Effect of oral propranolol on splanchnic oxygen uptake and haemodynamics in patients with cirrhosis

In order to elucidate the effect of beta-adrenergic blockade on liver metabolism and haemodynamics, splanchnic oxygen uptake, hepatic removal of indocyanine green (ICG) and splanchnic and systemic haemodynamics were studied in 13 patients with cirrhosis before and 1.5-2 h after an oral dose of 80 mg propranolol. All patients underwent hepatic vein catheterization and had a primed continuous intravenous infusion of ICG. Azygos vein catheterization was performed in six patients. Splanchnic (hepatic-intestinal) oxygen uptake (median control 68 ml/min vs. beta-blockade 56 ml/min, P less than 0.01), azygos venous oxygen saturation (76 vs. 67%, P less than 0.05), ICG clearance (263 vs. 226 ml/min, P less than 0.01), wedged-to-free hepatic vein pressure (16 vs. 13.5 mm Hg, P less than 0.01), hepatic blood flow (1.18 vs. 0.78 l/min, P less than 0.01), cardiac index (3.42 vs. 2.53 l/min . min 2, P less than 0.01), and heart rate (72 vs. 56 beats per min, P less than 0.01) decreased significantly after oral beta-blockade. The hepatic extraction ratio of ICG increased significantly (0.32 vs. 0.45, P less than 0.01), whereas estimated 'intrinsic' ICG clearance (289 vs. 300 ml/min, n.s.), arterial blood pressure, stroke volume, and systemic vascular resistance remained essentially unchanged. The results indicate that besides the well-known cardiovascular effects of propranolol, beta-adrenergic blockade may also reduce hepatic metabolic functions as evidenced by the significantly decreased splanchnic oxygen uptake. The raised hepatic extraction ratio of ICG may be caused by reduction in hepatic blood flow as well as in intrahepatic shunting.     

Influence of the degree of liver failure on systemic and splanchnic haemodynamics and on response to propranolol in patients with cirrhosis

Systemic and splanchnic haemodynamics were studied in patients with cirrhosis who had been classified in three groups (A, B, and C) according to the degree of liver failure (modified Pugh's classification). In patients of group A, cardiac index was significantly lower than that of group C and systemic vascular resistance was higher, but not significantly so, than that of patients with liver failure. Wedged hepatic venous pressure was significantly lower in the former group than in the latter. In patients in group B, corresponding values fell between those of groups A and C. Azygos blood flow averaged 0.477 +/- 0.242 l/min (mean +/- SD) in group A and it was significantly lower than in groups B and C (0.642 +/- 0.224 and 1.061 +/- 0.476 l/min, respectively). In the three groups, acute administration of propranolol induced statistically significant changes in systemic and splanchnic haemodynamics. In patients of group C but not of group B, the mean value of azygos blood flow after propranolol remained significantly higher than in group A. Moreover, the fraction of azygos blood flow to cardiac output decreased in groups A and B while slightly increased in group C. This study shows that in patients with cirrhosis, the degree of liver failure may be a determinant for the haemodynamic responses to drugs acting on portal hypertension.     

Effect of oral propranolol on circulating catecholamines in cirrhosis: relationship to severity of liver disease and splanchnic haemodynamics

Patients with cirrhosis, especially those with decompensated disease have enhanced sympathetic nervous activity. We have investigated the effect of a single oral dose of 80 mg propranolol on circulating catecholamines and related the effect to splanchnic and systemic haemodynamics in 22 patients with cirrhosis. Plasma noradrenaline (NA) was significantly above normal average (NA: 0.52 vs. 0.23 ng/ml, p less than 0.01) and increased with the severity of the liver disease (p less than 0.01). NA was negatively correlated with liver function as estimated by ICG clearance (r = -0.74, p less than 0.01). Azygos blood flow was increased (0.75 l/min) and positively related to plasma NA (r = 0.57, p = 0.05, n = 12). After propranolol intake, plasma NA increased from 0.52 to 0.59 ng/ml (p less than 0.01). This response was found in all Child-Turcotte classes (A: 0.37 to 0.43; B: 0.49 to 0.56; C: 0.78 to 0.88 ng/ml), and in patients with as well as without ascites. Plasma adrenaline increased in the same way (p less than 0.01). Hepatic blood flow (from 1.10 to 0.93 l/min, p less than 0.01) and azygos blood flow (from 0.75 to 0.55 l/min, n = 9, p less than 0.05) decreased significantly after oral propranolol. A borderline significant correlation was observed between the decrease in azygos blood flow and the increase in NA (r = 0.64, p = 0.06). Our results suggest that besides a relationship to liver function and severity of disease, sympathetic nervous activity, as reflected by circulating NA, will further enhance during beta-adrenergic blockade, probably by a compensatory mechanism.(ABSTRACT TRUNCATED AT 250 WORDS)     

Influence of ascites on splanchnic and systemic hemodynamics in patients with alcoholic cirrhosis

The effect of ascites on splanchnic and systemic hemodynamics was retrospectively studied in 256 patients with alcoholic cirrhosis. The patients were divided into 3 classes: no ascites, moderate ascites, and large ascites. They were also classed into 3 groups according to a modified Pugh classification (ascites was not taken into account). In patients without ascites, cardiac output was positively related to the severity of liver disease. This result was not found in patients with large ascites. Similarly, in patients with no or moderate ascites, the degree of portal hypertension estimated by the hepatic venous pressure gradient was associated with liver failure. In patients with large ascites, hepatic venous pressure gradient was higher than in patients without ascites but this relation was observed only in patients without liver failure. These results show that ascites reduces the relation between cardiac output and liver failure and increases the degree of portal hypertension but not cardiac output.     

Effects of glypressin on the splanchnic and systemic circulation in patients with cirrhosis

Although not demonstrated in patients with cirrhosis, it is generally claimed that administration of vasopressin in the form of triglycyl-lysine-vasopressin (glypressin) may prevent untoward systemic effects of this former hormone. The aim of this study was to assess the effects of intravenous administration of 2 mg of glypressin on splanchnic and systemic hemodynamics in 9 patients with cirrhosis under stable circulatory conditions. One hour after the injection, the following statistically significant changes were observed as compared to the baseline values (m +/- SEM): wedged hepatic venous pressure, -9 +/- 2 p. 100; hepatic venous pressure gradient, -16 +/- 3 p. 100; azygos blood flow, -24 +/- 6 p. 100; heart rate, -16 +/- 3 p. 100; cardiac index, -23 +/- 2 p. 100; systemic vascular resistances, +47 +/- 11 p. 100; wedged pulmonary arterial pressure, +44 +/- 15 p. 100. In conclusion, in patients with cirrhosis in a stable hemodynamic condition, intravenous administration of glypressin decreased portal venous pressure and blood flow into the superior portal systemic collateral circulation but did not prevent the untoward systemic hemodynamic effects of vasopressin.     

Non-invasive prediction of oesophageal varices in cirrhosis

Non-invasive predictors of varices in cirrhosis would reduce the need for screening endoscopies. Platelet count and spleen size have been shown to be useful parameters, in mixed groups of cirrhotics with different aetiologies. We evaluated this in two homogeneous groups with cirrhosis due to hepatitis C and alcohol. Non-invasive predictors appear promising in the former group, but less so in the latter group.     

Non-invasive predictors of the presence of large oesophageal varices in patients with cirrhosis

BACKGROUND/AIMS: The usual clinical practice is to screen all patients with established cirrhosis at the time of diagnosis by upper endoscopy for the presence of varices. Patients with large varices should be treated with non-selective beta blockers to reduce the incidence of first variceal bleeding. However, fewer than 50% of cirrhotic patients have varices at screening endoscopy and most have small sized varices, with a low risk of bleeding. The aim of the present study was to determine whether clinical or laboratory non-endoscopic parameters could predict the presence of large oesophageal varices. PATIENTS/METHODS: Seventeen variables considered relevant to the prevalence of oesophageal varices were tested in 184 patients with cirrhosis, who underwent screening endoscopy. Small varices were regarded as those which flatten with insufflation or slightly protrude into the lumen, while large varices are those which protrude into the lumen or touch each other. None of the patients was on beta blockers or other vasoactive drugs or had a history of variceal bleeding. RESULTS: Oesophageal varices were present in 92 patients (50%), and large varices in 33 patients (17.9%).Variables associated with the presence of large oesophageal varices on univariate analysis were the presence of ascites and splenomegaly either by clinical examination or by ultrasound (p < 0.01), the presence of spiders (p = 0.02), platelet count (p < 0.0001), and bilirubin (p = 0.01). Factors independently associated with the presence of large oesophageal varices on multivariate analysis were platelet count, size of spleen and presence of ascites by ultrasound. Using mean values as cut-off points, it is noteworthy that only five out of 39 patients (12.8%) with platelets > or = 18(x 10(9)/l), spleen length < or = 135 mm and no ascites had varices. Moreover, all these patients had small sized varices. On the other hand, 15 out of 18 patients (83.3%) with a platelet count < 118 x 10(9)/l, spleen length > 135 mm and ascites had varices. Moreover, five out of those 18 patients had large varices (28.3%). CONCLUSION: Thrombocytopenia, splenomegaly and ascites are independent predictors of large oesophageal varices in cirrhotic patients. We suggest that endoscopy could be avoided safely in cirrhotic patients with none of these predictive factors, as large varices are absent in this group of patients.     

Effects of alpha-adrenergic stimulation and beta-adrenergic blockade on azygos blood flow and splanchnic haemodynamics in patients with cirrhosis

The effects of beta-blockade with propranolol and of alpha-adrenergic stimulation with methoxamine, a powerful alpha-agonist, on azygos blood flow and on systemic and hepatic haemodynamics were investigated in 26 cirrhotic patients with portal hypertension. Beta-adrenergic blockade with propranolol (n = 12), evidenced by a significant reduction of heart rate (-17 +/- 1%, P less than 0.001) and cardiac index (-17 +/- 2%, P less than 0.001), caused a mild but significant decrease of hepatic venous pressure gradient (-10 +/- 2%, P less than 0.05) and a marked fall of azygos venous blood flow (-31 +/- 5%, P less than 0.05). Alpha-adrenergic stimulation with methoxamine (n = 14), manifested by a significant increase of mean arterial pressure (19 +/- 2%, P less than 0.001), mimicked the effects of propranolol on hepatic venous pressure gradient (-10 +/- 4%, P less than 0.05) and cardiac index (-11 +/- 2%, P less than 0.001). However, azygos blood flow was not significantly reduced by methoxamine (0.7 +/- 0.1 vs 0.6 +/- 0.1 l/min). On the contrary, hepatic blood flow was significantly reduced by methoxamine (-19 +/- 4%, P less than 0.01) but not by propranolol (-7 +/- 7%, ns). Similarly, in 8 patients who received methoxamine after being beta-blocked by propranolol, azygos blood flow, that was markedly reduced by beta-blockade, did not experience a further reduction but increased slightly by alpha-adrenergic stimulation, while hepatic blood flow, that was not reduced by propranolol, decreased significantly during the subsequent methoxamine infusion.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of meal induced splanchnic arterial vasodilatation on renal arterial haemodynamics in normal subjects and patients with cirrhosis

Aims—To investigate the relation between changesin splanchnic arterial haemodynamics and renal arterial haemodynamicsin controls and patients with cirrhosis.
Methods—Superior mesenteric artery pulsatilityindex (SMA-PI) and renal artery pulsatility index (R-PI) were measuredusing Doppler ultrasonography in 24 controls and 36 patients withcirrhosis. These measurements were repeated 30 minutes after ingestionof a liquid meal or placebo. Sixteen controls and 24 patients received the meal, and eight controls and 12 patients received placebo.
Results—In the fasting condition, patients withcirrhosis had a lower SMA-PI (p<0.01) and a greater R-PI (p<0.01)compared with controls. Placebo ingestion had no effect on splanchnicand renal haemodynamics. In contrast, ingestion of the meal caused anotable reduction in SMA-PI (p<0.01, p<0.01) and an increase in R-PI(p<0.01, p<0.01) in controls and patients with cirrhosis. The mealinduced haemodynamic change in SMA-PI was inversely correlated withthat in R-PI in controls (t=−0.42, p<0.05) and inpatients with cirrhosis (t=−0.29, p<0.05).
Conclusions—Results support the hypothesis thatrenal arterial vasoconstriction seen in patients with cirrhosis is oneof the kidney's homoeostatic responses to underfilling of thesplanchnic arterial circulation.

Keywords:cirrhosis; Doppler ultrasonography; pulsatilityindex; renal artery; superior mesenteric artery

     

Prediction of oesophageal varices in patients with compensated cirrhosis: A novel scoring system

Background and study aimsPatients with liver cirrhosis are recommended to undergo an evaluation of oesophageal varices to assess their risk of bleeding. Predicting the presence of oesophageal varices through non-invasive means may reduce the number of unnecessary endoscopies. This study was designed to develop a predictive model for varices in patients with Child-Pugh A liver cirrhosis.Patients and methodsRetrospective analysis was performed on 70 patients with compensated cirrhosis. Clinical and laboratory parameters Child-Pugh class and platelet count were assessed. Ultrasonographic characteristics of splenic axis and portal vein diameter were noted. The data were assessed by univariate analysis and a multivariate logistic regression analysis.ResultsWe found the prevalence of oesophageal varices in patients with child A liver cirrhosis to be 64.3%. Platelet count, splenic axis, portal vein diameter, platelet count/splenic axis ratio, portal vein congestive index, and renal resistive index were found to be significantly associated with the presence of oesophageal varices on univariate analysis. A platelet count of 100,000, platelet count/splenic axis ratio <900, renal resistive index ?0.68, and a portal vein congestive index of ?0.07 had the highest discriminating value, at which the number of true positive patients was highest and the number of false positive patients was lowest (50% and 3%, 63% and 13%, 41% and 0%, 57% and 1%, respectively). Multivariate analysis identified platelet count, platelet count/splenic axis ratio, renal resistive index, portal vein congestive index as independent factors for the presence of oesophageal varices.ConclusionOur data suggest that a new score system composed of some laboratory and ultrasonographic parameters may predict the presence of varices in patients with Child-Pugh A cirrhosis, and that the score system may help physicians to identify patients who would most likely benefit from screenings for oesophageal varices.     

Systemic haemodynamics, renal and platelet function during chronic propranolol administration in patients with compensated cirrhosis

Chronic propranolol administration is followed by some haemodynamic alterations, which may impair renal function. It has also been suggested that it may reduce platelet production of proaggregatory thromboxane (TX) A2. We therefore evaluated cardiac index (CI), systemic vascular resistance (SVR), creatinine clearance, daily sodium excretion under controlled sodium intake, platelet aggregation and platelet TXA2 production during whole blood clotting in eight patients with cirrhosis, portal hypertension and no ascites, before and after 3 months of propranolol administration. Liver function was also assessed by evaluating the galactose elimination capacity (GEC) and galactose clearance (Cgal). The expected, significant reduction of CI and increase of SVR was observed. Creatinine clearance and sodium balance were unchanged throughout the study. Furthermore, the renal prostaglandin system, as reflected by urinary prostaglandin E2 and TXB2 excretion, was also unaffected by the drug. No modification of platelet aggregation, platelet TXA2 production during whole blood clotting, GEC and Cgal was observed. We conclude that chronic propranolol administration is followed by alterations of CI and SVR, but it does not impair renal function and platelet aggregation in patients with cirrhosis, portal hypertension and no ascites. The maintenance of renal function during beta-adrenergic blockade is not due to an increased renal production of vasodilating prostaglandins.     

Comparative haemodynamic effects of betaxolol and propranolol in patients with cirrhosis

The acute effects of betaxolol (10 mg, intravenously), a new cardioselective beta-blocker, and propranolol (15 mg, intravenously) on splanchnic and systemic circulations were studied in two matched groups of six patients with portal hypertension due to cirrhosis. Similar decreases in hepatic venous pressure gradient and azygous blood flow--an estimation of superior portosystemic shunts--were observed after both drugs, whereas hepatic blood flow was not modified. The decreases in heart rate and cardiac index were also similar after betaxolol and propranolol. Both drugs induced a significant decrease in the fraction of cardiac output flowing through superior portosystemic shunts. These findings confirm that the marked effect of beta-adrenoceptor blocking agents on splanchnic circulation results both from the reduction in cardiac output and from a vasoconstriction of the portal vein territory, and demonstrate that this vasoconstriction of the portal vein area does not necessitate a beta 2-blocking activity of the drug. The similar efficiency of the two agents in decreasing the hyperkinetic circulation suggests that betaxolol merits further long-term study in the pharmacologic treatment of portal hypertension.     

Liver stiffness measurement selects patients with cirrhosis at risk of bearing large oesophageal varices

BACKGROUND/AIMS: Periodic endoscopic screening for oesophageal varices is recommended in patients with cirrhosis, but might be limited to a subgroup of patients if a simple non-invasive test was available to select those at risk of bleeding. METHODS: We studied in 165 patients with cirrhosis the relation between the presence of oesophageal varices assessed by endoscopy, and liver stiffness measurement by Fibroscan, a non-invasive parameter related to liver fibrosis. The results were compared to those of other parameters reflecting portal hypertension, splenic size, platelet count, and platelet count/spleen size ratio. RESULTS: Liver stiffness measurement was correlated to the grade of oesophageal varices (r = 0.6, p < 0.0001). AUROC values of liver stiffness measurement were 0.84 (95% CI: 0.78-0.90) for the presence of oesophageal varices and 0.83 (0.76-0.89) for varices grade > or = II. Liver stiffness measurement value < 19 kPa was highly predictive of the absence of oesophageal varices grade > or = II (Se: 84%, PPV: 47%, NPV: 93%). CONCLUSIONS: Liver stiffness measurement allows to predict the presence of large oesophageal varices in patients with cirrhosis, and may help to select patients for endoscopic screening.     

Changes of hepatic and systemic haemodynamics following somatostatin administration in patients with hepatitis B-related cirrhosis

Abstract Somatostatin has been used to effectively control acute variceal haemorrhage, with conjectured mechanisms on portal hypertension. We, therefore, evaluated the effects of somatostatin on hepatic and systemic haemodynamics in 15 patients with hepatitis B-related cirrhosis and portal hypertension. All patients received an intravenous, continuous infusion of somatostatin 250 μg/h, following a bolus injection of 250 μg. In systemic haemodynamics, the mean arterial pressure (MAP) increased ( P < 0.05), associated with a reflex bradycardia within 3 min following bolus injections, compared with basal values. The right atrial pressure, pulmonary capillary wedge pressure, inferior vena cava pressure, cardiac index, and systemic vascular resistance remained unaffected after drug infusion. In hepatic haemodynamics, the wedge hepatic vein pressure remained unchanged after drug administration. However, there was an increase in free hepatic vein pressure (FHVP; P < 0.05), and a trend toward a decrease in the hepatic vein pressure gradient (HVPG; P = 0.063), within 3 min after bolus injection. Furthermore, the hepatic blood flow decreased significantly at 10 and 30 min after somatostatin infusion ( P < 0.05). The effective sinusoidal perfusion assessed by indocyanine green infusion also decreased progressively at 10 min ( P = 0.057) and 30 min ( P < 0.05). We concluded that somatostatin, at the dose used in this study, caused a transient and bolus-related vasoconstrictive effect, resulting in increases in MAP and FHVP, a decrease in heart rate, and a trend toward lower HVPG. In addition, somatostatin reduced the hepatic blood flow and effective sinusoidal perfusion which may be hazardous to cirrhotic patients during variceal haemorrhage.