Scoring system for portal hypertension.
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Humans↗
Biomedical subjects
A Koshy
Publications and source records attributed to A Koshy.
Effects of haemorrhage and volume expansion on portal-systemic collateral vascular resistance in conscious portal hypertensive rats.
1. In order to study the acute effects of blood volume changes on the vascular resistance of portal-systemic collaterals (collateral vascular resistance), a model of total portal vein occlusion with 100% portal-systemic shunts was developed in the rat. In this model, we determined the haemodynamic effects of haemorrhage (1.8 ml/100 g body weight) or intravenous infusion of a volume expander (1.8 ml/100 g body weight). Cardiac output and regional blood flows were measured by the radioactive microsphere method. 2. Haemorrhage significantly reduced arterial pressure from 108 +/- 4 to 92 +/- 4 mmHg (mean +/- SEM), cardiac output from 56 +/- 4 to 24 +/- 2 ml min-1 100 g-1 body weight, portal pressure from 15.1 +/- 1.5 to 10.0 +/- 1.4 mmHg and portal tributary blood flow from 19.9 +/- 2.3 to 8.3 +/- 1.4 ml/min. Consequently, collateral vascular resistance significantly increased from 6.6 +/- 0.9 x 10(3) to 11.1 +/- 2.0 x 10(3) kPa 1(-1) s. 3. Volume expansion reduced arterial pressure from 98 +/- 3 to 90 +/- 3 mmHg, and significantly increased cardiac output from 43 +/- 3 to 55 +/- 3 ml min-1 100 g-1 body weight, portal pressure from 13.9 +/- 0.7 to 16.5 +/- 0.8 mmHg and portal tributary blood flow from 16.4 +/- 1.3 to 28.2 +/- 3.2 ml/min. Consequently, collateral vascular resistance significantly decreased from 7.0 +/- 0.5 x 10(3) to 4.9 +/- 0.4 x 10(3) kPa l-1 s. 4. This study shows that in rats with portal hypertension, portal-systemic collateral vascular resistance is modified by alterations in blood volume.
Animals↗
Heterogeneous hepatic venous pressures in patients with liver cancer.
We carried out hepatic vein catheterization in 73 patients with liver cancer, 52 with primary and 21 with metastatic cancer. A heterogeneous hepatic venous pressure gradient, defined as a difference of greater than 4 mmHg between the highest and lowest values of the pressure gradient in any patient, was found in 46% of the hepatocellular carcinoma cases and 43% of the metastatic cancers. Comparing the diagnostic efficacy of this phenomenon with an elevated alpha-fetoprotein, based on 500 randomly selected catheterizations, showed that the heterogeneous gradient was 46% sensitive and 99% specific for the diagnosis of hepatocellular carcinoma, while the alpha-fetoprotein was 67% sensitive and 99% specific. Positive and negative predictive values were 86 and 95%, respectively, for the heterogeneous gradient, and 83 and 97% for the alpha-fetoprotein. Its expense and relative invasiveness make hepatic vein catheterization an unacceptable routine in patients suspected of having hepatic malignancy. However, we suggest that the unexpected finding of a heterogeneous pressure gradient should trigger a search for hepatic cancer.
Adult↗
Combination of ketanserin and verapamil or propranolol in patients with alcoholic cirrhosis: search for an additive effect.
Drugs reported to reduce portal pressure through different mechanisms were combined in the hope of either additive portal hypotensive effects in "responders," or inducing a portal hypotensive effect in "nonresponders" to the initial drug. Seven patients with alcoholic cirrhosis received verapamil, 10 mg i.v., and, 60 min later, ketanserin, 5 mg i.v. Verapamil decreased heart rate and increased free hepatic venous pressure but had no effect on hepatic venous pressure gradient or azygos blood flow. When combined with verapamil, ketanserin significantly diminished wedged hepatic venous pressure and hepatic venous pressure gradient. Ten other patients with alcoholic cirrhosis received propranolol, 15 mg i.v., and 45 min later, ketanserin, 5 mg i.v. In all patients, heart rate, cardiac index and azygos blood flow significantly decreased after propranolol. After propranolol alone, however, wedged hepatic venous pressure decreased in only five patients, responders. In five other patients, defined as nonresponders, propranolol did not decrease this pressure. The addition of ketanserin to propranolol induced further significant reduction in wedged hepatic venous pressure, hepatic venous pressure gradient and azygos blood flow. Among the five nonresponders, three had a reduced wedged hepatic venous pressure after ketanserin was combined. We conclude that verapamil does not reduce portal pressure or collateral blood flow in patients with alcoholic cirrhosis. The splanchnic hemodynamic effects of propranolol and ketanserin appear to be independent and additive, without significant systemic alteration.
Drug Synergism↗
Discrepancy between portal pressure and systemic hemodynamic changes after incremental doses of propranolol in awake portal hypertensive rats.
The effects of increasing doses of propranolol were studied in awake portal hypertensive rats in order to elucidate the relative effects of the beta-blocker on systemic and splanchnic circulation. Hemodynamic responses to 0.1, 0.2 and 0.4 mg per min infusions of propranolol were compared with placebo in awake rats with portal hypertension due to portal vein stenosis. Heart rate significantly and progressively decreased from 356 +/- 13 to 293 +/- 10 beats per min (mean +/- S.E.). Cardiac output significantly decreased from 54 +/- 3 to 42 +/- 3 ml per min per 100 gm body weight at the highest dose. Significant decrease in portal tributary blood flow from 27 +/- 1 to 18 +/- 1 ml per min, at 0.4 mg per min dose, was due not only to the decrease in cardiac output but also to a significant increase in portal tributary vascular resistance from 269 +/- 17 to 368 +/- 31 dyne per sec per cm5 x 10(3). However, portal pressure showed only an insignificant decrease from 14.9 +/- 1.1 to 14.1 +/- 1.4 mmHg. The reduction in portal pressure being minimal, in spite of a significant decrease in portal tributary blood flow, is explained by an increase in combined hepatic and collateral resistance from 44 +/- 2 to 66 +/- 4 dyne per sec per cm5 x 10(3), p less than 0.05, at 0.4 mg per min dose. We conclude that the systemic and splanchnic effects of propranolol show discrepancy at two levels.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Effects of oxygen inhalation on tissue oxygenation in patients with cirrhosis. Evidence for an impaired arterial baroreflex control.
In patients with cirrhosis, O2 uptake, i.e., O2 consumption, is abnormally decreased. We administered 50% O2 for 30 min in eight patients with alcoholic cirrhosis to determine whether the subsequent increase in arterial O2 content may correct the low O2 consumption. In addition, we studied in these patients the reflex control of cardiac output and blood pressure by arterial baroreceptors, as O2 inhalation induces a systemic vasoconstriction. Arterial O2 tension, oxyhaemoglobin saturation and arterial O2 content significantly increased as well as systemic vascular resistance and arterial pressure. In contrast, O2 consumption (which was below normal values) under basal conditions, O2 transport, O2 extraction ratio, heart rate, right atrial and pulmonary wedged pressures, cardiac output, hepatic venous pressures, hepatic and azygos blood flows were unaffected by O2 administration. In three patients receiving air, no significant change was observed. Our results show that, in patients with cirrhosis, inhalation of 50% O2 does not correct O2 consumption. We may conclude that reflex control of cardiac output and arterial pressure by arterial baroreceptors is impaired in these patients.
Blood Pressure↗
Reduction of portal pressure by acute administration of furosemide in patients with alcoholic cirrhosis.
In patients with cirrhosis, it has been demonstrated that blood volume and degree of portal hypertension are correlated. Hence, a reduction of blood volume by furosemide could decrease portal pressure and could thereby be useful in the treatment of portal hypertension. Splanchnic and systemic haemodynamics were evaluated before and 1 h after intravenous administration of furosemide (0.75 mg/kg) in 10 patients with cirrhosis. Furosemide significantly increased haemoglobin from 12.4 to 13.0 g/dl and patients passed more than 1 l of urine within the 3 h following furosemide administration. These findings confirm that blood volume decreased after diuretic administration. Cardiac output significantly decreased from 6.6 +/- 2.3 to 5.5 +/- 2.2 l/min, while arterial pressure and heart rate did not change significantly. Furosemide significantly decreased wedged hepatic venous pressure from 31.1 +/- 6.2 to 27.7 +/- 5.2 mmHg, but not free hepatic venous pressure. Accordingly, the hepatic venous pressure gradient significantly decreased from 22.1 +/- 5.4 to 19.5 +/- 4.0 mmHg. Azygos blood flow and hepatic blood flow also significantly decreased from 0.40 +/- 0.17 to 0.31 +/- 0.13 l/min and from 1.49 +/- 0.50 to 0.82 +/- 0.30 l/min, respectively. These results show that diuretic therapy markedly influences splanchnic haemodynamics.
Adult↗
Effects of glucagon on systemic and splanchnic circulation in conscious rats with biliary cirrhosis.
To elucidate the relationship between the haemodynamic changes and glucagon in cirrhosis, we infused physiologic and supraphysiologic doses of this hormone in conscious rats with portal hypertension due to biliary cirrhosis. Cardiac output and splanchnic organ blood flows were measured by the radioactive microsphere method before and 30 min after glucagon infusion at doses of 2, 5 and 10 ng/min. Serum glucagon increased from a basal level of 92 +/- 17 pg/ml (mean +/- S.E.) to 399 +/- 89, 1151 +/- 136 and 2064 +/- 328 pg/ml, respectively, in sham-operated rats, and from 743 +/- 75 pg/ml to 1497 +/- 197, 1583 +/- 356 and 2957 +/- 649 pg/ml, respectively, in cirrhotic animals at 2, 5 and 10 ng/min doses. In both groups, cardiac output did not change after glucagon infusion at 2 and 5 ng/min doses, suggesting that factors other than glucagon are primarily responsible for the systemic hyperdynamic circulation in cirrhosis. Portal tributary blood flow increased significantly after glucagon infusion in sham-operated rats by 34 and 65% at doses of 5 ng/ml and 10 ng/ml, respectively, and in cirrhotic rats by 29% at a dose of 10 ng/ml. However, portal tributary blood flow did not change after glucagon infusion at the physiologic dose of 2 ng/min. This study shows that glucagon infused at a physiologic dose does not increase splanchnic blood flow, although it increases portal tributary blood flow at supraphysiologic doses. The discrepancy between blood glucagon levels and splanchnic haemodynamic responses suggests that glucagon plays only a minor role and that other factors are primarily responsible for the hyperdynamic state of the splanchnic circulation in rats with biliary cirrhosis.
Animals↗
Somatostatin analogue improves survival in conscious cirrhotic rats subjected to gastrointestinal bleeding.
1. The continuing doubt concerning the value of vasoconstrictive therapy for gastrointestinal bleeding may be related to the complexity of clinical trials in such a situation. 2. The effect of SM 201-995, a somatostatin analogue, was investigated in conscious cirrhotic rats before, during and after experimental bleeding from the portal territory. 3. Before haemorrhage, somatostatin analogue (8 micrograms h-1 kg-1 body weight, intravenously) produced a significant decrease in portal pressure (17%), whereas a placebo (saline) lacked significant effect. 4. The rats were then subjected to spontaneous bleeding, by disconnection of the portal catheter from the pressure gauge, for a 5 min period. At the end of the haemorrhage, haemodynamic parameters did not significantly differ between the group receiving somatostatin analogue and that receiving placebo. 5. Fifteen minutes after the end of the bleeding period, portal pressure was significantly lower in rats receiving somatostatin analogue [8.5 +/- 0.5 mmHg (1.13 +/- 0.07 kPa), mean +/- SEM] than in rats receiving placebo [11.0 +/- 1.1 mmHg (1.50 +/- 0.15 kPa)]. 6. The volume of blood lost and mortality were significantly lower in the group treated with somatostatin analogue (2.3 +/- 0.1 ml/100 g body weight and 8%, respectively) than in the group receiving placebo (3.0 +/- 0.1 ml/100 g body weight and 50%, respectively). 7. These results demonstrate, in an experimental model, the beneficial effect of somatostatin analogue for the treatment of gastrointestinal bleeding due to portal hypertension. They suggest that administration of this substance should be started as soon as possible after the beginning of haemorrhage and continued after the cessation of bleeding.
Animals↗
How to develop leadership in others.
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Humans↗
Circulatory effects of somatostatin analogue in two conscious rat models of portal hypertension.
A somatostatin analogue, a long-acting octapeptide (SMS 201-995), has been reported to decrease portal pressure, but the mechanism is unclear. To elucidate the effects of this drug on both systemic and splanchnic hemodynamics, it was administered in two conscious rat models of portal hypertension. The dose-response curves showed that the somatostatin analogue significantly decreased portal pressure at a lower dose in rats with cirrhosis than in portal vein-stenosed rats. Calculated ED50 values were significantly different among all groups. Intravenous infusion of 8 micrograms/kg body wt.h of somatostatin analogue significantly decreased cardiac output by approximately 20% in both groups of portal hypertensive rats and increased mean arterial pressure by 7%. Accordingly, systemic vascular resistance markedly increased, indicating vasoconstrictor effects of this drug. The somatostatin analogue also significantly decreased portal tributary blood flow by 18% in portal vein-stenosed rats and 27% in cirrhotic rats. In sham-operated rats, somatostatin analogue had no effect on the systemic or splanchnic circulation. This study shows that somatostatin analogue decreases portal pressure principally by reducing portal tributary blood flow. This reduction may be due to either a direct vasoconstrictive effect or diminution in vasoactive hormone release.
Animals↗
Model for the study of portal-systemic collateral vascular resistance in the conscious rat.
In order to obtain a model for the study of portal-systemic collateral vascular resistance, total portal vein occlusion was performed in rats 48 hr or 3 wk after partial obstruction. Four groups of conscious restrained rats were studied: a) sham-operated, b) partial portal vein ligated, c) 48 hr-total portal vein occluded, and d) 3 wk-total portal vein occluded. In comparison with the sham group, the three portal vein ligated groups had significantly higher cardiac output, portal tributary blood flow, portal pressure (7.7 +/- 0.4 versus 13.5 +/- 0.5, 13.6 +/- 0.8, and 17.7 +/- 1.1 mmHg, mean +/- SE, respectively) and hepatic arterial blood flow (5.8 +/- 0.6 versus 9.5 +/- 0.7, 8.3 +/- 0.5, and 13.9 +/- 1.9 ml/min, respectively). Cardiac output and portal tributary blood flow did not differ between the portal vein ligated groups, but portal pressure and hepatic arterial blood flow were significantly higher in the 3 wk-total portal vein occlusion group. The 3 wk-total portal vein occlusion group showed 99.1 +/- 0.3% shunting, different from the partial (29.7 +/- 16.9%, p less than 0.01) and 48 hr-total portal vein occlusion (46.5 +/- 14.7%, p less than 0.05) groups. Portography confirmed absence of portal-portal collaterals in the 3 wk-total portal vein occlusion group. It is suggested that rats with 3 wk-total portal vein occlusion are useful for the study of acute modifications of portal-systemic collateral circulation, as shunting is total and consistent in this model.
Animals↗
Regional blood flows by the microsphere method: reproducibility in portal hypertensive rats and influence of a portal vein catheter.
To determine the reproducibility of splanchnic blood flow measurements by the microsphere method in rats with portal hypertension and the effects of laparotomy with portal vein cannulation, eight groups of 10 rats were studied. Cardiac output and regional blood flows were measured twice, 10 min apart, in pentobarbital anesthetized or awake, sham-operated or portal vein-ligated rats, with or without portal cannulation. Variability between the two successive measurements was not affected by portal hypertension or portal cannulation, and was not different in the splanchnic territory and in other organs. Laparotomy with portal cannulation had no significant effect in sham-operated rats. In awake portal hypertensive rats, cardiac output (53.9 +/- 3.0 vs 45.8 +/- 2.9 ml.min-1.100 g body wt-1, P less than 0.01) and splanchnic blood flow (12.31 +/- 0.72 vs 9.34 +/- 0.85 ml.min-1.100 g body wt-1, P less than 0.01) were lower in portal vein cannulated rats compared with those of non-cannulated animals. In anesthetized portal hypertensive rats blood flows were unaffected by portal cannulation, but arterial pressure (100.2 +/- 4.3 vs 119.9 +/- 3.4 mm Hg, P less than 0.01) and heart rate (366.5 +/- 10.0 vs 405.5 +/- 7.4 beats.min-1, P less than 0.01) were elevated. Anesthesia also decreased portal pressure (14.8 +/- 0.5 vs 12.0 +/- 0.4 mm Hg, P less than 0.05) in portal hypertensive rats. We conclude that the microsphere method remains reproducible in portal hypertensive rat models. Laparotomy with portal cannulation can alter systemic and splanchnic hemodynamics in portal hypertensive rats; these effects can also be changed during pentobarbital anesthesia. Regional blood flow measurements in portal hypertensive rats should be performed in animals without portal cannulation and preferably in the awake state.
Animals↗
Retrograde filling of the right main hepatic vein on percutaneous splenoportography.
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Child↗
Possible deleterious hemodynamic effect of nifedipine on portal hypertension in patients with cirrhosis.
The acute effects of nifedipine, 10 mg administered sublingually, were studied in 10 patients with alcoholic cirrhosis. Nifedipine significantly increased cardiac output and reduced systemic vascular resistance. Nifedipine also increased the hepatic venous pressure gradient by 15% (P less than 0.01). Hepatic blood flow and azygos blood flow did not change significantly. It is suggested that nifedipine increases portal pressure and thus may be deleterious to patients with portal hypertension.
Blood Pressure↗
Functional characterization of platelet-bound factor XIa: retention of factor XIa activity on the platelet surface.
Previously we have shown that both factor XI and factor XIa are bound specifically to distinct, high-affinity sites on the surface of activated platelets in the presence of high Mr kininogen. To determine the functional significance of factor XIa binding to platelets, bound factor XIa has now been compared with the unbound enzyme. Platelets incubated with thrombin, high Mr kininogen, and 125I-labeled factor XIa bound 130 to 500 molecules of factor XIa per platelet. Scatchard analysis of binding data give a dissociation constant (Kd) of 822 pmol/L +/- 140 (SEM). Rates of factor IX activation, assayed by release of trichloroacetic acid-soluble 3H-labeled activation peptide from purified [3H]-factor IX, were similar when factor XIa was bound to platelets and when it was free in solution. The platelet-bound factor XIa was isolated by centrifugation through 20% sucrose and was functionally characterized both in a factor XIa coagulation assay and in the factor IX activation peptide release assay in comparison with unbound factor XIa in the presence of treated platelets. The functional activity of platelet-bound factor XIa as a factor IX activator as well as its structural integrity were shown to be fully retained on the platelet surface. Since platelets bind factor XI and promote its proteolytic activation to factor XIa, factor XIa binding to platelets may serve to localize factor IX activation to the hemostatic plug, where factor XIa is protected from inactivation by plasma protease inhibitors and where acceleration of subsequent coagulation reactions can occur.
Binding Sites↗
Blood counts in portal hypertension of non-cirrhotic origin: correlation with splenic size and splenic pulp pressure.
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Adolescent↗
Functional characterization of human blood coagulation factor XIa using hybridoma antibodies.
During the initiation of intrinsic coagulation factors XI and XIa interact intimately with several other coagulation proteins (factor XIIa, high Mr kininogen, and factor IX) as well as with the platelet surface. To help elucidate these complex intramolecular interactions, we have prepared a collection of monoclonal antibodies directed against various epitopes in factor XI. We have utilized these reagents to isolate factor XI and the light chain of factor XIa on affinity columns, and to probe structure-function relationships involved in the interactions of factor XIa with factor IX. The isolated light chain of factor XIa retained greater than 90% of its amidolytic activity against the oligopeptide substrate pyro-Glu-Pro-Arg-pNA (S-2366), but only 3.8% of its clotting activity in a factor XIa assay and 1% of its factor IX activating activity in an activation peptide release assay. This suggests that regions of the heavy chain are required for development of coagulant activity and specifically for the interaction of factor XIa with factor IX. To test this hypothesis, the effects of three of the monoclonal antibodies (5F4, 1F1, and 3C1) on the function of factor XIa were examined. The results show that in a clotting assay the light chain-specific antibody (5F4) inhibits 100% of the factor XIa activity, whereas of the heavy chain-specific antibodies, one (3C1) inhibits 75% and another (1F1) only 17%. Similarly in the factor IX activation peptide release assay, antibody 5F4 inhibits 100% of the factor XIa activity, whereas 3C1 inhibits 75% and 1F1 inhibits 33%. We conclude that regions located in the heavy chain, in addition to those in the light chain, are involved in the interaction of factor XIa with factor IX and in the expression of the coagulant activity of factor XI.
Antibodies, Monoclonal↗