The effects of chronic treatment with octreotide versus octreotide plus midodrine on systemic hemodynamics and renal hemodynamics and function in nonazotemic cirrhotic patients with ascites

OBJECTIVES: The adrenergic agonist midodrine improved circulatory and renal dysfunction when acutely administered in nonazotemic cirrhotic patients with ascites while its combination with octreotide has recently been proposed as an effective treatment of type 1 hepatorenal syndrome (HRS). However, the effects of octreotide on systemic hemodynamics and renal function in cirrhotic patients are controversial. This study evaluated the effects of chronic treatment with octreotide versus octreotide plus midodrine on systemic hemodynamics and renal hemodynamics, and function in nonazotemic cirrhotic patients with ascites. METHODS: Twenty-five patients were studied at baseline and 11 days after administration of subcutaneous octreotide 300 mug, b.i.d. alone (n = 12) or together with oral midodrine 7.5 mg, t.i.d. (n = 13). RESULTS: Octreotide did not improve systemic hemodynamics whereas the addition of midodrine significantly decreased cardiac index (CI) and heart rate (HR), and increased mean arterial pressure (MAP) and systemic vascular resistance (SVR). Octreotide caused a decrease in renal vascular resistance (RVR) and increased renal blood flow (RBF) but significantly reduced glomerular filtration rate. The association of midodrine to octreotide did not modify renal hemodynamics and function as compared to baseline while it caused an almost significant minor increase in RVR and a significant minor decrease in RBF as compared to octreotide alone. Consequently, a significant minor increase in glomerular filtration rate was demonstrated. The plasma values of active renin, aldosterone, and glucagon were significantly reduced in either group. CONCLUSIONS: Octreotide does not improve systemic hemodynamics in nonazotemic cirrhotic patients with ascites while it impairs renal function. On the other hand, the addition of midodrine can ameliorate the hyperdynamic circulation without inducing renal dysfunction in these patients.     

The effect of single oral low-dose losartan on posture-related sodium handling in post-TIPS ascites-free cirrhosis

Post-TIPS ascites-free patients with cirrhosis and previous refractory ascites demonstrate subtle sodium retention when challenged with a high sodium load. This is also observed in pre-ascitic patients with cirrhosis. This phenomenon is dependent on an intrarenal angiotensin II (ANG II) mechanism related to the assumption of erect posture. We investigated whether similar mechanisms were involved in post-TIPS ascites-free patients, by studying 10 patients with functioning TIPS and no ascites. We measured the effect of changing from supine to erect posture on sodium excretion at baseline and after single oral low dose losartan (7.5 mg) which has been shown to blunt proximal and distal tubular sodium reabsorption in pre-ascites. At baseline, the assumption of erect posture produced a reduction in sodium excretion (from 0.30+/-0.06 to 0.13+/-0.02 mmol/min, P=.05), which was mainly due to an increase in proximal tubular reabsorption of sodium (PTRNa) (69.7+/-3.1% to 81.1+/-1.8%, P=.003). The administration of losartan resulted in a blunting of PTRNa (supine 69.7+/-3.1% to 63.9+/-3.9%, P=.01 and erect 81.1+/-1.8% to 73.8+/-2.4%, P=.01), accompanied by an increased distal tubular reabsorption of sodium in both postures, with no overall improvement in sodium excretion on standing. In conclusion, post-TIPS ascites-free patients with cirrhosis exhibit erect posture-induced sodium retention. We speculate that (1) this effect is partly mediated by the effect of ANG II on PTRNa and (2) that the inability of low dose losartan to block the erect posture-induced sodium retention may be related to the erect posture-induced rise in aldosterone which is unmodified by losartan.     

Nitric oxide and renal functions in liver cirrhosis.

BACKGROUND/AIMS: Nitric oxide, a potent vasodilating agent, has been proposed to play a role in pathogenesis of ascites and hepatorenal syndrome. The aim of this study was to evaluate the interaction between the plasma nitric oxide, nitric oxide synthetase levels and renal functions in patients with different degrees of chronic liver disease. METHODS: The study population included 38 subjects: 14 patients with chronic hepatitis, 11 with preascitic cirrhosis and 13 with ascitic cirrhosis. Nitric oxide and nitric oxide synthetase were determined by colorometric assay. We calculated glomerular filtration rate and fractional sodium excretion. RESULTS: Nitric oxide levels in groups were as follows: 79.28+/-24.86, 99.03+/-21.31, 197.05+/-49.61 microm, respectively. Nitric oxide synthetase levels were 2.64+/-0.56, 3.64+/-0.89, 7.75+/-2.46 micromol/L/sec, respectively. Nitric oxide and nitric oxide synthetase levels in the ascitic cirrhotic group were significantly higher than in the others (p<0.05). When glomerular filtration rates were compared, the only significant difference was determined between the groups with chronic hepatitis and ascitic cirrhosis (92.31+/-25.21, 48.46+/-16.45, p<0.05). Fractional sodium excretion was significantly increased in the ascitic cirrhotic group (4.42+/-2.76, p<0.05). CONCLUSIONS: Nitric oxide and nitric oxide synthetase increased with progression of liver disease, especially in ascitic cirrhosis. We also showed that this increase negatively affects the renal tubular and glomerular functions.     

Long-term renal sodium handling in patients with cirrhosis treated with transjugular intrahepatic portosystemic shunts for refractory ascites

PURPOSE: The long-term effects of transjugular intrahepatic portosystemic shunts on renal sodium excretion are not known. We sought to determine these long-term effects, as well as to measure the effects of a sodium load in patients who are free of ascites. SUBJECTS AND METHODS: Ten patients with cirrhosis who had been successfully treated with transjugular intrahepatic portosystemic stent shunt for refractory ascites were studied before the shunt and again at 6 and 14 months after the shunt while on a 22 mmol sodium/day diet. At 14 months they were also studied on a 200 mmol sodium/day diet for 7 days without diuretics. Renal sodium handling, central blood volume, neurohumoral factors, and hepatic function were measured. RESULTS: Sodium balance was negative at 6 months (urinary sodium excretion [mean +/- SD] 51 +/- 11 mmol/day versus 7 +/- 2 mmol/day pre-shunt; P < 0.05), was maintained at 14 months (22 +/- 4 mmol/day; P < 0.05 versus pre-shunt), and was associated with normalization of renin activity and aldosterone levels, but not norepinephrine levels, as well as significantly improved renal hemodynamic measurements. Sodium loading with 200 mmol/day resulted in weight gain associated with increased central blood volume and appropriate renal sodium handling in most but not all patients (urinary sodium excretion 188 +/- 14 mmol/day), despite persistent nonsuppressibility of sympathetic hyperactivity. CONCLUSIONS: In cirrhotic patients with refractory ascites treated with a transjugular intrahepatic portosystemic stent shunt, long-term renal sodium handling is improved. Adequate intravascular filling in ascites-free cirrhotic patients with normal portal pressure permits an improved but not normalized renal response to a sodium load, possibly due to persistently elevated sympathetic activity. Therefore, these patients should increase their sodium intake cautiously.     

Hepatorenal syndrome

Opinion statement Hepatorenal syndrome (HRS) is defined as functional renal failure that develops in patients with advanced liver disease. HRS may be either slowly or rapidly progressive (type I and II HRS, respectively). Untreated HRS carries a high mortality. Liver transplantation is the best available treatment for HRS. However, all patients with HRS are not suitable candidates for transplantation. Moreover, an organ is often not available in a timely manner in those who are candidates for transplantation. Treatment with vasoconstrictors (terlipressin, octreotide, and midodrine) and plasma expansion with albumin is beneficial and serves as a bridge to transplantation in such cases. The vasopressin analog, terlipressin, produces a sustained reversal of HRS in about 57% to 78% of the patients. The benefits of terlipressin are seen mainly in those who are also receiving albumin simultaneously. In those who improve, recurrence of HRS is reported to be relatively uncommon in the short and intermediate term. In the United States, terlipressin is not available, and octreotide and midodrine are often used for the medical management of HRS. Unfortunately, there are only limited uncontrolled data to support the use of these drugs for HRS. In those who respond to octreotide and midodrine, the subsequent placement of a transjugular intrahepatic portasystemic shunt (TIPS) has been shown to produce a sustained improvement in renal function. TIPS alone also improves renal functions in selected patients with HRS. The exact role of TIPS in HRS needs further evaluation, as patients with HRS are particularly at risk for complications such as encephalopathy and liver failure. Molecular adsorbent recirculating system (MARS) is an albumin-based dialysis system that has a promising role in the treatment of HRS and liver failure. MARS is a very expensive form of treatment, and further clinical trials are needed to establish its utility. Development of HRS can be prevented by adding albumin to the antibiotic regimen to treat spontaneous bacterial peritonitis and through pentoxifylline administration to the patients with acute alcoholic hepatitis.     

The management of ascites in cirrhosis: report on the consensus conference of the International Ascites Club

Ascites is a common complication of cirrhosis, and heralds a new phase of hepatic decompensation in the progression of the cirrhotic process. The development of ascites carries a significant worsening of the prognosis. It is important to diagnose noncirrhotic causes of ascites such as malignancy, tuberculosis, and pancreatic ascites since these occur with increased frequency in patients with liver disease. The International Ascites Club, representing the spectrum of clinical practice from North America to Europe, have developed guidelines by consensus in the management of cirrhotic ascites from the early ascitic stage to the stage of refractory ascites. Mild to moderate ascites should be managed by modest salt restriction and diuretic therapy with spironolactone or an equivalent in the first instance. Diuretics should be added in a stepwise fashion while maintaining sodium restriction. Gross ascites should be treated with therapeutic paracentesis followed by colloid volume expansion, and diuretic therapy. Refractory ascites is managed by repeated large volume paracentesis or insertion of a transjugular intrahepatic portosystemic stent shunt (TIPS). Successful placement of TIPS results in improved renal function, sodium excretion, and general well-being of the patient but without proven survival benefits. Clinicians caring for these patients should be aware of the potential complications of each treatment modality and be prepared to discontinue diuretics or not proceed with TIPS placement should complications or contraindications develop. Liver transplantation should be considered for all ascitic patients, and this should preferably be performed prior to the development of renal dysfunction to prevent further compromise of their prognosis.     

Reversal of type 1 hepatorenal syndrome with the administration of midodrine and octreotide.

The aim of the study was to verify the effects of the administration of an inhibitor of the release of endogenous vasodilators together with a vasoconstrictor agent in patients with hepatorenal syndrome (HRS). This new medical perspective was compared with a traditional medical approach for HRS, such as the infusion of nonpressor doses of dopamine to produce renal vasodilation. Thirteen patients with type 1 HRS were enrolled in the study. Five of them were treated with the oral administration of midodrine and the parenteral administration of octreotide. In addition, the patients received 50 to 100 mL of 20% human albumin solution daily for 20 days. Midodrine and octreotide were dosed to obtain a stable increase of at least 15 mm Hg of mean arterial pressure. Eight patients were treated with the intravenous administration of nonpressor doses of dopamine (2-4 micrograms/kg/min) and the same daily amount of albumin. After 20 days of treatment with midodrine and octreotide, an impressive improvement in renal plasma flow (RPF), glomerular filtration rate, and urinary sodium excretion was observed in patients. This was accompanied by a significant reduction in plasma renin activity, plasma vasopressin, and plasma glucagon. No side effects were observed. Three patients were discharged from the hospital. One of them successfully underwent liver transplantation. One of the two remaining patients is still alive after 472 days with a preserved renal function, and the other died from terminal liver failure after 76 days. One of the two patients who were not discharged from the hospital successfully underwent liver transplantation, and the other died from pneumonia after 29 days. Seven out of eight patients who were treated with dopamine experienced a progressive deterioration in renal function and died during the first 12 days. Only one patient recovered renal function and underwent liver transplantation. In conclusion, the long-term administration of midodrine and octreotide seems to be an effective and safe treatment of type 1 HRS in patients with cirrhosis.     

Atrial natriuretic factor in cirrhotic patients with tense ascites. Effect of large-volume paracentesis

The plasma levels of atrial natriuretic factor in liver cirrhosis can be affected by various factors, such as ascites, renal function, use of diuretics drugs and dietary sodium intake. Moreover, the influence of high intra-abdominal pressure on cardiac atrial natriuretic factor release in patients with tense ascites has not been investigated. The aim of the present study was to evaluate the circulating levels of atrial natriuretic factor and their relationships to plasma renin activity, aldosterone concentration, and urinary sodium excretion in 45 cirrhotic patients divided into 4 groups: (a) cirrhotics without ascites; (b) nonazotemic cirrhotics with ascites; (c) cirrhotics with ascites and functional renal failure; and (d) cirrhotics with ascites taking diuretics. In some patients with tense ascites, atrial natriuretic factor was also measured after rapid abdominal relaxation by large volume paracentesis. Plasma levels of atrial natriuretic factor obtained in 13 healthy control subjects after 5 days on a 40-50 mEq sodium daily intake were 22.8 +/- 3.3 pg/ml. Mean plasma atrial natriuretic factor levels were normal in patients without ascites (35.1 +/- 11.4 pg/ml) and in those with ascites taking diuretics (27 +/- 9.2 pg/ml), but elevated in patients with ascites not taking diuretics (59.6 +/- 12 pg/ml) and in those with ascites and functional renal failure (58.5 +/- 16.6 pg/ml). These data show that plasma atrial natriuretic factor levels are elevated only in cirrhotic patients who are ascitic and not taking diuretics. In these patients atrial natriuretic factor levels were directly correlated with urinary sodium excretion, even though sodium balance was positive. This could be the consequence of the contrasting effects of antinatriuretic factors, as suggested by the inverse relationships between atrial natriuretic factor and urinary sodium on the one hand and plasma renin activity and plasma aldosterone concentration on the other. Twenty-six patients with tense ascites (12 taking diuretics and 14 not) were treated with rapid large-volume paracentesis (6500 +/- 330 ml of ascitic fluid removed in 168 +/- 16 min). At the end of the procedure, plasma atrial natriuretic factor levels had increased in all patients (from 45.5 +/- 10.1 to 100 +/- 17 pg/ml), whereas plasma renin activity and plasma aldosterone concentration had decreased (from 10.3 +/- 1.6 to 7 +/- 1.3 ng/ml/h, and 1160 +/- 197 to 781 +/- 155 pg/ml, respectively).(ABSTRACT TRUNCATED AT 400 WORDS)     

Thromboxane-receptor blockade increases water diuresis in cirrhotic patients with ascites.

This study was undertaken to investigate the role of increased renal thromboxane (TX) A2 production in modulating renal hemodynamics and sodium and water retention in cirrhotic patients with ascites. In a randomized, double-blind, placebo-controlled, crossover trial, 15 nonazotemic cirrhotic patients with ascites and elevated urinary TXB2 excretion received the thromboxane-receptor antagonist ONO-3708 (3 micrograms.kg-1.min-1) in a 4-hour continuous infusion. Administration of ONO-3708 significantly blocked TXA2 receptors; bleeding time showed a twofold increase (432 +/- 65 vs. 131 +/- 17 seconds; P less than 0.005), and platelet aggregation to U-46619 (an agonist of TXA2 receptors) was abolished in all patients studied. The drug induced a significant increase in free water clearance (3.06 +/- 0.70 vs. 1.72 +/- 0.57 mL/min; P less than 0.001) and diuresis (4.74 +/- 0.79 vs. 3.94 +/- 0.66 mL/min; P less than 0.05) compared with placebo, as well as a significant (14%) increase in renal plasma flow. The increases in both free water clearance and diuresis induced by ONO-3708 were directly related to basal urinary TXB2 excretion. These results suggest a role for renal TXA2 as a modulator of water handling in cirrhotic patients with ascites.     

Variability of atrial natriuretic peptide plasma levels in ascitic cirrhotics: pathophysiological and clinical implications.

Ascitic cirrhotic patients are a heterogenous population with respect to factors that may affect plasma human atrial natriuretic peptide levels (such as degree of plasma volume and plasma levels of angiotensin II, vasopressin and norepinephrine). Thus the proven variability of plasma human atrial natriuretic peptide values in ascitic cirrhotic patients may be due also to the selection of patients, not only to the study conditions. The response to standardized stepped-care medical treatment of ascites makes it possible to characterize ascitic cirrhotic patients with different patterns of renal sodium excretion, intrarenal sodium handling, plasma renin activity, plasma aldosterone and thus, probably, effective circulating volume. Consequently, we evaluated human atrial natriuretic peptide plasma levels in controls (n = 23), in ascitic cirrhotic patients who underwent spontaneous diuresis (group A, n = 7) and in cirrhotic patients who required diuretic treatment (group B, n = 44). The last group was then divided into two subgroups. Subgroup B-R (n = 25) included patients who responded to spironolactone alone, whereas subgroup B-NR (n = 19) included patients who did not respond to 500 mg/day spironolactone. All patients were maintained on identical normocaloric restricted sodium intake (80 mEq/day) throughout the study. Ascitic cirrhotic patients, as a whole, had higher values of human atrial natriuretic peptide than did controls (70.8 +/- 46.6 pg/ml vs. 41.7 +/- 16.3 pg/ml, p < 0.025). No difference was found in human atrial natriuretic peptide/plasma renin activity between the two groups (87 +/- 160 pg/ng/hr vs. 44 +/- 73 pg/ng/hr, p = NS).(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of OKY 046, a thromboxane-synthase inhibitor, on renal function in nonazotemic cirrhotic patients with ascites

To assess the possible role of increased renal thromboxane A2 (TXA2) synthesis in nonazotemic patients with cirrhosis and ascites and to establish the potential beneficial effect of inhibitors of renal TXA2 production in this clinical setting, we administered OKY 046, a selective TXA2 synthase inhibitor, 200 mg t.i.d. for 5 days, to 9 nonazotemic cirrhotic patients with ascites and avid sodium retention. OKY 046 inhibited platelet TXA2 production, as expressed by serum thromboxane B2 (TXB2) concentration, by approximately 85% (p less than 0.001 vs. baseline values) and reduced urinary TXB2 excretion by 72% (p less than 0.01). A significant increase of approximately 19% in inulin clearance was observed during the treatment (from 61.0 +/- 8.42 to 72.7 +/- 7.45 ml/min, p less than 0.05), whereas renal blood flow was unchanged (from 408.50 +/- 19.97 to 424.50 +/- 30.84 ml/min). Drug administration did not affect positive sodium balance [sodium excretion was 4.67 +/- 1.22 mEq/day before drug administration and 6.26 +/- 1.05 mEq/day during drug administration (on day 7)], plasma renin activity, plasma aldosterone concentration, or the urinary excretion of prostaglandin E2, 6-keto prostaglandin F1 alpha, or prostaglandin F2 alpha. These results suggest that renal TXA2 synthesis contributes to the regulation of renal hemodynamics in nonazotemic cirrhotic patients with ascites and avid sodium retention, but it does not seem to affect sodium balance.     

Relationship between pre-TIPS hepatic hemodynamics and postoperative incidence of hepatic encephalopathy

BACKGROUND: Hepatic encephalopathy (HE) is one of the complications that have limited the effectiveness of transjugular intrahepatic portosystemic shunt (TIPS) most significantly. Up to the present, the predicting factors of HE post-TIPS have been debated controversially. This study was undertaken to verify the relationship between pre-TIPS intrahepatic hemodynamics and the incidence of post-TIPS HE. METHODS: The hepatic blood dynamics was evaluated in 41 patients with liver cirrhosis before TIPS and at one month after TIPS by ultrasonography. The patients were divided into two groups according to Doppler findings before TIPS: group 1, patients with prograde portal flow, and group 2, patients with hepatofugal or back-forth portal flow. The clinical characteristics (age, sex, etiology of liver disease, pre-TIPS Child-Pugh score, incidence of pre-TIPS HE, and portacaval pressure gradient), incidence of post TIPS HE, and pre-/post-TIPS hepatic arterial resistant index (RI) in the two groups were compared. The independent prognostic value of pre-TIPS variables for the onset of HE after TIPS, including age, Child-Pugh score, presence of HE before TIPS, and the pattern of portal flow, was tested with a multiple-factor regression analysis. RESULTS: No significant difference in age, etiology of liver disease, indications of TIPS placement, incidence of HE before TIPS, and portacaval gradient before and after TIPS was observed between the two groups; but liver failure was more severe in group 2 (P<0.05). The incidence of post-TIPS HE in group 2 was significantly lower than that in group 1 (P<0.01). Pre-TIPS, the RI of the hepatic artery in group 1 was significantly higher than that in group 2 (P<0.01). However, TIPS induced a significantly decreased RI in group 1 (P <0.01), but not in group 2. Multiple-factor regression analysis demonstrated that the pattern of portal flow before TIPS was closely associated with the onset of post TIPS HE. CONCLUSIONS: Pre-TIPS intrahepatic hetnodynamics is closely related to the incidence of post-TIPS HE. Hepatic hetnodynamics of patients with hepatofugal portal blood flow only changes a little after TIPS and still provides compensatory blood supply of the hepatic artery, and the hepatic function is less affected. Hence HE is unlikely. Hepatic hemodynamics of patients with prograde portal blood flow changes a lot after TIPS, and dual blood supply of the portal vein and hepatic artery changes into compensatory blood supply of the hepatic artery, and hepatic function suffers greatly in a short time. Thus HE is mostly likely.     

双介入治疗肝硬化门脉高压和脾功能亢进症

目的 探讨经颈内静脉肝内门体分流术(Transjugular intrahepatic portosystemic shunt,TIPS)和部分脾栓塞术(Partial splenic embolization,PSE)联合治疗肝硬化门脉高压及脾功能亢进症的疗效.方法 30例均为肝硬化门脉高压及脾功能亢进症患者,行TIPS术后再行PSE术.用超声检测门、脾静脉内径、门脉主干血流速度、脾脏长径和厚度;血细胞分析仪检测血象.结果 30例患者TIPS术后的门脉压力较术前降低(P＜0.01).门、脾静脉内径较术前缩小(P＜0.01),门脉主干血流速度较术前增快(P＜0.01);术后3～6月的脾脏长径及厚度、白细胞、血小板及血红蛋白较术前均无明显变化(P＞0.05).30例患者PSE术后的门、脾静脉内径、门脉主干血流速度与TIPS术后的比较无明显变化(P＞0,05);而白细胞、血小板及血红蛋白较TIPS术后明显升高(P＜0.01),脾脏长径和厚度较TIPS术后缩小(P＜0.05).结论 联合TIPS和PSE术治疗,能有效降低肝硬化患者的门脉压力,同时又能缓解脾功能亢进.     

Cyclic AMP-phosphodiesterases inhibitor improves sodium excretion in rats with cirrhosis and ascites.

BACKGROUND: The mechanisms responsible for renal dysfunction and sodium retention in cirrhosis remain unclear. Cyclic AMP (cAMP) regulates sodium reabsorption in the proximal nephron. This study investigates the role of cAMP metabolism in renal dysfunction in cirrhosis. METHODS: Renal function was studied by the clearance technique in anesthetized control and cirrhotic rats with or without ascites. cAMP phosphodiesterase (PDE) activity was measured in the renal cortex in vitro. Moroever, the effects on renal function of the intravenous administration of cAMP and rolipram, a powerful and specific cAMP-PDE4 inhibitor, were evaluated. RESULTS: In control and in non-ascitic cirrhotic rats, cAMP administration significantly increased sodium and phosphate excretions, but did not change these excretions in cirrhotic rats with ascites. cAMP-PDE activity was higher in ascitic than in control rats (P < 0.05). Rolipram infusion significantly increased sodium and phosphate excretion only in cirrhotic rats with ascites. CONCLUSION: These results suggest that increased renal cAMP-PDE activity is responsible for resistance to the natriuretic effects of cAMP in cirrhosis and plays a role in the development of ascites.     

Muscle sympathetic nerve activity and renal responsiveness to atrial natriuretic factor during the development of hepatic ascites.

PURPOSE: Sodium retention in cirrhosis has been attributed to an imbalance between vasoconstrictive antinatriuretic forces such as the sympathetic nervous system and vasodilatory natriuretic agents such as atrial natriuretic factor (ANF). With the development of refractory ascites, cirrhotic patients become unresponsive to the natriuretic effect of ANF. Animal data suggest that the sympathetic nervous system plays a key role in mediating the refractoriness to ANF. We therefore studied the relationship between sympathetic nerve activity (SNA) and the natriuretic response to ANF in normal subjects and cirrhotic patients. We also attempted to localize the intrarenal site of refractoriness to ANF by lithium clearance. PATIENTS AND METHODS: Twenty-six patients with biopsy-proven cirrhosis and seven age- and sex-matched normal volunteers were studied after a week of 20 mmol/day sodium intake and no diuretics. Muscle SNA was recorded from the peroneal nerve (microneurography) and correlated with responsiveness to a 2-hour ANF infusion. Lithium clearance was used as a marker of sodium reabsorption proximal to the intramedullary collecting duct, the main site of ANF action. Plasma norepinephrine, renin, and aldosterone levels were also determined. Patients were categorized into three groups: nine patients free of ascites (by ultrasonography), five ascitic patients who responded to a 2-hour ANF infusion (i.e., had a natriuretic response to ANF above 0.83 mmol/hour), and 12 ascitic patients who did not respond. RESULTS: Muscle SNA was greatly increased in the ascitic nonresponder patients compared with the normal subjects (64 +/- 4 versus 27 +/- 7 bursts/minute, p less than 0.001), moderately increased in ascitic responders (47 +/- 6 bursts/minute, p less than 0.05), but not significantly increased in nonascitic patients with cirrhosis (34 +/- 5 bursts/minute). SNA was positively correlated with plasma norepinephrine levels (r = 0.69; p less than 0.005) and inversely correlated with peak sodium excretion during the ANF infusion (r = -0.63; p less than 0.001). Plasma renin activity and aldosterone were markedly elevated in ascitic nonresponders, and normal in ascitic responders and nonascitic patients. Lithium clearance was reduced in ascitic patients compared with nonascitic patients, did not change after the ANF infusion, and correlated inversely with SNA (r = -0.61; p less than 0.01). CONCLUSION: These results support the concept that the sympathetic nervous system is a factor in renal sodium handling in cirrhosis, especially in the initiation of sodium retention and the development of refractory ascites. Refractoriness to ANF might be explained, at least in part, by increased neurally mediated sodium reabsorption proximal to the intramedullary collecting duct, the main site of ANF action.     

Increased sympathetic outflow in cirrhosis and ascites: direct evidence from intraneural recordings

OBJECTIVE: To determine if central sympathetic outflow is increased in patients with cirrhosis and ascites. PATIENTS: Eleven patients with cirrhosis and ascites, 8 patients with cirrhosis but without ascites, and 7 age-matched and 8 young healthy volunteers. METHODS: With subjects supine, direct microneurographic recordings of efferent post-ganglionic muscle sympathetic nerve activity were obtained from the peroneal nerve, and sympathetic burst frequency was compared with subjects' blood pressure, heart rate, sodium excretion, catecholamines, and plasma renin activity. All patients with cirrhosis were studied at least 5 days after withdrawal from all medications and after 7 days of a 20 mmol/d sodium, 1-L fluid-restricted diet. Age-matched volunteers were studied after 7 days of 20 mmol/d sodium intake and young healthy volunteers after 7 days of 150 mmol/d sodium intake. RESULTS: Sympathetic nerve activity in ascitic patients (65 +/- 15 bursts/min; mean +/- SD) was markedly increased, whether compared with patients with cirrhosis but without ascites (34 +/- 16 bursts/min; P less than 0.001), age-matched healthy volunteers on similar sodium intake (27 +/- 22 bursts/min; P less than 0.001), or young healthy subjects (21 +/- 10 bursts/min; P less than 0.001). The frequency of muscle sympathetic nerve discharge was directly related to plasma norepinephrine and epinephrine concentrations, plasma renin activity, and heart rate, all of which were increased in those patients with cirrhosis and ascites, and inversely related to 24-hour urinary sodium excretion, the fractional excretion of sodium, and subjects' pulse pressures. Sympathetic nerve activity fell from 78 to 6 bursts/min in one patient after liver transplantation. CONCLUSIONS: This study provides the first direct evidence that elevated plasma norepinephrine concentrations in patients with cirrhosis and ascites are due to increased central sympathetic outflow. Sympathetic nerve activity is not increased in patients with cirrhosis but without ascites. Because there were direct positive correlations of sympathetic nerve activity with plasma norepinephrine concentrations, plasma epinephrine concentrations, plasma renin activity, and heart rate, the increase in central sympathetic outflow in patients with cirrhosis and ascites appears generalized and not restricted to muscle nerves. The anti-natriuretic effects of parallel increases in renal and muscle sympathetic nerve activity could account for the inverse correlation between muscle sympathetic nerve activity and sodium excretion.     

Effects of amiloride on renal lithium handling in nonazotemic ascitic cirrhotic patients with avid sodium retention.

The reliability of lithium clearance as an index of distal fluid delivery in cirrhosis with ascites and in other clinical conditions characterized by low fractional sodium excretion has not yet been proven. In particular, lithium reabsorption in the amiloride-sensitive segment of the distal tubule, as evidenced in experimental studies, has not been excluded in such clinical conditions. Thus the acute effect of amiloride on renal lithium handling in 15 nonazotemic ascitic cirrhotic patients with avid sodium retention was evaluated after at least 5 days of controlled sodium intake. Renal plasma flow, glomerular filtration rate, fractional sodium excretion, fractional lithium excretion, fractional potassium excretion, fractional excretion of uric acid, plasma renin activity, plasma aldosterone and human atrial natriuretic peptide were evaluated before and for 6 hr after the administration of amiloride (20 mg/os). After amiloride administration a volume replacement scheme was enacted with intravenous amounts of saline solution, determined by the diuretic and natriuretic effect of the drug, to avoid volume depletion. Amiloride induced a prompt and sustained increase in fractional sodium excretion (from 0.28% +/- 0.09% to 1.0% +/- 0.41%, p less than 0.001) and a decrease in fractional potassium excretion (from 9.38% +/- 5.98% to 3.28% +/- 2.24%, p less than 0.0025), whereas it did not affect fractional lithium excretion and fractional excretion of uric acid. No change was observed in renal plasma flow, glomerular filtration rate, plasma renin activity, plasma aldosterone and human atrial natriuretic peptide. It was concluded that lithium is not reabsorbed in the amiloride-sensitive segment of the distal tubule in nonazotemic ascitic cirrhotic patients with avid sodium retention.     

Abnormal sympathetic and renal response to sodium restriction in compensated cirrhosis

It has been proposed that in liver cirrhosis portal hypertension causes splanchnic vasodilation and this induces blood volume expansion to maintain blood pressure. The current study was designed to explore the homeostatic response to sodium restriction, a maneuver aiming to contract blood volume, in compensated cirrhosis. Mean blood pressure, sympathetic nervous activity, and proximal sodium reabsorption were evaluated in 16 healthy control and 21 nonazotemic cirrhotic patients (11 without ascites and 10 with ascites) under two experimental conditions: after 4 days on a free sodium diet (basal condition) and after 4 days on a restricted sodium diet (40 mmol/day). No differences were observed in basal conditions in the above parameters between control and cirrhotic patients without ascites. However, cirrhotic patients with ascites showed lower basal values of mean blood pressure and higher basal levels of both plasma norepinephrine and fractional proximal sodium reabsorption than controls. Neither control nor cirrhotic patients with ascites showed significant changes in the measured parameters after sodium restriction. In contrast, in nonascitic patients, this maneuver induced an elevation in plasma norepinephrine concentration (164.4 +/- 24.6 vs. 270.1 +/- 24.9 pg/mL; mean +/- SEM; P less than 0.005) and in fractional proximal sodium reabsorption (86.4 +/- 2.1 vs. 91.8% +/- 0.5%; P less than 0.01). In addition, the nonascitic cirrhotic patients became hypotensive compared with controls (80.9 +/- 1.6 vs. 88.5 +/- 4.8 mm Hg; P less than 0.05) when subjected to the low-sodium diet. In patients without ascites, under conditions of sodium restriction, the decrease in mean arterial pressure correlated inversely with the increase in plasma norepinephrine concentration (r = -0.713; P less than 0.05), whereas the levels of plasma norepinephrine correlated directly with fractional proximal sodium reabsorption (r = 0.893; P less than 0.01). These findings suggest that ineffective circulatory volume is detected in nonascitic cirrhotic patients only under conditions of sodium restriction, but it is always present in cirrhotic patients with ascites, irrespectively of the amount of sodium in the diet. These results are compatible with the existence of fixed arterial vasodilation in cirrhosis.     

QT interval in patients with non-cirrhotic portal hypertension and in cirrhotic patients treated with transjugular intrahepatic porto-systemic shunt

BACKGROUND/AIMS: A prolonged QT interval is frequent in chronic liver disease and its aetiology remains unsettled. The study's aim was to assess the role of portal hypertension in the pathogenesis of QT prolongation. METHODS: We measured the QT interval in: (1) 10 patients with non-cirrhotic portal hypertension (NCPH) and preserved liver function; (2) 19 cirrhotic patients before, 1-3 and 6-9 months after transjugular intrahepatic porto-systemic shunt (TIPS) insertion. RESULTS: Baseline corrected maximum QT interval (QTcmax) was prolonged (>440 ms) in eight NCPH and 16 cirrhotic patients, and its value did not differ between the two groups (453+/-8 vs. 465+/-6 ms, P=NS). No patients showed an abnormal baseline QT dispersion. In cirrhotic individuals, QTcmax further increased 1-3 months after TIPS (P=0.042), thereafter remaining steadily elevated. QT dispersion only increased at the second post-TIPS determination (P=0.030). Such changes occurred despite no deterioration of liver function, plasma electrolytes and haemoglobin. CONCLUSIONS: QT interval is frequently prolonged in patient with both non-cirrhotic and cirrhotic portal hypertension and portal decompression by TIPS worsens this abnormality. These results suggest that the porto-systemic shunting is responsible for the altered ventricular repolarisation possibly through a dumping into the systemic circulation of splanchnic-derived cardioactive substances.     

经颈静脉肝内门体分流术后早期肝性脑病的危险因素

目的 研究经颈静脉肝内门体分流术(TIPS)术后早期肝性脑病(HE)的危险因素,并观察术后HE与患者长期生存情况的相关性.方法 收集2003年1月-2008年12月接受TIPS治疗食管胃底静脉曲张出血或顽固性腹水的患者.对术后3个月内有HE(术后早期HE组)和术后3个月内无HE(无术后早期HE组)的两组患者的临床特征进行单因素分析和多因素logistic回归分析,并对两组患者的生存情况进行分析比较.结果 共收集190例患者资料,中位随访时间为30.5个月(四分位间距为30个月).术前血清纤维蛋白酶原(OR=0.414,P=0.023)及Child-Pugh评分(OR=1.744,P=0.024)与术后早期HE相关.并且术后早期HE组患者与无术后早期HE组患者的3年累积生存率分别为44.9%(95%可信区间为53.5%～36.3%)和79.5%(95%可信区间为83.2%～75.7%).结论 TIPS术前高Child-Pugh评分及低血清纤维蛋白酶原的患者术后3个月内发生HE的可能性大.发生术后早期HE的患者比不发生术后早期HE患者长期累积生存率低.

Abstract：

Objective To identify the risk factors of early post-TIPS hepatic encephalopathy (HE) and the long-time survival of patients with or without early post-TIPS HE. Methods Consecutive cirrhotic patients who underwent TIPS for variceal rebleeding or refractory ascites in our center from January 2003 to December 2008 were included in this study. More than 60 clinical characteristics were enrolled in univariate analysis and logistic regression analysis to define the risk factors of HE in 3 months after TIPS procedure (early post-TIPS HE). The long-time survival of patients with or without early post-TIPS HE was compared by Cox regression with several covariates. Results According to our inclusion criteria, 190 patients were included. The median follow-up was 30.5 months. Lower serum concentration of fibrinogen and higher Child-Pugh score were the independent risk factors for suffering early post-TIPS HE. Patients without early post-TIPS HE after TIPS showed better prognosis than those with early post-TIPS HE after TIPS (P = 0.044). Conclusion Patients with lower serum fibrinogen and higher Child-Pugh score before TIPS might be more probably attacked by early post-TIPS HE which indicated worse long-term survival.