入肝血流阻断和全肝血流阻断对肝组织氧压影响

目的 研究兔常温下入肝血流阻断（portal triad clamp,PTC)及全肝血流阻断（total hepatic vascular exclusion,THVE)对肝组织氧压（tissue oxygen pressure,Ptio2)的影响。方法 24只兔均分二组即PTC和THVE组。分别测定二组缺血前、缺血30min及再灌注30min后肝Ptio2值及血清丙氨酸氨基转氨酶（ALT）值变化。结果 PTC和THVE组均表现为肝Ptio2下降，但THVE较PTC组肝Ptio2值下降更显著（P＜0．01）、血清ALT值也明显升高（P＜0．05）。结论 PTC组较THVE组对肝缺血的耐受性增加。     

入肝血流阻断和全肝血流阻断对胆道梗阻兔肝脏损伤的研究

目的 研究入肝血流阻断和全肝血流阻断对胆道梗阻兔肝脏的缺血-再灌注损伤。方法 36只兔随机均分为3组:胆道梗阻组(A组,BCDL)、入肝血流阻断组(B组,PTC)和全肝血流阻断组(C组,THVE)。组织气体分析仪持续测定肝组织氧分压(P_(ti)O_2);全自动生化仪测定血流总胆红素(TBIL)、丙氨酸氢基转氨酶(ALT);光镜观察肝脏病理改变。结果 B、C组在肝血流阻断后,肝 P_(ti)O_2值均明显下降,再灌注 60 min仅恢复到缺血前的 87.5％和 73.4％(P<0.05),C组较 B组肝P_(ti)O_2 值恢复更慢(P<0.05)。B、C两组 ALT值在肝缺血-再灌注期间均有不同程度升高,C组ALT值升高更明显,且与肝细胞损伤的病理学改变相一致。结论 急性胆道梗阻兔行PTC和THVE均可导致肝脏缺血-再灌注损伤,PTC较THVE对肝脏的损伤明显减轻。     

Attenuation of ischemia and reperfusion injury of canine livers by inhibition of type II phospholipase A2 with LY329722

BACKGROUND: Membrane phospholipid breakdown, caused by ischemia and reperfusion (I/R) of the liver, releases free fatty acids including arachidonic acids and lysophospholipids, which serve as precursors of various inflammatory lipid derivatives. Phospholipase A2 (PLA2) is a key enzyme that initiates this reaction. In this study, we tested our hypothesis that a type II PLA2 inhibitor, LY329722, could attenuate hepatic I/R injury caused by a 2-hr total hepatic vascular exclusion (THVE) in dogs. METHODS: Eighteen beagle dogs, subjected to a 2-hr THVE, were divided into three groups. Group 1 (n=6) was untreated and served as a control group. LY329722 was administered to animals in group 2 (n=6) intravenously (0.2 mg x kg(-1) x hr(-1)) for 60 min before ischemia, and to animals in group 3 (n=6) for 60 min starting 15 min before reperfusion (0.2 mg x kg(-1) x hr(-1)). Animal survival, systemic and splanchnic hemodynamics, hepatic tissue blood flow, liver functions, energy metabolism, hepatic venous thromboxane B2 and endothelin-1 levels, phospholipid levels and tumor necrosis factor-a mRNA expression in liver tissue, and histopathologic findings were evaluated. RESULTS: Two-week animal survival was 33% (two of six) in group 1, and 100% (six of six) in groups 2 and 3. LY329722 improved systemic and splanchnic hemodynamics, hepatic tissue blood flow, and energy metabolism, reduced liver enzyme, thromboxane B2, and endothelin-1 release, prevented hepatic phospholipid degradation and tumor necrosis factor-alpha mRNA expression, and lessened histopathologic damage and the number of neutrophil infiltrating into the liver tissue. CONCLUSION: The present study demonstrated that a type II PLA2 inhibitor, LY329722, attenuated hepatic I/R injury caused by a 2-hr THVE model in dogs.     

The effect of antagonism of adenosine A1 receptor against ischemia and reperfusion injury of the liver

BACKGROUND: Adenosine is known to exert protective roles in hepatic ischemia and reperfusion injury, while all adenosine receptors do not play the cytoprotective roles. We have tested our hypothesis that blockage of adenosine binding to A(1) receptor by its antagonist, KW3902 [8-(noradamantan-3-yl)-1,3-dipropylxanthine] attenuates hepatic ischemia-reperfusion injury. METHODS: Adult female beagle dogs underwent a 2 h total hepatic vascular exclusion (THVE) with a venovenous bypass. Nontreated animals that underwent THVE with a venovenous bypass alone were used as the control (Group CT, n=6). KW3902 was given to the animals by continuous intraportal infusion for 60 min before ischemia at a dose of 1 microg/kg/min (Group KW, n=6). Two wk survival, hemodynamics, hepatic tissue blood flow (HTBF), liver function, energy metabolism, cAMP concentration, and histopathological findings were studied. RESULTS: Two wk animal survival was significantly improved in group KW compared with that in group CT (group CT: 16.7% versus group KW: 83.3%). HTBF, liver function, and hepatic adenine nucleotide concentration were remarkably better in group KW than group CT. In addition, cAMP concentration in group KW was maintained significantly higher than group CT. Histopathological examination revealed preservation of hepatic architecture and suppression of neutrophil infiltration into hepatic tissue in group KW. CONCLUSION: Administration of adenosine A(1) receptor antagonist before ischemia attenuates hepatic ischemia-reperfusion injury. To elicit the beneficial effect of adenosine against ischemia and reperfusion injury of the liver, it is important to oppose adenosine A1 receptor activation.     

Effects of isovolaemic haemodilution on oxygenation of liver and skeletal muscle

BACKGROUND AND OBJECTIVE: Hydroxyethyl starch is frequently used for volume substitution during surgical procedures and for isovolaemic haemodilution. Haemodilution has also been shown to improve tissue oxygen tension in skeletal muscle: However, effects of this volume substitute on tissue oxygen tension of the liver during haemodilution remains unknown. METHODS: Fourteen foxhounds were anaesthetized with fentanyl/midazolam and mechanically ventilated with 30% oxygen. Following splenectomy animals were randomly assigned to a control group without haemodilution but fluid substitution with Ringer's lactate (Group C) or underwent isovolaemic haemodilution to a haematocrit of 25% with hydroxyethyl starch 70/0.5 (Group H). Haemodynamic parameters and oxygen transport during 100 min following isovolaemic haemodilution were measured. Liver oxygen tension was recorded using a flexible polarographic electrode tonometer, whereas in the muscle a polarographic needle probe was used. RESULTS: Animal characteristics and baseline haematocrit were similar in both groups. At baseline the tissue oxygen tension of liver and skeletal muscle were not different between groups. Haemodilution with hydroxyethyl starch 70/0.5 provided augmentation of mean liver tissue oxygen tension (baseline: 46 +/- 13 mmHg; 20 min: 60.3 +/- 12 mmHg; 60 min: 60 +/- 16 mmHg; 100 min: 63 +/- 16 mmHg; P < 0.05 vs. baseline), while oxygen tensions in Group C remained unchanged (baseline: 48 +/- 16 mmHg; 20 min: 52 +/- 19 mmHg; 60 min: 49 +/- 12 mmHg; 100 min: 52 +/- 16 mmHg) and no differences could be detected between groups. Oxygen tension in skeletal muscle changed as follows: Group H - baseline: 24 +/- 32 mmHg; 20 min: 32 +/- 3 mmHg; 60 min: 33 +/- 7 mmHg; 100 min: 33 +/- 11 mmHg. Group C - baseline: 22 +/- 6 mmHg; 20 min: 21 +/- 3 mmHg; 60 min: 24 +/- 4 mmHg; 100 min: 18 +/- 4 mmHg (P < 0.05 vs. baseline, p < 0.05 vs. Group C). CONCLUSION: In this animal model, isovolaemic haemodilution with hydroxyethyl starch 70/0.5 increased tissue oxygen tension in liver and skeletal muscle in comparison with baseline values. However, when compared between groups haemodilution only resulted in an increase of tissue oxygen tension in the muscle but not in the liver.     

Oxygenation in the stomach and the effect of truncal vagotomy

A Clark polarographic oxygen electrode allowed detailed mapping of tissue oxygen (PtO2) levels on the anterior surface of the stomach in five patients undergoing cholecystectomy. No significant difference in mean PtO2 was detectable between greater and lesser curvatures. A significant difference in mean PtO2 was detected between the body of the stomach and the pylorus (Mann-Whitney, P less than 0.01). The effect of truncal vagotomy on PtO2 was evaluated in six patients undergoing this procedure for duodenal ulceration. Mean postvagotomy stomach PtO2 levels (46 +/- 12 mmHg) were significantly lower (Wilcoxon test, P less than 0.001) than prevagotomy levels (59 +/- 14 mmHg). Truncal vagotomy did not have any significant effect on small intestinal PtO2. This work provides the first objective evidence of the relatively diminished tissue oxygenation in the gastric antrum and pyloric region, and confirms blood flow studies of the effects of vagotomy.     

Electron paramagnetic resonance assessment of brain tissue oxygen tension in anesthetized rats

The adequacy of cerebral tissue oxygenation (PtO(2)) is a central therapeutic end point in critically ill and anesthetized patients. Clinically, PtO(2) is currently measured indirectly, based on measurements of cerebrovascular oxygenation using near infrared spectroscopy and experimentally, using positron emission tomographic scanning. Recent developments in electron paramagnetic resonance (EPR) oximetry facilitate accurate, sensitive, and repeated measurements of PtO(2). EPR is similar to nuclear magnetic resonance but detects paramagnetic species. Because these species are not abundant in brain (or other tissues) in vivo, oxygen-responsive paramagnetic lithium phthalocyanine crystals implanted into the cerebral cortex are used for the measurement of oxygen. The line widths of the EPR spectra of these materials are linear functions of PtO(2). We used EPR oximetry in anesthetized rats to study the patterns of PtO(2) during exposure to various inhaled and injected general anesthetics and to varying levels of inspired oxygen. Rats anesthetized with 2.0 minimum alveolar anesthetic concentration isoflurane maintained the largest PtO(2) (38.0 +/- 4.5 mm Hg) and rats anesthetized with ketamine/xylazine had the smallest PtO(2) (3.5 +/- 0.3 mm Hg) at a fraction of inspired oxygen (FIO(2)) of 0.21, P < 0.05. The maximal PtO(2) achieved under ketamine/xylazine anesthesia with FIO(2) of 1.0 was 8.8 +/- 0.3 mm Hg, whereas PtO(2) measured during isoflurane anesthesia with FIO(2) of 1.0 was 56.3 +/- 1.7 mm Hg (P < 0.05). These data highlight the experimental utility of EPR in measuring PtO(2) during anesthesia and serve as a foundation for further study of PtO(2) in response to physiologic perturbations and therapeutic interventions directed at preventing cerebral ischemia. IMPLICATIONS: Using in vivo electron paramagnetic resonance oximetry, we studied the patterns of cerebral tissue oxygenation (PtO(2)) during exposure to various inhaled and injected general anesthetics, and to varying levels of inspired oxygen. These data show that inhaled anesthetics result in larger levels of PtO(2) in the brain than do several injectable anesthetics. The results highlight the experimental utility of electron paramagnetic resonance in measuring PtO(2) during anesthesia and serve as a foundation for further study of PtO(2) in response to physiologic perturbations and therapeutic interventions directed at preventing cerebral ischemia.     

Studies on tissue PO2 and biochemical analysis of the skeletal muscle of legs with chronic arterial occlusive diseases

Measurements of maximum tissue PO2 during 100% O2 inhalation (PtO2max) and biochemical analysis of the skeletal muscle were performed in 3 legs without ischemia and 14 legs with chronic arterial occlusive disease requiring amputation. There were significant good correlations between PtO2max and levels of pH, lactate, enzymes (CPK, LDH, Aldolase) and ATP in the skeletal muscle with ischemia. In regions in which PtO2max was below 10mmHg, ischemic changes in the muscle were considered to be irreversible. On the contrary, primary wound healing was obtained in regions with 40mmHg or more of PtO2max. Measurements of the PtO2max of the ischemic muscles provided much useful information concerning the reversibility of muscle ischemia and for decision of the amputation level.     

The comparative effects of total hepatic vascular isolation techniques performed at different durations in rat

BACKGROUND: Total hepatic vascular exclusion (THVE) leads to massive venous congestion below the level of diaphragm and may promote undesirable hemodynamic disturbances in some patients. Supraceliac aortic clamping during THVE may achieve hemodynamic stability at the price of arterial ischemia. However, the parenchymal injury of venous congestion has been a greater concern than of arterial ischemia in various settings. We hypothesized that supraceliac aortic occlusion during THVE may attenuate the reperfusion injury and improve the outcome that would be acquired after THVE alone. MATERIAL AND METHODS: Rats were randomly assigned to (1) THVE alone, (2) THVE plus aortic occlusion, (3) THVE plus celio-mesenteric arterial occlusion or (4) sham during 30, 45, or 60 min followed by 180 min reperfusion period. Serum enzymes (alanine aminotransferase, lactate dehydrogenase) and creatinine as well as tissue "thiobarbituric acid reactive substances" (TBARS) and histopathology were evaluated. Seven animals per group were followed for survival up to 7 d. RESULTS: After 30 min, no difference was found in serum enzyme, creatinine and tissue TBARS measures among the isolation methods used. In these, all rats survived to 7 d. However, after 45 and 60 min isolation, aortic occlusion resulted in significant rise in serum enzyme and tissue TBARS measures as well as poor survival (14% and 0%, respectively). In contrast, all rats survived even after 60 min of THVE. CONCLUSIONS: THVE was tolerated up to 60 min with less reperfusion injury and better survival than celio-mesenteric arterial occlusion and supraceliac aortic occlusion in the rat, if needed, aortic clamping should not exceed 30 min. Beyond that, selective celio-mesenteric arterial occlusion may be considered.     

Tissue Po2 Measured in Man by an Implanted Latex Rubber Tube

A latex rubber tube easily permeable to O2 was implanted in a triceps muscle of six volunteers. Seven days later, PO2 in muscle tissue (PtO2) was measured repeatedly by filling the tube with saline. After a 2-minute equilibration, the saline was sampled in a glass capillary and its PO2 measured by polarographic technique. PaO2 and venous oxygen tension (PvO2) were measured simultaneously. Measurements were performed under four conditions: (1) air breathing, (2) breathing 100% O2, (3) breathing 14% O2, and (4) 50 Warm exercise. During (1) breathing air PaO2 was on an average 90 mmHg, PvO2 36 MMHg and PtO2 40 mmHg. During (2) PaO2 reached 570 mmHg in 2 min, PvO2 rose slightly and PtO2 increased to 80-90 mmHg in 30-40 min. During (3) PaO2 fell rapidly to 45 mmHg and PtO2 decreased from 40 to 30 mmHg in 8 min. During (4) PaO2 did not change, PvO2 decreased slightly and PtO2 fell to approximately 30 mmHg within 2-4 min. The interindividual scatter was of equal magnitude in tissue and blood. A PtO2 higher than PvO2 during oxygen breathing and less than PvO2 during hypoxia and physical exercise is explained by the existence of oxygen gradients in the extravascular space. The present technique proved to be simple despite a 1-week delay before measurements. There were no complications, and no discomfort was complained of. Thus, the latex rubber tube seems suitable for clinical use.     

Variations in superficial renal cortical blood flow and tissue oxygenation: an experimental porcine model

Renal cortical microcirculation and its relation to inulin clearance, central haemodynamics and pulmonary gas exchange were studied in eight pigs under continuous intravenous chlormethiazole-pancuronium anaesthesia. The animals were studied during six consecutive 30-min periods. Four of the animals were also studied 19 h after the first period. In the superficial renal cortex, regional blood flow (Qsrc) was measured by laser Doppler flowmetry (LDF) and tissue oxygenation (PtO2) by surface microelectrode technique. Central haemodynamics and pulmonary gas exchange values were distributed within normal ranges. The importance of stable central haemodynamics in order to perform accurate microcirculatory measurements in the renal cortex was documented. A significant relation between Qsrc and pulmonary capillary wedge pressure (PCWP) was found (P less than 0.0001) despite the fact that PCWP was distributed within a range of only 0.7 kPa (all values were well within the normal range for pigs). No other relationships were found between central haemodynamics or pulmonary gas exchange variables and renal microcirculatory parameters. Concerning renal microcirculation and inulin clearance, at least 2-3 h may be required for stabilization after surgery. The average temporal variability between measurements performed every 30 min in each animal was 6 +/- 7% (s.d.) in the LDF values and 21 +/- 21% in the PtO2 values (mean PtO2). No correlations were found between Qsrc or PtO2 and inulin clearance. Since the haemodynamic parameters, pulmonary gas exchange variables and haematocrit were distributed within narrow ranges, we regard the temporal microcirculatory variability obtained here as normal in this experimental situation, and consider the porcine model well suited for further studies concerning renal microcirculation.     

Intraoperative blood flow measurements in organ allografts can predict postoperative function

A reliable method to recognize the extent of ischemia/reperfusion injury in transplantation is needed in order to tailor the immunosuppressive scheme to the needs of a damaged organ. This study sought to assess the correlation between the total and the parenchymal blood flow into a transplanted kidney (n = 71) or liver (n = 15) shortly after revascularization with the early function of the organ after transplantation. The total blood flow in the renal artery in kidney recipients or in the hepatic artery and portal vein in liver recipients was measured by an electromagnetic flowmeter. The parenchymal blood flow (in several parts of the transplanted organ) was assessed using a laser-Doppler flowmeter. Two measurements were always taken after revascularization (5 to 60 minutes apart). Vascular resistance (VR) as calculated by the difference between the mean arterial pressure (MAP) and the central venous pressure (CVP) was correlated with immediate kidney or liver function parameters. Neither total renal blood flow (RBF) nor VR was different between the immediate function (IF) and delayed graft function (DGF) groups of kidney transplant patients. However, the cortical (parenchymal) blood flow was significantly greater in the IF than the DGF group at 5 minutes: 29.98 +/- 6.13 mL/min/100 g vs 23.56 +/- 6.46 mL/min/100 g (P < .001). The difference was even more significant at 35 minutes: 33.94 +/- 7.47 mL/min/100 g vs 15.47 +/- 3.34 mL/min/100 g (P < .0001). Among liver transplant patients, the results suggested a correlation between hepatic arterial blood flow and early graft viability and function. The most reliable predictor of early graft function was the portal blood flow, which correlated with the volume of secreted bile as well as the bilirubin, and transaminase levels and coagulation profile. Further studies must confirm the value of measurements of total and parenchymal blood flow in organ transplant recipients.     

Uptake of indocyanine green by hepatocytes under inflow occlusion of the liver

BACKGROUND: It is not clear that hepatic venous backflow actually contributes to hepatic tissue oxygenation under inflow occlusion of the liver. In order to prove that substances delivered via the hepatic vein can be utilized and/or metabolized in hepatocytes during inflow occlusion, hepatic uptake in bile and excretion of indocyanine green (ICG) were investigated in pigs. MATERIALS AND METHODS: Animals were divided into two groups: an inflow occlusion (IO) group (N = 6) and a total hepatic vascular exclusion (THVE) group (N = 3) using a bypass. One milligram of ICG per kilogram body weight was administered at the beginning of blood flow occlusion, the retention rate in the blood (ICG R) measured, and the ICG in the hepatic tissue measured by near-infrared (NIR) spectroscopy. Furthermore, the ICG concentration was measured in bile excreted by intermittent perfusion of the liver. RESULTS: ICG R declined with time in both groups; however, ICG R in the IO group decreased much faster than in the THVE group. There were significant differences between the two groups after 30 min of occlusion (P < 0.05). ICG in the hepatic tissue could be detected as a peak at 805 nm 10 min after ICG injection, and the peak became steeper with time. On the other hand, ICG was not detected at all in the hepatic tissue after 180 min in the THVE group. ICG was excreted in the bile after 60 min under IO and increased with time. On the contrary, ICG was not excreted in the bile at all under THVE. There were significant differences between the two groups after 90 min (P < 0.05). CONCLUSION: These results indicate that ICG can be extracted in hepatocytes and excreted in bile under IO of the liver. Consequently, substances such as oxygen and drugs, which are delivered via the hepatic vein, can be utilized and/or metabolized in hepatocytes under IO.     

Vascular occlusions for liver resections. Operative management and tolerance to hepatic ischemia: 142 cases.

The intra- and early postoperative courses of 142 consecutive patients who underwent liver resections using vascular occlusions to reduce bleeding were reviewed. In 127 patients, the remnant liver parenchyma was normal, and 15 patients had liver cirrhosis. Eighty-five patients underwent major liver resections: right, extended right, or left lobectomies. Portal triad clamping (PTC) was used alone in 107 cases. Complete hepatic vascular exclusion (HVE) combining PTC and occlusion of the inferior vena cava below and above the liver was used for 35 major liver resections. These 35 patients had large or posterior liver tumors, and HVE was used to reduce the risks of massive bleeding or air embolism caused by an accidental tear of the vena cava or a hepatic vein. Duration of normothermic liver ischemia was 32.3 +/- 1.2 minutes (mean +/- SEM) and ranged from 8 to 90 minutes. Amount of blood transfusion was 5.5 +/- 0.5 (mean +/- SEM) units of packed red blood cells. There were eight operative deaths (5.6%). Overall, postoperative complications occurred in 46 patients (32%). The patients who experienced complications after surgery had received more blood transfusion than those with an uneventful postoperative course (p less than 0.001). The length of postoperative hospital stay was also correlated with the amount of blood transfused during surgery (p less than 0.001). On the other hand, there was no correlation between the durations of liver ischemia of up to 90 minutes and the lengths of postoperative hospital stay. The longest periods of ischemia were not associated with increased rates of postoperative complications, liver failures, or deaths. There was no difference in mortality or morbidity after major liver resections performed with the use of HVE as compared with major liver resections carried out with PTC alone, although the lesions were larger in the former group. It is concluded that the main priority during liver resections is to reduce operative bleeding. Vascular occlusions aim at achieving this goal and can be extended safely for up to 60 minutes.     

Epidural Anesthesia and Acutely Increased Intracranial Pressure: Lumbar Epidural Space Hydrodynamics in a Porcine Model

Background: The effects of epidural injection on intracranial pressure (ICP), lumbar epidural pressure, cerebral blood flow (CBF), and spinal cord blood flow (SCBF) were studied after acutely increased ICP in swine.

Methods: Twenty pigs, anesthetized with isoflurane and mechanically ventilated to maintain normocarbia, had two Tuohy needles placed in the lumbar epidural space. The ICP, lumbar epidural pressure, heart rate, mean arterial pressure, and central venous pressure were monitored. All animals had a Fogarty catheter placed in the parietal epidural space. Six pigs were randomized to a normal ICP group (group N) and eight pigs to an increased ICP group by inflation of the Fogarty catheter balloon (group R). Each pig had 0.33 ml [centered dot] kg sup -1 of 2.0% carbonated lidocaine injected over 20 s via an epidural needle placed at L3. The ICP and lumbar epidural pressure were then monitored continuously for 30 min. Pressure-time data were fit to traditional compartmental models. Epidural elastance and resistance were calculated using a derivation of the Windkessel theory. An additional six pigs had ICP elevated as in group R and CBF and SCBF measured using radioactive microspheres at five time periods: baseline, 0-60 s, 100-160 s, 200-260 s, and at 30 min after epidural injection.

Results: The animals did not differ with respect to heart rate, central venous pressure, or mean arterial pressure at baseline. The ICP was 10 +/- 2 mmHg in group N, and 24 +/- 2 mmHg after balloon inflation in group R. After epidural injection, peak ICP was significantly greater in group R (76 +/- 22 vs. 54 +/- 17 mmHg) but not different by 30 min (17 +/- 5 vs. 11 +/- 1 mmHg). Epidural elastance in group N was 8.3 +/- 3.1 mmHg [centered dot] ml sup -1 and 12.8 +/- 3.0 mmHg [centered dot] ml sup -1 in group R (P = 0.045). Epidural resistance was 1,330 +/- 590 mmHg [centered dot] s [centered dot] ml sup -1 in group N and 2,220 +/- 600 mmHg [centered dot] s [centered dot] ml sup -1 in group R (P = 0.038). The CBF and SCBF were less than 10% of baseline during the 0- to 60-s time period after epidural injection. Thereafter, CBF and SCBF did not differ from baseline values.     

Role of anti-tumor necrosis factor-alpha in ischemia/reperfusion injury in isolated rat liver in a blood-free environment

BACKGROUND: Warm ischemia/reperfusion injury during liver transplantation is the most important cause of primary nonfunction of liver allografts. Tumor-necrosis factor (TNF)-alpha apparently mediates tissue damage by inducing apoptosis and/or necrosis in liver transplants. The aim of the study was to determine, using an isolated rat liver model, if pretreatment with anti-TNF-alpha monoclonal antibodies can attenuate ischemia/reperfusion liver injury. Specifically, its effect on liver cell apoptosis through the modulation of caspase activity was examined in a blood-free environment. METHODS: Isolated rat livers were perfused with Krebs-Henseleit solution and randomly divided into three groups: (1) continuous perfusion for 165 min (control); (2) perfusion for 90 min, break for 60 min (ischemia), and reperfusion for 15 min; (3) as with group 2, but with administration of monoclonal mouse anti-rat TNF-alpha monoclonal antibodies before induction of ischemia. Caspase-3- and -9-like activity was measured by fluorometric assay, and apoptotic cells were identified by morphological criteria and application of the terminal deoxnucleotidyl transferase-mediated dUTP nick-end-labeling (Tunel) assay. RESULTS: Portal pressure increased significantly in group 2 (14.8+/-2.3 mm Hg) compared to group 3, which showed no change (P<0.05). Significant amounts of TNF-alpha were detected in the effluent in group 2 at 1 min of reperfusion (147+/-8.9 pg/ml) compared to group 3 (30+/-6.7 pg/ml, P<0.05). Statistically significant reductions in liver enzyme levels were also noted in the animals pretreated with TNF-alpha antibodies (P<0.02). Caspase-3 and -9 activity was significantly decreased (270 and 160%, respectively) in group 3 compared to group 2 (P<0.005 and <0.05, respectively). A significant reduction in postischemic hepatic injury was noted on Tunel assay: many apoptotic hepatocyte cells were detected in group 2 but not in livers pretreated with monoclonal mouse anti-TNF-alpha antibodies (group 3). CONCLUSIONS: Neutralization with specific monoclonal antibodies against TNF before ischemia induction can attenuate postischemic hepatic injury. Apoptotic injury seems to be ameliorated through modulation of caspase-3- and -9-like activity.     

Skeletal muscle tissue oxygen pressure distribution during early reperfusion after prolonged ischaemia.

OBJECTIVES: The aim of this study was to investigate the skeletal muscle tissue oxygen pressure (PtO2) distributions during early reperfusion (10-45 min) after prolonged ischaemia in a rat animal model. MATERIAL AND METHODS: Skeletal muscle ischaemia was induced in anaesthetised rats by applying a tourniquet on the left thigh for 3 h (group I) or 4 h (group II), and tissue oxygen pressure measurements were made after 10-45 min of reperfusion. Assessment of PtO2 was made by a multiwire Clark-type oxygen microelectrode, placed on the surface of the left tibialis anterior muscle. RESULTS: During reperfusion a similar PtO2 pattern was evaluated after both 3 and 4 h of total ischaemia, where the sum PtO2 distributions were shifted to the left associated with low tissue oxygen pressure values. After 10 min of reperfusion the median PtO2 was 0.28 kPa and 0.18 kPa, in groups I and II, respectively; after 45 min of reperfusion 0.61 kPa and 0.60 kPa, respectively. The median PtO2 in the non-ischaemic muscle in groups I and II were 2.19 and 2.17 Pa. CONCLUSION: The results show that local skeletal muscle oxygenation is severely impaired during the initial 45 min of reperfusion after both 3 and 4 h of total muscle ischaemia with a slow-reflow phenomenon generally present, despite pronounced needs.     

Experimental study on platelet activating factor and systemic circulatory failure caused by ischemic liver]

Ischemic hepatic failure is often accompanied by systemic circulatory failure. In hepatic graft failure, this circulatory derangement is reported to be cured by retransplantation. This suggests that ischemic liver might release some substance which causes circulatory depression. In the present study, the role of platelet activating factor (PAF) in systemic circulatory failure after liver ischemia was investigated. Partial hepatic ischemia was induced in ten dogs by clamping the afferent vessels to almost 70% of the liver for 60 minutes, and non-ischemic lobes were resected after declamping. Five were pretreated with 3 mg/kg of PAF antagonist (CV6209) i.v. (PAF antagonist group), and the others were pretreated with saline (control group). The mean arterial pressure markedly decreased after declamping in control group (89 +/- 25mmHg 25 min after declamping), but it did not fall in PAF antagonist group (155 +/- 221mmHg). Three died from either shock or hepatic failure within a week in control group, but none died in PAF antagonist group. In conclusion, ischemic liver was suggested to release PAF and depress systemic circulation. And a PAF antagonist was expected to be an effective drug for the circulatory derangement caused by ischemic liver.     

The Effects of Isoflurane and Desflurane on Intracranial Pressure, Cerebral Perfusion Pressure, and Cerebral Arteriovenous Oxygen Content Difference in Normocapnic Patients with Supratentorial Brain Tumors

Background: Desflurane is a volatile anesthetic agent with low solubility whose use in neurosurgery has been debated because of its effect on intracranial pressure and cerebral blood flow. The purpose of this study was to determine the variations on intracranial pressure (ICP) and cerebral perfusion pressure (CPP) as well as on cerebral arteriovenous oxygen content difference (AVDo2) in normocapnic patients scheduled to undergo removal of supratentorial brain tumors with no evidence of mass effect during anesthesia with isoflurane or desflurane.

Methods: In 60 patients scheduled to undergo craniotomy and removal of supratentorial brain tumors with no evidence of midline shift, anesthesia was induced with intravenous fentanyl, thiopental, and vecuronium and was maintained with 60% nitrous oxide in oxygen. Patients were assigned to two groups randomized to receive 1 minimum alveolar concentration isoflurane or desflurane for 30 min. Heart rate, mean arterial pressure, intraparenchymal ICP, and CPP were monitored continuously. Before and after 30 min of continuous administration of the inhaled agents, AVDo2 was calculated.

Results: There were no significant differences between groups in heart rate, mean arterial pressure, ICP, and CPP. ICP measurements throughout the study did not change within each group compared to baseline values. Mean arterial pressure decreased significantly in all patients compared to baseline values, changing from 105 +/- 14 mmHg (mean +/- SD) to 85 +/- 10 mmHg in the isoflurane group and from 107 +/- 11 mmHg to 86 +/- 10 mmHg in the desflurane group (P < 0.05 in both groups). CPP also decreased within each group compared with baseline values, changing from 95 +/- 15 mmHg to 74 +/- 11 mmHg in the isoflurane group and from 95 +/- 16 mmHg to 74 +/- 10 mmHg in the desflurane group (P < 0.05 in both groups). Cerebral AVDo2 decreased significantly in both groups throughout the study, changing from 2.35 +/- 0.77 mm to 1.82 +/- 0.61 mm (mmol/l) in the isoflurane group (P < 0.05) and from 2.23 +/- 0.72 mm to 1.94 +/- 0.76 mm in the desflurane group (P < 0.05), without differences between groups.     

Cerebrovascular resuscitation after polytrauma and fluid restriction

BACKGROUND: There are few reproducible models of blast injury, so it is difficult to evaluate new or existing therapies. We developed a clinically relevant polytrauma model to test the hypothesis that cerebrovascular resuscitation is optimized when intravenous fluid is restricted. STUDY DESIGN: Anesthetized swine (42+/-5 kg, n=35) received blasts to the head and bilateral chests with captive bolt guns, followed by hypoventilation (4 breaths/min; FiO(2)=0.21). After 30 minutes, resuscitation was divided into phases to simulate typical prehospital, emergency room, and ICU care. For 30 to 45 minutes, group 1, the control group (n=5), received 1L of normal saline (NS). For 45 to 120 minutes, additional NS was titrated to mean arterial pressure (MAP) > 60 mmHg. After 120 minutes, mannitol (1g/kg) and phenylephrine were administered to manage cerebral perfusion pressure (CPP) > 70 mmHg, plus additional NS was given to maintain central venous pressure (CVP) > 12 mmHg. In group 2 (n=5), MAP and CPP targets were the same, but the CVP target was>8 mmHg. Group 3 (n=5) received 1 L of NS followed only by CPP management. Group 4 (n=5) received Hextend (Abbott Laboratories), instead of NS, to the same MAP and CPP targets as group 2. RESULTS: Polytrauma caused 13 deaths in the 35 animals. In survivors, at 30 minutes, MAP was 60 to 65 mmHg, heart rate was >100 beats/min, PaO(2) was < 50 mmHg, and lactate was>5 mmol/L. In two experiments, no fluid or pressor was administered; the tachycardia and hypotension persisted. The first liter of intravenous fluid partially corrected these variables, and also partially corrected mixed venous O(2), gastric and portal venous O(2), cardiac output, renal blood flow, and urine output. Additional NS (total of 36+/-1 mL/kg/h and 17+/-6 mL/kg/h, in groups 1 and 2, respectively) correlated with increased intracranial pressure to 38+/-4 mmHg (group 1) and 26+/-4 mmHg (group 2) versus 22+/-4 mmHg in group 3 (who received 5+/-1 mL/kg/h). CPP was maintained only after mannitol and phenylephrine. By 5 hours, brain tissue PO(2) was>20 mmHg in groups 1 and 2, but only 6+/-1 mmHg in group 3. In contrast, minimal Hextend (6+/-3 mL/kg/h) was needed; the corrections in MAP and CPP were immediate and sustained, intracranial pressure was lower (14+/-2 mmHg), and brain tissue PO(2) was> 20 mmHg. Neuropathologic changes were consistent with traumatic brain injury, but there were no statistically significant differences between groups. CONCLUSIONS: After polytrauma and resuscitation to standard MAP and CPP targets with mannitol and pressor therapy, we concluded that intracranial hypertension was attenuated and brain oxygenation was maintained with intravenous fluid restriction; cerebrovascular resuscitation was optimized with Hextend versus NS; and longer term studies are needed to determine neuropathologic consequences.