Central nervous system manganese induced lesions and clinical consequences in patients with hereditary hemorrhagic telangiectasia.

BACKGROUND: Around 47-74% of patients with hereditary hemorrhagic telangiectasia (HHT) have hepatic vascular malformations (HVMs); magnetic resonance images (MRI) of the central nervous system (CNS) might show in T1 sequences a hyper-intensity signal in different areas, mainly in the basal ganglia (BG) as consequence of manganese (Mn) deposits as observed in cirrhotic patients. These patients might suffer from different neuropsychiatric disorders (hepatic encephalopathy). In HHT patients, even in the presence of hepatic shunts, hepatocellular function is usually preserved. Additionally, Mn shares iron absorption mechanisms, transferrin and CNS transferrin receptors. In iron deficiency conditions, the Mn may harbor transferrin and access BG. The objectives were to describe frequency of BG Mn deposit-induced lesions (BGMnIL) in HHT patients, its relationship with iron deficiency anemia (IDA) and HVMs. Finally, explore the association between neuropsychological and motor consequences. We performed a cross-sectional study. We determined HHT patients with or without BG-MnIL by the MRI screening of the CNS. We included all patients with lesions and a random sample of those without lesions. All patients underwent standardized and validated neuropsychological assessment to evaluate BG actions. Results were analyzed with multiple logistic regression, adjusting for potential confounders. RESULTS: Among 307 participants from a cohort included in the Institutional HHT Registry, 179 patients had MRI performed and Curaçao Criteria ≥3. The prevalence of BG-MnIL was 34.6% (95%CI 27.69-42.09). While neuropsychological symptoms were present in all patients, BG-MnIL patients performed poorly in three of the neuropsychological tests (serial dotting, line tracing time, number connection test A). HVMs frequency in BG-MnIL was 95.1%, versus 71.4% in those without lesions (p < 0.001). IDA frequency was 90.3% versus 54% (p < 0.001). When IDA is present, estimated risk for BG-MnIL is remarkably high (OR 7.73, 95%CI 2.23-26.73). After adjustment for possible confounders (gender, age, presence of HVMs), IDA was still associated with increased risk of BG-MnIL (adjusted OR 6.32, 95% CI 2.32-17.20; p < 0.001). CONCLUSIONS: Physicians should assess BG-MnIL in HHT patients in CNS-MRI. IDA and HVMs present increased risk of lesions. Patients with BG-MnIL have neuropsychological impairment, and they might benefit from sparing IDA, or undergoing future therapeutic options. TRIAL REGISTRATION: NCT01761981 . Registered January 3rd 2013.

Use of liver grafts from anti-hepatitis B core-positive donors: a multicenter study in Argentina.

Liver transplantation success is limited by the availability of donors. To overcome this limitation, anti-core-positive donors are increasingly being accepted, but underutilization of this resource still occurs. We performed the current study to determine the prevalence of anti-core-positive donors in our region and to describe the management of these donors and their recipients. Between January 2005 and July 2011, the national transplant database included 2,262 registered liver donors among whom 106 (4.7%) were anti-core-positive including 59 (56%) discarded and 47 (44%) implanted organs. A median of 14.5 offers (range 4-60) were rejected before harvesting and implanting the accepted grafts. The only difference between the implanted and the discarded grafts was found for the alanine aminotransferase level, which was higher among the discarded ones (50 ± 59 UI/L vs 25 ± 16, P < .05). Among 40 recipients included in the study, 5 (12.5%) did not receive any prophylaxis; 18 (45%) a nucleos(t)ide analog 11 (25.5%), heptitis B immunoglobulin and nucleos(t)ide analogs and 6 (15%) pretransplant hepatitis B vaccination. Over a mean follow-up of 871 ± 585 days, 4 de novo hepatitis B cases were identified at 545, 720, 748, and 1,080 days posttransplantation. None of these patients had received any prophylaxis. In all cases entecavir successfully controlled viral replication. We believe that better utilization of these donors and careful management of their recipients represent safe strategies to expand the liver donor pool in Argentina.

Chronic administration of propylthiouracil ameliorates hyperdynamic circulation in portal hypertensive rats.

OBJECTIVE: To evaluate the effect of a hypothyroid state, induced by chronic propylthiouracil administration, on splanchnic and systemic hemodynamic parameters in rats with portal hypertension due to portal vein ligation. METHODS: Portal hypertension was induced by surgical stenosis of the portal vein. Cardiac index and portal blood flow were measured using radioactive microspheres. Measurements were performed after treatment with propylthiouracil (1 mg/ml in drinking water) for 5 days. RESULTS: Propylthiouracil-treated portal hypertensive rats had a lower portal pressure (12.4 +/- 1.9 versus 16.3 +/- 0.7 mmHg; p < 0.05) and portal blood flow (11.6 +/- 0.7 versus 13.2 +/- 1.3 ml/min/100 g; p < 0.05) than non-treated animals. Splanchnic vasoconstriction in treated animals was associated with a higher peripheral vascular resistance (2.3 +/- 0.4 versus 1.8 +/- 0.3 mmHg/ml/min/100 g; p < 0.05) than controls. CONCLUSION: These results suggest that portal pressure can be lowered by inducing a hypothyroid state by chronic administration of propylthiouracil.

Nitric oxide synthase activity in the splanchnic vasculature of patients with cirrhosis: relationship with hemodynamic disturbances.

BACKGROUND/AIMS: It has been demonstrated that an overproduction of nitric oxide plays an important role in the pathogenesis of the hyperdynamic circulation exhibited by cirrhotic patients. Nevertheless, evidence is supported by studies performed in experimental models or by indirect measurements in humans. The purpose of this study has been to evaluate nitric oxide production in splanchnic vasculature of patients with cirrhosis and to investigate its possible relationship with systemic and splanchnic hemodynamics. METHODS: Nitric oxide synthase (NOS) activity was measured in hepatic artery and portal vein tissues of nine cirrhotic patients. Samples were obtained during liver transplantation. Control samples were obtained simultaneously from the corresponding tissues of the liver donors. Hemodynamic parameters were determined with Doppler ultrasonography. RESULTS: NOS activity was significantly higher in hepatic artery of cirrhotic patients than in controls (8.17 +/- 1.30 vs 4.57 +/- 0.61 pmoles/g of tissue/min, P < 0.05). Patients with ascites showed a higher hepatic artery NOS activity than patients without ascites. Highly significant correlation was observed between cardiac output and hepatic artery NOS activity as well as between portal blood flow and hepatic artery NOS activity. CONCLUSIONS: The present study demonstrates an enhanced production of nitric oxide in the splanchnic vasculature of patients with cirrhosis.

Desensitization to the effects of intravenous octreotide in cirrhotic patients with portal hypertension.

BACKGROUND & AIMS: Octreotide has been suggested for the treatment of variceal bleeding, but detailed dose-finding studies are not available. We performed a dose-finding study investigating the hemodynamic effects of several forms of intravenous octreotide administration. METHODS: Splanchnic hemodynamics and plasma glucagon levels were measured in 68 cirrhotics in baseline conditions and (1) after a double-blind intravenous injection of octreotide (50 microg [n = 9] or 500 microg [n = 8]) or placebo (n = 7); (2) after a 50-microg octreotide bolus followed by continuous infusion of 50 microg/h (n = 8), 250 microg/h (n = 8), or placebo (n = 6); (3) after repeated 50-microg injections of octreotide (n = 9) or placebo (n = 6) after an initial bolus (50 microg octreotide); and (4) after a placebo bolus and continuous octreotide infusion (50 microg/h; n = 7). RESULTS: Placebo caused no significant changes. Octreotide caused a marked and transient decrease in portal pressure and azygos blood flow and an increase in mean arterial pressure. These effects lasted only 5 minutes despite addition of continuous octreotide infusions. Repeated octreotide injections had shorter, less marked effects than the first bolus. A continuous octreotide infusion did not decrease portal pressure. Glucagon levels were markedly reduced by octreotide, but gradually returned to baseline despite continuous infusions or repeated injections of octreotide. CONCLUSIONS: Octreotide injection caused marked but transient reductions in portal pressure and azygos blood flow. Adding a continuous octreotide infusion neither maintained nor prolonged its effects. Repeated boluses caused significant tachyphylaxis. This rapid desensitization to the effects of octreotide may explain the divergent effects achieved with octreotide infusions in acute variceal bleeding.

CO(2) wedged hepatic venography in the evaluation of portal hypertension.

BACKGROUND/AIMS/METHODS: During hepatic vein catheterisation, in addition to measurement of hepatic venous pressure gradient (HVPG), iodine wedged retrograde portography can be easily obtained. However, it rarely allows correct visualisation of the portal vein. Recently, CO(2) has been suggested to allow better angiographic demonstration of the portal vein than iodine. In this study we investigated the efficacy of CO(2) compared with iodinated contrast medium for portal vein imaging and its role in the evaluation of portal hypertension in a series of 100 patients undergoing hepatic vein catheterisation, 71 of whom had liver cirrhosis. RESULTS: In the overall series, CO(2) venography was markedly superior to iodine, allowing correct visualisation of the different segments of the portal venous system. In addition, CO(2), but not iodine, visualised portal-systemic collaterals in 34 patients. In cirrhosis, non-visualisation of the portal vein on CO(2) venography occurred in 11 cases; four had portal vein thrombosis and five had communications between different hepatic veins. Among non-cirrhotics, lack of portal vein visualisation had a 90% sensitivity, 88% specificity, 94% negative predictive value, and 83% positive predictive value in the diagnosis of pre-sinusoidal portal hypertension. CONCLUSIONS: Visualisation of the venous portal system by CO(2) venography is markedly superior to iodine. The use of CO(2) wedged portography is a useful and safe complementary procedure during hepatic vein catheterisation which may help to detect portal thrombosis. Also, lack of demonstration of the portal vein in non-cirrhotic patients strongly suggests the presence of pre-sinusoidal portal hypertension.

The role of portal pressure in the severity of bleeding in portal hypertensive rats.

The aim of this study was to investigate the role of portal hypertension determining the severity of bleeding in portal hypertensive rats. The effects of section of branches of the ileocolic vein were studied in sham-operated (SO), partial portal vein-ligated (PPVL), and common bile duct-ligated (CBDL) rats. The ensuing hemorrhage was compared with that caused by section of femoral vein, where the portal hypertensive factor is excluded. In PPVL rats, section of branches of increasing size (divided into fourth, third, second, and first order) resulted in increasingly severe bleeding (arterial pressure: / +/- 4%, / 6 +/- 12%, / /15 +/- 8%, and / 28 +/- 13%; P <.005; hematocrit / 4 +/- 2%, / 6 +/- 1%, / 7 +/- 2%, and / 10 +/- 4%; P <.005). Bleeding from first-order branches was mild in SO, moderate in PPVL, and severe in CBDL rats, as shown by increasing changes in arterial pressure (/ 3 +/- 3%, / 12 +/- 16% and, / 43 +/- 23%; P <.01), hematocrit (/ 4 +/- 1%, / 12 +/- 2%, and / 32 +/- 19%; P <.01), and mortality (0%, 0%, and 56%; P <.001). Greater blood loss in CBDL rats was associated with higher portal pressure (16.6 +/- 2.7 vs. 13. 1 +/- 1.1 mm Hg in PPVL; P <.01) and more prolonged bleeding time (70 +/- 4 vs. 35 +/- 3 seconds in PPVL; P <.001). Vessels were similarly dilated in CBDL and PPVL (0.7 +/- 0.2 and 0.7 +/- 0.1 vs. 0.4 +/- 0.1 mm in SO; P <.05). Section of femoral vein caused equal blood loss in SO, PPVL, and CBDL rats, assessed by falls in hematocrit (/ 8 +/- 2%, / 7 +/- 1%, / 8 +/- 1%, respectively; NS) and by the blood loss (3.6 +/- 0.7, 3.5 +/- 0.9, and 3.8 +/- 0.7 g; NS). The study shows that the degree of portal pressure elevation is a major determinant of the severity of portal hypertension-related bleeding in PPVL and CBDL rats.

[Dexamethasone, an inhibitor of the expression of inducible nitric oxide synthase, does not modify the hyperdynamic state in cirrhotic rats]. / La dexametasona, un inhibidor de la expresion de la óxido nítrico sintasa inducible, no modifica el estado hiperdinámico en ratas cirróticas.

Increased nitric oxide formation has been shown to be involved in the hyperdynamic circulation of portal hypertension. It has been proposed that it could be related to stimulation of the inducible nitric oxide synthase by endotoxin. Therefore, the aim of the present study was to evaluate whether dexamethasone treatment, an inhibitor of the expression of the inducible enzyme, ameliorates the hyperdynamic circulation observed in cirrhotic rats due to chronic bile duct ligation. Systemic and splanchnic hemodynamic parameters were measured after administration of dexamethasone (3 mg/kg/day during 3 days, i.p.) or its vehicle. In cirrhotic rats dexamethasone treatment caused a mild but not significantly higher mean arterial pressure in comparison with vehicle while similar values of cardiac output, peripheral vascular resistance, portal blood flow and portal pressure were observed in both group of animals. A significant body weight loss over the three days of treatment was observed in rats receiving dexamethasone. In sham-operated rats, dexamethasone administration caused similar changes as observed in cirrhotic animals. Endotoxemia was observed in five of six cirrhotic rats while it was not detected in the control group. Our results show that dexamethasone administration does not modify systemic and splanchnic hemodynamic parameters in endotoxemic cirrhotic rats. This finding suggests that stimulation of the inducible nitric oxide synthase may not play a role in the increased nitric oxide production in portal hypertension.

Hyperkinetic circulation and decreased sensitivity to vasoconstrictors following portacaval shunt in the rat. Effects of chronic nitric oxide inhibition.

BACKGROUND/AIMS: This study aimed to investigate: (i) whether the hyperkinetic circulation that develops after portacaval shunt is associated with decreased vascular sensitivity to vasoconstrictors and (ii) the role of nitric oxide on its pathogenesis. METHODS: Portacaval-shunted and sham-operated rats received long-term treatment with the nitric oxide inhibitor L-NAME (osmotic minipump) or its inactive enantiomer D-NAME. Measurements of arterial pressure, cardiac output and superior mesenteric artery blood flow (transit-time flow probe) were done 4 days later in baseline conditions and after increasing doses of methoxamine. Peripheral and superior mesenteric vascular resistance were calculated. RESULTS: Portacaval shunted rats showed a significantly lower peripheral and superior mesenteric vascular resistance and a significant reduction in their response to incremental doses of methoxamine than sham-operated controls. Chronic nitric oxide inhibition attenuated the systemic but not the splanchnic vasodilatation and totally corrected the hyposensitivity to methoxamine of portacaval-shunted rats. However, they still had a significantly lower peripheral and superior mesenteric vascular resistance than sham-operated rats. CONCLUSIONS: This study shows that the splanchnic and systemic hyporesponsiveness to methoxamine observed in portacaval-shunted rats could be explained by an excess of nitric oxide. However, other factors may be involved in maintaining splanchnic and systemic vasodilatation despite NO-inhibition.

Prognostic value of early measurements of portal pressure in acute variceal bleeding.

BACKGROUND & AIMS: Variceal bleeding is the most important complication of portal hypertension. However, the relationship between the increase in portal pressure and the outcome of variceal bleeding has not been well defined. METHODS: We measured the hepatic venous pressure gradient (HVPG) of 65 cirrhotic patients with acute variceal hemorrhage, early after admission (20.6 +/- 15.6 hours). RESULTS: Twenty-three patients had a poor evolution (failure to control bleeding or early variceal rebleeding), and 42 had an uneventful evolution. The only variable associated with outcome was the HVPG, which was higher in patients with a poor evolution (23.7 +/- 6.1 vs. 19.2 +/- 3.3 mm Hg; P < 0.0004). This was confirmed by multivariate analysis. HVPG was >/=20 mm Hg in 19 of 23 patients with poor evolution vs. 12 of 42 patients with uneventful evolution (P < 0.0001). An initial HVPG of >/=20 mm Hg was associated with a significantly longer intensive care unit stay (7 +/- 5 vs. 4 +/- 2 days; P < 0.02), longer hospital stay (19 +/- 10 vs. 14 +/- 6 days; P < 0.02), greater transfusion requirements (9.0 +/- 7.7 vs. 4.7 +/- 3.2 UU; P < 0.007), and a worse actuarial probability of survival (1-year mortality, 64% vs. 20%; P < 0.002). CONCLUSIONS: Early measurement of HVPG in cirrhotic patients during acute variceal bleeding provides useful prognostic information on the evolution of the bleeding episode and long-term survival.

Prolonged bleeding time in experimental cirrhosis: role of nitric oxide.

BACKGROUND/AIMS: Nitric oxide is a powerful in vitro inhibitor of platelet adhesion and aggregation. Our aim was to investigate whether the in vivo inhibition of nitric oxide release shortens bleeding time, in rats with cirrhosis induced by chronic bile duct ligation. METHODS: Mean arterial pressure and bleeding time were measured under basal conditions and 5, 15 and 30 min after administration of vehicle (0.9% saline) or an inhibitor of nitric oxide synthesis, Nw-nitro-L-arginine (5 mg/kg, iv). Mean arterial pressure was measured with an intra-arterial catheter and bleeding time with a standardized Simplate device. RESULTS: Cirrhotic rats showed a lower mean arterial pressure (116+/-4 mmHg) and a prolonged bleeding time (177+/-40 s) compared to control animals (133+/-6 mmHg and 95+/-12 s, respectively, p<0.01). In cirrhotic rats, Nw-nitro-L-arginine significantly increased mean arterial pressure (from 116+/-5 to 141+/-11 mmHg, p<0.05) and completely normalized bleeding time (from 170+/-39 to 103+/-21 s, p<0.05) 15 min after administration. Pretreatment with L-arginine (300 mg/kg, iv) prevented the hemodynamic and hemostatic changes induced by Nw-nitro-L-arginine. A trend to normalize platelet adhesion was observed in cirrhotic rats after the inhibition of nitric oxide production. In control animals, Nw-nitro-L-arginine increased mean arterial pressure, while no effect on bleeding time was observed. CONCLUSIONS: These findings support the concept that nitric oxide may be a mediator in the bleeding time abnormalities associated with experimental cirrhosis.

Effects of increasing blood hemoglobin levels on systemic hemodynamics of acutely anemic cirrhotic patients.

BACKGROUND/AIMS: In experimental portal hypertension, blood hemoglobin levels have been shown to influence the hyperdynamic circulatory state. The aim of this study was to assess the hemodynamic effects of increasing hemoglobin concentration in human portal hypertension. METHODS: Sixteen cirrhotic patients recovering from a variceal bleeding episode were randomly assigned to receive two units of packed red cells or 500 ml of a protein solution. Systemic and portal hemodynamics, and rheological and hormonal parameters were measured at baseline and after expansion. RESULTS: Both groups were similar with respect to the degree of liver failure, severity of the bleeding episode, activation of the endogenous vasopressor systems, and hemodynamic parameters. The administration of either erythrocytes or a protein solution prompted a similar increase in total blood volume and suppression of vasopressor systems. Both groups of patients experienced similar increases in wedged hepatic venous pressure. Hepatic venous pressure gradient was not significantly modified but tended to increase in erythrocyte-transfused patients. Cardiopulmonary pressures increased, but this increment was significant in the non-blood-transfused patients only. Cardiac output decreased in erythrocyte-transfused patients, while it increased in the group receiving a protein solution. Red blood cell transfusion resulted in an increase in systemic vascular hindrance (resistance/blood viscosity), whereas the administration of a protein solution prompted a decrease in this parameter, thus reflecting true vasoconstriction and vasodilation, respectively. CONCLUSIONS: An increase in blood hemoglobin in acutely anemic cirrhotic patients attenuates their hyperdynamic circulation beyond viscosity-dependent changes, an effect which might be counteracted by the effects on portal venous pressure gradient.

Effects of propranolol on the hepatic hemodynamic response to physical exercise in patients with cirrhosis.

Physical exercise increases portal pressure (hepatic venous pressure gradient [HVPG]) in patients with cirrhosis. It is unknown if this deleterious effect is associated with changes in gastroesophageal collateral blood flow and if these can be prevented by propranolol administration. The aim of this study was to characterize the effects of propranolol on the splanchnic hemodynamic response to exercise in patients with cirrhosis. Twenty-three patients with cirrhosis and portal hypertension had hemodynamic measurements in baseline conditions, and during moderate cycling exercise (40 W) under double-blind propranolol or placebo administration. In patients receiving placebo, HVPG significantly increased during exercise (from 16.7 +/- 0.9 to 19.0 +/- 1.0 mm Hg; P < .01), hepatic blood flow (HBF) decreased (-18% +/- 4%; P < .01), while azygos blood flow (AzBF) was unchanged (4% +/- 12%; ns). In patients receiving propranolol, portal pressure did not increase during exercise, but decreased from 16.3 +/- 1.0 to 12.9 +/- 1.1 mm Hg (P < .01). The lack of increase in HVPG in response to exercise in patients receiving propranolol may be related to a more pronounced decrease in HBF, as compared with patients receiving placebo, and to a blunted increase in cardiac output (CO). Moderate physical exercise adversely influences the hepatic hemodynamics in patients with cirrhosis, causing a significant increase in portal pressure. This is effectively prevented by propranolol pretreatment.

Transjugular intrahepatic portosystemic shunt in hepatorenal syndrome: effects on renal function and vasoactive systems.

Little information exists on the effects of transjugular intrahepatic portosystemic shunts (TIPS) in the management of cirrhotic patients with hepatorenal syndrome (HRS). The current study was aimed to prospectively evaluate the effects of TIPS on renal function and vasoactive systems in patients with type I HRS. Glomerular filtration rate (GFR) (inulin clearance), renal plasma flow (RPF) (para-aminohippurate clearance), plasma renin activity (PRA), aldosterone (ALDO), norepinephrine (NE), and endothelin (ET) were determined in baseline conditions and at different time intervals after TIPS in 7 patients with type I HRS. TIPS induced a marked reduction of portal pressure gradient (PPG) (20 +/- 1 to 10 +/- 1 mm Hg; P < .05). Renal function improved in 6 of the 7 patients. Serum creatinine and blood urea nitrogen (BUN) decreased from 5 +/- 0.8 and 109 +/- 7 to 1.8 +/- 0.4 mg/dL and 56 +/- 11 mg/dL, respectively (P < .05 for both), and GFR and RPF increased from 9 +/- 4 and 103 +/- 33 to 27 +/- 7 mL/min and 233 +/- 40 mL/min, respectively (P < .05 for both), 30 days after TIPS. These beneficial effects on renal function were associated with a significant (P < .05) reduction of PRA (18 +/- 5 to 3 +/- 1 ng/mL x h), ALDO (279 +/- 58 to 99 +/- 56 ng/dL), and NE (1,257 +/- 187 to 612 +/- 197 pg/mL). ET did not change significantly (28 +/- 8 to 27 +/- 11 pg/mL). Mean survival was 4.7 +/- 2 months (0.3-17 months). Three patients remained alive more than 3 months after TIPS insertion. In conclusion, TIPS improves renal function and reduces the activity of the renin-angiotensin and sympathetic nervous systems in cirrhotic patients with type I HRS. Nevertheless, the efficacy of TIPS in the management of these patients should be confirmed in controlled investigations.

Propranolol plus prazosin compared with propranolol plus isosorbide-5-mononitrate in the treatment of portal hypertension.

BACKGROUND & AIMS: The association of prazosin to propranolol enhances the decrease in portal pressure but may cause hypotension and sodium retention. The aim of this study was to compare the portal pressure reduction and safety of the combination of propranolol plus prazosin with that of propranolol plus isosorbide-5-mononitrate (ISMN). METHODS: Fifty-six portal-hypertensive cirrhotics received randomly propranolol plus prazosin (n = 28) or propranolol plus ISMN (n = 28) orally for 3 months. Hemodynamics and liver and renal function were assessed at baseline and after 3 months. RESULTS: Propranolol plus prazosin caused a greater reduction in hepatic venous pressure gradient (HVPG) than propranolol plus ISMN (-24.2% +/- 11% vs. -16.1% +/- 11%; P < 0.01). A reduction in HVPG of > 20% was significantly more frequent in the propranolol plus prazosin group than in the propranolol plus ISMN group (85% vs. 53%; P < 0.05). Neither treatment modified hepatic blood flow, quantitative liver function test results, glomerular filtration rate, plasma renin activity, or plasma aldosterone level. Side effects occurred in 13 patients receiving propranolol plus prazosin compared with 7 receiving propranolol plus ISMN (P = 0.16). CONCLUSIONS: Propranolol plus prazosin has a greater portal pressure-lowering effect than propranolol plus ISMN. Both therapies were safe for liver and renal function. However, the combination of propranolol plus prazosin caused a greater decrease in arterial pressure and was less well tolerated than propranolol plus ISMN.

Clinical events after transjugular intrahepatic portosystemic shunt: correlation with hemodynamic findings.

BACKGROUND & AIMS: Transjugular intrahepatic portosystemic shunt (TIPS) procedures are increasingly being used, but the relationship between the hemodynamic effects of TIPS and the clinical events on follow-up remains undefined. Hence, we have investigated the hemodynamic correlations of portal hypertension-related events after a TIPS procedure. METHODS: Prospective follow-up of 122 cirrhotic patients who had a TIPS procedure performed because of variceal hemorrhage was conducted. RESULTS: The portacaval pressure gradient (PPG) significantly decreased after the TIPS procedure (from 19.7 +/- 4.6 to 8.6 +/- 2.7 mm Hg; P > 0.001), but increased thereafter and at rebleeding (n = 25) was > 12 mm Hg in all patients (18.4 +/- 4.6 mm Hg). Twenty-six patients developed ascites; the PPG (measured in 19) was always > 12 mm Hg. Increasing the PPG to > 12 mm Hg occurred very frequently (83% at 1 year). Within 1 year, 77% of patients underwent balloon angioplasty or restenting. However, 80% had again a PPG of > 12 mm Hg 1 year after reintervention. Hepatic encephalopathy developed in 31% of patients at 1 year; 21 of 23 patients had a PPG of < 12 mm Hg. CONCLUSIONS: Total protection from the risk of recurrent complications of portal hypertension after a TIPS procedure requires that the PPG be decreased and maintained < 12 mm Hg. However, reintervention will be required in most patients within 1 year and again the second year. On the other hand, such portal decompression is associated with an increased risk of hepatic encephalopathy.

Effects of F-180, a new selective vasoconstrictor peptide, compared with terlipressin and vasopressin on systemic and splanchnic hemodynamics in a rat model of portal hypertension.

The present study is aimed at characterizing the portal, splanchnic, and systemic circulatory effects of F-180, a new long-acting analog of vasopressin (VP) with selective effect on the vascular (V1) receptor, both in normal rats and in portal-hypertensive animals. In preliminary vasopressor tests, F-180 was 18 times more potent than terlipressin (TP) (164 +/- 10 IU x mmol(-1) vs. 9.2 +/- 1.2 IU x mmol(-1)) and four times less potent than arginine VP (614 +/- 25 IU x mmol(-1)). F-180 had negligible antidiuretic potency, resulting in vascular selectivity (V1/V2) of 858 compared with 1.0 for VP and 2.2 for TP. In portal-hypertensive rats with partial portal vein ligation (PPVL), the vasopressor effect of F-180 was 19 times that of TP on a molar basis (ED50 F-180: 0.54 vs. TP: 10.02 nmol x kg(-1)). At low doses (0.405 nmol x kg(-1)), F-180 significantly reduced portal pressure (PP) (-13.8% +/- 6.7%) and superior mesenteric artery blood flow (SMABF) (-25.6% +/- 4.5%), whereas TP at 8.10 nmol x kg(-1) was required to achieve comparable splanchnic effects; however, this dose caused a significantly greater increase in mean arterial pressure (MAP) than F-180 at 0.405 nmol x kg(-1) (28.2% +/- 2.7% vs. 8.9% +/- 2.7% at 20 minutes; P < .05). F-180 at 0.405 nmol x kg(-1) had effects on PP and SMABF similar to a 30-minute intravenous infusion of VP at 10 mU x kg(-1) in PPVL rats, but VP caused a significantly greater elevation in systemic vascular resistance (SVR) and MAP, and more pronounced reduction in cardiac index (P < .05).

Pentoxifylline reduces nephrotoxicity associated with cyclosporine in the rat by its rheological properties.

BACKGROUND: The goals of this study were to evaluate whether administration of pentoxifylline (POF) reduces the nephrotoxicity associated with cyclosporine (CsA) in the rat, and whether the effect of POF is related to its rheological properties. METHODS: Mean arterial pressure was measured by an intraarterial catheter. Glomerular filtration rate and renal plasma flow were determined by measuring inulin and para-aminohippurate clearances, after double-blind coadministration for 10 days of CsA (25 mg/kg/day) with either vehicle or POF (45 mg/kg every 12 hr). These results were compared with those obtained in control rats. Blood viscosity and erythrocyte deformability were also evaluated after treatment using a cone plate viscometer and a filtration method, respectively. RESULTS: No changes were observed in mean arterial pressure in both groups compared with controls. Glomerular filtration rate was significantly lower in CsA-treated rats (0.3+/-0.1 ml/min/100 g) than in control animals (0.6+/-0.1 ml/min/100 g, P<0.02). The coadministration of CsA with POF normalized the glomerular filtration rate (0.6+/-0.1 ml/min/100 g). A parallel decrease in renal plasma flow was observed in CsA-treated rats compared with controls (CsA+vehicle: 1.5+/-0.2 vs. control: 2.2+/-0.1 ml/min/100 g, P<0.02), this effect completely reversed by cotreatment with POF (3.1+/-0.2 ml/min/100 g). Blood viscosity was significantly higher in CsA-treated rats than in the control group (CsA+vehicle: 5.6+/-0.7 vs. control: 5.0+/-0.4 m x Pa x s, P<0.05). This effect was associated with a lower erythrocyte deformability (CsA+vehicle: 1.2+/-0.2 vs. control: 1.5+/-0.3 ml/min, P<0.05). These rheological abnormalities were normalized by coadministration with POF (blood viscosity: 4.9+/-0.7 m x Pa x s and erythrocyte deformability: 1.9+/-0.4 ml/min, P<0.05). CONCLUSIONS: Our results show that administration of POF prevents the nephrotoxicity associated with CsA. This beneficial effect could be related to its rheological properties.

Circulatory effects of graded diversion of portal blood flow to the systemic circulation in rats: role of nitric oxide.

Total portal-systemic shunting in normal animals is associated with splanchnic and systemic vasodilation, suggesting that vasodilation in cirrhosis may be facilitated by spontaneous shunts promoted by portal hypertension. However, the mechanism of this vasodilation is unknown. The aim is to study the acute effects of the graded diversion of portal blood flow to the systemic circulation in normal and portal hypertensive rats. Portal and systemic hemodynamics were measured in normal and portal hypertensive rats before and during graded portacaval diversion of portal blood flow, in basal conditions, and after nitric oxide inhibition. In portal hypertensive rats, graded portal flow diversion caused a rate-related decrease in portal pressure (from 15.3 +/- 0.6 to 11.2 +/- 0.7 mm hg at 6 mL x min(-1), P < .001) and a redistribution of portal-collateral blood flow from the spontaneous portal-systemic collaterals to the portacaval circuit, without changing total portal-systemic shunting. Graded portal diversion caused an immediate systemic vasodilation, with reduced peripheral resistance. This vasodilatory response was more pronounced in normal than in portal hypertensive rats (increase in cardiac index 23.6% +/- 2.8% vs. 8.5% +/- 4.9%, P < .02, fall in peripheral resistance -24.5% +/- 3.4% vs. -16.5% +/- 2.6%, P = .08), and was totally prevented by nitric oxide inhibition. The graded diversion of portal blood flow caused a flow-rate-related reduction in portal pressure and blood flow through spontaneous portal-systemic collaterals in portal hypertensive rats, and caused a nitric-oxide dependent systemic vasodilatory response, which was greater in normal than in portal hypertensive rats. These results suggest that portal-systemic shunting per se may contribute to the vasodilatation in portal hypertension.