Hepatic Oxygen Delivery Research Articles

1127 Hepatic Blood Flow and Oxygen Delivery in Metabolic Syndrome

INTRODUCTION: Metabolic syndrome MS is defined as the co-occurrence of metabolic risk factors for both DMII and cardiovascular disease. There is no consensus on the diagnostic criteria of the MS due to unclear pathogenesis uniting its components. We propose that compromised hepatic arterial blood supply and oxygen delivery as a response to a nutrient load in patients with MS will lead to hepatorenal activation of sympathetic overdrive, which can be the single common factor in MS pathogenesis METHODS: This prospective case-control study included patients 18-65 y/o diagnosed with MS and control healthy individuals with BMI 30-50 kg/m2. Subjects underwent an initial pre-prandial US, followed by drinking 8 oz of TwoCal high calorie drink immediately and in 15 mins. A second post-prandial US was performed 15mins after completing the second drink. US using the standard procedure for mesenteric artery examination for intestinal ischemia was performed to evaluate the diameter, velocity and flow of the superior mesenteric artery, hepatic artery, and portal vein. Both US images were interpreted by experienced diagnostic US radiologist. The results were analyzed using t-test RESULTS: Ten MS patients (age 55 ± 8) and ten control subjects (age 38 ± 11) with BMI 30-50 kg/m2 (37.6 ± 6.1) were compared. The relative change in blood flow in response to the nutrient load was reflected by the ratio of post- to pre-prandial readings. Total hepatic blood flow was calculated as the sum of HA and PV blood flow. The mean difference between post to pre-prandial ratio of total hepatic blood flow and total blood flow in all three vessels in MS group vs control group were 1.66 ± 0.57 vs 1.37 ± 0.40 (P = 0.162), 1.80 ± 0.42 vs 1.42 ± 0.27 (P = 0.025); respectively. The increase in postprandial total hepatic blood was 17.65% less in MS group. CONCLUSION: Why some obese patients develop MS while others don't raises the question of what is different between these cohorts. Excessive eating can produce obesity by causing chronic relative hypoxia in the liver. This produces sympathetic overdrive which causes insulin resistance, hypertension and dyslipidemia. Bariatric surgeries limit contact of nutrient with the GI mucosa resulting in increased splanchnic O2 delivery to the liver and preventing the hepatorenal reflex. The relative increase in total hepatic blood flow in response to a nutrient load was less in patients with MS compared to healthy obese controls. The difference was not statistically significant. Further studies with larger sample size needed.

Mapping hepatic blood oxygenation by quantitative BOLD (qBOLD) MRI.

Abnormalities in hepatic oxygen delivery and oxygen consumption may serve as a significant indicator of hepatic cellular dysfunction and may predict treatment response. However, conventional and oxygen-enhanced hepatic BOLD MRI can only provide semiquantitative assessment of hepatic oxygenation. A hepatic quantitative BOLD (qBOLD) model was proposed for noninvasive mapping of hepatic venous blood oxygen saturation (Yv ) and deoxygenated blood volume (DBV) in human subjects. The validity and the estimation bias of the proposed model were evaluated by Monte Carlo simulations. Eight healthy subjects were scanned after written consent with institutional review board approval. Monte Carlo simulations demonstrated that the proposed single-compartment hepatic qBOLD model leads to significant deviation of the predicted T2* decay profile from the simulated signal due to high hepatic blood volume fraction. Small relative estimation bias for hepatic Yv and significant overestimation for hepatic DBV were observed, which can be corrected by applying the calibration curves established from simulations. After correction, the mean hepatic Yv in human subjects was 56.8 ± 6.8%, and the mean hepatic DBV was 0.190 ± 0.035, consistent with measurements from other invasive approaches. Except in regions with significant vascular contamination, the maps for hepatic Yv and DBV were relatively homogenous. With estimation bias correction, the hepatic qBOLD approach enables noninvasive mapping of hepatic blood volume and oxygenation in human subjects. The established protocol may be used to quantitatively assess hepatic tissue hypoxia in multiple liver diseases.

Determination of Minimal Hemoglobin Level Necessary for Normothermic Porcine Ex Situ Liver Perfusion.

In current studies of ex situ liver perfusion there exists considerable variability in perfusate composition, including the type of oxygen carrier. Herein, we aim to clarify the minimal hemoglobin level necessary during normothermic porcine ex situ liver perfusion. Livers procured from 35 to 45 kg domestic pigs were connected to our experimental ex situ circuit (n = 10). In the treatment group, perfusate was sequentially diluted hourly to predetermined hemoglobin levels. At the end of each hemoglobin dilution, perfusate samples were analyzed for liver transaminases, lactate dehydrogenase (LD), total bilirubin, and lactate levels. Liver oxygen consumption was measured. In the control group, livers were perfused continually for a duration of 24 hours at target hemoglobin levels of 30 and 20 g/L. Rising liver transaminases, significantly higher lactate (P < 0.001), and LD levels (P < 0.001) were noted at lower perfusate hemoglobin levels in the treatment group. Liver oxygen utilization (P < 0.001) and hepatic artery oxygen delivery (P < 0.001) were significantly lower at lower hemoglobin levels, whereas liver vessel resistance remained relatively constant. Histology demonstrated increasing parenchymal damage at lower hemoglobin levels. In control livers, higher perfusate transaminases, higher lactate, and LD levels were noted at a perfusion hemoglobin level of 20 g/L. Ex situ liver function decompensated during perfusion between a mean hemoglobin level of 30 to 20 g/L, as evidenced by notably rising lactate and LD levels. This study demonstrates optimal hemoglobin concentration during normothermic ex situ liver perfusion to ensure a fully metabolically functioning graft.

The liver in systemic disease: Sepsis and critical illness.

The liver in systemic disease: Sepsis and critical illness.

Benefcial effects of splenectomy on liver regeneration in a rat model of massive hepatectomy

Small-for-size syndrome is a widely recognized clinical complication after living donor liver transplantation or extended hepatectomy due to inadequate liver mass. The purpose of this study was to investigate the role of splenectomy in rats after massive hepatectomy, a surrogate model of small-for-size graft. Rats were divided into eight groups, each with 20 animals: 50% hepatectomy (50% Hx), 50% hepatectomy+splenectomy (50% Hx+Sp), 60% Hx, 60% Hx+Sp, 70% Hx, 70% Hx+Sp, 90% Hx and 90% Hx+Sp. The following parameters were evaluated: liver function tests (ALT, AST and TBIL), liver regeneration ratio, DNA synthesis, proliferation cell nuclear antigen, hepatic oxygen delivery (HDO2) and hepatic oxygen consumption (HVO2). The liver regeneration ratio was enhanced in the Hx+Sp groups (P<0.05). In addition, compared with the Hx groups, the Hx+Sp groups had better liver functions (P<0.05). DNA synthesis and proliferation cell nuclear antigen were also increased in the Hx+Sp groups compared with the Hx groups (P<0.05). Furthermore, in the Hx+Sp groups, HDO2 and HVO2 were increased over those in the Hx groups (P<0.05), and were positively correlated with the liver regeneration ratio. Splenectomy significantly improved liver function, and enhanced DNA synthesis and proliferation cell nuclear antigen after massive hepatectomy in rats. This operation could be mediated through increased HDO2 and HVO2, which facilitate liver regeneration.

Experimental study of protective mechanism of Lipo-PGE(1) on hepatic ischemia-reperfusion injury

To explore protective mechanism of Lipo-PGE(1) on hepatic ischemia-reperfusion injury. Twenty-one adult dogs were divided into three groups randomly: CON group, IV group and SMA group, each group includes seven dogs. Animals were occluded porta hepatis 45 min and reperfused 60 min to establish I/R injury models. Lipo-PGE(1) administration was conducted once before porta occlusion 5 min and after reperfusion 60 min in IV and SMA group, the dosage of Lipo-PGE(1) was microgxkg(-1) and rate was 0.05 microgxkg(-1)xmin(-1); and 0.9% sodium chloride administration was conducted once at same time, the rate of NS was 2 mlxkg(-1). CT perfusion imaging, free pressure of portal vein, oxygen content of portal vein and hepatic oxygen delivery, index of liver function (ALT, LDH and TB) were performed in succession and compared before and after I/R. Simultaneously, the morphology of liver samples were observed by light microscope and electron microscope. (1) The liver perfusion was markedly decreased in the CON group, and moderately decreased in IV group and mildly in SMA group. (2) There was no significant difference of CpvO(2) in group comparison (P > 0.05) before and after I/R, but there was an increasing tendency in SMA group after I/R. There was significant difference of HDO(2) in group comparison before and after I/R (P < 0.05), but mildly in SMA group. (3) FPP increased obviously after I/R in control group, but there were no significant differences in the other groups. (4) The serious injury of liver in CON group after I/R was detected under light microscope and electron microscope, and moderately improved in IV group and markedly improved in SMA group. The protective mechanisms of Lipo-PGE(1) on hepatic ischemia-reperfusion injury include: improving microcirculation, releasing FPP, increasing CpvO(2) and HDO(2), as well as alleviating parenchyma injury.

Tezosentan normalizes hepatomesenteric perfusion in a porcine model of cardiac tamponade

To investigate endothelin-1 (ET-1)-dependent hepatic and mesenteric vasoconstriction, and oxygen and lactate fluxes in an acute, fixed low cardiac output (CO) state. Sixteen anesthetized, mechanically ventilated pigs were studied. Cardiac tamponade was established to reduce portal venous blood flow (Q(PV)) to 2/3 of the baseline value. CO, hepatic artery blood flow (Q(HA)), Q(PV), hepatic laser-Doppler flow (LDF), hepatic venous and portal pressure, and hepatic and mesenteric oxygen and lactate fluxes were measured. Hepatic arterial (R(HA)), portal (R(HP)) and mesenteric (R(mes)) vascular resistances were calculated. The combined ET(A)-ET(B) receptor antagonist tezosentan (RO 61-0612) or normal saline vehicle was infused in the low CO state. Measurements were made at baseline, after 30, 60, 90 min of tamponade, and 30, 60, 90 min following the infusion of tesozentan at 1 mg/kg/h. Tamponade decreased CO, Q(PV), Q(HA), LDF, hepatic and mesenteric oxygen delivery, while hepatic and mesenteric oxygen extraction and lactate release increased. R(HA), R(HP) and R(mes) all increased. Ninety minutes after tesozentan, Q(PV), LDF and hepatic and mesenteric oxygen delivery and extraction increased approaching baseline values, but no effect was seen on CO or Q(HA). Hepatic and mesenteric handling of lactate converted to extraction. R(HA), R(HP) and R(mes) returned to baseline values. No changes were observed in these variables among control animals not receiving tesozentan. In a porcine model of acute splanchnic hypoperfusion, unselective ET-1 blockade restored hepatomesenteric perfusion and reversed lactate metabolism. These observations might be relevant when considering liver protection in low CO states.

Systematic evaluation of nitric oxide, tetrahydrobiopterin, and anandamide levels in a porcine model of endotoxemia

Using a lipopolysaccharide (LPS)-treated porcine model, we examined: (1) whether nitric oxide (NO), anandamide, and tetrahydrobiopterin (BH4) increased or not in early endotoxic shock; and (2) the location of the major site of production of these molecules, by comparing their concentrations in arteries and the portal and hepatic veins. Ten pigs received an infusion of LPS at 1.7 microg x kg(-1)x h(-1) via the portal vein for 240 min. Consecutive changes in systemic hemodynamics, hepatosplanchnic circulation, and oxygen delivery were measured. Furthermore, the variable changes in the concentrations of nitrite and nitrate (NOx), anandamide, and BH4 were measured. To access the effects of surgery, anesthesia, and fluid management on BH4, an experiment without LPS infusion was performed in two other animals. Mean arterial pressure and cardiac index started to decrease at 60 min after LPS infusion. However, systemic vascular resistance remained unchanged. Total hepatic blood flow and hepatic oxygen delivery also decreased significantly. NOx and anandamide did not change during LPS infusion. BH4 values did not change without LPS infusion. However, BH4 values increased significantly in the arterial, portal, and hepatic circulation during LPS infusion, especially in the hepatic vein (from 136.8 +/- 27.5 to 281.3 +/- 123.2 mol/ml; P < 0.01). Our data suggest that the BH4 values were significantly increased in several organs, especially in the liver during endotoxic shock. Impaired cardiac output and decreased blood pressure appeared in the early phase of porcine endotoxemia. Longer-term observation of these parameters after LPS treatment should be performed as the next step in future studies.

Effect of propofol on hepatic blood flow and oxygen balance in rabbits

Propofol has been reported to alter hepatic blood flow and to increase hepatic oxygen consumption. This study was designed to determine the effect of propofol on hepatic blood flow and oxygenation in rabbits, in order to establish its net effect on hepatic oxygen balance. Twenty, adult male, New Zealand white rabbits were randomly divided into two groups: Group P (propofol, 0.6 mg.kg(-1).min(-1)) or Group C (10% intralipid, 0.6 mg.kg(-1).min(-1)). An electromagnetic flowmeter was used to measure hepatic blood flow, and blood, from the carotid artery, the portal vein, and the hepatic vein, was used to determine hepatic oxygenation. After we obtained baseline values, we repeated measurements ten, 30, and 60 min after initiating the infusion. Intralipid did not affect systemic hemodynamics, hepatic blood flow, or oxygenation during the 60 min infusion; however, propofol caused a time-dependent decrease in mean arterial blood pressures and an increase in portal venous flow and total hepatic blood flow. In contrast, hepatic arterial blood flow remained unchanged during the propofol infusion. Hepatic oxygen delivery and consumption increased in a time-dependent manner to maximums of 25% and 21.4% (both, P < 0.05) above baseline, respectively. Hepatic venous oxygen saturation and extraction was unchanged throughout the study period. Propofol increases total hepatic blood flow, primarily by increasing hepatic portal venous flow. The increase in liver oxygen consumption was fully compensated by an increase in oxygen supply to the liver, resulting in a preserved, hepatic oxygen balance.

Hepatic Arterial Buffer Response Fails to Restore Hepatic Oxygenation After Temporary Liver Dearterialization in Canines

Background Hepatic artery thrombosis is a rare but extremely troublesome condition after liver transplantation. Recently, urgent arterial revascularization has been used as rescue therapy, leading to improved graft and patient survivals. Hepatic artery ligation produces a progressive reduction in portal vein blood flow. Theoretically, a hyperemic response may be expected following hepatic artery reperfusion (hepatic artery buffer response, HABR). In this study, we tested the hypothesis that HABR can maintain adequate liver oxygenation after temporary liver dearterialization. Methods Seven dogs (19.7 ± 1.2 kg) subjected to 60 minutes of hepatic artery occlusion were observed for 120 minutes thereafter. Systemic hemodynamics was evaluated through Swan-Ganz and arterial catheters, and splanchnic perfusion by portal vein and hepatic artery blood flows (PVBF and HABF) via an ultrasonic flowprobe. Liver enzymes (ALT and LDH) and systemic and hepatic oxygen delivery (DO 2hepat) were calculated using standard formulae. Results Hepatic artery occlusion induced a progressive reduction in PVBF and DO 2hepat. A complete restoration of HABF after hepatic artery declamping was observed; however, the DO 2hepat (33.3 ± 5.9 to 16.5 ± 5.9 mL/min) did not return to the baseline levels. Conclusion Temporary hepatic artery occlusion induced a progressive decrease in portal vein blood flow during ischemia, an effect that continued during the reperfusion period. The hepatic artery blood flow was promptly restored after declamping. However, HABR was not able to restore hepatic oxygen delivery to baseline levels during the reperfusion period.

Effects of olprinone on hepatosplanchnic circulation and mitochondrial oxidation in a porcine model of endotoxemia

This study was performed in order to assess the effects of olprinone, a phosphodiesterase III inhibitor, on hepatic oxygen delivery (DO2H), oxygen consumption (VO2H), and mitochondrial oxidation in the liver of a porcine endotoxemia model. Fourteen pigs received continuous infusion of endotoxin via the portal vein for 240 min. From t = 150 to t = 240 min, animals were randomly divided into two groups to receive saline (control [CONT]; n = 7), or olprinone (OLP; n = 7) via the central vein. In the OLP group, prior to olprinone treatment at 150 min, endotoxin induced significant decreases in the cardiac index (CI; from 120 +/- 31 to 65 +/- 13 ml.kg(-1).min(-1); P < 0.01) and DO2H (from 3.58 +/- 0.81 to 1.55 +/- 0.49 ml.kg(-1).min(-1); P < 0.01), while VO2H was maintained. After administration of olprinone (from t = 150 to t = 240 min), CI was unchanged, while DO2H increased from 1.55 +/- 0.49 to 1.93 +/- 0.38 ml.kg(-1).min(-1) (P < 0.01) and VO(2)H increased from 0.42 +/- 0.28 to 0.69 +/- 0.38 ml.kg(-1).min(-1) (P < 0.01). At t = 240 min, the oxidation level of cytochrome aa3 was significantly higher in the OLP group than in the CONT group (OLP, 66.2 +/- 19.3% vs CONT, 26.4 +/- 17.3%; P < 0.01). Our data for this porcine endotoxemia model suggest that olprinone may have beneficial therapeutic effects in restoring not only systemic and hepatic circulation but also mitochondrial oxidation in the liver.

Vanishing Bile Duct Syndrome and Sclerosing Cholangitis in Patients with Critical Illness and Long Term Intensive Care Treatment

Background: Sepsis associated cholestasis in intensive care patients usually subsides with treatment of the underlying cause. However, in a subgroup of these patients a progressive destruction of intrahepatic bile ducts and sclerosing cholangitis with the typically appearance of segmental strictures and cholangiectasies develops. In this respect, a progressive form of sclerosing cholangitis after septic shock and long term intensive care treatment has been described. We herein report the clinical course and endoscopic treatment in patients with sclerosing cholangitis due to critical illness. Patients: Twelve patients (6 male, age: 48.8+12.7, (mean, years+SD)) with sclerosing cholangitis, diagnosed by endoscopic retrograde cholangiopancreaticography were identified. No patient had evidence of preexisting hepato-biliary disease or inflammatory bowel disease. Transfer to the ICU was necessary because of sepsis in 2, extensive surgery in 4, polytrauma in 2, cardiopulmonary resuscitation in 2 and respiratory failure in 2 patients, respectively. All patients needed mechanical ventilation, had a preexisting pulmonary disease and/or developed a severe adult respiratory distress syndrome. Results: Cholestasis or jaundice developed 60 [13-110] days (median[range]) after transfer to the ICU. The laboratory findings were: Bilirubin: 7.5[0.4-62.1], Alkaline Phosphatase: 10.6[2.6-22.5], GGT: 34.0[10.3-91.4], ALT: 2.0[0.8-18.7], AST: 3.6[0.8-34.0],(xULN, median[range]). ERCP demonstrated sclerosing cholangitis in all patients. Severe ductopenia was seen in two patients. In 9 patients endoscopic sphincterotomy was performed. Casts and sludge were extracted in 5 patients. Biliary stenting was performed in one patient with a dominant stenosis. Two patients were lost for follow up. During a median follow up of 11 [4–46] months 7 patients (58%) progressed to liver cirrhosis. Two patients died of liver failure and 2 patients underwent orthotopic liver transplantation. Stabilization or biochemical improvement of cholestasis was achieved in 3 patients. Discussion: Reduced hepatic oxygen delivery may lead to initial bile duct injury in ICU patients. As a second hit septicemia, ischemia, translocation of endotoxins from the gut may further lead to progressing sclerosing cholangitis. Long term outcome of endoscopic treatment is poor as a high proportion of these patients develop liver cirrhosis, for whom liver transplantation should be considered. Background: Sepsis associated cholestasis in intensive care patients usually subsides with treatment of the underlying cause. However, in a subgroup of these patients a progressive destruction of intrahepatic bile ducts and sclerosing cholangitis with the typically appearance of segmental strictures and cholangiectasies develops. In this respect, a progressive form of sclerosing cholangitis after septic shock and long term intensive care treatment has been described. We herein report the clinical course and endoscopic treatment in patients with sclerosing cholangitis due to critical illness. Patients: Twelve patients (6 male, age: 48.8+12.7, (mean, years+SD)) with sclerosing cholangitis, diagnosed by endoscopic retrograde cholangiopancreaticography were identified. No patient had evidence of preexisting hepato-biliary disease or inflammatory bowel disease. Transfer to the ICU was necessary because of sepsis in 2, extensive surgery in 4, polytrauma in 2, cardiopulmonary resuscitation in 2 and respiratory failure in 2 patients, respectively. All patients needed mechanical ventilation, had a preexisting pulmonary disease and/or developed a severe adult respiratory distress syndrome. Results: Cholestasis or jaundice developed 60 [13-110] days (median[range]) after transfer to the ICU. The laboratory findings were: Bilirubin: 7.5[0.4-62.1], Alkaline Phosphatase: 10.6[2.6-22.5], GGT: 34.0[10.3-91.4], ALT: 2.0[0.8-18.7], AST: 3.6[0.8-34.0],(xULN, median[range]). ERCP demonstrated sclerosing cholangitis in all patients. Severe ductopenia was seen in two patients. In 9 patients endoscopic sphincterotomy was performed. Casts and sludge were extracted in 5 patients. Biliary stenting was performed in one patient with a dominant stenosis. Two patients were lost for follow up. During a median follow up of 11 [4–46] months 7 patients (58%) progressed to liver cirrhosis. Two patients died of liver failure and 2 patients underwent orthotopic liver transplantation. Stabilization or biochemical improvement of cholestasis was achieved in 3 patients. Discussion: Reduced hepatic oxygen delivery may lead to initial bile duct injury in ICU patients. As a second hit septicemia, ischemia, translocation of endotoxins from the gut may further lead to progressing sclerosing cholangitis. Long term outcome of endoscopic treatment is poor as a high proportion of these patients develop liver cirrhosis, for whom liver transplantation should be considered.

Hepatosplanchnic blood flow control and oxygen extraction are modified by the underlying mechanism of impaired perfusion

To assess the effects of low hepatosplanchnic blood flow on regional blood flow control and oxygenation. Three randomized, controlled animal experiments. Two university experimental research laboratories. Pigs of either gender. Isolated abdominal blood flow reduction: An extracorporeal shunt with reservoir and roller pump was inserted between proximal and distal aorta in 11 pigs. Abdominal aortic blood flow was reduced by 50% by activating the shunt. Mesenteric ischemia: In seven pigs, superior mesenteric arterial flow was reduced to 4 mL.kg.min for 4 hrs. Cardiac tamponade: In 12 pigs, aortic blood flow was reduced by cardiac tamponade to 50 mL (moderate tamponade) and further to 30 mL.kg.min (severe tamponade) for 1 hr each. In each experimental condition, the same number of control animals was used. Abdominal blood flow reduction, acute mesenteric ischemia, and moderate tamponade resulted in a portal venous flow (QPV) reduction to 51 +/- 23%, 52 +/- 18%, and 61 +/- 25% (mean +/- sd) of baseline flow, respectively. During abdominal blood flow reduction, QPV and hepatic arterial flow (QHA) decreased proportionally, whereas in moderate tamponade and acute mesenteric ischemia QPV reduction was associated with an increase in QHA of 30 +/- 39% and 102 +/- 108%, respectively (p = .001 and .018). Prolonged mesenteric ischemia restored total hepatic blood flow (Qliver) completely. During all conditions, decreasing mesenteric oxygen consumption was partly prevented by increased mesenteric oxygen extraction (p < .001 for all conditions). In contrast, decreasing hepatic oxygen delivery was associated with increased oxygen extraction in tamponade (p = .009) but not in abdominal blood flow reduction. Blood flow redistribution can restore Qliver totally when mesenteric blood flow is reduced selectively, partially when cardiac output is reduced, and not at all during abdominal blood flow reduction. Since hepatic oxygen extraction does not increase in abdominal blood flow reduction, hepatic oxygenation is at risk in this condition.

The hepatosplanchnic contribution to hyperlactatemia in endotoxic shock: effects of tissue ischemia.

We investigated the role of the hepatosplanchnic region in the hyperlactatemia observed during endotoxic shock. The study included 18 dogs anesthetized with pentobarbital and mechanically ventilated. After baseline measurements, including gut lactate production (GLP), liver lactate uptake (LLU), liver lactate extraction (LLE), and hepatosplanchnic lactate production (HSLP), each dog received 2 mg/kg of E. coli endotoxin. After a second set of measurements, cardiac tamponade was induced in 12 dogs (EDTX + Tamp) by repeated injections of normal saline into the pericardial sac to progressively reduce cardiac output and hepatic blood flow. The six remaining dogs served as septic controls (EDTX). From a net lactate consumer before endotoxin infusion, the gut became a lactate producer after the endotoxin infusion, with GLP increasing from -11.4 +/- 27.0 to 32.9 +/- 38.2 x 10(-3) mEq/min (P < 0.05). LLU increased from 48.1 +/- 26.2 to 86.6 +/- 45.2 x 10(-3) mEq/min (P < 0.05), so that LLE and HSLP did not change. In the EDTX + Tamp group, LLE became negative, and HSLP became positive only when hepatic oxygen delivery reached its critical value during cardiac tamponade. In the EDTX group, LLE remained positive and HSLP negative. In endotoxic shock, GLP is increased, but the liver can metabolize this additional load of lactate, so that the hepatosplanchnic area is not a major source of lactate unless the liver becomes profoundly hypoxic.

Efficacy of continuous infusion of prostaglandin E1 through the superior mesenteric artery against ischemic liver cell necrosis after hepatic artery occlusion

Hepatic artery occlusion (HAO) can cause severe ischemic liver injury, especially after an interruption of collateral circulation after extensive hepatobiliary surgery. To minimize a decrease in oxygen delivery after HAO, a continuous infusion of prostaglandin (PG)E1 through the superior mesenteric artery (SMA) was studied in comparison with other infusion routes. Twenty-four pigs were assigned to four groups: HAO without PGE1 (control group); HAO with PGE1 (0.02 microg/kg/min, continuously) through the jugular vein (intravenous group); HAO with PGE1 through the portal vein (PV group); and HAO with PGE1 through the SMA (SMA group). PV flow, hepatic oxygen delivery, and serum aspartate aminotransferase were measured after infusion. In addition, 72-hr survival rates were observed, and histologic examination of liver specimens was performed. PGE1 infusion through the SMA seems to affect PV flow and elevate the oxygen content of portal blood, whereas other routes of administration do not. The reduction of hepatic oxygen delivery after HAO was 51% in the control group, 46% in the intravenous group, and 49% in the PV group, whereas it was limited to 13% in the SMA group. Serum aspartate aminotransferase values 24 hr after HAO were lowest in the SMA group, which was statistically significant, as confirmed by histology. The survival rate of animals was 100% in the SMA group and 33% in the other three groups. These findings indicate that continuous PGE1 infusion through the SMA may prove useful in clinical settings to prevent liver damage after HAO.

Sepsis-induced failure of hepatic energy metabolism

Hypothesis. Recent evidence suggests that sepsis may induce an uncoupling of oxidative phosphorylation. The purpose of this study was to quantify temporal changes in hepatic oxygen consumption and cellular energy state with increasing severity of sepsis and thus assess the interrelationship of these parameters as either primary defect or compensatory response. Main outcome measures. Pseudomonas aeruginosa was infused intravenously in eight instrumented anesthetized swine inducing a progressive severity of sepsis to shock. Eight other animals served as instrumented controls. Hepatic blood flow, oxygen use, and concentrations of ATP, ADP, AMP, NAD +, and NADH were measured at baseline and then sequentially during the study. Results. Except for an increase in heart rate, there were no temporal changes in measured values for the control animals. For swine receiving P. aeruginosa, hepatic oxygen delivery and consumption increased with early sepsis whereas there were no alterations in the concentrations of adenine nucleotides or NAD +/NADH within liver. Septic shock was notable for a decrease in oxygen delivery yet oxygen consumption remained elevated because of an increase in percent oxygen extraction. The hepatic concentrations of ATP and NADH decreased during septic shock. Conclusions. These findings suggest that any sepsis-induced limitation in phosphorylation may be initially compensated by an increase in oxygen use. This study also suggests that decreases in NADH availability may be a principal factor in the decompensation of sepsis to shock.

Hemorrhagic shock primes the hepatic portal circulation for the vasoconstrictive effects of endothelin-1.

To test whether hemorrhagic shock and resuscitation (HSR) alters the vascular responsiveness of the portohepatic circulation to endothelins (ETs), we studied the macro- and microcirculatory effects of the preferential ET(A) receptor agonist ET-1 and of the selective ET(B) receptor agonist sarafotoxin 6c (S6c) after 1 h of hemorrhagic hypotension and 5 h of volume resuscitation in the isolated perfused rat liver ex vivo using portal pressure-flow relationships and epifluorescence microscopy. Although HSR did not cause major disturbances of hepatic perfusion per se, the response to ET-1 (0.5 x 10(-9) M) was enhanced, leading to greater increases in portal driving pressure, total portal resistance, and zero-flow pressures and more pronounced decreases in portal flow, sinusoidal diameters, and hepatic oxygen delivery compared with time-matched sham shock controls. In sharp contrast, the constrictive response to S6c (0.25 x 10(-9) M) remained unchanged. Thus HSR primes the portohepatic circulation for the vasoconstrictive effects of ET-1 but does not alter the effects of the ET(B) receptor agonist S6c. The enhanced sinusoidal response may contribute to the subsequent development of hepatic microcirculatory failure after secondary insults that are associated with increased generation of ET-1.

The effects of olprinone (a phosphodiesterase III inhibitor) on hepatic vascular bed in a porcine model of endotoxemia.

Decreased hepatic blood flow, and impaired hepatic oxygen delivery caused by endotoxin, result in hepatic metabolic deterioration followed by liver dysfunction and multiple organ failure. Among phosphodiesterase III inhibitors, only olprinone increases hepatosplanchnic blood flow. We evaluated the effects of olprinone on systemic hemodynamics, hepatic circulation, and hepatic oxygen delivery in a porcine model of endotoxemia. Fifteen pigs received a continuous infusion (1.7 microg. kg(-1). h(-1)) of endotoxin (lipopolysaccharide [LPS]) via the portal vein for 240 min. Seven of these pigs received olprinone infusion (0.3 microg. kg(-1). min(-1)) via a central vein from t = 150 min to t = 240 min, whereas the eight remaining pigs served as LPS controls. Continuous infusion of LPS caused significant reductions in hemodynamic variables and a significant increase in arterial lactate. After the administration of olprinone during the LPS infusion, portal venous flow and hepatic oxygen delivery were increased and were higher than in the LPS group. Furthermore, olprinone prevented any further increase in arterial lactate. We conclude that the administration of olprinone halted the disturbances in the hepatic circulation, especially in portal venous flow and hepatic oxygen delivery, in a porcine model of endotoxemia. Endotoxin is a causative factor in peripheral vascular failure, resulting in a hemodynamic depression that includes a reduction in liver blood flow. The administration of olprinone (phosphodiesterase III inhibitor) improves the liver blood flow circulation in a porcine model of endotoxemia.

The effects of dopamine and epinephrine on hemodynamics and oxygen metabolism in hypoxic anesthetized piglets.

The most appropriate inotropic agent for use in the newborn is uncertain. Dopamine and epinephrine are commonly used, but have unknown effects during hypoxia and pulmonary hypertension; the effects on the splanchnic circulation, in particular, are unclear. The effects on the systemic, pulmonary, hepatic, and mesenteric circulations of infusions of dopamine and epinephrine (adrenaline) were compared in 17 newborn piglets. Three groups [control (n = 5), dopamine (n = 6) and epinephrine (n = 6)] of fentanyl anesthetized newborn piglets were instrumented to measure cardiac index (CI), hepatic arterial and portal venous blood flow, mean systemic arterial pressure (SAP), mean pulmonary arterial pressure (PAP), and arterial, portal and mixed venous oxygen saturations. Systemic, pulmonary, and mesenteric vascular resistance indices [systemic vascular resistance index (SVRI), pulmonary vascular resistance index (PVRI), mesenteric vascular resistance index (MVRI)], and systemic and splanchnic oxygen extraction and consumption were calculated. Alveolar hypoxia was induced, with arterial oxygen saturation being maintained at 55-65%. After 1 h of stabilization during hypoxia, each animal received either dopamine or epinephrine; randomly administered doses of 2, 10, and 32 microg kg-1 min-1 and 0.2, 1.0, and 3.2 microg kg-1 min-1 respectively were infused for 1 h at each dose. Results were compared with the 1 h hypoxia values by two-way analysis of variance. Epinephrine increased CI at all doses, with no significant effects on SAP and SVRI. Although epinephrine increased PAP at 3.2 microg kg-1min-1, it had no effect on PVRI. Dopamine had no effect on CI, SAP, and SVRI, but increased PAP at all doses and PVRI at 32 microg kg-1min-1. The SAP/PAP ratio was decreased with 32 microg kg-1min-1 dopamine, whereas epinephrine did not affect the ratio. In the mesenteric circulation, dopamine at 32 microg kg-1 min-1 increased portal venous flow and total hepatic blood flow and oxygen delivery, and decreased MVRI; epinephrine had no effect on these variables. Epinephrine increased hepatic arterial flow at 0.2 microg kg-1 min-1; dopamine had no effect on hepatic arterial flow at any dose. Despite these hemodynamic changes, there were no differences in systemic or splanchnic oxygen extraction or consumption at any dose of dopamine or epinephrine. Epinephrine is more effective than dopamine at increasing cardiac output during hypoxia in this model. Although epinephrine preserves the SAP/PAP ratio, dopamine shows preferential pulmonary vasoconstriction, which might be detrimental if it also occurs during the management of infants with persistent fetal circulation. Dopamine, but not epinephrine, increases portal flow and total hepatic flow during hypoxia.

Dependency of the [ 18f]fluoromisonidazole uptake on oxygen delivery and tissue oxygenation in the porcine liver

We have previously shown that the accumulation of fluorine-18-labeled fluoromisonidazole ([ 18F]FMISO) is inversely correlated to tissue oxygenation, allowing the quantification of porcine liver tissue hypoxia in vivo. We determined the activity from administered [ 18F]FMISO in relation to the hepatic oxygen availability and the partial pressure of oxygen in tissue (tPO 2) to define a critical oxygen delivery on a regional basis. [ 18F]FMISO was injected 2 h after onset of regional liver hypoxia due to arterial occlusion of branches of the hepatic artery in 10 domestic pigs. During the experimental procedure the fractional concentration of inspired oxygen (FiO 2) was set to 0.67 in group A ( N=5) and to 0.21 in group B ( N=5) animals. Immediately before sacrifice, the tPO 2 was determined in normal flow and flow-impaired liver segments. The standardized uptake values (SUV) for [ 18F]FMISO was calculated from 659 single tissue samples obtained 3 h after injection of approximately 10 MBq/kg body weight [ 18F]FMISO and was compared with the regional total hepatic oxygen delivery (DO 2) calculated from the regional arterial and portal venous flow (based on 141Ce- and 99mTc-microspheres measurements) and the oxygen content of the arterial and portal venous blood. In 121 tPO 2-measured liver tissue samples, the mean DO 2 was significantly decreased in occluded liver tissue samples [group A: 0.063 (0.044–0.089); group B: 0.046 (0.032–0.066)] compared to normal flow segments [group A: 0.177 (0.124–0.252); group B: 0.179 (0.128–0.25) mL· min −1· g −1; geometric mean (95% confidence limits); p < 0.01 in group A and p < 0.001 in group B]. The tPO 2 of occluded segments [group A: 5.1 (3.2–8.1); group B: 3.9 (2.4–6.2) mm Hg] was significantly decreased compared to normal flow segments [group A: 20.2 (12.6–32.5); group B: 22.4 (14.3–35.2) mm Hg; p < 0.01 in group A and p < 0.001 in group B]. Three hours after [ 18F]FMISO administration, the mean [ 18F]FMISO SUV determined in tPO 2-measured occluded segments was significantly higher [group A: 4.08 (3.12–5.34), group B: 5.43 (4.14–7.13)] compared to normal liver tissue [group A: 1.57 (1.2–2.06), group B: 1.5 (1.16–1.93); p < 0.001 for both groups]. The [ 18F]FMISO SUV allowed prediction of the tPO 2 with satisfying accuracy in hypoxic regions using the exponential regression curve { [ 18F]FMISO=1.05+6.7 (−0.117 tPO 2 ); r 2 =0.75;p < 0.001 }. In addition, regardless of ventilation conditions, a significant exponential relationship between the DO 2 and the [ 18F]FMISO SUV was found ( r 2 =0.39,p < 0.001 ). Our results suggest that the reduction of the oxygen delivery below the critical range of 0.1–0.11 mL· min −1· g −1 regularly causes liver tissue hypoxia. The severity of hypoxia is reflected by the [ 18F]FMISO accumulation and allows the in vivo estimation of the tPO 2 in hypoxic regions.