Acute effects of the oral administration of midodrine, an alpha-adrenergic agonist, on renal hemodynamics and renal function in cirrhotic patients with ascites.

The effects of the acute administration of arterial vasoconstrictors on renal plasma flow (RPF) and urinary sodium excretion (UNaV) in cirrhotic patients with ascites with or without hepatorenal syndrome (HRS) are still controversial. As a consequence, vasoconstrictors are not actually used in the treatment of renal sodium retention or HRS in these patients, regardless of the several lines of evidence suggesting that these renal functional abnormalities are related to a marked arterial vasodilation. The lack of an orally available effective arterial vasoconstrictor probably represents a further reason for this omission. Consequently, the present study was made to evaluate the acute effects of the oral administration of midodrine, an orally available -mimetic drug, on systemic and renal hemodynamics and on UNaV in cirrhotic patients with ascites. Mean arterial pressure (MAP), heart rate (HR), cardiac index (CI), systemic vascular resistance (SVR), left forearm blood flow (LFBF), left leg blood flow (LLBF), RPF, glomerular filtration rate (GFR), UNaV, plasma renin activity (PRA), plasma concentration of antidiuretic hormone (ADH), and the serum levels of nitrite and nitrate (NOx) were evaluated in 25 cirrhotic patients with ascites (17 without HRS and 8 with type 2 HRS) before and during the 6 hours following the oral administration of 15 mg of midodrine. During the first 3 hours after the drug administration, a significant increase in MAP (89.6 +/- 1.7 vs. 81.80 +/- 1.3 mm Hg; P < .0001) and SVR (1, 313.9 +/- 44.4 vs. 1,121.2 +/- 60.1 dyn . sec . cm-5; P < .0001) accompanied by a decrease in HR (69 +/- 2 vs. 77 +/- 3 bpm; P < .005) and CI (2,932.7 +/- 131.4 vs. 3,152.5 +/- 131.4 mL . min-1 . m2 BSA; P < .0025) was observed in patients without HRS. No change was observed in LFBF and LLBF. The improvement in systemic hemodynamics, which was also maintained during the the 3- to 6-hour period after midodrine administration, was accompanied by a significant increase in RPF (541.5 +/- 43.1 vs. 385.7 +/- 39.9 mL . min-1; P < .005), GFR (93.1 +/- 6.5 vs. 77.0 +/- 6.7 mL . min-1; P < .025), and UNaV (92.7 +/- 16.4 vs. 72.2 +/- 10.7 microEq . min-1; P < .025). In addition, a decrease in PRA (5.33 +/- 1.47 vs. 7.74 +/- 2.17 ng . mL-1 . h; P < .05), ADH (1.4 +/- 0.2 vs. 1.7 +/- 0.2 pg . mL-1; P < .05), and NOx (33.4 +/- 5.0 vs. 49.3 +/- 7.3 micromol-1; P < .05) was found. In patients with HRS, the effects of the drug on the systemic hemodynamics was smaller and shorter. Accordingly, regardless of a significant decrease in PRA (15.87 +/- 3.70 vs. 20.70 +/- 4.82 ng . mL-1 . h; P < .0025) in patients with HRS, no significant improvement was observed in RPF, GFR, or UNaV. In conclusion, the acute oral administration of midodrine is associated with a significant improvement in systemic hemodynamics in nonazotemic cirrhotic patients with ascites. As a result, renal perfusion and UNaV also improve in these patients. By contrast, midodrine only slightly improves systemic hemodynamics in patients with type 2 HRS, with no effect on renal hemodynamics and renal function.

Lack of effect of verapamil and isosorbide dinitrate on the hepatic clearance of indocyanine green in cirrhosis.

1. Vasodilators are currently under investigation as possible therapeutic agents in the treatment of portal hypertension. Among them calcium-channel antagonists and organic nitrates have been of particular interest. Few and conflicting data, however, have been reported on their effect on liver function. 2. Twenty patients with biopsy-proven alcoholic cirrhosis were studied before and 25-35 min following the acute administration of 5 mg verapamil i.v. (eight patients) or 5 mg isosorbide dinitrate sublingually (12 patients). The plasma clearance of indocyanine green (ICG) and its intrinsic hepatic clearance were used as indices of liver function. Seven further patients were investigated before and after a placebo infusion according to the same methodology. 3. No significant change in ICG kinetics was found after verapamil or isosorbide dinitrate.

Indocyanine green intrinsic hepatic clearance as a prognostic index of survival in patients with cirrhosis.

The prognostic value of quantitative liver function tests in patients with cirrhosis is not clearly established. Indocyanine green intrinsic hepatic clearance (ICG-IHC) is a quantitative liver function parameter independent of liver blood flow, which was shown to correlate strictly with the Child-Turcotte-Pugh (CTP) classification of severity of liver disease. Few data are available on its prognostic value. One hundred and five patients with cirrhosis were studied. ICG-IHC was measured according to the 'sinusoidal perfusion' model. Median ICG-IHC in the whole series was 374 ml/min (interquartile range: 214-496 ml/min). During follow-up (mean 31 months; max. 48 months) 38 patients died. The probability of survival was lower in patients with ICG-IHC lower than 300 ml/min (35% at 48 months) than in patients with ICG-IHC between 300 and 1000 ml/min (70%), or with ICG-IHC over 1000 ml/min (80%) (P = 0.02). Also s-albumin (P less than 0.01), ascites (P = 0.001) and CTP class (P less than 0.001) were significant predictors of survival. On incorporation of age, sex, etiology of cirrhosis, ICG-IHC, s-albumin, s-bilirubin, prothrombin index, ascites and encephalopathy, into a multiple regression analysis according to the Cox's model, the results showed only ascites and s-albumin to be independent significant predictors of survival, while ICG-IHC was not among the covariates independently predictive of survival. When CTP class was added to the investigated covariates, the results showed it as the only independent predictor of survival.(ABSTRACT TRUNCATED AT 250 WORDS)

The calcium-channel blocker, verapamil, does not improve portal pressure in patients with alcoholic cirrhosis.

1. Recently the calcium-channel blocker, verapamil, has been reported to decrease portal pressure in rats with experimental cirrhosis and in patients with liver cirrhosis. 2. In eight patients with alcoholic cirrhosis the effect of verapamil (5 mg i.v.) on systemic and splanchnic haemodynamics was investigated. 3. Mean arterial pressure, wedged hepatic venous pressure, hepatic venous pressure gradient, and verapamil plasma concentrations were measured before and at 10, 20, 30 min following 5 mg i.v. administration of verapamil. At 30-40 min cardiac output, systemic vascular resistance and hepatic blood flow were also measured. 4. Verapamil plasma concentrations averaged 47.9 +/- 52.0, 36.5 +/- 36.3, 31.3 +/- 33.9 ng ml-1 at 10, 20, 30 min respectively: mean arterial pressure and systemic vascular resistance decreased significantly (-9% and -14% respectively), and cardiac index increased significantly (+8%). Wedged hepatic venous pressure and hepatic venous pressure gradient remained unchanged, variations never exceeding 0.2 kPa. Hepatic blood flow increased significantly by 12%. 5. These results show that i.v. administration of 5 mg verapamil does not decrease portal pressure in alcoholic cirrhosis. This lack of effect is probably the consequence of a balance between decrease in porto-hepatic vascular resistance and increase in splanchnic blood inflow.

Long-term effect of nadolol on quantitative liver function tests in patients with cirrhosis.

Nadolol, a non-cardioselective beta adrenoreceptor blocking agent, has been reported to decrease portal pressure without affecting liver function in cirrhotic patients treated for 1 month. There were no data about the long-term effects of nadolol on liver function. In 11 patients with cirrhosis and portal hypertension galactose eliminating capacity, aminopyrine metabolic capacity, ICG clearance and IGC intrinsic hepatic clearance according to the "parallel tube" model were measured before and after 6 months of treatment with nadolol at a dose reducing resting heart rate by approximately 25%. No significant variation in any of these parameters was found. Thus 6 months of continuous oral administration of nadolol did not further impair liver function in cirrhotics.

Verapamil pharmacokinetics and liver function in patients with cirrhosis.

In seven patients with liver cirrhosis, verapamil plasma levels were measured in blood drawn simultaneously from the hepatic vein and from an artery during the post-distributive phase after an intravenous bolus infusion of 5 mg of verapamil. In addition the hepatic plasma flow was measured using the indocyanine-green constant infusion technique. From these data the verapamil hepatic clearance and verapamil intrinsic clearance were calculated. The verapamil hepatic clearance was 423 +/- 92 ml/m, the hepatic plasma flow was 819 +/- 318 ml/m, and the verapamil intrinsic clearance was 1431 +/- 961 ml/m. As compared to values reported in the literature, a decrease of the verapamil hepatic clearance by 50% approximately was found, while the hepatic plasma flow was in the normal range and the verapamil intrinsic clearance was reduced by 75%. These data show that in patients with cirrhosis the decrease in verapamil clearance is due to an impairment in the capacity of the liver to remove the drug, and not to a decrease in liver perfusion.

Long-term effects of beta-adrenergic blockade with nadolol on hepatic and renal haemodynamics and function in cirrhotics.

Non-cardioselective beta-blockers are used for prevention of re-bleeding from oesophageal varices in cirrhotics with portal hypertension. Nadolol, a non-cardioselective beta-blocker with a low liposolubility and a low hepatic metabolism, has been demonstrated to decrease portal pressure in cirrhotic patients. Since cirrhotics need long-term treatment, we investigated long-term effects of beta-adrenergic blockade with nadolol on hepatic and renal haemodynamics and function in a group of patients with cirrhosis and portal hypertension. In 19 patients with cirrhosis, after one and six months of treatment with nadolol hepatic venous pressure gradient showed a significant and persistent decrease, averaging 19% and 22%, respectively. Hepatic function and renal haemodynamics and function remained unaffected. Oesophageal varices severity was lowered in 11/19 patients after one month, in 9/16 after six months, in 8/14 after 12 months and in 5/10 after 18 months. Our results showed that, also after long-term treatment, nadolol decreases portal pressure and, in approximately 50% of patients, oesophageal varices severity, without side-effects on liver and renal function.

Effect of nadolol on liver haemodynamics and function in patients with cirrhosis.

Beta-adrenoceptor blockers used in the medical management of portal hypertension decrease liver blood flow. The sporadic onset of hepatic encephalopathy during propranolol treatment was ascribed to this decrease. The aim of the present study was to evaluate the effect of chronic treatment with nadolol on liver blood flow and liver function. Nadolol, a non-cardioselective beta-adrenoceptor blocker, has been reported to be as powerful as propranolol in decreasing portal pressure. Before and after 1 month of treatment with nadolol at a dose reducing heart rate by 25%, in 15 cirrhotic patients with portal hypertension, the following parameters were determined: hepatic venous pressure gradient, hepatic blood flow, galactose eliminating capacity, aminopyrine metabolic activity, ICG clearance and intrinsic hepatic clearance. Hepatic venous pressure gradient and hepatic blood flow were decreased by nadolol. However liver function was not affected by the drug. We conclude that, despite a lowered hepatic blood flow, liver function is not affected by 1 month of nadolol treatment.

Effect of somatostatin on splanchnic hemodynamics in patients with liver cirrhosis and portal hypertension.

The effect of somatostatin on splanchnic hemodynamics in patients with liver cirrhosis is not clearly defined, as some authors report a decrease in portal pressure and in liver blood flow during intravenous administration of this hormone, while others do not. In 19 subjects with liver cirrhosis and portal hypertension the following parameters were measured before and during intravenous administration of somatostatin (7.5 micrograms/min): porto-hepatic gradient, estimated hepatic blood flow, specific splenic blood flow, cardiac index. Estimated hepatic blood flow decreased significantly during somatostatin infusion (p less than 0.05), averaging a 13% decrease; porto-hepatic gradient, splenic specific blood flow and cardiac index did not vary significantly. These data indicate that somatostatin infused at a dose of 7.5 micrograms/min induces a slight decrease in liver blood flow without affecting portal hypertension.

[Effect of somatostatin on splanchnic hemodynamics in liver cirrhosis]. / Effetto della somatostatina sull'emodinamica splancnica nella cirrosi epatica.

The effect of somatostatin on splanchnic haemodynamics in patients with liver cirrhosis is not clearly defined, as some Authors reported a decrease in portal pressure and in liver blood flow during i.v. administration of this hormone, while others did not. In 19 subjects with liver cirrhosis and portal hypertension the following parameters were measured before and during i.v. infusion of somatostatin (7.5 micrograms/min): porto-hepatic gradient, effective hepatic plasma flow, specific splenic blood flow, cardiac output. Moreover the gastrin-G-17 plasma levels, those of insulin and growth hormone were measured. Effective hepatic plasma flow decreased significantly during somatostatin infusion (P less than 0.05), averaging a 15% decrease. Porto-hepatic gradient, specific splenic blood flow, cardiac output did not vary significantly. Gastrin, insulin and growth hormone plasma levels decreased significantly (P less than 0.02, 0.01, 0.05). These data indicate that somatostatin infused at the dose of 7.5 micrograms/min provokes endocrine effects, but as far as the splanchnic circulation is concerned, it induces a slight decrease in liver blood flow without affecting portal hypertension.