Ricardo Mastai

Endoscopic Measurement of Variceal Pressure in Cirrhosis: Correlation With Portal Pressure and Variceal Hemorrhage+++

This study evaluated the clinical application of a pressure-sensitive gauge that allows the noninvasive measurement of the pressure of esophageal varices at endoscopy. The study was performed in 70 patients with cirrhosis and portal hypertension. Among them, 47 had bled from the varices and 23 had varices but had not bled. In addition to measurements of variceal pressure, the size of the varices was estimated semiquantitatively at endoscopy. This allowed an estimate of the tension on the wall of the varices as the product of the transmural pressure and the estimated radius of the varices. Most patients had a standard hemodynamic evaluation of portal hypertension, with measurements of wedged and free hepatic venous pressures, and of azygos blood flow. These were performed within 24 h of the variceal pressure measurements. Variceal pressure was significantly higher in bleeders than in nonbleeders (15.7 +/- 2.8 vs. 12.1 +/- 2.6 mmHg, p less than 0.001) in spite of a similar portal pressure in both groups (20.1 +/- 5.1 vs. 20.4 +/- 7.6 mmHg, NS). More than 60% of the bleeders, but only 22% of the nonbleeders had a variceal pressure greater than or equal to 15 mmHg (p less than 0.005). Among nonbleeders, variceal pressure was higher in patients with large varices (13.9 +/- 2 mmHg, n = 9) than in those with small varices (10.9 +/- 2.4 mmHg, n = 14) (p less than 0.01). Estimates of variceal wall tension further exaggerated the differences between bleeders and nonbleeders (66.1 +/- 22.6 vs. 32.0 +/- 19.8 mmHg.mm, p less than 0.001). More than 50% of bleeders, but just 9% of nonbleeders had an estimated variceal tension greater than 50 mmHg.mm (p less than 0.001). Our findings support the role of an increased variceal pressure in the pathogenesis of variceal hemorrhage, and suggest that this noninvasive technique can be valuable in assessing the risk of variceal hemorrhage in patients with portal hypertension.

Measurement of azygos venous blood flow in the evaluation of portal hypertension in patients with cirrhosis: Clinical and haemodynamic correlations in 100 patients*

Blood flow in the azygos vein, an index of blood flow through gastro-oesophageal collaterals, was measured by continuous thermal dilution in 100 patients with cirrhosis. Azygos blood flow was directly related to portal pressure (r = 0.54, P less than 0.001). Patients with portal hypertension had very high azygos blood flow (692 +/- 32 ml/min) in comparison with controls (n = 11, 174 +/- 29 ml/min). Patients with previous oesophageal bleeding had similar azygos blood flow as those without, but azygos blood flow was significantly greater in patients with massive or recurrent bleeding than in those with less severe haemorrhage, suggesting that the magnitude of collateral flow may influence the course of variceal bleeding. Patients with grade III varices had higher azygos blood flow than those with grades II or I. In addition, both oesophageal tamponade and vasopressin infusion, procedures of known value in variceal bleeding, markedly reduced azygos blood flow (-40% and -25%, respectively). Measurement of azygos blood flow allows evaluation of haemodynamic changes in the oesophageal collaterals of patients with portal hypertension, and provides useful information on the effect of therapeutic procedures aimed at arresting or preventing variceal haemorrhage.

Effects of prostaglandin inhibition on systemic and hepatic hemodynamics in patients with cirrhosis of the liver

The role of prostaglandins in the pathogenesis of the circulatory abnormalities of cirrhosis was investigated by studying the effects of prostaglandin inhibition with indomethacin (50 mg/8 h for 24 h) on the systemic and splanchnic hemodynamics in 13 patients with cirrhosis of the liver. Indomethacin administration significantly reduced cardiac output (from 7.44 +/- 0.7 to 6.78 +/- 0.7 L/min, p less than 0.05) and increased peripheral vascular resistance (from 990 +/- 104 to 1155 +/- 140 dyn X s X cm-5, p less than 0.05). Arterial pressure was not modified. These changes in systemic hemodynamics were associated with a significant reduction in hepatic blood flow (from 1.88 +/- 0.43 to 1.48 +/- 0.3 L/min, p less than 0.05) and with a slight decrease of portal pressure (from 18.8 +/- 1.3 to 17.5 +/- 1.4 mmHg, p less than 0.05). These results suggest that endogenous prostaglandins contribute to the increased cardiac output and diminished vascular resistance observed in cirrhosis of the liver. In addition, by promoting splanchnic vasodilation, prostaglandins may contribute to increased portal pressure in these 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)

Von Willebrand factor could be an index of endothelial dysfunction in patients with cirrhosis: relationship to degree of liver failure and nitric oxide levels.

BACKGROUND/AIMS The aim of this study was to evaluate the relationship between plasma levels of von Willebrand factor (vWF), a marker of endothelial cell activation, and nitric oxide, a powerful vasodilator synthesized by endothelial cells, in 27 patients with cirrhosis at different stages of the disease. These results were compared with those of age-matched normal, healthy subjects (n=10). METHODS vWF:antigen was measured by electro-immunodiffusion test and serum nitrite and nitrate levels, the stable end products of nitric oxide metabolism, were determined by an enzymatic procedure. RESULTS vWF:antigen and nitrite/nitrate levels were significantly higher in cirrhotic patients (367+/-185% and 29.3+/-10.8 micromol/l) than in healthy subjects (92+/-20% and 19.2+/-8.3 micromol/l, p<0.05, respectively). Higher levels of vWF:antigen and nitrites/nitrates were observed in patients with more advanced degrees of liver failure, as reflected by quantitative Child-Pughs score (516+/-154% and 38.3+/-7.8 micromol/l in Child-Pugh > or = 9 vs 227+/-61% and 21.0+/-6.1 micromol/l in Child-Pugh <9, p<0.001, respectively). Moreover, both endothelial-related factors were higher in patients with ascites than those without ascites (543+/-158% and 37.8+/-8.9 micromol/l vs 262+/-103% and 24.4+/-8.8 micromol/l, p<0.001, respectively). In the overall series, a highly significant linear correlation between nitrites/nitrates and vWF:antigen levels was observed in patients with cirrhosis (r=0.79, p<0.001). CONCLUSIONS These results support a cirrhosis-related endothelial dysfunction and suggest that plasma vWF measurement could be useful as a marker of endothelial disturbance in patients with cirrhosis.

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 Somatostatin in Patients with Portal Hypertension

Portal hypertension is a common complication of chronic liver disease. Conventional therapy consists of surgery and palliative measures for the hemodynamic problem. It has been recently reported that somatostatin may reduce portal pressure without altering the systemic circulation and so reducing hepatic blood flow. This peptide also causes a significant fall in azygos circulation in patients with esophageal varices. The mechanism of this effect is unclear although suppression of intestinal vasodilating hormones and of glucagon have been claimed to play a role. Comparative clinical studies have shown somatostatin to be superior to the standard vasopressin treatment. Recent findings suggest that the efficacy of somatostatin can be increased by administering this peptide in repeated intravenous bolus injections. New derivatives, specially long-acting peptides, may eventually prove beneficial in the chronic treatment of this complication.

Extremely Marginal Liver Grafts From Deceased Donors Have Outcome Similar to Ideal Grafts

BACKGROUND Although there is a worldwide need to expand the donor pool, many cadaveric marginal livers are usually discarded for transplantation. Herein, we report the outcome of a series of patients receiving marginal grafts. METHODS We analyzed all patients who underwent liver transplantation in our unit from August 2006 to March 2011 (n = 125) with the use of a prospectively collected database. Patients with ≥3 of donor (prolonged hypotensive episodes, donor age >55 years, high vasopressor drug requirement, hypernatremia, prolonged intensive care unit stay, elevated transaminases) and graft-related (cold ischemia >12 hours, warm ischemia time >40 minutes and steatosis >30%) extended criteria were defined as extremely marginal liver grafts (EMLG). The outcomes of patients receiving EMLG were compared with the recipients of grafts without any marginal criteria (ideal grafts). RESULTS The EMLG group (n = 36) showed higher operative transfusion requirement (66.6% vs 55.6%) as well as 30-day (11.1% vs 55%) and 1-year (22.2% vs 5.5%) mortality rates, compared with the ideal grafts group (n = 18) but without a significant difference. Other variables, such as major complications, postoperative hemodialysis, ICU and hospital stay, and 1-year survival also were not significantly different. CONCLUSIONS The liver pool can be safely expanded using EMLG from deceased donors for liver transplantation. These usually discarded liver grafts showed similar early and long-term outcomes compared with ideal organs.

Liver transplantation using Chagas-infected donors in uninfected recipients: a single-center experience without prophylactic therapy.

Organ shortage is the first cause of death on liver transplant waiting lists. As a consequence, we recently decided to expand liver acceptance to those organs that could potentially transmit infectious diseases to their recipients. On January 2010, we initiated a prospective protocol using livers from Chagas‐infected donors for transplanting uninfected recipients without using prophylactic therapy. During a 13‐month period, 9 of 37 (24%) liver transplants were performed within this protocol. After transplant, each recipient was sequentially and strictly monitored for infection transmission using the Strout method and promptly treated with benznidazole if this occurs. During follow‐up, two patients died without Chagas infection and only two (donor‐derived T. cruzi transmission rate: 2/9; 22%) patients developed donor‐derived Chagas transmission without clinical symptoms. The median follow‐up time of the seven live patients was 15 months (range: 13–20). At present, all are symptoms‐free with excellent allograft function and without evidence of Chagas disease. In conclusion, we consider that Chagas‐infected donors are a promising source of liver grafts that could reduce the growing mortality on liver waiting lists in America. Relevant data from larger prospective studies are required to confirm these preliminary excellent results.

Hyperglucagonism and glucagon resistance in cirrhosis: Paradoxical effect of propranolol on plasma glucagon levels

Propranolol, a non-selective beta-blocker, is known to decrease glucagon release in normal subjects. The present study was aimed at investigating the effects of propranolol on the hyperglucagonism commonly observed in patients with cirrhosis. Eight cirrhotic patients and 6 matched healthy controls were studied. The plasma concentrations of glucagon, insulin, c-peptide and glucose were measured in basal conditions and after stimulating glucagon secretion by an i.v. infusion of arginine (0.4 g/kg/30 min). The study was repeated 24 h later after inducing beta-blockade by the i.v. infusion of propranolol (10 mg). In baseline conditions, patients with cirrhosis, despite normal levels of insulin and glucose, had a marked hyperglucagonism (654 +/- 303 pg/ml vs. 269 +/- 90 in controls, P less than 0.01). Prior to propranolol, arginine infusion caused greater glucagon release in cirrhotics (71 +/- 31 ng.h.ml-1) than in controls (33 +/- 17 ng.h.ml-1, P less than 0.02), but despite a similar insulin secretion (assessed from c-peptide), blood glucose did not increase. After propranolol, glucagon secretion decreased as expected in controls (29 +/- 12 ng.h.ml-1, P less than 0.05) but experienced a paradoxical increase in cirrhotics (113 +/- 64 ng.h.ml-1, P less than 0.05). Again, despite the marked increase in glucagon release, there was no increase in glucose production, providing further evidence of the glucagon resistance that accompanies hyperglucagonism in cirrhosis. Our results suggest that hyperglucagonism with glucagon resistance might be the initial disturbance in carbohydrate metabolism in patients with cirrhosis. Contrary to what could be expected, propranolol does not correct but further accentuates this disturbance.