Evidence-based care at the end of life

Ascites due to cirrhosis can usually be managed successfully by dietary sodium restriction and carefully monitored diuretic therapy. However, paracentesis with an albumin infusion is a relatively safe alternative that has gained widespread acceptance. Other plasma expanders offer a cheaper alternative to albumin. Other recently developed techniques include peritoneovenous shunt and transjugular intrahepatic portosystemic stent shunt. Each of these is associated with an operative mortality and substantial complications, but for diuretic-resistant ascites a peritoneovenous shunt has comparable results to paracentesis/albumin. For patients with spontaneously occurring renal failure the prognosis is poor. None of the above treatments improves renal function. Management should therefore be symptomatic with paracentesis as necessary.     

A controlled trial of choleretic and hepatoprotective actions of Livzon and dehydrocholic acid in a model of obstructive jaundice in albino rats

Ascites becomes refractory to medical treatment in nearly 10% of cirrhotic patients, who then require repeated large-volume paracentesis. In this prospective study we evaluated the use of transjugular intrahepatic portosystemic shunt (TIPS) in 30 patients with refractory ascites. TIPS was successful in all and resulted in a 54% reduction in portacaval gradient (from 22.8 +/- 0.8 to 10.4 +/- 0.6 mm Hg). Ascites became easily controlled with diuretics in 26 patients following TIPS. Ascites recurrence associated with shunt stenosis was observed during follow-up in eight patients; revision could be undertaken in five of them and resulted in good control of ascites. In responders, a marked decrease in plasma aldosterone and renin activity, a reduction in serum creatinine, and a rise in urinary sodium excretion were observed. Creatinine and inulin clearances improved significantly; PAH clearance remained unchanged. However, new-onset or worsening hepatic encephalopathy was seen in 14 patients. Severe disabling chronic encephalopathy occurred in five patients; it could be reversed successfully by balloon occlusion of the shunt in three. The cumulative survival rate was 41 and 34% at 1 and 2 years, respectively. In summary, TIPS can control refractory ascites in a majority of patients but is associated with a high rate of chronic disabling HE. In addition, the survival rate is poor. Randomized trials are needed to evaluate the exact role of TIPS in the management of refractory ascites. It is unlikely to improve survival but can ameliorate quality of life in nontransplant candidates and be useful as a bridge to transplantation, in particular, to improve denutrition associated with longstanding tense ascites.     

Current treatment of ascites and spontaneous bacterial peritonitis in Spain: analysis of a survey of gastroenterologists and hepatologists

During the XXII Congress of the Spanish Association for the Study of the Liver a questionnaire was distributed with the aim of describing the current therapeutic attitude of those attending the meeting, concerning two of the most frequent complications of cirrhosis: ascites and spontaneous bacterial peritonitis (SBP). One hundred twelve of the 135 physicians who answered the questionnaire (83%) use to treat tense ascites by therapeutic paracentesis, while 86 physicians (63.7%) managed moderate ascites with diuretics, with spironolactone being the drug most commonly used (n = 117; 87.3%). The most used diuretic schedule for the treatment of ascites was the isolated administration of spironolactone. Frusemide was associated with spironolactone only when moderate or high doses of the latter were found to be insufficient for increasing urinary sodium excretion and eliminating ascites. Following therapeutic paracentesis however, 79 of those surveyed (58.3%) administered a combination of both diuretics on initiation to avoid reaccumulation of ascitic fluid. Sixty-eight of the physicians (50.3%) used transhepatic intrajugular portosystemic shunt in the treatment of refractory ascites. Cefotaxime was the antibiotic most widely used in the treatment of SBP (n = 119; 88%). Most of the physicians surveyed performed prophylaxis of this infection (generally by the oral administration of norfloxacin) in patients with a previous history of SBP (n = 125; 92.6%) or an episode of gastrointestinal hemorrhage (n = 108; 80%) but not in those patients with no previous history of SBP and with low protein concentrations in the ascitic fluid (n = 40; 29.6%). On the appearance of SBP in patients undergoing prophylactic treatment, cefotaxime remained the antibiotic of choice (n = 104; 79%).     

Role of surgical therapy in the treatment of refractory ascites

In 5-10% of cases ascites is not controlled by medical therapy and is defined refractory. These patients may be submitted to one of the four following surgical options: portal-systemic shunt, peritoneo-venous shunt, transjugular intrahepatic portal-systemic shunt, orthotopic liver transplantation. Although the portal-systemic shunt is efficient in clearing ascites, it does not improve the survival, which depends on liver function, and it is complicated by an important incidence of encephalopathy. Since the patients with refractory ascites and good hepatic risk are not usually many, it is possible to understand why derivative surgery has been disappointing with this indication. Although the peritoneo-venous shunt is associated with a significant rate of valve obstruction, it is an easy, effective and not expensive treatment. So, till now, it has been considered the first choice procedure of refractory ascites, if any situations, determinating the onset of postoperative complications, are not present. Recently a new method has been introduced in the therapy of portal hypertension, the transjugular intrahepatic portal-systemic shunt. This is a bloodless portal-systemic derivation and so it has caused great enthusiasm even if the available data are insufficient to give a definitive opinion on its role in management of ascites. Certainly the liver transplantation, which presents the great advantage to treat both the cirrhosis and its complications, seems to be the most rational therapy for these patients. However, at least for this moment, the well-known absence of organ donors makes still actual the palliative surgical measures.     

Methylphenidate does not modify the impact of response frequency or stimulus sequence on performance and event-related potentials of children with attention deficit hyperactivity disorder

Nephrogenic ascites is an entity that manifests as refractory ascites in patients with end-stage renal disease, where portal hypertensive, infectious, and malignant processes have been excluded. Most of these patients are undergoing hemodialysis. Hypoalbuminemia may predispose these uremic patients to ascites formation. The characteristics of the ascitic fluid suggest that the pathogenesis of the ascites is an alteration in peritoneal membrane permeability or impaired resorption due to peritoneal lymphatic channel obstruction. The ascitic fluid has a high protein content, low serum-ascites albumin gradient (SAAG), and low leukocyte count. Daily hemodialysis should be the initial therapy and is successful in one-third to three-fourths of patients within 3 weeks. Continuous ambulatory peritoneal dialysis or insertion of a peritoneovenous shunt are alternative treatments. Other therapies include instillation of intraperitoneal corticosteroids and binephrectomy, which have less predictable outcomes. Renal transplantation is the definitive treatment for nephrogenic ascites. Control of ascites reverses the progressive cachexia associated with uncontrolled disease, resulting in improved quality of life and survival approaching that of end-stage renal disease patients without ascites.     

Nephrotoxicities of nonsteroidal anti-inflammatory drugs

While the relative incidence of serious nephrotoxicities in the population consuming nonsteroidal anti-inflammatory drugs (NSAIDs) is very low, the frequency of adverse events in patients at risk has considerably increased due to the rising popularity of the use of the drugs in recent years. Under normal conditions, NSAIDs have relatively little effect on the kidney because of low renal production of prostaglandins. However, in the presence of renal hypoperfusion in which local synthesis of vasodilator prostaglandins is increased to protect the glomerular hemodynamics and to maintain appropriate renal tubular transport of fluid and electrolytes, inhibition of prostaglandin synthesis by NSAIDs can lead to vasoconstrictive acute renal failure as well as fluid and electrolyte disorders such as sodium retention and resistance to diuretics, hyponatremia and hyperkalemia. Conditions that increase the risk for NSAID-induced nephrotoxicities include volume depletion from diuretics and other causes, edematous states such as congestive heart failure and cirrhosis of the liver, old age and underlying renal disease, especially in the presence of renal functional impairment. In addition, renal parenchymal diseases may develop in susceptible patients taking NSAIDs. These include acute tubulointerstitial nephritis, frequently associated with nephrotic syndrome, and chronic progressive renal disease, with or without renal papillary necrosis. Rare cases of vasculitis and glomerulonephritis have also been reported. Finally, NSAIDs may aggravate hypertension by interacting with antihypertensive drugs, especially with diuretics and beta-blockers. Withdrawal of NSAIDs in patients at risk can frequently reverse or improve the nephrotoxicities. It is recommended that physicians be aware of the clinical settings that increase the risk for NSAID-induced nephrotoxicities and take preventive or therapeutic measures accordingly.     

Are diuretics in the treatment of portal hypertension rational?]

When ascites develops in a patient with cirrhosis his probability to survive the following 2 years amounts to 50%. It is determined essentially by the residual functional capacity of the liver. In 80 to 90% of patients ascites due to portal hypertension can be managed by salt restriction and diuretics. Aldosterone-antagonists are more efficient and have fewer side effects than loop diuretics. They may lower portal tension by an additional direct effect on the vasculature. A daily reduction of body weight of 0.5 to 0.75 kg should not be exceeded because (prerenal) renal failure may become a threat. If diuretics are insufficient or when a rapid therapeutic success is needed paracentesis of 4-6.1 is a safe option if intravascular volume is substituted simultaneously. Albumin has proven superior to other plasma expanders (protection of renal function, survival). Only in the few patients whose ascites is intractable by the forementioned measures should alternatives such as peritoneo-, venous or porto-systemic shunts (nowadays mostly by interventional techniques via a transjugular catheter) be evaluated. The only treatment which not only attacks ascites symptomatically but also corrects the underlying disease is liver transplantation.     

Evaluation of trauma care in a developing country highlighted by a major aircraft accident

Transjugular intrahepatic portosystemic shunt (TIPS) is a side-to-side portocaval shunt for threatening complications of portal hypertension. The purpose of this study was to evaluate in first 33 patients indicated for TIPS insertion in our institution the efficacy, complications, and mortality. Indication was failure of sclerotherapy or ligation in control either of acute (n = 4) or repetitive (n = 25) variceal bleeding and refractory ascites (n = 4). The technical success rate was with 70% (21/30) lower than expected, but the complication rate was also very low. There were no fatal complications, only one subcapsular liver hematome, and in one patient repetitive punction of biliary tract. The 30-days mortality was 10% (2/21) and rebleeding was 15% (3/20), caused always by thrombosis of the shunt. TIPS seems to be a promising therapeutic procedure after failed endoscopic therapy of esophageal varices without the mortality and morbidity of an open surgical procedure. Recent indications for TIPS are acute variceal hemorrhage refractory to endoscopic treatment and recurrent variceal bleeding despite sclerotherapy or band ligation. Promising seems to be TIPS insertion in the treatment of refractory ascites.     

Urinary endothelin-like immunoreactivity in patients with cirrhosis

BACKGROUND/AIMS: To investigate a possible relationship between the renal production of endothelin and the presence of renal dysfunction and activation of vasoactive systems in cirrhosis, the urinary excretion and the circulating plasma levels of immunoreactive endothelin (irET) and the plasma levels of vasoactive hormones were measured in 19 healthy subjects, 12 cirrhotic patients without ascites and 39 patients with ascites and different degrees of renal dysfunction. METHODS: The urinary excretion and the circulating levels of irET were assessed after 5 days on a 40 mEq sodium diet and off diuretics. Renal function parameters and the plasma levels of vasoactive hormones were also measured. RESULTS: Patients with and without ascites had similar values of urinary irET as compared with healthy subjects (30+/-3, 31+/-3 and 29+/-2 ng/day, respectively, p>0.10). By contrast, patients with ascites had higher circulating levels of irET (15+/-1.2 pg/ml) than patients without ascites and healthy subjects (11+/-1.6 and 5+/-0.4 pg/ml, p<0.01). In patients with cirrhosis, no correlation was found between urinary irET and circulating irET. Moreover, urinary irET did not correlate with liver tests, serum and urine sodium, glomerular filtration rate or vasoactive substances. Patients with hepatorenal syndrome had similar urinary irET to patients with ascites without hepatorenal syndrome. CONCLUSIONS: Urinary excretion of irET is not increased in cirrhotic patients with ascites and does not correlate with abnormalities in renal function.     

Drug administration in patients with renal insufficiency. Minimising renal and extrarenal toxicity

Renal insufficiency has been associated with an increased risk of adverse effects with many classes of medications. The risk of some, but not all, adverse effects has been linked to the patient's degree of residual renal function. This may be the result of inappropriate individualisation of those agents that are primarily eliminated by the kidney, or an alteration in the pharmacodynamic response as a result of renal insufficiency. The pathophysiological mechanism responsible for alterations in drug disposition, especially metabolism and renal excretion, is the accumulation of uraemic toxins that may modulate cytochrome P450 enzyme activity and decrease glomerular filtration as well as tubular secretion. The general principles to enhance the safety of drug therapy in patients with renal insufficiency include knowledge of the potential toxicities and interactions of the therapeutic agent, consideration of possible alternatives therapies and individualisation of drug therapy based on patient level of renal function. Although optimisation of the desired therapeutic outcomes are of paramount importance, additional pharmacotherapeutic issues for patients with reduced renal function are the prevention or minimisation of future acute or chronic nephrotoxic insults, as well as the severity and occurrence of adverse effects on other organ systems. Risk factors for the development of nephrotoxicity for selected high-risk therapies (e.g. aminoglycosides, nonsteroidal anti-inflammatory drugs, ACE inhibitors and radiographic contrast media) are quite similar and include pre-existing renal insufficiency, concomitant administration of other nephrotoxins, volume depletion and concomitant hepatic disease or congestive heart failure. Investigations of prophylactic approaches to enhance the safety of these agents in patients with renal insufficiency have yielded inconsistent outcomes. Hydration with saline prior to drug exposure has given the most consistent benefit, while sodium loading and use of pharmacological interventions [e.g. furosemide (frusemide) dopomine/dobutamine, calcium antagonists and mannitol] have resulted in limited success. The mechanisms responsible for altered dynamic responses of some agents (benzodiazepines, theophylline, digoxin and loop diuretics) in renally compromised patients include enhanced receptor sensitivity secondary to the accumulation of endogenous uraemic toxins and competition for secretion to the renal tubular site of action. Application of the pharmacotherapeutic principles discussed into clinical practice will hopefully enhance the safety of these agents and optimise patient outcomes.     

Tetracycline-induced pleural symphysis for recurrent hydrothorax complicating cirrhosis. A new approach to treatment

Two patients with cirrhosis and ascites complicated by extensive unilateral pleural transudates refractory to therapy with dietary sodium restriction, diuretics, and repeated thoracentesis were successfully managed by tetracycline-induced pleural symphysis. The intrapleural instillation of this antibiotic prevented the recurrence of the effusion and substantially relieved the patients' symptoms with minimal undesirable side effects.     

Refractory ascites due to portal vein thrombosis in liver cirrhosis--report of two cases

Portal vein thrombosis as a complication of liver cirrhosis has been reported to be extremely rare in Japan, as compared with European countries. There are few reports discussing the correlation of portal vein thrombosis with refractory ascites. Between January 1994 and December 1995, 20 cases (91%) of 22 patients with liver cirrhosis with ascites admitted to our hospital responded well within 2 months to a combination therapy of diuretics and albumin infusion, and the other two cases (9%) with refractory ascites were associated with portal vein thrombosis. The ascites in the first patient continued for 1 year, despite diuretics and albumin infusion therapy, and portal vein thrombosis was confirmed by autopsy. The ascites in the other patient continued for more than 4 months, and portal vein thrombosis was detected by ultrasound. Portal vein thrombosis was not found in the other 20 cirrhotic patients with ascites. These two cases suggest that portal vein thrombosis may be a contributing factor to refractory ascites in patients with decompensated liver cirrhosis.     

Transjugular intrahepatic portosystemic shunts (TIPS)

Transjugular intrahepatic portosystemic shunt (TIPS) is a procedure recently introduced for the management of complications of portal hypertension. TIPS can be placed in the liver with relative ease by a skilled radiologist with a low risk of mortality. The major complications following the procedure are infection, especially in patients undergoing emergency TIPS, intra-abdominal haemorrhage from capsular punctures, and long-term problems related to encephalopathy and stenosis of the shunt. Encephalopathy is more of a problem in older patients with wide diameter shunts. Stenosis of the shunt is related to pseudo-intimal hyperplasia, probably related to transection of bile ductules during placement of the shunt. In view of the high rate of encephalopathy and stenosis following the shunt, a careful follow-up of all patients, including ultrasonographic and angiographic examination of the shunt, is mandatory. TIPS is used predominantly for the control of acute variceal haemorrhage, prevention of recurrent variceal bleeding, and refractory ascites when conventional treatment has failed. However, the role of TIPS in the management of complications of portal hypertension still awaits the outcome of clinical trials.     

Cardiovascular, renal, and neurohumoral responses to single large-volume paracentesis in patients with cirrhosis and diuretic-resistant ascites

OBJECTIVE: Large volume paracentesis is an effective treatment for refractory ascites, but the need for routine infusion of albumin or other volume expanders remains controversial. The aim of this study was to assess the short term effects of a single 5-L paracentesis without albumin replacement on total central blood volume, systemic and renal hemodynamics, sodium homeostasis, and neurohumoral factors. PATIENTS AND METHODS: Twelve patients with biopsy-proven cirrhosis and tense, diuretic-resistant ascites were studied before and 48 h after a single 5-L paracentesis without albumin infusion. Systemic hemodynamics and total central blood volume were assessed using radionuclide angiography. Glomerular filtration rate and effective renal plasma flow were measured by inulin and para-aminohippurate clearances, respectively. Lithium clearance was used as an index of proximal tubular reabsorption of sodium. In addition, plasma concentrations of neurohumoral factors were determined. RESULTS: Total central blood volume was 2.41 +/- 0.33 L/m2 (mean +/- SEM) before and 2.34 +/- 0.18 L/m2 48 h after large volume paracentesis (p = 0.76). Similarly, no differences were detected in the cardiac index, glomerular filtration rate, effective renal plasma flow, urinary sodium excretion, hematocrit, plasma renin activity, or concentrations of plasma aldosterone, norepinephrine, or atrial natriuretic factor. CONCLUSIONS: A single large volume paracentesis without albumin replacement causes no disturbances in systemic and renal hemodynamics 48 h after the procedure. These results suggest that a single 5-L paracentesis without albumin infusion is a safe and satisfactory short term option for the management of patients with cirrhosis and tense, diuretic-resistant ascites.     

Experimental, clinical, and metabolic results of side-to-side portacaval shunt for intractable cirrhotic ascites

BACKGROUND: Intractable ascites, refractory to medical therapy, occurs in approximately 10 percent of patients with ascites from cirrhosis and is almost always fatal. Sinusoidal hypertension resulting from hepatic venous outflow obstruction plays a primary role in the pathogenesis of cirrhotic ascites and provides the rationale for decompression of the liver by side-to-side portacaval shunt in treatment of intractable ascites. This report presents the experimental basis for the use of side-to-side shunt and long-term results of a prospective study in 34 selected patients with intractable cirrhotic ascites. STUDY DESIGN: In the experimental studies, hepatic venous outflow obstruction and massive ascites were produced in dogs by ligation of the hepatic veins, and the effect of portacaval shunts on ascites, thoracic duct lymph flow, and aldosterone secretion were measured. In the clinical study, 34 carefully selected patients with cirrhosis (91 percent alcoholic) and truly intractable ascites (failure of medical therapy for 5 to 24 months) underwent side-to-side portacaval shunt. The effects on ascites, survival, metabolic abnormalities, and quality of life were studied prospectively during follow-up that was longer than 5 years in all but two patients. Quantitative Child's risk classes in percent of patients were A in 0, B in 68, and C in 32. RESULTS: In the experimental studies, side-to-side portacaval shunt permanently relieved severe ascites, reduced the 13-fold increase in thoracic duct lymph flow rate to almost normal, and abolished the aldosterone hypersecretory response to minimal hepatic venous outflow obstruction. End-to-side portacaval shunt was much less effective. In the clinical study, side-to-side portacaval shunt reduced mean portal vein-inferior vena cava pressure gradient from 282 mm saline to 4 mm and permanently relieved all patients of ascites without subsequent requirement of diuretic therapy. Two patients who died of hepatoma, and one who died of heart failure developed terminal ascites. Thirty-day mortality rate was 6 percent, and long-term survival rates at 5, 10, and 15 years were 75 percent, 74 percent, and 73 percent. In metabolic studies, side-to-side shunt produced marked diuresis and natriuresis and abolished hypersecretion of aldosterone. Quality of life was generally improved as a result of a low incidence of recurrent portal-systemic encephalopathy (6 percent), abstinence from alcohol in 91 percent, improvement in liver function in 81 percent, and improvement in Child's risk class. The portacaval anastomosis remained permanently patent in every patient. CONCLUSIONS: Side-to-side portacaval shunt is very effective treatment of intractable ascites from cirrhosis. Our results are attributable to careful selection of patients, an organized system of care, and a program of rigorous, lifelong follow-up that emphasizes abstinence from alcohol and dietary protein restriction.     

Ascites and renal functional abnormalities in cirrhosis. Pathogenesis and treatment

In the past few years, there have been important advances in the field of pathogenesis and management of ascites and hepatorenal syndrome in cirrhosis. A new pathogenic theory of ascites and renal dysfunction in cirrhosis has been presented and previously ill-defined conditions, such as refractory ascites and hepatorenal syndrome, have been defined precisely. The link between the diseased liver and the disturbances in renal function and vasoactive systems is not completely known, but a large body of evidence indicates that it consists of a circulatory dysfunction that affects mainly the arterial circulation and is characterized by an inability to maintain an effective arterial blood volume within normal limits. The research on the mechanisms of this circulatory dysfunction will give valuable information in the design of more pathophysiologically oriented therapeutic approaches to the management of ascites.     

Management of ascites in cirrhosis

Ascites is one of the earliest and most common complications of patients with cirrhosis. A typical circulatory dysfunction characterized by arterial vasodilation, high cardiac output and stimulation of vasoactive systems is commonly present in these patients and is associated with a poor prognosis. The treatment of ascites has been based on the combination of a low-sodium diet and the administration of diuretics. The reintroduction of paracentesis and the recent introduction of the transjugular intrahepatic portosystemic shunt (TIPS) are the most relevant innovations in the treatment of ascites during the past two decades, although controlled trials in large series of patients are needed to delineate whether TIPS is a safe and useful treatment for these patients.     

Captopril and spironolactone therapy for refractory congestive heart failure

Short- and long-term clinical effects of the angiotensin-converting enzyme (ACE) inhibitor captopril in severe congestive heart failure (CHF) were evaluated during a 3-year open study of 124 inpatients with New York Heart Association (NYHA) functional class III or IV CHF refractory to treatment with cardiac glycosides and high doses of loop diuretics. Captopril was added to each patient's regimen, which comprised combinations of furosemide (124 patients), digitalis (117 patients), and spironolactone (90 patients). By the end of the first month of captopril administration, improvement in NYHA functional class was seen in 89 patients (72%). During the first year of captopril treatment, the number of hospital admissions and hospital days declined significantly (p < 0.001) and functional class improved significantly (p < 0.001). Although most patients tolerated captopril well, 44% experienced hypotension, which in 10% of patients necessitated termination of captopril therapy. Although mean serum potassium levels tended to increase, serious hyperkalemia did not occur. After 1 year, a subset of 30 patients who had not initially received spironolactone deteriorated clinically and manifested increasing urinary aldosterone levels. Hypotension precluded increasing the captopril dose, but introduction of spironolactone improved clinical status in this cohort. The results suggest that rational therapy for severe CHF includes addition of the aldosterone antagonist spironolactone to low doses of captopril (or another ACE inhibitor) and high doses of loop diuretics, provided renal function is adequate.     

Influence of probenecid and spironolactone on furosemide kinetics and dynamics in man

The pharmacokinetics and pharmacodynamics following administration of furosemide (40 mg intravenously) have been studied before and after treatment with probenecid (0.5 gm orally every 6 hr for 3 days) and spironolactone (200-mg initial oral dose followed by 50 mg every 6 hr for 3 days) in 6 normal male subjects. Urine losses during each study period were replaced with saline-dextrose-KCl intravenously. The study was performed with the use of a Latin-square design. Probenecid pretreatment induced significant reductions in renal clearance of furosemide by 78%, the extrarenal clearance by 56%, and the volume of distribution by 52%. As a consequence, furosemide half-life was increased by 54%. Probenecid significantly reduced the rate of sodium excretion at all plasma concentrations of furosemide, but the ratio between urinary furosemide concentration and urinary sodium concentration was not altered. Since the proportion of furosemide excreted unchanged in the urine was not markedly changed, total diuretic response was not influenced by probenecid. There was no evidence of any pharmacokinetic interaction between spironolactone and furosemide. The relationship of furosemide kinetics to dynamics observed in these studies confirms that, in man, the diuretic response is determined by drug that reaches the renal tubule rather than the drug level in plasma.