We also evaluated whether the cardiac protection seen with cooling could be added to that from ischemic preconditioning. Recently it was reported that lowering myocardial temperature by only several degrees greatly slows the extent of myocardial infarction in the beating heart experiencing regional ischemia. To further explore the potential of hypothermia for myocardial protection, rabbits underwent either a 30-, 45- or 60-min coronary artery occlusion and 3-h reperfusion. Blood from a carotid artery was allowed to circulate through a heat exchanger immersed in ice water and return to a jugular vein until the blood temperature in the left atrium reached the target temperature of 35 or 32°C. Furthermore, to elucidate the mechanism of hypothermia's protection, we also examined its effect on isolated cardiomyocytes. Rewarming began upon reperfusion in all protocols. Cooling to 32°C before a 30-min ischemia reduced infarct size from 37.3±2.5% (n=6) of the risk zone in normothermic controls to 3.6±0.3% (n=6). When cooling was begun 10 or 20 min after the onset of ischemia infarct size was still significantly smaller [8.1±1.2% and 22.8±1.8%, respectively (n=6 in each group)]. Less but significant protection was also seen with cooling to 35°:C. Cooling caused only mild bradycardia and hypotension and no apparent arrhythmias. Forty-five min of regional ischemia caused 50.7±3.3% (n=6) of risk zone to infarct in untreated hearts. Preconditioning with 5-min ischemia/10-min reperfusion reduced infarct size to 27.5±2.5% (n=6). Cooling to 32°C starting 20 min after the onset of ischemia protected the heart (28.7±2.6% infarction, n=8), and this protection could be added to the effect from ischemic preconditioning delayed the progressive increase in osmotic fragility that occurs during simulated ischemia in an additive way, but only hypothermia delayed the appearance of contracture suggesting that different mechanisms are involved. Hence blood pool cooling was easily induced and well tolerated and protected the beating heart against infarction even when hypothermia was started after the onset of coronary occlusion. We conclude that hypothermia might be a simple and useful therapy for patients presenting with acute myocardial infarction. Received: 5 January 1998, Returned for 1. revision: 3 February 1998, 1. Revision received: 24 February 1998, Returned for 2. revision: 1 April 1998, 2. Revision received: 7 April 1998, Accepted: 14 July 1998     

Long-term outcome of intracardiac repair under simple deep hypothermia

Development of cardiopulmonary bypass has contributed to pediatric cardiac surgery, but at the dawn of cardiac surgery, simple deep hypothermia was used to avoid the deleterious effect of cardiopulmonary bypass. Between 1981 and 1990, 45 patients with simple cardiac anomalies underwent definitive surgery under deep hypothermia. Age at operation was 35 days to 20 months, and body weight was 2.3 to 8.0 kg. Under morphine and ether anesthesia, a median sternotomy was performed when the esophageal temperature reached 26.3 degrees C +/- 1.3 degrees C by the application of surface cooling. At a minimum esophageal temperature of 19.6 degrees C +/- 2.3 degrees C, inflow occlusion and cold cardioplegia were applied to induce circulatory arrest for 32.4 +/- 10.2 min. Direct cardiac massage was used to restore cardiac activity during rewarming. All but one patient was in New York Heart Association functional class I postoperatively. The latest cardiothoracic ratio was 49.8% +/- 4.7%. All but 2 patients are free from medication. Five of 30 patients showed developmental delay in the long-term; 2 of these had a long circulatory arrest period, and 3 had prolonged heart failure postoperatively. The other 25 patients had excellent physiologic and mental development. The long-term outcome of perfusionless hypothermic cardiac surgery is satisfactory when applied appropriately.     

Hypothermia and prostaglandin E(1) produce synergistic attenuation of ischemia-reperfusion lung injury.

Current methods of preserving lung tissue for transplantation are inadequate. In this study, we tested whether the combination of hypothermia plus prostaglandin E(1) (PGE(1)) treatment would have synergistic attenuation on ischemia-reperfusion (I/R) lung injury. Isolated rat lung experiments with ischemia for 1 h then reperfusion for 1 h, were conducted using six different perfusates: (1) University of Wisconsin solution (UW) at 30 degrees C (n = 5), (2) UW at 22 degrees C (n = 5), (3) UW at 10 degrees C (n = 4), (4) UW+PGE(1) at 30 degrees C (n = 4), (5) UW+PGE(1) at 22 degrees C (n = 4), and (6) UW+PGE(1) at 10 degrees C (n = 4). Hemodynamic changes, lung weight gain, capillary filtration coefficients, and lung pathology were analyzed to evaluate the I/R injury. Compared with 30 degrees C UW, animals treated with 22 degrees C UW and 10 degrees C UW had less I/R lung injury, with the groups receiving 22 degrees C UW showing superior results to group receiving 10 degrees C UW. The addition of PGE(1) to UW solution produced more attenuation of I/R injury than did UW alone. Among the six groups, 10 degrees C UW+PGE(1) produced the most reduction of I/R injury. This study has shown that hypothermia can attenuate I/R injury with the optimal flushing temperature being near 22 degrees C. PGE(1) also has a protective effect on I/R. Furthermore, hypothermia and PGE(1) have synergistic attenuation of I/R lung injury. We propose that pulmonary artery flushed with cooling UW+PGE(1) might improve lung preservation and improve results in lung transplantation.     

Liver protection by hypothermic perfusion at different temperatures during total vascular exclusion.

INTRODUCTION: In situ hypothermic perfusion (HP) can be applied to attenuate ischemia and reperfusion (I/R) injury during liver resection under total vascular exclusion (TVE). This study examines the protective effect of cooling by HP at 20 and 28 degrees C as compared with no HP during TVE in a porcine liver I/R model. METHODS: Twenty-one pigs underwent 60 min TVE of the liver followed by 24 h reperfusion. HP was performed via the portal vein using ringerlactate solution of 4 degrees C. Pigs were assigned to three groups: TVE without HP (no-HP, n=9), TVE with HP at 28 degrees C (HP-28, n=6) and TVE with HP at 20 degrees C (HP-20, n=6). RESULTS: Perfusion volumes during TVE were 5.1+/-0.5 and 17.3+/-1.7 l in HP-28 and HP-20, respectively (P<0.05). Aspartate aminotransferase (AST) after 24 h reperfusion was 1172+/-440 U/l in no-HP as compared with 223+/-69 and 180+/-22 U/l in HP-28 and HP-20, respectively (P<0.05). No differences in liver function or histopathology were found between the HP-28 and HP-20 groups. CONCLUSIONS: HP at 20 degrees C is equally effective in preserving liver function and preventing hepatocellular injury under TVE as compared with HP at 28 degrees C. HP at 28 degrees C is advised, because of the lesser perfusion volume necessary for cooling of the liver.     

Mild hypothermia delays the onset of coma and prevents brain edema and extracellular brain glutamate accumulation in rats with acute liver failure

Mild hypothermia is effective in the prevention of brain edema associated with cerebral ischemia and traumatic brain injury. Brain edema is also a serious complication of acute liver failure (ALF). To assess the effectiveness of hypothermia in ALF, groups of rats were subjected to hepatic devascularization (portacaval anastomosis, followed 48 hours later by hepatic artery ligation), and body temperatures were maintained at either 35 degrees C (hypothermic) or 37 degrees C (normothermic). Mild hypothermia resulted in a significant delay in the onset of severe encephalopathy and in reduction of brain water content compared with normothermic ALF rats (control [n = 8] 80.22%; ALF-37 degrees C [n = 8] 81.74%; ALF-35 degrees C [n = 8] 80.48% [P <.01 compared with ALF-37 degrees C]). This protective effect was accompanied by a significant reduction of cerebrospinal fluid (CSF) (but not plasma) ammonia concentrations (CSF ammonia: control: 0.05 mg/dL; ALF-37 degrees C: 1.01 mg/dL; ALF-35 degrees C: 0.07 mg/dL, P <.01 compared with ALF-37 degrees C). In vivo cerebral microdialysis studies revealed that mild hypothermia resulted in a significant reduction of extracellular glutamate concentrations in the brains of rats with ALF (control: 1. 06 micromol/L; ALF-37 degrees C: 2.74 micromol/L; ALF-35 degrees C: 1.49 micromol/L [P <.01 compared with ALF-37 degrees C]). These findings suggest that: 1) mild hypothermia is an effective approach to the prevention of the central nervous system consequences of experimental ALF; and that 2) the beneficial effect of hypothermia is mediated via mechanisms involving reduced blood-brain transfer of ammonia and/or reduction of extracellular brain glutamate concentrations. Mild hypothermia may be an effective approach to delay the onset of brain edema in patients with ALF awaiting liver transplantation.     

Enhanced inflammatory cytokine production at ischemia/reperfusion in human liver resection

BACKGROUND/AIMS: Clinical implications of acute reactant cytokine responses remain to be clarified in the setting of ischemia/reperfusion of human liver during liver resection and transplantation. METHODOLOGY: In serial samples of portal and systemic venous blood we examined acute inflammatory cytokine activities at the time points--before i), at the end of clamping ii), and one hour iii) and day 1 iv) after continuous hepatic inflow occlusion in 25 patients undergoing elective hepatectomy (15 major and 10 minor). Responses of tumor necrosis factor-alpha, interleukin-1 beta, interleukin-6 and interleukin-8 were compared with intraoperative parameters such as the duration of hepatic inflow occlusion and portal venous pressure during the occlusion, postoperative hepatocyte injury markers such as serum transaminases and bilirubin and also related complications. RESULTS: Portal interleukin-6 levels were significantly elevated during hepatic inflow occlusion, as compared with the systemic events (P < 0.02, at time point ii), but there were no differences in the interleukin-8 levels between the portal and systemic circulation. The increase in portal interleukin-6 levels during liver resection (time points, ii and iii) significantly correlated with the duration of hepatic inflow occlusion (48 +/- 9 min, mean +/- SD), portal venous pressure (500 +/- 127 mmH2O), and postoperative serum levels of transaminases (day 1; S-ALT, 705 +/- 1023 U/L; S-AST 892 +/- 1255 U/L) and maximum bilirubin (2.6 +/- 2.5 mg/dL). Interleukin-8 levels in the portal circulation showed no such correlation, but the levels in systemic blood showed significant positive relationships with the intra- and postoperative parameters. One patient who died had an enhanced generation of the cytokines in the presence of an elevated portal venous pressure. CONCLUSIONS: These observations suggest that overproduction of acute reactant cytokines (interleukin-6 from the portal system and interleukin-8 from the systemic circulation) in hepatic ischemia/reperfusion relates positively with postoperative hepatocyte injury in humans. We propose that hepatectomy done under a prolonged continuous inflow occlusion should be reconsidered when an enhanced generation of acute cytokines is anticipated, especially in case of a markedly high portal pressure during hepatic pedicle clamping.     

Combination therapy for maximal myocardial infarct size reduction

The aim of this study was to test whether myocardial infarct size reduction would be optimized by combining three known effective therapies: cariporide, regional hypothermia, and ischemic preconditioning (CHIP). Before coronary artery occlusion (CAO), treated rabbits (CHIP, n = 7) received cariporide (0.3 mg/kg), ischemic preconditioning (7 minutes ischemia and 5 minutes reperfusion), then 20 minutes of mild regional hypothermia (34 degrees C). Control rabbits (n = 7) received saline and a 34-minute waiting period. All received 30 minutes of CAO and reperfusion. In another study, rabbits (n = 8 in each group) received 90 minutes of CAO. In the 30-minute protocol, the authors found that hearts in both groups were equally ischemic during CAO. Mean ischemic risk zones were similar in both groups; however, in CHIP hearts, infarct size was 4 +/- 1% of risk zone, a reduction of 91% compared with control rabbits (44 +/- 7% of the risk zone, P = 0.001). In the 90-minute protocol, risk zone size was similar in both groups, but infarct size in control hearts was 76 +/- 3% of the risk zone compared with 34 +/- 7% in CHIP treated hearts (P = 0.0003). In summary, the combined treatment provided extraordinary protection. Infarct comprised only 4% of the risk region after 30-minute ischemia-a far greater reduction than was previously observed in the same laboratory using any single intervention. After 90 minutes of ischemia, infarct was 55% lower in CHIP hearts, suggesting that this therapeutic approach dramatically reduces ischemia/reperfusion cell death, even during long occlusions.     

Reduction of ischemia reperfusion injury after liver resection and hepatic inflow occlusion by α-Iipoic acid in humans

AIM: To evaluate the protective effects of preconditioning by alpha-lipoic acid (LA) in patients undergoing hepatic resection under inflow occlusion of the liver. METHODS: Twenty-four patients undergoing liver resection for various reasons either received 600 mg LA or NaCl 15 min before transection performed under inflow occlusion of the liver. Blood samples and liver wedge biopsy samples were obtained after opening of the abdomen immediately after inflow occlusion of the liver, and 30 min after the end of inflow occlusion of the liver. RESULTS: Serum levels of aspartate transferase and alanine transferase were reduced at all time points in patients who received LA in comparison to those who received NaCL. This was accompanied by reduced histomorphological features of oncosis. We observed TUNEL-positive hepatocytes in the livers of the untreated patients, especially after 30 min of ischemia. LA attenuated this increase of TUNEL-positive hepatocytes. Under preconditioning with LA, ATP content was significantly enhanced after 30 min of ischemia and after 30 min of reperfusion. CONCLUSION: This is the first report on the potential for LA reducing ischemia/reperfusion injury (IRI) of the liver in humans who were undergoing liver surgery. Beside its simple and rapid application, side effects did not occur. LA might therefore represent a new strategy against hepatic IRI in humans.     

Reduction of ischemia reperfusion injury after liver resection and hepatic inflow occlusion by α-lipoic acid in humans

AIM:To evaluate the protective effects of preconditioning by α-lipoic acid (LA) in patients undergoing hepatic resection under inflow occlusion of the liver.METHODS:Twenty-four patients undergoing liver resection for various reasons either received 600 mg LA or NaCl 15 min before transection performed under inflow occlusion of the liver. Blood samples and liver wedge biopsy samples were obtained after opening of the abdomen immediately after inflow occlusion of the liver, and 30 min after the end of inflow occlusion of the liver.RESULTS:Serum levels of aspartate transferase and alanine transferase were reduced at all time points in patients who received LA in comparison to those who received NaCL. This was accompanied by reduced histomorphological features of oncosis. We observed TUNELpositive hepatocytes in the livers of the untreated patients, especially after 30 min of ischemia. LA attenuated this increase of TUNEL-positive hepatocytes. Under preconditioning with LA, ATP content was significantly enhanced after 30 min of ischemia and after 30 min of reperfusion.CONCLUSION:This is the first report on the potential for LA reducing ischemia/reperfusion injury (IRI) of the liver in humans who were undergoing liver surgery.Beside its simple and rapid application, side effects did not occur. LA might therefore represent a new strategy against hepatic IRI in humans.     

Tolerance to intermittent ischemia of damaged rat liver by thioacetamide

BACKGROUND/AIMS: Tolerance of damaged rat livers for intermittent ischemia was assessed. Clinically, tolerance of operative ischemia by diseased livers, long thought minimal, is being reexamined. METHODOLOGY: A rat model using 0.04% thioacetamide-induced liver damage followed by pedicle occlusion was used to study partial hepatic ischemia in injured livers in terms of survival, hepatic tissue blood flow, beta-ATP content, liver enzymes and histology. Prior to continuous ischemia (150 min) or intermittent ischemia (alternating every 15 min with reperfusion for 10 cycles) animals were divided into mild (B) and severe (A) thioacetamide-induced injury groups according to the hepatic clearance rate of indocyanine green from plasma. RESULTS: The survival rates for 1 week after intermittent ischemia were 43%, 77%, and 93% in groups A and B and in controls (group C), respectively. No group A or B animals receiving continuous ischemia survived. Hepatic tissue blood flow and liver beta-ATP levels in serum were significantly higher in group A than in other groups. Marked damage also was observed histologically in group A. CONCLUSIONS: Intermittent liver circulation blockage may be relatively safe in a damaged liver, but a more severe degree of damage predisposes to serious ischemia-reperfusion injury.     

Mild hypothermia protects liver against ischemia and reperfusion injury

AIM: To determine whether mild hypothermia could protect liver against ischemia and reperfusion injury in pigs. METHODS: Twenty-four healthy pigs were randomly divided into normothermia, mild hypothermia and normal control groups. The experimental procedure consisted of temporary interruption of blood flow to total hepatic lobe for different lengths of time and subsequent reperfusion. Hepatic tissue oxygen pressure (PtiO2) and aspartate aminotransferase (AST) values were evaluated, and ultrastructural analysis was carried out for all samples. RESULTS: Serum AST was significantly lower, and hepatic PtiO2 values were significantly higher in the mild hypothermia group than in the normothermia group during liver ischemia-reperfusion periods (P= 0.032, P= 0.028). Meanwhile, the histopathologic injury of liver induced by ischemia-reperfusion was significantly improved in the mild hypothermia group, compared with that in the normothermia group. CONCLUSION: Mild hypothermia can protect the liver from ischemia-reperfusion injury in pigs.     

Myocardial hypothermia: a potential therapeutic technique for acute regional myocardial ischemia

The importance of temperature in the development of necrosis after myocardial ischemia in the beating heart is becoming apparent. Recent studies have shown that the proportion of the ischemic risk zone that becomes necrotic is directly correlated with temperature. This fact suggests the potential therapeutic benefits of reducing myocardial temperature after coronary artery occlusion. We have shown in a number of experimental protocols in the rabbit model of myocardial infarction that topical regional hypothermia reduces infarct size even when instituted after coronary artery occlusion. The reduction in myocardial temperature required to obtain this benefit is modest ( 30 degrees C to 34 degrees C). Topical regional hypothermia allows targeted cooling of a zone of the heart. Myocardial cooling can also be achieved by perfusing the pericardial sac with a chilled fluid by using a closed-circuit catheter system that does not cause cardiac tamponade. This technique also protects myocardium during ischemia. Myocardial hypothermia might be a useful technique to limit ischemic damage during infarction or as adjunctive therapy during minimally invasive cardiac surgery.     

Hepatic resection under in situ hypothermic hepatic perfusion

BACKGROUND/AIMS: Temporary inflow occlusion of the portal triad has been used frequently in hepatectomy to minimize bleeding. On the other hand, Pringle's maneuver produces ischemic-reperfusion injury especially in patients with underlying liver disease. METHODOLOGY: Thirty-seven cases of hepatic resections were performed with intermittent Pringle's maneuver (IP group; n = 17) and in situ hypothermic perfusion (CP group; n = 20). In the CP group, hepatic inflow was continuously occluded, and 4-degree Centigrade Ringer's lactate was administered by drip during resection. Hepatic outflow occlusion was not performed. RESULTS: All patients tolerated the procedures well. Cold perfusion technique significantly decreased both the times required and the blood loss in hepatectomy (p < 0.05). Serum hyaluronic acid levels gradually increased after the induction of hepatectomy and peaked 10 minutes after reperfusion in the both groups. Thereafter, it decreased and showed a significantly lower level in the CP group until 60 minutes after reperfusion (p < 0.05). Hepaplastin levels remained significantly higher in the CP group one week after operation (p < 0.05). CONCLUSIONS: Using the technique of in situ hypothermic perfusion, we can prolong the ischemic time safely with minimal systemic influence even in cases with underlying liver diseases. This may compare favorably with intermittent Pringle's maneuver in terms of reducing hepatic sinusoidal endothelial cell damage during hepatectomy and reperfusion.