Hypoxemia in patients with cirrhosis: relationship with liver failure and hemodynamic alterations.

BACKGROUND/AIMS: The relationship between hypoxemia, liver failure and the hemodynamic alterations in cirrhosis are unknown. This study examined the relationship between arterial hypoxemia, the severity of liver disease and hyperkinetic circulation in patients with cirrhosis. METHODS: Arterial blood gases, the severity of cirrhosis (Child-Pugh score), and splanchnic and systemic hemodynamics were measured in 120 patients with cirrhosis and without cardiopulmonary disease. Hypoxemia was considered to be present when PaO2 was < or = 70 mmHg. RESULTS: Seventeen patients had hypoxemia (14%). Hypoxemic patients had significantly lower pulmonary vascular resistance and a significantly higher alveolar-arterial oxygen gradient, Child-Pugh score and hepatic venous pressure gradient than non-hypoxemic patients. Cardiac index and right atrial and pulmonary pressures did not significantly differ between the two groups. CONCLUSIONS: Hypoxemia occurs mainly in patients with severe liver disease and is associated with pulmonary vasodilation.

Relationship between portal pressure, esophageal varices, and variceal bleeding on the basis of the stage and cause of cirrhosis.

BACKGROUND AND METHODS: Hepatic venous pressure gradient, esophageal varices, and variceal bleeding were investigated in 957 patients with cirrhosis. The causes (alcoholic/virus) and stage (Child-Pugh's classification) of cirrhosis were also taken into account. RESULTS: The prevalence of variceal bleeding was 35% in patients with large varices and 17% in those with small varices (P < 0.05). It was higher in patients with alcoholic cirrhosis (41% and 19%, respectively) than in those with viral cirrhosis (22% and 10%, respectively). In patients with alcoholic cirrhosis the hepatic venous pressure gradient was higher in Child A and B patients with small or large varices than in those with no varices; these differences were not found in Child C patients and in patients with viral cirrhosis. In all subgroups the pressure gradient was higher in Child C patients than in Child A patients. There was no significant difference in the hepatic venous pressure gradient between patients with varices and previous variceal bleeding and those with no bleeding whatever the stage of cirrhosis. CONCLUSIONS: This study shows that the hepatic venous pressure gradient is associated with the stage and causes of cirrhosis and the presence of varices. These factors should be taken into account in studies evaluating the hepatic venous pressure gradient in heterogeneous groups of patients.

Natriuretic response to the combination of atrial natriuretic peptide and terlipressin in patients with cirrhosis and refractory ascites.

BACKGROUND/AIMS: Refractory ascites, which occurs in certain patients with cirrhosis, is associated with a blunted natriuretic response to exogenous atrial natriuretic peptide (ANP). Since this blunting seems to be related to ANP-induced arterial hypotension, a vasoconstrictor, such as terlipressin (a vasopressin analogue), may restore natriuresis to exogenous ANP. Moreover, since cirrhosis-elicited vasodilation is thought to play a role in sodium retention, a vasoconstriction caused by terlipressin alone may lead to an increase in sodium excretion. This study aimed to evaluate the natriuretic response to either a combination of ANP with terlipressin or terlipressin alone in patients with cirrhosis and refractory ascites. METHODS: Sixteen consecutive patients with cirrhosis and refractory ascites were randomly assigned to receive either a combination of terlipressin (1-2 mg, i.v. bolus) with ANP (35 ng/kg, i.v. bolus followed by 15 ng x kg(-1) x min(-1) for 60 min) (n=8) or terlipressin alone (1-2 mg, i.v. bolus) (n=8). Sodium excretion and urine output, systemic, splanchnic and renal hemodynamics and renal oxygen consumption were measured before and during treatments. RESULTS: Combined therapy did not change arterial pressure but significantly increased urinary sodium excretion and urine output. These effects were associated with a significant increase in glomerular filtration rate and a decrease in renal oxygen consumption. Terlipressin alone significantly increased arterial pressure but did not change urinary sodium excretion or urine output. Moreover, terlipressin did not change either glomerular filtration rate or renal oxygen consumption. CONCLUSIONS: The combination of exogenous ANP with terlipressin, but not terlipressin alone, increases sodium excretion in patients with cirrhosis and refractory ascites.

Acute effects of propylthiouracil on hemodynamics and oxygen content in patients with alcoholic cirrhosis.

BACKGROUND/AIMS: The antithyroid drug propylthiouracil has been suggested for the treatment of alcoholic liver disease. Its beneficial effects could be due to either a decrease in hepatic oxygen consumption or an increase in hepatic blood flow. The aim of this study was to test these two hypotheses in patients with proven alcoholic cirrhosis. METHODS: The pharmacokinetic parameters after intravenous administration of 300 mg of propylthiouracyl were first determined in four patients. Then, the effects on systemic and splanchnic hemodynamics, and oxygen content were measured 45 and 90 min after the intravenous administration of 300 mg (n=6) or 600 mg (n=6) of propylthiouracil. RESULTS: Systemic hemodynamics (heart rate, arterial pressure, cardiac output and systemic vascular resistance) and splanchnic hemodynamics (hepatic venous pressure gradient, hepatic and azygos blood flows) were not modified 45 and 90 min after the administration of 300 mg or 600 mg of propylthiouracil. Moreover, neither oxygen content in the radial artery, pulmonary artery or hepatic vein, nor systemic oxygen uptake was modified after propylthiouracyl administration. The absence of effect of propylthiouracyl administration was also confirmed in patients with cirrhosis with proven acute alcoholic hepatitis (n=7). CONCLUSIONS: In patients with alcoholic cirrhosis, acute administration of propylthiouracyl has no effect on systemic and splanchnic hemodynamics or on oxygen contents. The presence of acute alcoholic hepatitis does not modify these results.

Plasma concentrations of cyclic 3', 5'-guanosine monophosphate in patients with cirrhosis: relationship with atrial natriuretic peptide and haemodynamics.

Little is known about the plasma concentrations of cyclic 3',5'-guanosine monophosphate (cGMP) in patients with cirrhosis. However, plasma cGMP concentrations provide information on cellular cGMP production by particulate guanylyl cyclases (which are stimulated by natriuretic peptides, such as atrial natriuretic peptide; ANP). In contrast, because intracellular cGMP elicits vasorelaxant mechanisms, plasma cGMP concentrations may be related to haemodynamic alterations in patients with cirrhosis. The aim of the present study was to measure plasma cGMP concentrations in patients with cirrhosis and controls and to examine the relationship between cGMP levels and plasma ANP concentrations and haemodynamic values. Plasma concentrations of cGMP and ANP and splanchnic and systemic haemodynamics were measured in 23 subjects; 13 subjects had cirrhosis and 10 were controls. All subjects had normal glomerular filtration. Plasma cGMP concentrations were significantly higher in patients (6.5 +/- 0.8 pmol/mL) than in controls (2.7 +/- 0.4 pmol/mL), while plasma ANP concentrations did not significantly differ between the two groups (127 +/- 22 and 123 +/- 27 pg/mL, respectively). In patients with cirrhosis, no significant correlation was found between plasma cGMP concentrations and plasma ANP concentrations, hepatic venous pressure gradient, cardiac output or systemic vascular resistance. In conclusion, in patients with cirrhosis, increased plasma cGMP concentrations may be due to an activation of particulate guanylyl cyclases by natriuretic peptides other than ANP. The present study suggest that plasma cGMP concentrations are not related to cirrhosis-induced haemodynamic alterations.

Relationship between hepatic blood flow, liver tests, haemodynamic values and clinical characteristics in patients with chronic liver disease.

Although hepatic blood flow (HBF) has been measured in patients with liver disease for many years, the results of these studies have not provided clear information concerning the usefulness of this measurement. Hepatic blood flow was measured in 392 patients with either cirrhosis (n = 356) or hepatic fibrosis (n = 36). The control group included 59 subjects with normal liver architecture. Hepatic clearance of indocyanine green (ICG) was markedly reduced in patients with cirrhosis and hepatic fibrosis compared with controls (182 +/- 5, 276 +/- 22 and 421 +/- 25 mL/min, respectively). In patients with cirrhosis, ICG clearance and extraction were significantly correlated, but were not correlated to HBF. Although HBF did not differ between patients with cirrhosis and controls (1.26 +/- 0.04 vs 1.35 +/- 0.07 L/min, respectively), patients with hepatic fibrosis had lower HBF (1.04 +/- 0.07 L/min; P < 0.05). In patients with cirrhosis, no correlation was observed between HBF and cardiac output, mean arterial pressure, azygos blood flow, the hepatic venous pressure gradient or Pugh's score. However, a significant difference in HBF was observed in patients with and without hepatic encephalopathy (1.00 +/- 0.09 vs 1.28 +/- 0.03 L/min, respectively; P < 0.05). In conclusion, the present study shows that, in patients with cirrhosis, HBF is normal and is not related to other haemodynamic values or liver tests. These results discourage the measurement of HBF in the evaluation of patients with cirrhosis.

[Influence of anemia on hemodynamic changes in patients with cirrhosis]. / Influence de l'anémie sur les modifications hémodynamiques des malades atteints de cirrhose.

OBJECTIVE: The aim of this retrospective study was to evaluate the systemic and splanchnic hemodynamic changes induced by anemia in patients with cirrhosis. METHOD: 148 patients (Child-Pugh A: 46 patients, Child-Pugh B: 64 patients and Child-Pugh C: 38 patients) were included in the study. Anemia was defined by a blood hemoglobin level < 12 g/dL. A systemic and splanchnic hemodynamic study was performed in all patients. RESULTS: A significant elevation of the hepatic venous pressure gradient was observed in Child-Pugh A patients with anemia but not in Child-Pugh B and C patients. In the 2 latter groups, cardiac index was significantly increased and systemic vascular resistance decreased in patients with anemia. CONCLUSION: Anemia may worsen the hemodynamic changes associated with cirrhosis.

Systemic and splanchnic hemodynamic changes in patients with hepatic schistosomiasis.

Although hepatic schistosomiasis is a common cause of portal hypertension, only a few hemodynamic studies, in humans, have been published on this subject. The aim of this study was to determine the systemic and splanchnic hemodynamic changes in hepatic schistosomiasis and to evaluate the influence of liver fibrosis on these changes. A retrospective analysis of a series of 13 patients with hepatic schistosomiasis who had undergone hemodynamic studies was performed. Portal or perisinusoidal fibrosis was present at liver biopsy in 8 patients. The control group included 22 patients with chronic hepatitis and normal hepatic venous pressure gradients. Patients with schistosomiasis exhibited high cardiac index (4.11 +/- 1.15 l.min-1.m-2 vs 2.99 +/- 0.85 l.min-1.m-2; p < 0.05) and low systemic vascular resistance (1039 +/- 316 dyn.s.cm-5 vs 1334 +/- 336 dyn.s.cm-5; p < 0.05). The hepatic venous pressure gradient and hepatic blood flow were normal. Azygos blood flow was markedly increased (0.90 +/- 0.66 l.min-1 vs 0.13 +/- 0.04 l.min-1; p < 0.05). Hemodynamic values were not significantly different between patients with liver fibrosis and those without fibrosis at liver biopsy. In conclusion, patients with hepatic schistosomiasis had a hyperkinetic systemic and splanchnic circulation. In patients with esophageal varices, a normal hepatic venous pressure gradient confirmed presinusoidal portal hypertension. The presence of portal or perisinuoidal fibrosis did not influence hyperdynamic splanchnic state.

Hemodynamic and metabolic effects of terlipressin in patients with cirrhosis receiving a nonselective beta-blocker.

Terlipressin (Glypressin), a vasopressin analog, may be administered to patients with cirrhosis receiving a beta-adrenergic antagonist. Since terlipressin alone and beta-blockers alone both decrease portal pressure, a combination of these substances may have additional portal hypotensive effects. However, the negative side effects of terlipressin may be accentuated by long-term beta-blockade. Thus, the present study examined hemodynamic and metabolic responses to terlipressin in 12 patients receiving nonselective beta-blockers (propranolol or nadolol). Hemodynamics and oxygen (O2) -derived variables were measured prior to and 30 min after the administration (intravenous bolus) of terlipressin (1 to 2 mg, according to body weight). The hepatic venous pressure gradient and azygos blood flow significantly decreased (from 15.3 +/- 1.1 to 12.5 +/- 1.1 mm Hg, and from 0.6 +/- 0.1 to 0.5 +/- 0.1 liters/min, respectively). Arterial and pulmonary wedged pressures significantly increased. Heart rate, cardiac index, and O2 consumption were not significantly affected by terlipressin. In conclusion, in patients with cirrhosis being treated with a nonselective beta-blocker, terlipressin administration decreased portal pressure. Moreover, terlipressin induced only mild systemic hemodynamic effects in these patients. These results suggest that terlipressin can be administered in patients receiving a beta-adrenergic blocker.

Role of sympathetic cardiovascular tone in control of arterial pressure in rats with cirrhosis.

Although an increase in sympathetic nervous activity has been recognized in cirrhosis, the contribution of this overactivity to the regulation of arterial pressure is unknown. The arterial pressure response to increasing doses of hexamethonium (0.05 to 3.2 mg.kg-1.min-1), a ganglionic blocker that decreases sympathetic cardiovascular tone, was explored in normal rats and in two models of portal hypertension, i.e., rats with cirrhosis and rats with portal vein stenosis. Changes in plasma norepinephrine concentrations were greater in rats with cirrhosis (356 +/- 50 vs 166 +/- 30 pg/ml, p = 0.04) than in normal rats (186 +/- 23 vs 86 +/- 31 pg/ml, p = 0.06) and rats with portal vein stenosis (103 +/- 37 vs 93 +/- 5 pg/ml, p = 0.10). The maximum decrease in arterial pressure was obtained at a dose of 1.6 mg.kg-1.min-1 in each group. However, the decrease in arterial pressure was significantly greater in rats with cirrhosis (-25 +/- 2%) than in normal rats (-11 +/- 1%) and in rats with portal vein stenosis (-13 +/- 2%) (p = 0.04). In conclusion, the results of this study suggest that the sympathetic cardiovascular tone is more important for the maintenance of arterial pressure in rats with cirrhosis than in normal rats and in rats with portal vein stenosis.

Acute haemodynamic responses and inhibition of tumour necrosis factor-alpha by pentoxifylline in rats with cirrhosis.

1. Although pentoxifylline has been shown to reduce portal hypertension, the mechanism for this is unclear. Since pentoxifylline decreases tumour necrosis factor-alpha production and since this cytokine may induce vasodilatation per se, a pentoxifylline-induced decrease in tumour necrosis factor-alpha production may limit arterial vasodilatation and decrease portal pressure. The aim of the present study was to examine the effects of pentoxifylline administration on plasma tumour necrosis factor-alpha concentration and haemodynamics in normal and cirrhotic rats. 2. In both groups, systemic and splanchnic haemodynamics and plasma tumour necrosis factor-alpha concentrations were measured before and 120 min after the administration of saline or pentoxifylline (20 mg/kg intravenous bolus). 3. In cirrhotic rats, pentoxifylline significantly decreased portal pressure (24 +/- 13%) and tributary blood flow (33 +/- 30%). On the other hand, pentoxifylline significantly increased vascular resistance in portal and hepatic arterial territories. Systemic haemodynamics were not altered. In normal rats, pentoxifylline significantly decreased portal pressure but induced no other significant changes in splanchnic or systemic haemodynamics. In cirrhotic rats, plasma tumour necrosis factor-alpha concentrations were significantly reduced after pentoxifylline administration but not after saline administration. No significant correlations were found between pentoxifylline-induced changes in tumour necrosis factor-alpha levels and changes in splanchnic haemodynamics. In normal rats, plasma tumour necrosis factor-alpha concentrations significantly decreased after pentoxifylline or saline administration. 4. This study shows that in rats with cirrhosis, pentoxifylline induces a decrease in both portal pressure and plasma tumour necrosis factor-alpha concentrations. These reductions were not correlated however.

Role of pentobarbitone anaesthesia and sympathetic tone in the haemodynamic effects of isosorbide dinitrate in rats with cirrhosis.

The haemodynamic effects of nitrovasodilators and their mechanisms of action on portal hypertension remain unclear. The splanchnic and systemic haemodynamic response to the infusion of isosorbide dinitrate (100 micrograms/kg per min), a nitrovasodilator, was investigated in cirrhotic rats. The role of the conscious state in the haemodynamic response to isosorbide dinitrate was examined using rats that were anaesthetized with pentobarbitone. The role of sympathetic tone in the haemodynamic response to isosorbide dinitrate was examined using rats pretreated with the ganglion blocker hexamethonium. Isosorbide dinitrate had no haemodynamic effects in conscious, unblocked normal and cirrhotic rats. Isosorbide dinitrate had no haemodynamic effects in normal and cirrhotic rats treated with hexamethonium. In normal anaesthetized rats, isosorbide dinitrate significantly decreased systemic vascular resistance (414 +/- 25 vs 290 +/- 26 dyn.s/cm-5 per 100 g). In cirrhotic anaesthetized rats, isosorbide dinitrate significantly decreased mean arterial pressure (98 +/- 6 vs 79 +/- 7 mmHg), systemic vascular resistance (318 +/- 30 vs 207 +/- 10 dyn.s/cm-5 per 100 g), portal pressure (14.0 +/- 1.0 vs 11.3 +/- 0.9 mmHg) and portal territory vascular resistance (1362 +/- 163 vs 1031 +/- 182 dyn.s/cm5 per 100 g). In conclusion, this study shows that the portal hypotensive effects of isosorbide dinitrate depend upon the alterations of vascular tone by pentobarbitone.

Plasma endotoxin and tumor necrosis factor-alpha in the hyperkinetic state of cirrhosis.

BACKGROUND/AIMS: The factors which trigger the hyperdynamic circulation in cirrhosis remain poorly defined. Plasma levels of the potent vasodilators endotoxin and tumor necrosis factor-alpha may be elevated in patients with cirrhosis, and therefore the potential role of these substance was assessed in the hyperkinetic circulation in cirrhosis. METHODS: Forty-nine patients in stable condition underwent systemic and hepatic hemodynamic measurements, and right atrial blood sampling for endotoxin and tumor necrosis factor-alpha assays. Patients were divided into three groups according to the severity of the disease: group 1 consisted of eight patients with normal liver or mild hepatic fibrosis, and groups 2 and 3 contained 17 and 24 patients with Child A and Child B or C cirrhosis, respectively. RESULTS: Systemic vascular resistance decreased and cardiac index increased from group 1 to 3: 1530 +/- 196 dyn.s.cm-5 to 990 +/- 72 dyn.s.cm-5 (mean +/- S.E.; p<0.05) and 3.1 +/- 0.3 l.min-1.m-2 to 4.2 +/- 0.2 l.min-2.m-2, respectively. Endotoxin was not detectable in any of the groups and tumor necrosis factor-alpha was increased in one patient from group 1, six from group 2 and six from group 3. Mean tumor necrosis factor-alpha levels were not different among the groups (10 +/- 5, 18 +/- 5 and 17 +/- 7 pg/ml in groups 1, 2 and 3, respectively). Systemic vascular resistance and cardiac index were not correlated to plasma tumor necrosis factor-alpha levels; patients with increased levels of this cytokine did not have worse hyperdynamic circulation in any of the groups. CONCLUSIONS: These results suggest that tumor necrosis factor-alpha and endotoxin do not play a role in the maintenance of the hyperkinetic state of cirrhosis.

Hemodynamics after orthotopic liver transplantation: study of associated factors and long-term effects.

Among 68 liver transplant recipients, 190 hemodynamic studies were performed to evaluate the role of sepsis, anemia, acute graft rejection, and persistent portosystemic shunts. The hemodynamic outcome after orthotopic liver transplantation (OLT) in stable patients was also determined. Patients with sepsis showed a significant increase in cardiac index (5.1 +/- 0.9 vs. 3.4 +/- 0.7 L/min m2) and hepatic venous pressure gradient (6.3 +/- 2.9 vs. 3.3 +/- 2.1 mm Hg), compared with patients without sepsis. Cardiac index was higher in patients with, than in patients without, anemia (4.1 +/- 0.6 vs. 3.0 +/- 0.6 L/min m2). The hepatic venous pressure gradient was higher in patients with than in patients without acute graft rejection (5.1 +/- 2.9 vs. 2.6 +/- 1.2 mm Hg). Among patients with acute rejection, the hepatic venous pressure gradient was higher in patients with severe rejection than in those with moderate or mild rejection (7.2 +/- 3.3 vs. 4.6 +/- 2.4 and 2.8 +/- 0.9 mm Hg). In the postoperative period, in patients undergoing transplantation for acute liver failure, the hepatic blood flow was normal and significantly lower than in patients receiving transplant for cirrhosis (1.15 +/- 0.37 vs. 1.96 +/- 0.71 L/min). In patients undergoing transplantation for cirrhosis, cardiac index, azygos, and hepatic blood flows significantly decreased after 1 year compared with the first 6 postoperative months. Multivariate analysis showed that sepsis, anemia, and time after OLT were independent variables influencing cardiac index. Sepsis, time after OLT, and the existence of portosystemic shunts were independent variables influencing hepatic blood flow.(ABSTRACT TRUNCATED AT 250 WORDS)

Hemodynamic effects of acute administration of furosemide in patients with cirrhosis receiving beta-adrenergic antagonists.

In patients with cirrhosis, both beta-blockers and diuretics decrease the degree of portal hypertension. Since their mechanisms of action differ, the combination of these two substances should induce a more pronounced effect on portal pressure than one of these substances alone. Thus, the hemodynamic effects of furosemide were evaluated in ten patients with cirrhosis receiving beta-blockers. One hour after furosemide (0.75 mg/kg intravenously) administration, cardiac output decreased significantly from 6.2 +/- 0.6 to 5.2 +/- 0.3 l/min and blood volume from 8.0 +/- 1.6 to 5.3 +/- 0.5 l. Mean arterial pressure was not affected. Wedged and free hepatic venous pressures did not change significantly; nor did the hepatic venous pressure gradient (19.6 +/- 1.7 to 18.6 +/- 1.5 mmHg). Azygos blood flow was not affected (0.46 +/- 0.05 to 0.50 +/- 0.07 l/min). In conclusion, this study did not demonstrate that the addition of furosemide to propranolol further decreased portal pressure in patients with cirrhosis. The long-term effects of this combination are unknown and should be tested.

[Relationships between plasma concentrations of endothelin and the severity of liver cirrhosis]. / Relations entre les concentrations plasmatiques d'endothéline et la sévérité de la cirrhose.

OBJECTIVES: Results of studies on plasma endothelin concentrations in patients with cirrhosis are conflicting. Moreover, the relationships between plasma endothelin concentrations and the severity of cirrhosis have not yet been studied. The aim of this study was to measure plasma endothelin concentrations in controls and in patients with cirrhosis. In addition, this study examined the relationships between plasma endothelin concentrations, and the severity of liver disease, splanchnic and systemic hemodynamics. METHODS: Plasma endothelin concentrations (in the hepatic vein and the right atria), hepatic venous pressures, arterial pressure, cardiac output, pulmonary pressures and plasma concentrations of sodium and creatinine were measured in 7 controls and 28 patients with cirrhosis. RESULTS: Plasma endothelin concentrations in the hepatic vein and the right atria were significantly higher in patients with cirrhosis (18.9 +/- 2.9 and 20.2 +/- 3.1 pg/mL, respectively) than in controls (6.1 +/- 1.1 and 7.2 +/- 1.1 pg/mL, respectively). In these patients, hepatic venous plasma endothelin concentrations were significantly correlated with Pugh's score (r = 0.49), hepatic venous pressure gradient (r = -0.44), and plasma sodium concentrations (r = -0.46). No significant correlation was found between plasma endothelin concentrations and systemic hemodynamics. CONCLUSION: Plasma endothelin concentrations are increased in patients with cirrhosis. Moreover, this increase is more marked in patients with severe liver disease than in patients with no or moderate impairment of liver function.