Effects of hemodynamic instability on brain death-induced prepreservation liver damage

BACKGROUND: Brain death (BD) is an important multifactorial variable contributing to donor-specific liver damage. Our study aimed at assessing the specific effects of hemodynamic instability on systemic and hepatic parameters of perfusion, bowel ischemia, and oxidative stress in a porcine model of BD. METHODS: BD was induced in 16 pigs (German Landrace, 18-28 kg) in two groups (hypotension-BD [HYPO-BD], n=8; normotension-BD [NORM-BD], n=8), which were compared with control animals/living donors (n=6) for a period of 2 hr. We analyzed systemic hemodynamic parameters, bowel ischemia (intramucosal pH in the stomach and colon, plasma endotoxin levels, and endotoxin-neutralizing capacity [ENC]), and oxidative stress (total glutathione levels in erythrocytes) and compared the findings with hepatic parameters of perfusion (hepatic arterial flow, portal venous flow, and microperfusion) and liver oxidative stress (reduced glutathione and oxidized glutathione levels in the liver). RESULTS: Independent of the hemodynamic stability, liver macrocirculation and microcirculation decreased (HYPO-BD, 79+/-6 to 69+/-10 mL/100 g/min; NORM-BD, 81+/-10 to 73+/-7 mL/100 g/min; P<0.05). Hepatocellular damage (aspartate aminotransferase: NORM-BD, 49+/-20 units/L; HYPO-BD, 170+/-140 units/L; P<0.01) and hepatic oxidative stress (reduced glutathione in the liver/oxidized glutathione in the liver: NORM-BD, 29.4+/-2.3 to 13.0+/-1.3; HYPO-BD, 29.4+/-2.3 to 9.05+/-0.81; P<0.001) increased in both BD groups. With dependence on systemic hemodynamic parameters, bowel ischemia increased (intramucosal pH in the colon, 7.22+/-0.01, P<0.01; ENC, 75+/-14 endotoxin-neutralizing units/mL, P<0.01; endotoxin levels, 7+/-2 to 43+/-10 pg/mL, P<0.01) in the HYPO-BD group but not in the NORM-BD group or the living donor group. Furthermore, systemic oxidative stress was increased in the HYPO-BD group only (total glutathione levels in erythrocytes, 2.65+/-0.25 to 0.15+/-0.25 mM; P<0.01). CONCLUSIONS: During BD, liver-specific parameters (portal venous flow, microperfusion, aspartate aminotransferase activity, ENC, and hepatic oxidative stress) were compromised, independent of the hemodynamic status. Therefore, the systemic hemodynamic status does not reflect the functional status of the liver during BD.     

Milrinone Modulates Endotoxemia, Systemic Inflammation, and Subsequent Acute Phase Response after Cardiopulmonary Bypass (CPB)

Background: Compromised splanchnic perfusion and the resulting intestinal mucosal injury leads to a decreased mucosal barrier function, which allows translocation of intestinal flora and endotoxemia. The authors evaluated the effects of milrinone on splanchnic oxygenation, systemic inflammation, and the subsequent acute-phase response in patients undergoing coronary artery bypass grafting.

Methods: This open, placebo-controlled randomized clinical study enrolled 22 adult patients in two groups. Before induction of anesthesia, baseline values were obtained and patients were randomized to receive milrinone (30 [micro sign]g/kg bolus administered progressively in 10 min, followed by a continuous infusion of 0.5 [micro sign]g [middle dot] kg-1 [middle dot] min-1) or saline. The following parameters were determined: hemodynamics; systemic oxygen delivery and uptake; arterial, mixed venous and hepatic venous oxygen saturation; intramucosal pH (pHi); and mixed and hepatic venous plasma concentrations of endotoxin, interleukin 6, serum amyloid A, and C-reactive protein.

Results: Milrinone did not prevent gastrointestinal acidosis as measured by pHi, but its perioperative administration resulted in significantly higher pHi levels compared with control. Venous and hepatic venous endotoxin and the interleukin 6 concentration were reduced significantly in the milrinone group. Serum amyloid A values were attenuated in the milrinone group 24 h after surgery. No significant differences could be seen in routinely measured oxygen transport-derived variables.     

Different impact of normo- and hypotensive brain death on renal macro- and microperfusion--an experimental evaluation in a porcine model.

BACKGROUND: Despite the growing use of kidneys from living donors, organs harvested from brain dead donors are the dominant graft types used in renal transplantation. It is accepted that brain death (BD) has a damaging effect on the renal allograft, with a lower graft survival. Amongst various causes, changes in renal microperfusion could be responsible. Renocortical microperfusion was assessed during BD using thermal diffusion in a porcine model. METHODS: Two types of BD were induced in two groups of pigs [hypotension (Hypo-BD): n = 11; normotension (Normo-BD): n = 10] and compared to controls (n = 5) over a period of 210 min. We analysed systemic parameters [heart rate (HR), mean arterial blood pressure (MAP)], aortic blood flow (ABF) and renal perfusion [renal artery blood flow (RABF) and renocortical blood flow (RCBF)]. RESULTS: Following the two distinct forms of BD induction, a stable normo- or hypotension was observed. Haemodynamic parameters were only slightly changed (control group: MAP, 62+/-2 mmHg; HR, 95+/-3/min; Normo-BD: MAP, 56+/-4 mmHg; HR, 104+/-8/min; Hypo-BD: MAP, 43+/-3 mmHg; HR, 112+/-7/min). Solely dependent on systemic haemodynamics, RABF and RCBF decreased in the Hypo-BD (RABF: 142+/-19 to 94+/-9 ml/100 g/min; RCBF: 80+/-4 to 52+/-2 ml/100 g/min), while in Normo-BD group RABF mildly changed (158+/-13 ml/100 g/min) and RCBF decreased slightly from 76+/-3 to 70+/-6 ml/100 g/min. As opposed to the Normo-BD group, animals with Hypo-BD showed a significant decrease in RABF (reduction of 34%) and RCBF (reduction of 35%) with a sharp drop of MAP (reduction of 25%), however ABF remained relatively constant. CONCLUSIONS: In this model, a reduction of renocortical microperfusion in brain dead pigs was only found during haemodynamic instability (hypotension) and could not be attributed to BD as such. Our findings would support intensive cardiocirculatory stabilization for potential BD donors in order to minimize kidney preservation damage.     

Hydrogen Gas Ameliorates Hepatic Reperfusion Injury After Prolonged Cold Preservation in Isolated Perfused Rat Liver

Hydrogen gas reduces ischemia and reperfusion injury (IRI) in the liver and other organs. However, the precise mechanism remains elusive. We investigated whether hydrogen gas ameliorated hepatic I/R injury after cold preservation. Rat liver was subjected to 48‐h cold storage in University of Wisconsin solution. The graft was reperfused with oxygenated buffer with or without hydrogen at 37° for 90 min on an isolated perfusion apparatus, comprising the H₂(+) and H₂(?) groups, respectively. In the control group (CT), grafts were reperfused immediately without preservation. Graft function, injury, and circulatory status were assessed throughout the perfusion. Tissue samples at the end of perfusion were collected to determine histopathology, oxidative stress, and apoptosis. In the H₂(?) group, IRI was indicated by a higher aspartate aminotransferase (AST), alanine aminotransferase (ALT) leakage, portal resistance, 8‐hydroxy‐2‐deoxyguanosine‐positive cell rate, apoptotic index, and endothelial endothelin‐1 expression, together with reduced bile production, oxygen consumption, and GSH/GSSG ratio (vs. CT). In the H₂(+) group, these harmful changes were significantly suppressed [vs. H₂(?)]. Hydrogen gas reduced hepatic reperfusion injury after prolonged cold preservation via the maintenance of portal flow, by protecting mitochondrial function during the early phase of reperfusion, and via the suppression of oxidative stress and inflammatory cascades thereafter.     

Markers of splanchnic perfusion and intestinal translocation of endotoxins during cardiopulmonary bypass: effects of dopamine and milrinone.

OBJECTIVES: To investigate markers of splanchnic perfusion and the extent of endotoxemia during cardiopulmonary bypass (CPB) and to compare the effects of dopamine and milrinone on both splanchnic perfusion and endotoxemia. DESIGN: Prospective, randomized, blinded study. SETTING: University teaching hospital. PARTICIPANTS: Twenty-four patients scheduled for elective coronary artery bypass graft surgery (CABG). INTERVENTIONS: Patients were allocated to receive placebo (eight patients), dopamine (eight patients), or milrinone (eight patients) during CPB, and at seven times intraoperatively assays were performed of arterial and hepatic venous endotoxin levels, as well as measurements and/or calculations of intramucosal gastric pH (pHi), arterial and hepatic venous lactate-pyruvate ratio (lac/pyr), and hepatic venous oxygen saturation (S(HV)O2). MEASUREMENTS AND MAIN RESULTS: Both splanchnic and systemic endotoxin levels increased significantly, and this was unaffected by either dopamine or milrinone. Gastric pHi did not change, and there were only modest increases in lac/pyr, which remained within the normal range of less than 10 in both splanchnic and systemic blood. In the placebo group, S(HV)O2 decreased at the onset of CPB and also significantly decreased during rewarming and at the end of CPB and surgery. In the dopamine-treated patients, S(HV)O2 was greater compared with placebo and milrinone during both hypothermic and rewarming phases. CONCLUSION: Endotoxemia occurs during routine CPB. Neither pHi nor lac/pyr values showed adverse change, but hepatic venous oximetry may be a more sensitive indicator of splanchnic dysoxia in that S(HV)O2 was reduced during rewarming. Whether dopamine or milrinone confer protection against splanchnic ischemia remains uncertain.     

Negative impact of systemic catecholamine administration on hepatic blood perfusion after porcine liver transplantation.

Catecholamines are often administered during and after liver transplantation (LTx) to support systemic perfusion and to increase organ oxygen supply. Some vasoactive agents can compromise visceral organ perfusion. We followed the hypothesis that the vasculature of transplanted livers presents with a higher sensitivity, which leads to an increased vulnerability for flow derangement after application of epinephrine (Epi) or norepinephrine (NorEpi). Hepatic macroperfusion and microperfusion during systemic Epi or NorEpi infusion were measured by Doppler flow and thermodiffusion probes in porcine native, denervated, and transplanted livers (n = 16 in each group). Epi or NorEpi were infused (n = 8 in each subgroup) in predefined dosages (low dose = 5 microg/kg/minute and high dose = 10 microg/kg/minute) over 240 minutes. Systemic cardiocirculatory parameters were monitored continuously. Hepatic perfusion data were compared between all groups at comparable time points and dosages. In all native, denervated, and transplanted liver groups, Epi and NorEpi induced an inconsistent rise of mean arterial pressure and heart rate shortly after onset of infusion in both dosages compared with baseline. No significant differences of cardiovascular parameters at comparable time points were observed. In native livers, Epi and NorEpi induced only temporary alterations of hepatic macrocirculation and microcirculation, which returned to baseline 2 hours after onset of infusion. No significant alterations of hepatic blood flow were detected after isolated surgical denervation of the liver. By contrast, transplanted livers showed a progressive decline of hepatic macrocirculation (33-75% reduction) and microcirculation (39-58% reduction) during catecholamine infusions in a dose-dependent fashion. Characteristics of liver blood flow impairment were comparable for both vasoactive agents. In conclusion, pronounced disturbances of hepatic macrocirculation and microcirculation were observed during systemic Epi and NorEpi infusion after LTx compared with native and denervated livers. Microcirculation disturbances after LTx might be explained by impairment of hepatic blood flow regulation caused by an increased sensitivity of hepatic vasculature after ischemia-reperfusion and by lengthening of vasopressor effects caused by reduced hepatocyte metabolism. Clinicians should be aware of this potentially hazardous effect. Therefore, application of catecholamines after clinical LTx should be indicated carefully.     

The reduced tolerance of rat fatty liver to ischemia reperfusion is associated with mitochondrial oxidative injury

BACKGROUND: Oxidative stress contributes to the pathogenesis of hepatic ischemia-reperfusion injury. This study aimed to determine whether fatty degeneration affects the oxidative damage during warm ischemia reperfusion and whether mitochondria, the major intracellular site of energy synthesis, represent a preferential target of this injury. MATERIALS AND METHODS: Fed rats with control or fatty liver induced by choline deficiency underwent 60' lobar ischemia and reperfusion. Oxidative damage was assessed by measuring in whole liver tissue and in isolated mitochondria the thiobarbituric acid-reactive substances (TBARs), protein carbonyls (PC), and total and oxidized glutathione (GSH and GSSG) concentrations. The mitochondrial F0-F1-ATPase content and the oxidative phosphorylation activity were also determined. Rat survival and ALT release were assessed as parameters of liver injury. RESULTS: In the whole liver tissue, with the exception of TBARs, no differences were observed for GSH, GSSG, and PC between the two groups throughout all of the experiment. In contrast, in isolated mitochondria, fatty infiltration was associated with a mild oxidative imbalance already under basal conditions. The preischemic differences in the mitochondrial TBARs, PC, and GSSG levels were significantly amplified by reperfusion in the presence of steatosis. The enhanced oxidative damage was associated to a reduced F0-F1-ATPase content and oxidative phosphorylation activity in fatty liver mitochondria. Finally, serum ALT levels were significantly greater and survival significantly lower in rats with steatotic liver. CONCLUSIONS: Fatty infiltration exacerbates mitochondrial oxidative injury during warm ischemia reperfusion. The increased oxidative stress can alter mitochondrial functions, including key processes for ATP synthesis, thus, contributing to the reduced tolerance to reperfusion injury.     

Oxidative stress, hepatocellular integrity, and hepatic function after initial reperfusion in human hepatic transplantation

BACKGROUND: The mechanisms underlying liver graft dysfunction are not completely defined, although much of the injury derives from oxidative stress in organ reperfusion. The antioxidant glutathione in its reduced form (GSH) is an important agent to detoxify oxygen species after reperfusion. However, this effect might be limited by low concentrations at the end of cold storage. The objective of this study was to evaluate GSH and glutathione oxidized (GSSG) hepatic levels pre- and postreperfusion and correlate with hepatocellular injury and liver function in the 5 subsequent days after transplantation. METHODS: Liver biopsies were taken immediately before implant and 2 hours after venous reperfusion in 34 grafts, determining GSH, GSSG levels, and GSSG/GSH ratio. Aminotransferases (ALT, AST) and PT were measured for 5 days. RESULTS: There was a strong decrease in GSH concentration (P <.0001), increase of GSSG levels (P <.01), and increase of the GSSG/GSH ratio (P <.0001). No correlations were found between GSH, GSSG, or GSH/GSSH levels and AST, ALT, and PT. CONCLUSION: Glutathione levels showed significant changes after 2 hours of reperfusion, due to intense oxidative stress. Therapies to replenish GSH should be considered as a protective measure to avoid liver graft dysfunction after transplantation.     

Hemodynamic Changes in Blood Flow Through the Denervated Liver in Pigs

We investigated the effects of liver denervation on hemodynamic circulation in seven anesthetized pigs. Simultaneous measurements of the hepatic artery and portal vein were performed with an ultrasound Doppler flow meter before and after liver denervation. Neither resting systemic nor hepatic hemodynamics changed following liver denervation. However, temporary occlusion of the portal vein resulted in a significant increase in hepatic artery flow in the innervated liver (from 123 ± 15 ml/min to 177 ± 17 mu/min, p <. 01), whereas, in the denervated liver, a significant decrease was observed (from 128 ± 11 ml/min to 106 ± 19 mu/min. p >. 05). Thus, the reciprocity between the hepatic artery and portal vein in the innervated liver disappeared in the denervated liver. The absence of an increase in the hepatic artery flow during portal vein occlusion might intensify symptoms of portal vein thrombosis in liver transplantation. In the denervated liver, a significant decrease also occurred in systolic blood pressure and central venous pressure from 1 to 3 min after portal vein occlusion. Since the liver plays a crucial role in the maintenance of cardiovascular homeostasis during blood loss, it is likely that denervation at the porta hepatis induced a lack of vasoconstriction in the portal territory. Liver denervation might further exacerbate this response to hypotension. The current study confirms that the hepatic nerves play an important role in hepatic arterial and portal venous interactions aimed at maintaining a constant blood flow through the liver. We also suggest that the hepatic nerves are important for cardiovascular homeostasis.     

Gastric intramucosal pH as a monitor of gut perfusion after thrombosis of the superior mesenteric vein

Gastric intramucosal pH (pHi) when measured by a tonometer is a simple and minimally invasive method to determine gut ischemia. In a case of severe mesenteric venous thrombosis, we measured pHi intra- and postoperatively over a period of five days. The goal was to monitor improvement or deterioration of gastrointestinal perfusion in the intensive care unit and to perform a second-look laparotomy if the condition worsened. We observed that gastric pHi is a more sensitive parameter for detecting intestinal ischemia than parameters such as arterial pH, base excess, or lactate. This patient's pHi rose continuously, which allowed us to proceed in a conservative way without any further invasive diagnostic interventions. Thus, the application of a gastric tonometer in cases of mesenteric venous thrombosis may help to reduce costs by preventing unnecessary postoperative diagnostic maneuvers such as angiography, computed tomography, or even second-look laparotomy.     

Changes in hepatic haemodynamics and hepatic perfusion index during the growth and development of hypovascular HSN sarcoma in rats

Experimental liver tumours were induced in the Hooded Lister rat by the intraportal inoculation of 10(6) HSN sarcoma cells. The hepatic perfusion index was raised 10 days after the inoculation of cells (at the micrometastatic stage) and when overt tumour was present 20 days after inoculation. Overt tumours were hypovascular compared with normal liver. Portal venous flow and portal venous inflow fell significantly when the hepatic perfusion index was increased, but hepatic arterial flow did not alter. Portal vascular resistance and splanchnic vascular resistance were both increased in tumour-bearing animals but portal pressure, arteriosystemic shunting and portosystemic shunting did not increase significantly at any stage during the growth of hepatic tumour. These findings confirm that the hepatic perfusion index can be elevated in the presence of both micrometastic and overt hepatic tumour and that the changes are not due to either arteriosystemic shunting or mechanical portal venous obstruction.     

Intralobular heterogeneity of oxidative stress and cell death in ischemia-reperfused rat liver

The relationship between zonal oxidative stress and cell death after ischemia-reperfusion injury in rat liver was investigated. Oxidative stress was detected in situ by perfusion with nitroblue tetrazolium, which is converted to insoluble blue formazan by reducting agents. Cell death was detected in situ by perfusion with trypan blue. When isolated liver was perfused after 30 or 60 min of warm ischemia, oxidative stress was detected in periportal parenchymal cells after 30 min of reperfusion. It spread in the shape of a doughnut to midzonal cells after 60 min of reperfusion. On the other hand, cell death was observed in parenchymal cells that were within the doughnut-like area in which oxidative stress was detected. The extent of oxidative stress and cell death was higher after 60 min of ischemia than after 30 min of ischemia. In nonparenchymal cells, oxidative stress was observed in midzonal and pericentral regions after only 12 min of reperfusion, but minor cell death was observed only in periportal and midzonal regions after 30 min of reperfusion. Administration of allopurinol, an inhibitor of xanthine oxidase, suppressed oxidative stress and cell death in periportal parenchymal cells. These findings indicate that periportal and midzonal parenchymal cell death can be caused by zone-specific and xanthine-oxidase-mediated oxidative stress in parenchymal cells.     

Detection of hepatic metastases using duplex/color Doppler sonography.

Current imaging modalities are unable to detect small liver metastases because of limited resolution and contrast differentiation. The association between liver metastases and altered liver blood flow has been demonstrated by dynamic scintigraphy, but the clinical feasibility of this test has been questioned. In this study a novel approach to detecting liver metastases was assessed by measurement of liver blood flow using a duplex/color Doppler System. Hepatic arterial and portal venous blood flows were measured in 16 controls, 50 patients with gastrointestinal cancer, and 6 patients with breast cancer. The ratio of hepatic arterial to total liver blood flow (Doppler perfusion index, DPI) and the ratio of hepatic arterial: portal venous blood flow (Doppler flow ratio, DFR) were calculated. The DPI and DFR values of controls and patients with overt liver metastases were clearly separated (p less than 0.0001). The results suggest that duplex/color Doppler ultrasound measurement of hepatic perfusion changes may be of value in the detection of liver metastases.     

Mesenteric venous hypertension: importance after portal systemic shunting?

Hepatic dysfunction after portacaval shunting (PCS) has been attributed to loss of portal perfusion to the liver. Proponents of selective systemic shunting state that reduced encephalopathy and hepatic dysfunction with this procedure result from the maintenance of portal perfusion to the liver through the hypertensive mesenteric venous circulation. We questioned the importance of maintaining the diminished portal flow to the cirrhotic liver because hepatofugal flow is known to develop in many of these patients. We sought to further define mechanisms that may contribute to the maintenance of critical flow to the liver in compensated hepatic cirrhosis. We demonstrated a primary relationship between mesenteric venous hypertension (MVH) and increased hepatic arterial blood flow after diversion of portal blood flow. Fifteen dogs had vena caval stenosis above an end-to-side PCS to establish MVH and deprive the liver of portal blood flow. Another 15 dogs had end-to-side PCS alone. A half hour after shunting, hepatic arterial blood flow had increased significantly in all dogs. Hemodynamic parameters remained stable throughout. Six weeks later, mesenteric pressure increased 98% +/- 3% with intracaval stenosis (from 9.6 +/- 0.1 to 19.0 +/- 0.3 cm H2O). Mesenteric pressure was unchanged with PCS alone (9.0 +/- 0.1 cm H2O). Increased hepatic arterial flow was significantly elevated in all dogs above pre-shunt values by 6 weeks postshunt. With MVH, however, further augmentation in hepatic arterial flow was noted in the chronic state (1.5 +/- 0.1 vs 0.9 +/- 0.1 ml/min/gm, p less than 0.05). There was significant correlation between MVH and increased hepatic arterial flow in the chronic state (r = 0.79, p = 0.05). Hepatic arterial flow 6 weeks after PCS with MVH was associated with lower blood ammonia and improved hepatocellular function compared with animals with PCS alone. These results support the hypothesis that MVH is important in maintaining blood supply--beyond providing driving force for sustained portal flow to the liver. This is an important consideration in the medical and surgical management of portal hypertension, a condition in which profound reduction in portal pressure may negatively affect compensatory hepatic arterial blood flow.     

Splanchnic circulation and regional sympathetic outflow during peroperative PEEP ventilation in humans

The splanchnic organs represent a major target for sympathetic outflow and an important region for haemodynamic effects on cardiovascular homeostasis. We have studied regional haemodynamic and sympathetic changes in the splanchnic bed during standardized circulatory stress from positive end-expiratory pressure ventilation (PEEP). We investigated eight patients undergoing major upper abdominal surgery using a radiotracer method to measure plasma spillover of norepinephrine as an index of sympathetic nerve activity using arterial, portal and hepatic venous blood sampling. Mesenteric and hepatic perfusion were measured by ultrasound transit time flowmetry and blood-gas analyses. Steady state measurements were performed before and during PEEP ventilation at 10 cm H2O. Plasma spillover of norepinephrine in the mesenteric and hepatic organs represented mean 49 (SEM 8)% and 7 (2)%, respectively, of systemic norepinephrine spillover at baseline, and PEEP ventilation did not cause any significant changes. However, PEEP ventilation significantly decreased portal venous blood flow while hepatic blood flow was preserved by a compensatory increase in hepatic arterial blood flow. Mesenteric and hepatic oxygen delivery changed according to blood flow, and there were no changes in regional oxygen consumption. Thus PEEP ventilation altered mesenteric and hepatic perfusion, independent of any change in corresponding sympathetic nerve activity. Regulation of hepatic blood supply, not related to sympathetic activity, maintained liver oxygenation during PEEP ventilation despite a simultaneous decrease in mesenteric perfusion.      

Ischaemic change of the human intestine after total portal occlusion during liver resection

This is a clinical study of the use of several monitoring techniques to evaluate the effect of total hepatic inflow occlusion on intestinal ischaemia during liver resection. A total of 8 patients was studied. Parameters measured included intestinal oxygen extraction ratio, portal venous and arterial lactate levels and intestinal intramucosal pH (pHi), measured by an intraluminal tonometer. When venous outflow of the intestine was occluded, intestinal oxygen extraction ratio increased and portal venous lactate increased significantly, but arterial lactate did not increase significantly until after 60 minutes of occlusion. Intestinal pHi decreased significantly after 60 minutes. Following release of the occlusion, oxygen extraction and pHi returned to normal in 7 out of 8 patients. The 1 patient who had a persistent decrease in pHi died postoperatively. These findings indicate that a marked drop in pHi after total portal occlusion and persistent low pHi following the release of a portal occlusion are associated with the development of complications and mortality during liver resection.     

Hepatic function during xenon anesthesia in pigs

BACKGROUND: Inhalation anesthetics decrease liver perfusion and oxygen consumption by changing the distribution pattern of perfusion between the hepatic artery and the portal vein and by direct effects on liver cells. The effects of xenon on liver perfusion and function have been not investigated until now. METHODS: Fourteen pigs were randomly assigned to two groups to receive either 73-78% xenon or 75% nitrogen in oxygen with additional supplementation of pentobarbital and buprenorphine. Microspheres were used to determine the arterial perfusion of the liver and splanchnic organs. Oxygen contents were measured by catheterization of the portal and a liver vein. Lactate and glucose plasma concentrations were measured in hepatic, mixed venous and arterial blood. Alanine aminotransferase (ALT) and lactate dehydrogenase (LOH) plasma concentrations were measured in arterial blood. Urea production rates were calculated to assess hepatic metabolic function. RESULTS: Significant higher oxygen contents were found in the liver venous blood during xenon anesthesia. No differences were found in any other investigated parameters. CONCLUSION: Higher oxygen content in liver venous blood observed during xenon anesthesia was not induced by changes in hepatic perfusion distribution or by an impairment of liver metabolic capacity. However, it can be explained by similar results known from inhalation anesthesia. Additionally, the effect can be caused by the reduction of plasma catecholamine concentrations during xenon anesthesia.     

Effect of dopamine infusion on hemodynamics after hepatic denervation

BACKGROUND:. The effects of dopamine (DA) on systemic hemodynamics are better understood than its effects on hepatic hemodynamics, especially after liver denervation occurring during liver transplantation. Therefore, a porcine model was used to study DA's effects on hemodynamics after hepatic denervation. MATERIALS AND METHODS: Fifteen pigs underwent laparotomy for catheter and flow probe placement. The experimental group (n = 7) also underwent hepatic denervation. After 1 week, all pigs underwent DA infusion at increasing doses (3-30 mcg/kg/min) while measuring hepatic parameters [portal vein flow (PVF), hepatic artery flow (HAF), total hepatic blood flow (THBF = HAF + PVF), portal and hepatic vein pressures] and systemic parameters [heart rate (HR), mean arterial pressure (MAP)]. RESULTS: There was a significant increase in HAF from baseline to the 30 mcg/kg/min DA infusion rate (within-subjects P < 0.01), but the differences between the two groups were not significant. PVF and THBF showed large effects (increases) with denervation, but the increase in flow with DA infusion was not present after denervation. Perihepatic pressures were unchanged by denervation or DA. Heart rate differed significantly between the control and denervated animals at baseline, 3, 6, 12 (all P < 0.05), and 30 mcg/kg/min DA (P = 0.10). Control vs denervation MAP at baseline was 100 +/- 4 vs 98 +/- 4 Torr and at 30 mcg/kg/min it was 110 +/- 3 vs 101 +/- 5 mm Hg. CONCLUSIONS: Hepatic flows tended to be higher after denervation. HAF showed similar increases with DA in both control and denervation groups. Increases in PVF and THBF with DA infusion were not present after denervation. HR was significantly decreased and MAP tended to be lower after denervation. The HR and MAP response to DA was similar in both groups. Therefore, both denervation and DA infusion have an effect on systemic and hepatic hemodynamics.     

Gadolinium chloride-induced improvement of postischemic hepatic perfusion after warm ischemia is associated with reduced hepatic endothelin secretion

Selective Kupffer cell blockade by gadolinium chloride (GdCl₃) pretreatment of liver donors previously proved to be effective in reducing ischemia/reperfusion injury in rat liver transplants. Physiological mechanisms of this effect have not been specified so far. Vasoactive peptides are involved in liver blood flow regulation. We tested the hypothesis, that hepatic hemodynamic effects of GdCl₃ pretreatment are mediated by intrahepatic endothelin‐1 (ET) secretion in a standardized porcine model of warm liver ischemia and reperfusion. Standardized warm hepatic ischemia (45 min) was induced after laparotomy in intubation narcoses (ITN) by Pringle‐maneuver in pigs (n = 12). Animals were either pretreated with GdCl₃ (20 mg/kg i.v.) or sodium chloride 0.9% (control group) in a randomized manner 24 h before investigation. Relaparotomy was performed at day 7. Before, during ischemia and until 6 h after liver reperfusion, transhepatic blood flow (portal venous + hepatic artery flow) was defined by ultrasonic flow probes and hepatic parenchymous microcirculation evaluated by implanted thermodiffusion electrodes. ET plasma concentrations were analyzed (commercial RIA) at all time points in the hepatic veins after selective canulation. GdCl₃ pretreatment of animals markedly improved hepatic macro‐ and microperfusion before and particularly after warm ischemia. Mean ET plasma concentrations in the hepatic vein were significantly lower before, 6 h and 7 days after ischemia, compared with controls. Kupffer cell destruction by GdCl₃ pretreatment improves hepatic micro‐ and macroperfusion after warm ischemia, thus indicating reduced ischemia/reperfusion injury. Documented reduction of postischemic liver blood flow impairment after GdCl₃ pretreatment could be mediated by a decreased hepatic ET secretion, as hemodynamic effects were associated with significantly reduced ET plasma levels in hepatic veins.     

Changes in Arterial and Portal Perfusion in Embolized and Nonembolized Hepatic Lobes After Portal Vein Embolization Evaluated by Helical Computed Tomography

We evaluated the changes in hepatic arterial and portal perfusion in nonembolized as well as in embolized lobes after portal venous branch embolization (PVE) with dynamic helical computed tomography (CT). Six patients with hepatic malignancies, who underwent PVE prior to a subsequent hepatectomy, were the subjects of this study. We performed CT examinations before PVE and 2 weeks after PVE to make a volumetric analysis. At the same time, we performed single-location dynamic sequences after the injection of a 50-ml bolus of contrast medium, and we then created time–density curves from circular regions of interest drawn over the aorta, parenchyma of the right and left lobe of the liver, and spleen. We calculated the arterial perfusion index (ml/min per ml of tissue) and the portal perfusion index by dividing the maximum rate of enhancement of the liver before and after the splenic peak by the peak aortic enhancement. We then calculated the arterial and portal flows (ml/min) from the perfusion index and values of CT volumetry. In the right lobe, where the portal flow was occluded, the arterial perfusion index and flow increased significantly after PVE. In contrast, the arterial perfusion index and flow both decreased in the left lobe after PVE in a reverse response to the increase in the portal perfusion index and flow. The total arterial flow of the liver thus seemed to slightly increase; however, the change was not significant. By performing PVE an increased arterial perfusion was induced in the embolized lobe, with a concomitant decrease in arterial perfusion in the nonembolized lobe. Received: September 7, 2000 / Accepted: July 17, 2001