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CLINICAL MANAGEMENT OF ASCITES AND ITS COMPLICATIONS
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CLINICAL MANAGEMENT OF ASCITES AND ITS COMPLICATIONS Suchat Wongcharatrawee, MD, and Guadalupe Garcia-Tsao, MD
Ascites is the accumulation of fluid in the peritoneal cavity and is a potentially lethal complication of cirrhosis. To place the management of cirrhotic ascites in the context of its pathophysiology, a brief overview of the currently most widely accepted mechanisms is first outlined. The remainder of this article is devoted to the management of ascites and two of its most severe complications, hepatorenal syndrome (HRS) and spontaneous bacterial peritonitis (SBP).
PATHOPHYSIOLOGY OF ASCITES
Portal hypertension can lead to exudation of fluid either from splanchnic capillaries or from hepatic sinusoids. Clinical and experimental evidence indicates that in cirrhosis the hepatic sinusoids are the main source of ascites. Sinusoidal hypertension results from hepatic venous outflow blockage caused by regenerative nodules and fibrosis. Sinusoidal hypertension alone, however, is not sufficient for the continuous formation of ascites. Plasma volume expansion, through sodium and water retention, allows the replenishment of the intravascular volume and is the other essential factor in the pathogenesis of cirrhotic ascites.
From the VA Connecticut Healthcare System and Section of Digestive Diseases, Yale University School of Medicine, New Haven, Connecticut
CLINICS IN LIVER DISEASE VOLUME 5 * NUMBER 3 * AUGUST 2001
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Clinically Significant Portal Hypertension
It is important to determine whether a threshold of portal (sinusoidal) pressure is necessary for the formation of ascites. If so, reduction of sinusoidal pressure below this level would constitute a therapeutic goal. As in the development of gastroesophageal varices, in which a minimal portal pressure gradient of 10 to 12 mm Hg is necessary (but not sufficient), the development of ascites seems to require a minimal portal pressure gradient of 12 mm Hg.13,55 In one study, in which portal pressure was determined indirectly by hepatic vein catheterization, every patient with ascites had an hepatic venous pressure gradient (a measure of sinusoidal pressure) of at least 12 mm Hg.55Another study showed that in most patients who developed ascites as the result of dysfunction of a transjugular intrahepatic portosystemic shunt (TIPS) the portal pressure gradient had risen to levels of 12 mm Hg or more.13 In fact, a recent consensus conference on portal hypertension, defined clinically sign$cant portal hypertension as a portal pressure gradient of 10 mm Hg or more.15 Decreased Effective Arterial Blood Volume
Even though sinusoidal hypertension is necessary for the accumulation of ascites in the peritoneal cavity, it alone is not sufficient for ascites formation. Without replenishment of fluid in the intravascular space, leakage of fluid into the peritoneal cavity would be a self-limited process. This replenishment is accomplished through sodium retention, the most common physiologic abnormality in cirrhotic patients with ascites. In fact, sodium retention has been shown to precede the development of as cite^.^^, 86 In more advanced cirrhosis, in addition to sodium retention, an abnormality in water handling (i.e., an impairment in free water excretion) results in hyponatremia. In even more advanced stages, renal vasoconstriction results in the HRS. Several theories have been proposed to explain the occurrence of sodium retention, abnormalities in water handling, and renal vasoconstriction in cirrhotic patients. The most widely accepted theory is the arterial vasodilation theory that attributes all these abnormalities to arterial 75 Blood volume sensed by vascular baroreceptors is va~odilatation.~~, defined as efective arterial blood volume (EABV). Arterial vasodilation results in reduction of EABV and leads to stimulation of neurohumoral systems, specifically the renin-angiotensin-aldosterone system (RAAS), the sympathetic nervous system, and the non-osmotic release of antidiuretic hormone. Activation of RAAS and the sympathetic nervous system result in sodium retention and, in extreme cases, in renal vasoconstriction. Activation of antidiuretic hormone leads to abnormalities in water handling and hyp~natremia.~~ This theory is consistent with the sequence of events seen in animal models in which vasodilatation has been shown to precede sodium retenti0n.l The presence of normal or
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low levels of plasma renin activity in patients with cirrhosis and ascites suggests that, in some cases, sodium retention is unrelated to vasodilation (primary renal sodium retention). Although the cause of vasodilatation in cirrhosis is still unclear, there is growing evidence, both in animal models and in humans, that an increased production of the vasodilator nitric oxide (NO) in the splanchnic and peripheral circulation is involved in vasodilation. Blocking NO synthesis has been shown to raise systemic blood pressure and increase sodium excretion while reducing the activation of the RAAS.45,50, 51 Other endogenous substances (e.g, glucagon) have also been shown to have vasoactive properties in patients with portal hypertension but seem to be of lesser importance.61,77 The mechanism by which NO production is increased in cirrhotic animals with ascites is still unknown. A recent study, however, identified a subgroup of cirrhotic animals with ascites, those with bacterial translocation, that had even higher levels of NO and further va~odilatation.~~ Bacterial translocation is the phenomenon by which viable microorganisms from the intestinal lumen migrate to mesenteric lymph nodes and other extraintestinal sites. In addition to worsening the vasodilatory state of cirrhosis, bacterial translocation has also been suggested as being one of the main mechanisms in the pathogenesis of SBP, a major complication of ascites. MANAGEMENT OF ASCITES
Even though treatment of ascites is not accompanied by a survival benefit, ascites should be treated to improve quality of life and to prevent serious complications of ascites, particularly HRS and SBP. As for any sodium-retaining state, achieving a negative sodium balance is the mainstay of therapy, and most patients respond to sodium restriction and diuretics. Based on the current understanding of the pathophysiology of ascites, patients who do not respond to diuretics or who develop complications of diuretics can receive treatments aimed at improving the EABV or reducing the hepatic sinusoidal pressure. Figure 1provides a summary of these potential therapeutic targets.
Sodium Restriction Sodium restriction is the first-line therapy for treatment of ascites. It is important to educate patients and their caregivers regarding the amount of sodium in various food substances. The goal is to achieve a negative sodium balance, that is, a urinary sodium excretion greater than dietary sodium intake. In approximately 10% of patients with ascites, restriction of sodium intake to 44 to 66 mEq/day (22 mEq = 1 g of sodium = 2.6 g of dietary salt) is sufficient to cause a negative
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Pathogenesis
Treatment
Cirrhosis
Transplantation
Portal (sinusoidal) hypertension
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TIPS
Arteriolar vasodilation
Systemic vasoconstrictors
Decreased effective blood volume
Plasma volume expanders; PVS, TIPS
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*
Activation of neiohumoral systems
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Sodium and water retention
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Ascites
Sodium restriction; Diuretics Paracentesis, PVS
Figure 1. Pathogenesis of ascites and therapeutic targets. *Activation of neurohumoral systems is a compensatory mechanism that maintains blood pressure. Renidangiotensin blockade can lead to significant arterial hypotension and has not resulted in ascites improvement. TIPS = transjugular intrahepatic portosystemic shunt, PVS = peritoneovenous shunt.
sodium balance and eliminate ascites. Further restriction of sodium is unrealistic and difficult to achieve. Patients who are likely to respond to sodium restriction are those who have a relatively high baseline urinary sodium excretion (> 50 mEq/day) and those in whom only a minimal or moderate amount of ascites is present. Even when sodium restriction alone is not sufficient, it should nonetheless help slow the accumulation of ascites. Virtually no complications are associated with sodium restriction. Clinicians should, however, be cautious about the nutritional status of patients on sodium restriction, because the nonpalatability of a saltrestricted diet may lead to an inadequate food intake. In these cases, liberalizing sodium restriction and adding diuretics is preferable. Diuretic Therapy In most patients with ascites, diuretic therapy is necessary because urinary sodium excretion is too low or because the patient is unable to comply with a sodium-restricted diet. Given that an increase in aldosterone levels leads to tubular reabsorption of sodium in cirrhosis, aldoste-
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rone antagonists such as spironolactone have long been used. Spironolactone works by inhibiting sodium-potassium (Na+-K') exchange in the distal tubule of the nephron, allowing more sodium to be excreted. Loop diuretics such as furosemide provide an additional benefit by blocking Na + -K+-2C1- cotransport in the loop of Henle,28thus, delivering more sodium to the distal portion of the nephron. Furosemide should not be used alone, because sodium that is not reabsorbed by the action of furosemide can still be reabsorbed at the distal tubule by the action of aldosterone. In fact, two randomized, controlled trials demonstrate that furosemide used alone is less effective in the treatment of cirrhotic ascites than spironolactone alone or the combination of spironolactone and furosemide.l7< 59 Diuretic therapy is generally well tolerated. Common side effects include renal dysfunction, electrolyte disturbances (hyponatremia, hypoand hyperkalemia), hepatic encephalopathy, gynecomastia, and muscle cramps.28Renal dysfunction is usually prerenal in nature and improves readily on diuretic withdrawal.20Nevertheless, clinicians should remember that the use of diuretics can lead to further decreases in intravascular volume and diuretic therapy should therefore not be initiated in patients with conditions that are associated with a decreased EABV. Such conditions include dehydration, gastrointestinal hemorrhage; SBP and other infections. In patients who develop complications, diuretics should be discontinued until complications resolve. Diuretics can then be resumed at a lower dose with careful monitoring of renal function. The effective dose of diuretics ranges from 50 to 400 mg/day for spironolactone and 20 to 160 mg/day for furosemide. Therapy is usually initiated with spironolactone, 100 mg in a single daily dose. Dosage should be increased at intervals of at least 4 days depending on response. For patients who do not respond to maximal doses of spironolactone or who develop hyperkalemia, furosemide can be added at an initial dose of 40 mg/day. Rapid diuresis should be avoided to minimize the rate of complications. Maximal weight loss should not exceed 1 lb/day in patients without edema or 2 lb/day in patients in whom edema is present. In patients with moderate or tense ascites, it is reasonable to perform a large-volume paracentesis (LVP) before the initiation of diuretic therapy, particularly if the patient is hospitalized, because LVP has been shown to shorten hospital stay when compared with diuretic thera~y.2~ Once ascites resolves, the dose of diuretics should be titrated down until a minimal effective dose is attained. The use of nonsteroidal anti-inflammatory drugs (NSAIDs) should be proscribed in cirrhotic patients with ascites because they have been shown to blunt the natriuretic effect of diuretics and can lead to renal failure.%, Approximately 10% to 20% of ascites cases are refractory to diuretic therapy. These patients either do not respond to the recommended maximal dose of diuretics or develop complications related to diuretics. Before declaring failure of diuretic therapy, however, clinicians need to ascertain that patients have adhered to the prescribed sodium-restricted diet and have not used NSAIDs. Noncompliance should be suspected if
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patients fail to lose weight despite an adequate 24-hour urine sodium excretion. For patients with true refractory ascites, other therapeutic options such as LVP should be considered. Therapeutic Paracentesis
In the mid-l980s, a study showed that LVP could be performed safely without significant effects on systemic hemodynamics, serum electrolyte levels, or renal function.43In this study, however, only 5 liters of ascites were removed, and paracentesis was only performed once. More subtle markers of EABV, such as plasma renin activity and aldosterone levels, were not assessed. Other trials in which larger volumes were removed showed significant increases in these markers 24 to 48 hours 57, 76 In another trial comparing repeated LVP (5 L/ after ~aracentesis.4~. day until disappearance of ascites) with and without intravenous albumin infusion, LVP without albumin was associated with a reduction in EABV as evidenced by increases in plasma renin activity and aldosterone levels, and by azotemia and hyp~natremia.~~ This postparacentesis circulatory dysfunction (PCD) is defined as an increase in plasma renin activity on the sixth day after paracentesis (the time at which renin activity peaks), and its incidence can be as high as 80% in patients undergoing LVP who do not receive plasma volume expander^.^^ Although PCD is not associated with abnormalities in routine blood tests such as blood urea nitrogen, creatinine, or electrolytes levels, patients who develop PCD have a higher rate of ascites reaccumulation and, more importantly, a shorter survival rate than patients who do not develop PCD.24 The pathogenesis of PCD is still pooriy understood, but it is likely to involve further reduction in EABV as the result of va~odilatation.~~ The use of plasma expanders, by increasing EABV, should therefore prevent the development of PCD. The administration of intravenous albumin as a plasma expander has been shown to reduce the incidence of PCD.24,49 Other types of plasma expanders have also been evaluated. In a study comparing albumin with the synthetic plasma expanders dextran-70 and polygeline it was found that for LVPs of less than 5 liters the incidence of PCD was similar in all patients, regardless of the type of plasma expander used. If more than 5 liters of ascites was removed, the incidence of PCD among patients who were given albumin was 1870,compared with 34% and 38% for patients given dextran-70 and polygeline, respectively. Albumin may be a more effective expander because of its longer half-life and greater oncotic property. In summary, LVP is a safe and effective means for management of ascites, provided that albumin is given for LVP of greater than 5 liters. The recommended dose is 6 to 8 grams of albumin for each liter of fluid removed. Large-volume paracentesis is recommended in patients with ascites that is refractory to diuretic treatment. It can also be used to provide temporary relief while awaiting an effect from diuretics. Al-
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though LVP can be associated with intraperit~neal~ or subcutaneous hemorrhage, its main complication is the development of PCD that can be minimized by the use of albumin. Synthetic crystalloids may be substituted for albumin if less than 5 liters of ascitic fluid are removed. In fact, the use of a plasma volume expander may not be necessary at all in this setting." Sodium restriction and diuretic therapy should be continued to minimize the recurrence of ascites after LVP. Portosystemic Shunts
Placement of a portosystemic shunt is another means of treating ascites. Because sinusoidal hypertension is one of the main forces driving ascites formation, the shunt chosen should relieve both portal pressure and sinusoidal pressure. End-to-side portacaval shunts are not effective in alleviating ascites, because this type of shunt does not reduce sinusoidal pressure. On the other hand, side-to-side portacaval shunts, mesocaVal shunts, and TIPS are effective because they relieve sinusoidal pressure. In addition to reducing pressure, portosystemic shunts also increase EABV, as evidenced by improvement in renal sodium handling.63,79, 87 Given the high morbidity and mortality rates of surgical shunts and the current availability of a nonsurgical shunt (i.e., TIPS), surgical shunts can no longer be recommended for the therapy of refractory ascites. As do surgical shunts, a TIPS reduces sinusoidal pressure and increases the EABV. Unlike conventional shunts, however, placement of a TIPS is less invasive and is performed by angiographic technique through a transjugular approach. Although a TIPS is effective in the treatment of ascites, its effect on survival remains under scrutiny. Two randomized, controlled trials comparing TIPS with LVP have been published. Both show that TIPS is superior with regards to resolution of ascites.44,70 This result is predictable, because LVP does not act on any of the mechanisms of ascites formation. In terms of survival, the results of these two studies are contradictory. One showed a higher mortality rate in patients treated with TIPS, particularly in Child class C patients, whereasM the other showed a tendency for a lower mortality rate in TIPS-treated patients.70 Neither of these trials routinely administered intravenous albumin with LVP. Interim results of two additional multicenter trials show no differences in survival rates between patients treated with TIPS and those treated with LVP plus albumin.83,84 As for any procedure that diverts blood away from the liver, the major complications of TIPS are portosystemic encephalopathy and liver failure. The balance between the reduction in portal pressure and the degree of shunting is quite precarious. The portal pressure gradient must be reduced below 12 mm Hg for ascites to disappear.13 With pressures below 10 mm Hg, however, the incidence of encephalopathy or liver failure increases.13,65 Patients with more severe liver dysfunction are at a higher risk of developing complications of TIPS; therefore, the procedure should be avoided in Child-Pugh class C patients. An addi-
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tional complication of TIPS is shunt stenosis or occlusion that occurs in up to 70% of the cases at 1year.I3Results of ongoing trials will establish the role of TIPS in the treatment of refractory ascites. At present, because of its unclear effect on survival, TIPS should be use as a bridge to liver transplantation in Child-Pugh class A and class B patients who develop refractory ascites and require frequent LVP. Other Treatments of Ascites
Peritoneovenous shunts (PVS) such as the Denver and Le Veen shunts act by transferring fluid from the peritoneal space directly into the systemic circulation. By removing intraperitoneal fluid and increasing the EABV, PVS has been shown to be as effective as LVP plus albumin in the treatment of ascites.26,30 The main drawback of PVS is the high incidence of shunt occlusion.26, 30, 37 Furthermore, the use of a jugular vein and the development of intra-abdominal adhesions may hinder future TIPS or transplant surgery, respectively. Vasoconstrictors have been used to counteract the vasodilatory state of cirrhosis and may be a therapeutic option for ascites in the future. Specifically, clinical investigations have used three vasoconstrictive agents, 0ctreotide7~ornipressin,46and m i d ~ d r i n eOctreotide, .~ a somatostatin analogue, was shown in one small study to suppress plasma renin activity and serum aldosterone level. There was no significant increase in natriuresis, however.73Intravenous ornipressin, a vasopressin analogue, was shown to improve systemic and renal hemodynamics as well as natri~resis.~~ The need for intravenous administration precludes its use in a routine outpatient setting. A single dose of midrodine, an oral a-adrenergic agonist, was shown to improve natriuresis and systemic hemodynamics in cirrhotic patients with ascites who had a normal renal f~nction.~ The effects of long-term administration have yet to be determined. In short, the use of vasoconstrictors for the treatment of ascites is at an experimental stage. Further investigations are needed before their role in ascites management can be defined. A step-wise scheme for the management of ascites is summarized in Figure 2. COMPLICATIONS OF ASCITES
The main morbidity caused by ascites is abdominal discomfort. In severe cases, tense ascites may interfere with respiratory function, ambulation, and other daily activities. Hyponatremia is another common complication seen in cirrhotic patients with ascites.6 Hyponatremia is defined as serum sodium concentration of less than 130 mmol/L. Hyponatremia in cirrhotics is usually dilutional and, as mentioned previously, results from impaired water handling caused by vasodilatation. Therapy
CLINICAL MANAGEMENT OF ASCITES A N D ITS COMPLICATIONS
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Sodium Restriction
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1.5-2 gm of sodiumiday
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Ascitss not controlled
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Diuretic Therapy
Spironolactone100-400 rnglday f furosernide 40-160 rnglday
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Ascites not controlled or complicationsof diuretics
Refractory Ascites**
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7 7 LVP+alburnin***
TIPS
Peritoneovenousshunt
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Investigational Therapy
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Vasoconstrictors LVP + vasoconstrictors
Figure 2. Step-wise management of ascites. *In patients with tense ascites, particularly if hospitalized, a single LVP albumin may be performed as the initial therapy; **Salt restriction and diuretics should be continued as tolerated; ***For paracentesis of less than 5 liters, synthetic plasma expanders may be considered. LVP = large volume paracentesis, TIPS = transjugular intrahepatic portosystemic shunt.
+
of hyponatremia is based on fluid restriction and adjustment of diuretic dosage. The use of aquaretics, drugs that preferentially promote renal water excretion, in the treatment of hyponatremia is currently being evaluated.lO, Severer complications of ascites are HRS and SBP. In the following sections the management of these two complications is described in more detail.
Hepatorenal Syndrome Hepatorenal syndrome represents an extreme end of the spectrum of hemodynamic abnormalities seen in cirrhosis. In this syndrome, vasodilatation and reduction of EABV are maximal, and so is the activation of the RAAS, resulting in extreme renal vasoconstriction and renal failure. Patients with ascites have probabilities of developing HRS of 27% and 40% at 1 and 5 years, respectivelyE Hepatorenal syndrome has been categorized as types I and 11, with type I being related to a more rapid
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deterioration of renal function. Hepatorenal syndrome type I also carries a much poorer prognosis, with a median survival of 2 weeks.25Further description and diagnostic criteria of HRS are available el~ewhere.~ Hepatorenal syndrome is a diagnosis of exclusion, and other possible causes of renal failure must be exhaustively ruled out. HRS is a functional renal failure associated with end-stage liver disease; that is, there are no anatomic renal abnormalities. At present, liver transplantation remains the standard therapy, and patients with HRS have a good long-term survival following tran~plantation.~~ Based on the theory that HRS results from extreme vasodilatation and reduction in EABV, ornipressin (a potent vasoconstrictor) in combination with albumin (a plasma expander) has been used with favorable results.40The use of TIPS, which, in addition to increasing the EABV, reduces sinusoidal pressure and thereby reduces ascites formation, has also shown promise.39,l1 Controlled trials involving a larger number of patients are required before either of these therapies can be recommended as a treatment for HRS. It is likely that in most cases these therapeutic maneuvers will be used as a bridge to liver transplantation. Because there are no effective specific therapies for HRS, efforts should be made to prevent its development. Although definite causes of HRS have not been identified, it seems wise to try to minimize maneuvers that will further decrease EABV in cirrhotic patients with ascites. For example, SBP should be treated promptly and possibly be accompanied by plasma volume expanders (as discussed later), and LVP or diuretics should be withheld in patients who exhibit signs of worsening renal function. Spontaneous Bacterial Peritonitis
Spontaneous bacterial peritonitis is defined as an infection of ascites in the absence of a contiguous source of infection such as an abdominal abscess or an intestinal perforation. Spontaneous bacterial peritonitis is common in hospitalized cirrhotic patients; the prevalence ranges between 10% and 30%. Although in earlier studies the in-hospital mortality rate of SBP was as high as 8O%, prompt institution of antibiotic therapy has reduced its mortality rate to around 30% in recent years. Early diagnosis of SBP is essential and requires a strong index of suspicion, because symptoms of SBP may be i n s i d i o ~ s Patients .~~ may not have any gastrointestinal complaints, or they may be asymptomatic. Worsening liver or renal function can often be the predominant features of SBP. As recommended in a recent consensus c~nference?~ a diagnostic paracentesis should be performed at the time of admission in every patient with ascites whether or not symptoms suggestive of SBP are present. Furthermore, a diagnostic tap should also be performed in hospitalized patients if they develop abdominal pain, signs of systemic infection, hepatic encephalopathy, worsening renal function without a clear precipitating factor, or gastrointestinal hemorrhage. In the last
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scenario, diagnostic paracentesis should be done before administration of prophylactic antibiotics. The diagnosis of SBP is established when the ascites polymorphonuclear leukocyte count (PMN) is greater than 250/mm3. In case of bloody ascites, 1 PMN should be subtracted for every 250 red blood cells (RBC). Ascites cultures (in blood culture bottles) and simultaneous blood cultures should be obtained in patients suspected of having SBP to increase the possibility of identifying a causative organism.67
Management of SBP Management of the acute infection. Once the diagnosis of SBP is made, empiric antibiotic therapy should be promptly instituted even before microbiologic results are available. The most common causative agents of SBP are gram-negative aerobic bacteria and nonenterococcal Streptococcus ~ p p . 2and ~ the empiric antibiotics should be selected accordingly. Randomized trials have demonstrated that cefotaxime, a thirdgeneration cephalosporin, is at least as effective as a p-lactam plus aminoglycoside combination and has a lower incidence of nephrotoxicity.16,52 Other cephalosporins (ceftriaxone, ceftizoxime, and cefonicid) More recently, seem to be equally effective in the treatment of SBP.34*53,69 the combination amoxicillin and clavulanic acid was shown to be as effective as cefotaxime." The recommended antibiotic dosage is that recommended for other severe infections; however, it has been shown that cefotaxime at a dose of 2 grams every 12 hours is as effective as more frequent dosings.68The use of readily absorbed quinolones such as ofloxacin may be considered in patients with uncomplicated SBP (creatinine < 3 g/dL and absence of shock, hemorrhage, ileus, or severe er~cephalopathy).~~ Aminoglycosides should be avoided because cirrhotic patients seem to be more susceptible to their nephrotoxic effect.22The duration of therapy can be determined by the ascites PMN count (i.e., therapy can be discontinued once ascites PMN count drops below 250/ mm3)19or when at least 5 days of therapy have been completed.72 The presence or development of renal failure constitutes the best It is postulated that infections predictor of death in patients with SBP.18,82 may worsen the vasodilatory physiology seen in cirrhotics, leading to a further decrease in EABV, renal vasoconstriction, and renal failure. Recent evidence suggests that the use of intravenous albumin as an adjuvant to antibiotic therapy can improve survival in patients with SBP.80 In this randomized study, patients who received albumin had a significantly lower incidence of renal failure (107'0 versus 33%), in-hospital mortality (loo/, versus 29%), and 3-month mortality rates (22% versus 41%) than patients who did not receive albumin. In this study, albumin was empirically given at the dose of 1.5 g/kg on the first day and 1 g/ kg on the third day of hospitalization. Patients who benefited more from adjuvant albumin therapy were those who had an abnormal renal function at baseline (blood urea nitrogen > 30 mg/dL or creatinine
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> 1.0 mg/dL) and those who had a serum bilirubin greater than 4 mg/ dL. Given the high cost and low availability of human albumin, future studies should further delineate subgroups of patients who will require this adjunctive therapy and determine the minimal effective dose. Maneuvers that can lead to a further decrease in EABV, such as LVP and diuretics, should be avoided in patients with SBP. Because of a high mortality rate in patients who do not respond to initial antibiotic therapy,19 it is important to identify treatment failure promptly. A follow-up diagnostic paracentesis is recommended after 48 hours of antibiotic therapy, particularly in patients who are asymptomatic at diagnosis or in whom no obvious clinical improvement is observed. Patients with an ascites PMN reduction of less than 25% from baseline have not responded to therapy and should be re-evaluated in terms of broadening or changing the antibiotic coverage and initiating investigations to rule out secondary p e r i t ~ n i t i sThere . ~ ~ is a subgroup of patients with SBP in whom cure and survival has been shown to occur in all patients kood prognosis SBP).56These are patients with communityacquired SBP, no encephalopathy, and no renal dysfunction at the time of diagnosis. In these patients and in those with obvious clinical improvement, a repeat paracentesis may not be necessary. In summary, it is important to diagnose SBP promptly. Intravenous cefotaxime and other third-generation cephalosporins and the combination of p-lactam plus p-lactamse seem to be equally effective. Oral ofloxacin may be considered in patients with uncomplicated SBP. Duration of treatment should be at least 5 days. Adjuvant albumin therapy should be given, at least to patients who exhibit abnormalities in renal function. A follow-up paracentesis is recommended after 48 hours of antibiotic treatment to assess response to therapy. Repeat paracentesis may not be necessary in the presence of marked clinical improvement or in patients with good-prognosis SBP. Prophylaxis for Spontaneous Bacterial Peritonitis. Two groups of patients clearly benefit from antibiotic prophylaxis. These are patients with a prior history of SBP and cirrhotic patients admitted with gastrointestinal hemorrhage. Whether or not a patient with ascites but no prior SBP should receive primary antibiotic prophylaxis is still under investigation. Patients with a previous episode of SBP are at a 40% to 70% risk of developing another episode within 1 year.81Gines et a1 demonstrated that the use of norfloxacin at a daily dose of 400 mg can reduce the risk of recurrent SBP from 68% to 27?'0.~*Because the mortality rate can be as high as 30% for each SBP episode, prophylaxis for this group of patients is justified. Additionally, because the median survival time of patients who have developed SBP is around 9 months, prophylaxis is not likely to be prolonged. Another group of patients who will benefit from antibiotic prophylaxis are cirrhotic patients who develop gastrointestinal hemorrhage. These patients, regardless of the presence of ascites, are at high risk of developing severe bacterial infections, including SBP.9,l4 As many as
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27% may already be infected at the time of admission, and another 50% will develop an infection during hospitalization. Five randomized, controlled trials showed a significant reduction in the probability of developing an infection with the use of prophylactic antibiotics.8,41, 58, 66, 78 A meta-analysis of these trials confirmed a significant reduction in the rate of infections and also showed a survival benefit from antibiotic pro phyla xi^.^ Norfloxacin (orally or by nasogastric tube) is the firstchoice antibiotic because it is only partially absorbed and hence effective in achieving selective intestinal decontamination. The recommended dose is 400 mg two times/day for a minimum of 7 days. Because patients may already be infected at the time of admission, it is important to obtain appropriate cultures before administration of prophylactic antibiotics. Unlike the two groups of patients already described, it is still unclear whether primary antibiotic prophylaxis is indicated in patients with ascites who are not experiencing gastrointestinal hemorrhage and who have no prior episodes of SBP.67Administration of prophylactic antibiotics will probably be more prolonged in these patients. Caution should always be exercised with the use of long-term antibiotics.60Concerns involve the emergence of quinolone-resistant organisms and also a change in the spectrum of organisms causing infection in cirrhosis (i.e., more infections caused by gram-positive organisms).l2.48 Several studies have been conducted to identify risk factors in the development of SBP. An ascites protein content above 1 g/dL is associated with a low incidence of SBP, with 1- and 3-year probabilities of developing SBP of 0% and 39'0, re~pectively,~~ provided that patients receive antibiotics during an acute hemorrhagic event. Prophylactic antibiotic therapy is therefore not recommended in this low-risk group. Patients who seem to be at a higher risk are those with low ascites protein, although the only placebo-controlled study performed in this group of patients did not show a significant benefit of prophylaxis with quinolones.36In addition to a low ascites protein, studies have identified a high serum bilirubin (> 2.5 or > 3.2 mg/dL)2,38 and a low platelet count (< 98,000/mm3)38as being independently associated with a higher risk of developing SBP. In the latter study, the l-year probability of developing the first episode of SBP in high-risk patients (low ascites protein, high bilirubin, low platelet count) was 55%, the highest reported so far.38Performance of placebo-controlled prophylactic trials in these patients will further clarify this issue. In summary, prophylactic antibiotic therapy should be used in patients who have prior history of SBP and in patients admitted with gastrointestinal hemorrhage. Because the objective of prophylaxis is to decontaminate the gut (the source of bacteria), prophylaxis with poorly absorbed antibiotics is ideal. In the first group, oral norfloxacin, 400 mg/day, is recommended, and therapy should continue indefinitely. In patients who are admitted with acute gastrointestinal hemorrhage, a 7day course of oral norfloxacin, 400 mg two times/day, is recommended. If administration by mouth or nasogastric tube is not feasible, intrave-
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nous quinolones can be used. Based on the currently available data, antibiotic prophylaxis cannot be recommended in other cirrhotic patients with ascites. More studies are needed to identify a high-risk group of patients who may benefit from primary antibiotic prophylaxis.
SUMMARY Development of ascites is a poor prognostic sign with a 1 year mortality rate of up to 50°/0. Cirrhotic patients who develop ascites should therefore be evaluated for liver transplantation. Even though current therapies of ascites are not associated with a survival benefit, the elimination of ascites will improve quality of life and prevent the development of lethal complications such as SBP and HRS. Therapy of ascites should be directed at correcting the pathophysiologic abnormalities that lead to ascites formation, namely sodium retention, reduced effective arterial blood volume, and sinusoidal hypertension.
References 1. Albillos A, Colombato LA, Groszmann RJ: Vasodilatation and sodium retention in prehepatic portal hypertension [see comments]. Gastroenterology 102:931-935, 1992 2. Andreu M, Sola R, Sitges-Serra A, et al: Risk factors for spontaneous peritonitis in cirrhotic patients with ascites. Gastroenterology 1041133-1138, 1993 3. Angeli P, Volpin R, Piovan D, et al: Acute effects of the oral administration of midodrine, an a-adrenergic agonist, on renal hemodynamics and renal function in cirrhotic patients with ascites. Hepatology 28:937-943, 1998 4. Arnold C, Haag K, Blum HE, et al: Acute hemoperitoneum after large-volume paracentesis. Gastroenterology 113:978-982, 1997 5. Arroyo V, Gines P, Gerbes AL, et al: Definition and diagnostic criteria of refractory ascites and hepatorenal syndrome in cirrhosis. Hepatology 233166176, 1996 6. Arroyo V, Rodes J, Gutierrez-Lizarraga MA, et al: Prognostic value of spontaneous hyponatremia in cirrhosis with ascites. American Journal of Digestive Diseases 21:249, 1976 7. Bernard B, Grange JD, Khac EN, et a1 Antibiotic prophylaxis for the prevention of bacterial infections in cirrhotic patients with gastrointestinal bleeding: A meta-analysis. Hepatology 29:1655-1661, 1999 8. Blaise M, Peterson D, Trinchet J-C, et a1 Systemic antibiotic therapy prevents bacterial infection in cirrhotic patients with gastrointestinal hemorrhage. Hepatology 20:34-38, 1994 9. Bleichner G, Boulanger R, Squara P, et al: Frequency of infections in cirrhotic patients presenting acute gastrointestinal hemorrhage. Br J Surg 73:724-726, 1986 10. Bosch-Marce M, Jinenez W, Angeli P, et al: Aquaretic effect of the kappa-opiod agonist RU 51599 in cirrhotics rats with ascites and water retention. Gastroenterology 109:217223, 1995 11. Brensing KA, Textor J, Perz J, et al: Long-term outcome after transjugular intrahepatic portosystemic shunt in non-transplant cirrhotics with hepatorenal syndrome: A phase I1 study. Gut 47288-295,2000 12. Campillo 8, Dupeyron C, Richardet JP, et al: Epidemiology of severe hospital-acquired infections in patients with liver cirrhosis: Effect of long-term administration of norfloxaxin. Clin Infect Dis 26:1066-1070,
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13. Casado M, Bosch J, Garcia-Pagan JC, et al: Clinical events after TIPS Correlation with hemodynamics findings. Gastroenterology 114:1296-1303, 1998 14. Deschenes M, ViLleneuve Jl? Risk factors for the development of bacterial infections in hospitalized patients with cirrhosis. Am J Gastroenterol942193-2197, 1999 15. DeFranchis R Updating consensus in portal hypertension: Report of the Baveno I11 Consensus Workshop on definitions, methodology and therapeutic strategies in portal hypertension. J Hepatol3384&852,2000 16. Felisart J, Rimola A, Arroyo V, et a1 Cefotaxime is more effective than ampicillintobramycin in cirrhotics with severe infections. Hepatology 5:457-462, 1985 17. Fogel MR, Sawhney VK, Neal A, et al: Diuresis in the ascitic patient: A randomized controlled trial of three regimens. J Clin Gastroenterol 3 (suppl 1):73-80, 1981 18. Follo A, Llovet JM, Navasa M, et al: Renal impairment after spontaneous bacterial peritonitis in cirrhosis: Incidence, clinical course, predictive factors and prognosis. Hepatology 20:1495-1501, 1994 19. Fong TL, Akriviadis EA, Runyon BA, et al: Polymorphonuclear cell count response and duration of antibiotic therapy in spontaneous bacterial peritonitis. Hepatology 9:423-426, 1989 20. Foms X, Gines A, Gines P, et al: The management of ascites and renal failure in cirrhosis. Semin Liver Dis 1482, 1994 21. Freedman AM, Sanyal AJ, Tisnado J, et al: Complications of transjugular intrahepatic portosystemic shunt: A comprehensive review. Radiographics 13:1185-1210, 1993 22. Garcia-Tsao G: Further evidence against the use of aminoglycosides in cirrhotic patients. Gastroenterology 114:612-613, 1998 23. Garcia-Tsao G: Spontaneous bacterial peritonitis. Gastroenterol Clin North Am 21257275, 1992 24. Gines A, Arroyo V, Monescillo A, et al: Randomized trial comparing albumin, dextran70 and polygeline in cirrhotic patients with ascites treated by paracentesis. Gastroenterology 111:1002, 1996 25. Gines A, Escorsell A, Gines P, et al: Incidence, predictive factors and prognosis of the hepatorenal syndrome in cirrhosis with ascites. Gastroenterology 105:229-236, 1993 26. Gines A, Planas R, Angeli P, et al: Treatment of patients with cirrhosis and refractory ascites by Le Veen shunt with titanium tip. Comparison with therapeutic paracentesis. Hepatology 22:124-131, 1995 27. Gines P, Arroyo V, Quintero E, et al: Comparison of paracentesis and diuretics in the treatment of cirrhotics with tense ascites. Results of a randomized study. Gastroenterology 93:234-241, 1987 28. Gines P, Arroyo V, Rodes J: Current guidelines for pharmacotherapy of ascites associated with cirrhosis. Drugs 43:316, 1992 29. Gines P, Arroyo V, Rodes J: Disorders of renal function in cirrhosis: Pathophysiology and clinical aspects. In Zakim D, Boyer TD (eds): Hepatology: A Textbook of Liver Disease, ed 3. Philadelphia, WB Saunders 1996, p 650 30. Gines P, Arroyo V, Vargas V, et a1 Paracentesis with intravenous infusion of albumin as compared with peritoneovenous shunting in cirrhosis with refractory ascites. N Engl J Med 325:829-835, 1991 31. Gines P, Berl T, Bernardi M, et al: Hyponatremia in cirrhosis: From pathogenesis to treatment. Hepatology 28:851-864, 1998 32. Gines P, Rimola A, Planas R, et al: Norfloxacin prevents spontaneous bacterial peritonitis recurrence in cirrhosis; results of double-blind, placebo-controlled trial. Hepatology 12:716-724, 1990 33. Gines P, Tito LI, Arroyo V, et al: Randomized comparative study of therapeutic paracentesis with and without intravenous albumin in cirrhosis. Gastroenterology 94:1493, 1988 34. Gomez-Jimknez J, Ribera E, Gasser J, et al: Randomized trial comparing ceftriaxone with cefonicid for treatment of spontaneous bacterial peritonitis in cirrhotic patients. Antimicrob Agents Chemother 371587-1592, 1993 35. Gonwa TA, Wilkinson AH: Liver transplantation and renal function: Results in patients with and without hepatorenal syndrome. In Epstein M (ed). The Kidney in Liver Disease, ed 4. Philadelphia, Hanley & Belfus, 1996, pp 529-542
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36. Grange JD, Roulot D, Pelletier G, et al: Norfloxacin primary prophylaxis of bacterial infections in cirrhotic patients with ascites-A double-blind randomized trial. J Hepatol 29:430436, 1998 37. Greig PD, Langer B, Blendis LM, et a1 Complications after peritoneovenous shunting. Am J Surg 139:125-131, 1980 38. Guamer C, Sola R, Soriano G, et al: Risk of a first community-acquired spontaneous bacterial peritonitis in cirrhotics with low ascitic fluid protein levels. Gastroenterology 117414-419, 1999 39. Guevara M, Gines P, Bandi JC, et al: Transjugular intrahepatic portosystemic shunt in hepatorenal syndrome: Effects of renal functions and vasoactive systems. Hepatology 28:41&422, 1998 40. Guevara M, Gines P, Fernandez-Esparrach G, et al: Reversibility of hepatorenal syndrome by prolonged administration of omipressin and plasma volume expansion. Hepatology 273541,1998 41. Hsieh W-J, Lin H-C, Hwang S-J, et al: The effect of ciprofloxacin in the prevention of bacterial infections in patients with cirrhosis after upper gastrointestinal bleeding. Am J Gastroenterol93:962-966, 1998 42. Inoue T, Ohnishi A, Matsuo A, et al: Therapeutic and diagnostic potential of a vasopressin-2 antagonist for impaired water handling in cirrhosis. Clin Pharmacol Ther 63:561-570, 1998 43 Kao HW, Rakov NE, Savage E, et al: The effect of large volume paracentesis on plasma volume-a cause of hypovolemia? Hepatology 5:403<07, 1985 44. Lebrec D, Giuily N, Hadengue A, et al: Transjugular intrahepatic portosystemic shunts: Comparison with paracentesis in patients with cirrhosis and refractory ascites: A randomized trial. J Hepatology 25:135-144, 1996 45. Lee FY, Colombato LA, Albillos A, et al: N omega-nitro-L-arginine administration corrects peripheral vasodilation and systemic capillary hypotension and ameliorates plasma volume expansion and sodium retention in portal hypertensive rats. Hepatology 1784-90, 1993 46. Lenz G, Hornatgl H, Drum1 W, et al: Omipressin in the treatment of functional renal failure in decompensated liver cirrhosis. Gastroenterology 101:1060-1067, 1991 47. Llach J, b o l a A, Navasa M, et al: Incidence and predictive factors of first episode of spontaneous bacterial peritonitis in cirrhosis with ascites: Relevance of ascitic fluid protein concentration. Hepatology 16724-727, 1992 48. Llovet JM, Rodriguez-Iglesias P, Moitinho E, et al:. Spontaneous bacterial peritonitis in patients with cirrhosis undergoing selective intestinal decontamination. A retrospective study of 229 spontaneous bacterial peritonitis episodes. J Hepatol 2688-95, 1997 49. Luca A, Garcia-Pagan JC, Bosch J, et al: Beneficial effects of intravenous albumin infusion on the hemodynamic and humoral changes after total paracentesis. Hepatology 22:753, 1995 50. Martin PY, Gines P, Schrier RW Nitric oxide as a mediator of hemodynamic abnormalities and sodium and water retention in cirrhosis. N Engl J Med 339:533-541, 1998 51. Martin PY, Ohara M, Gines P, et al: Nitric oxide synthase (NOS) inhibition for one week improves renal sodium and water excretion in cirrhotic rats with ascites. J Clin Invest 101:235-242, 1998 52. McCormick PA, Greenslade L, Kibbler CC, et al: A prospective randomized trial of ceftazidime versus nethylmicin plus mezlocillin in the empirical therapy of presumed sepsis in cirrhotic patients. Hepatology 252333436, 1997 53. Mercader J, Gomez J, Ruiz J, et al: Use of ceftriaxone in the treatment of bacterial infections in cirrhotic patients. Chemotherapy 35(suppl 2):23-26, 1989 54. Mirouze D, Zipser RD, Reynolds TB: Effects of inhibitors of prostaglandin synthesis on induced diuresis in cirrhosis. Hepatology 3:50-55, 1983 55. Morali GA, Sniderman KW, Deitel KM, et al: Is sinusoidal portal hypertension a necessary factor for the development of hepatic ascites? [letter]. J Hepatol 16:249-250, 1992 56. Navasa M, Follo A, Llovet JM, et a1 Randomized, comparative study of oral ofloxacin versus intravenous cefotaxime in spontaneous bacterial peritonitis. Gastroenterology 111:1011-1017, 1996
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57. Panos M Z , Moore K, Vlavianos P, et al: Single, total paracentesis for tense ascites: Sequential hemodynamic changes and right atrial size. Hepatology 11:662,1990 58. Pauwels A, Mostefa-Kara N, Debenes B, et al: Systemic antibiotic prophylaxis after gastrointestinal hemorrhage in cirrhotic patients with a high risk of infection. Hepatology 24802-806,1996 59. Perez-Ayuso RM, Arroyo V, Planas R, et al: Randomized comparative study of efficacy of furosemide versus spironolactone in nonazotemic cirrhosis with ascites. Relationship between the diuretic response and the activity of the renin-aldosterone system. Gastroenterology 84:961-968, 1983 60. Piddock LJV: Fluoroquinolone resistance. Overuse of fluoroquinolones in human and veterinary medicine can breed resistance. BMJ 3171029-1030, 1999 61. Pizcueta MP, Casamitjana R, Bosch J, et a1 Decreased systemic vascular sensitivity to norepinephrine in portal hypertensive rats: Role of hyperglucagonemia. Am J Physiol 258:G191-G195, 1995 62. Planas R, Arroyo V, Rimola A, et al: Acetylsalicylic acid suppresses the renal hemodynamic effect and reduces the diuretic action of furosemide in cirrhosis with ascites. Gastroenterology 84.247-252, 1983 63. Quiroga J, Sangro B, Nunez M, et al: Transjugular intrahepatic portosystemic shunt in the management of refractory ascites: Effect on clinical, renal, humoral and hemodynamic parameters. Hepatology 21:986, 1995 64. Ricart E, Soriano G, Novella MT, et al: Amoxicillin-clavulanic acid versus cefotaxime in the therapy of bacterial infections in cirrhotic patients. J Hepatol 32:596-602, 2000 65. Riggio 0, Merli M, Pedretti G, et a 1 Hepatic encephalopathy after transjugular intrahepatic portosystemic shunt: Incidence and risk factors. Dig Dis Sci 41:578-584, 1996 66. Rimola A, Bory F, Teres J, et a1 Oral, nonabsorbable antibiotics prevent infection in cirrhotics with gastrointestinal hemorrhage. Hepatology 5:463-467, 1985 67. Rimola A, Garcia-Tsao G, Navasa M, et al: Diagnosis, treatment and prophylaxis of spontaneous bacterial peritonitis: A consensus document. J Hepatol 32142-153,2000 68. b o l a A, Salmeron JM, Clemente G, et al: Two different dosages of cefotaxime in the treatment of spontaneous bacterial peritonitis: Results of a prospective, randomized, multicenter study. Hepatology 213674679, 1995 69. b o l a A, Tit6 L, Llach J, et al: Efficacy of ceftizoxime in the treatment of severe bacterial infections in patients with cirrhosis. Drug Invest 4 (suppl 1):35-37, 1992 70. Rossle M, Ochs M, Giilberg V, et al: A comparison of paracentesis and transjugular intrahepatic portosystemic shunting in patients with ascites. N Engl J Med 34217011707, 2000 71. Ruiz del Arbol L, Monescillo A, Jimenez W, et al: Paracentesis-induced circulatory dysfunction: Mechanism and effect on hepatic hemodynamics in cirrhosis. Gastroenterology 113~579-586,1997 72. Runyon BA, McHutchison JG, Antillon MR, et al: Short-course versus long-course antibiotic treatment of spontaneous bacterial peritonitis. Gastroenterology 100:17371742, 1991 73. Sabat M, Guamer C, Soriano G, et al: Effect of subcutaneous administration of octreotide on endogenous vasoactive systems and renal function in cirrhotic patient with ascites. Dig Dis Sci 4332184-2189, 1998 74. Schrier RW, Arroyo V, Bernardi M, et al: Peripheral arterial vasodilation hypothesis: A proposal for the initiation of renal sodium and water retention in cirrhosis. Hepatology 8:1151, 1988 75. Schrier RW, Neiderbeger M, Weigert A, et al: Peripheral arterial vasodilation: Determinant of functional spectrum of cirrhosis. Semin Liver Dis 1994; 14114, 1994 76. Simon DM, McCain JR, Bonkovsky HL, et al: Effects of therapeutic paracentesis on systemic and hepatic hemodynamics and on renal and hormonal function. Hepatology 7423, 1987 77. Sitzmann JV, Campbell KA, Wu Y, et al: Effect of portosystemic shunting on PgIZ and glucagon levels in humans. Ann Surg 217248-252,1993 78. Soriano G, Guamer C, Tomas A, et al: Norfloxacin prevents bacterial infection in cirrhotics with gastrointestinal hemorrhage. Gastroenterology 103:1267-1272, 1992 79. Somberg KA, Lake JR, Tomlanovich SJ, et al: Transjugular intrahepatic portosystemic
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shunts for refractory ascites: Assessment of clinical and hormonal response and renal function. Hepatology 21:709-716, 1995 80. Sort P, Navasa M, Arroyo V, et al: Effect of intravenous albumin on renal impairment and mortality in patients with cirrhosis and spontaneous bacterial peritonitis. N Engl J Med 341:403409, 1999 81. Tito L, Rimola A, Gines P, et al: Recurrence of spontaneous bacterial peritonitis in cirrhosis: Frequency and predictive factors. Hepatology 8:27-31, 1988 82. Toledo C, Salmeron JM, Rimola A, et al: Spontaneous bacterial peritonitis in cirrhosis: Predictive factors of infection resolution and survival of patients treated with cefotaxime. Hepatology 17:251-257, 1993 83. Uriz J, Gines P and The International Group of Refractory Ascites: Randomized, multicenter, comparative study between TIPS and paracentesis with albumin in cirrhosis with refractory ascites. J Hepatol 2001; 34(suppll):A10 84. Valeriano V, Salerno F, Merli M, et al: TIPS versus paracentesis in the treatment of refractory ascites: Preliminary results of a randomized controlled trial [abstract]. Gastroenterology 118:A980, 2000 85. Wiest R, Das S, Cadelina G, et al: Bacterial translocation in cirrhotic rats stimulates eNOS-derived NO production and impairs mesenteric vascular contractility. J Clin Invest 104:1223-1233, 1999 86. Wong F, Liu P, Allidina Y, et al: Pattern of sodium handling and its consequences in patients with preascitic cirrhosis. Gastroenterology 108:1820-1827, 1995 87. Wong W, Liu P, Blendis L, et al: Long-term renal sodium handling in patients with cirrhosis treated with transjugular intrahepatic portosystemic shunts for refractory ascites. Am J Med 106:315-322, 1999
Address reprint requests to Guadalupe Garcia-Tsao, MD Yale University School of Medicine Section of Digestive Diseases P.O. Box 208019 333 Cedar St - 1080 LMP New Haven, CT 06520-8019 e-mail: [email protected]
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CLINICAL MANAGEMENT OF ASCITES AND ITS COMPLICATIONS Suchat Wongcharatrawee, MD, and Guadalupe Garcia-Tsao, MD
Ascites is the accumulation of fluid in the peritoneal cavity and is a potentially lethal complication of cirrhosis. To place the management of cirrhotic ascites in the context of its pathophysiology, a brief overview of the currently most widely accepted mechanisms is first outlined. The remainder of this article is devoted to the management of ascites and two of its most severe complications, hepatorenal syndrome (HRS) and spontaneous bacterial peritonitis (SBP).
PATHOPHYSIOLOGY OF ASCITES
Portal hypertension can lead to exudation of fluid either from splanchnic capillaries or from hepatic sinusoids. Clinical and experimental evidence indicates that in cirrhosis the hepatic sinusoids are the main source of ascites. Sinusoidal hypertension results from hepatic venous outflow blockage caused by regenerative nodules and fibrosis. Sinusoidal hypertension alone, however, is not sufficient for the continuous formation of ascites. Plasma volume expansion, through sodium and water retention, allows the replenishment of the intravascular volume and is the other essential factor in the pathogenesis of cirrhotic ascites.
From the VA Connecticut Healthcare System and Section of Digestive Diseases, Yale University School of Medicine, New Haven, Connecticut
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Clinically Significant Portal Hypertension
It is important to determine whether a threshold of portal (sinusoidal) pressure is necessary for the formation of ascites. If so, reduction of sinusoidal pressure below this level would constitute a therapeutic goal. As in the development of gastroesophageal varices, in which a minimal portal pressure gradient of 10 to 12 mm Hg is necessary (but not sufficient), the development of ascites seems to require a minimal portal pressure gradient of 12 mm Hg.13,55 In one study, in which portal pressure was determined indirectly by hepatic vein catheterization, every patient with ascites had an hepatic venous pressure gradient (a measure of sinusoidal pressure) of at least 12 mm Hg.55Another study showed that in most patients who developed ascites as the result of dysfunction of a transjugular intrahepatic portosystemic shunt (TIPS) the portal pressure gradient had risen to levels of 12 mm Hg or more.13 In fact, a recent consensus conference on portal hypertension, defined clinically sign$cant portal hypertension as a portal pressure gradient of 10 mm Hg or more.15 Decreased Effective Arterial Blood Volume
Even though sinusoidal hypertension is necessary for the accumulation of ascites in the peritoneal cavity, it alone is not sufficient for ascites formation. Without replenishment of fluid in the intravascular space, leakage of fluid into the peritoneal cavity would be a self-limited process. This replenishment is accomplished through sodium retention, the most common physiologic abnormality in cirrhotic patients with ascites. In fact, sodium retention has been shown to precede the development of as cite^.^^, 86 In more advanced cirrhosis, in addition to sodium retention, an abnormality in water handling (i.e., an impairment in free water excretion) results in hyponatremia. In even more advanced stages, renal vasoconstriction results in the HRS. Several theories have been proposed to explain the occurrence of sodium retention, abnormalities in water handling, and renal vasoconstriction in cirrhotic patients. The most widely accepted theory is the arterial vasodilation theory that attributes all these abnormalities to arterial 75 Blood volume sensed by vascular baroreceptors is va~odilatation.~~, defined as efective arterial blood volume (EABV). Arterial vasodilation results in reduction of EABV and leads to stimulation of neurohumoral systems, specifically the renin-angiotensin-aldosterone system (RAAS), the sympathetic nervous system, and the non-osmotic release of antidiuretic hormone. Activation of RAAS and the sympathetic nervous system result in sodium retention and, in extreme cases, in renal vasoconstriction. Activation of antidiuretic hormone leads to abnormalities in water handling and hyp~natremia.~~ This theory is consistent with the sequence of events seen in animal models in which vasodilatation has been shown to precede sodium retenti0n.l The presence of normal or
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low levels of plasma renin activity in patients with cirrhosis and ascites suggests that, in some cases, sodium retention is unrelated to vasodilation (primary renal sodium retention). Although the cause of vasodilatation in cirrhosis is still unclear, there is growing evidence, both in animal models and in humans, that an increased production of the vasodilator nitric oxide (NO) in the splanchnic and peripheral circulation is involved in vasodilation. Blocking NO synthesis has been shown to raise systemic blood pressure and increase sodium excretion while reducing the activation of the RAAS.45,50, 51 Other endogenous substances (e.g, glucagon) have also been shown to have vasoactive properties in patients with portal hypertension but seem to be of lesser importance.61,77 The mechanism by which NO production is increased in cirrhotic animals with ascites is still unknown. A recent study, however, identified a subgroup of cirrhotic animals with ascites, those with bacterial translocation, that had even higher levels of NO and further va~odilatation.~~ Bacterial translocation is the phenomenon by which viable microorganisms from the intestinal lumen migrate to mesenteric lymph nodes and other extraintestinal sites. In addition to worsening the vasodilatory state of cirrhosis, bacterial translocation has also been suggested as being one of the main mechanisms in the pathogenesis of SBP, a major complication of ascites. MANAGEMENT OF ASCITES
Even though treatment of ascites is not accompanied by a survival benefit, ascites should be treated to improve quality of life and to prevent serious complications of ascites, particularly HRS and SBP. As for any sodium-retaining state, achieving a negative sodium balance is the mainstay of therapy, and most patients respond to sodium restriction and diuretics. Based on the current understanding of the pathophysiology of ascites, patients who do not respond to diuretics or who develop complications of diuretics can receive treatments aimed at improving the EABV or reducing the hepatic sinusoidal pressure. Figure 1provides a summary of these potential therapeutic targets.
Sodium Restriction Sodium restriction is the first-line therapy for treatment of ascites. It is important to educate patients and their caregivers regarding the amount of sodium in various food substances. The goal is to achieve a negative sodium balance, that is, a urinary sodium excretion greater than dietary sodium intake. In approximately 10% of patients with ascites, restriction of sodium intake to 44 to 66 mEq/day (22 mEq = 1 g of sodium = 2.6 g of dietary salt) is sufficient to cause a negative
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Pathogenesis
Treatment
Cirrhosis
Transplantation
Portal (sinusoidal) hypertension
1 1
TIPS
Arteriolar vasodilation
Systemic vasoconstrictors
Decreased effective blood volume
Plasma volume expanders; PVS, TIPS
1
*
Activation of neiohumoral systems
1
Sodium and water retention
.1
Ascites
Sodium restriction; Diuretics Paracentesis, PVS
Figure 1. Pathogenesis of ascites and therapeutic targets. *Activation of neurohumoral systems is a compensatory mechanism that maintains blood pressure. Renidangiotensin blockade can lead to significant arterial hypotension and has not resulted in ascites improvement. TIPS = transjugular intrahepatic portosystemic shunt, PVS = peritoneovenous shunt.
sodium balance and eliminate ascites. Further restriction of sodium is unrealistic and difficult to achieve. Patients who are likely to respond to sodium restriction are those who have a relatively high baseline urinary sodium excretion (> 50 mEq/day) and those in whom only a minimal or moderate amount of ascites is present. Even when sodium restriction alone is not sufficient, it should nonetheless help slow the accumulation of ascites. Virtually no complications are associated with sodium restriction. Clinicians should, however, be cautious about the nutritional status of patients on sodium restriction, because the nonpalatability of a saltrestricted diet may lead to an inadequate food intake. In these cases, liberalizing sodium restriction and adding diuretics is preferable. Diuretic Therapy In most patients with ascites, diuretic therapy is necessary because urinary sodium excretion is too low or because the patient is unable to comply with a sodium-restricted diet. Given that an increase in aldosterone levels leads to tubular reabsorption of sodium in cirrhosis, aldoste-
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rone antagonists such as spironolactone have long been used. Spironolactone works by inhibiting sodium-potassium (Na+-K') exchange in the distal tubule of the nephron, allowing more sodium to be excreted. Loop diuretics such as furosemide provide an additional benefit by blocking Na + -K+-2C1- cotransport in the loop of Henle,28thus, delivering more sodium to the distal portion of the nephron. Furosemide should not be used alone, because sodium that is not reabsorbed by the action of furosemide can still be reabsorbed at the distal tubule by the action of aldosterone. In fact, two randomized, controlled trials demonstrate that furosemide used alone is less effective in the treatment of cirrhotic ascites than spironolactone alone or the combination of spironolactone and furosemide.l7< 59 Diuretic therapy is generally well tolerated. Common side effects include renal dysfunction, electrolyte disturbances (hyponatremia, hypoand hyperkalemia), hepatic encephalopathy, gynecomastia, and muscle cramps.28Renal dysfunction is usually prerenal in nature and improves readily on diuretic withdrawal.20Nevertheless, clinicians should remember that the use of diuretics can lead to further decreases in intravascular volume and diuretic therapy should therefore not be initiated in patients with conditions that are associated with a decreased EABV. Such conditions include dehydration, gastrointestinal hemorrhage; SBP and other infections. In patients who develop complications, diuretics should be discontinued until complications resolve. Diuretics can then be resumed at a lower dose with careful monitoring of renal function. The effective dose of diuretics ranges from 50 to 400 mg/day for spironolactone and 20 to 160 mg/day for furosemide. Therapy is usually initiated with spironolactone, 100 mg in a single daily dose. Dosage should be increased at intervals of at least 4 days depending on response. For patients who do not respond to maximal doses of spironolactone or who develop hyperkalemia, furosemide can be added at an initial dose of 40 mg/day. Rapid diuresis should be avoided to minimize the rate of complications. Maximal weight loss should not exceed 1 lb/day in patients without edema or 2 lb/day in patients in whom edema is present. In patients with moderate or tense ascites, it is reasonable to perform a large-volume paracentesis (LVP) before the initiation of diuretic therapy, particularly if the patient is hospitalized, because LVP has been shown to shorten hospital stay when compared with diuretic thera~y.2~ Once ascites resolves, the dose of diuretics should be titrated down until a minimal effective dose is attained. The use of nonsteroidal anti-inflammatory drugs (NSAIDs) should be proscribed in cirrhotic patients with ascites because they have been shown to blunt the natriuretic effect of diuretics and can lead to renal failure.%, Approximately 10% to 20% of ascites cases are refractory to diuretic therapy. These patients either do not respond to the recommended maximal dose of diuretics or develop complications related to diuretics. Before declaring failure of diuretic therapy, however, clinicians need to ascertain that patients have adhered to the prescribed sodium-restricted diet and have not used NSAIDs. Noncompliance should be suspected if
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patients fail to lose weight despite an adequate 24-hour urine sodium excretion. For patients with true refractory ascites, other therapeutic options such as LVP should be considered. Therapeutic Paracentesis
In the mid-l980s, a study showed that LVP could be performed safely without significant effects on systemic hemodynamics, serum electrolyte levels, or renal function.43In this study, however, only 5 liters of ascites were removed, and paracentesis was only performed once. More subtle markers of EABV, such as plasma renin activity and aldosterone levels, were not assessed. Other trials in which larger volumes were removed showed significant increases in these markers 24 to 48 hours 57, 76 In another trial comparing repeated LVP (5 L/ after ~aracentesis.4~. day until disappearance of ascites) with and without intravenous albumin infusion, LVP without albumin was associated with a reduction in EABV as evidenced by increases in plasma renin activity and aldosterone levels, and by azotemia and hyp~natremia.~~ This postparacentesis circulatory dysfunction (PCD) is defined as an increase in plasma renin activity on the sixth day after paracentesis (the time at which renin activity peaks), and its incidence can be as high as 80% in patients undergoing LVP who do not receive plasma volume expander^.^^ Although PCD is not associated with abnormalities in routine blood tests such as blood urea nitrogen, creatinine, or electrolytes levels, patients who develop PCD have a higher rate of ascites reaccumulation and, more importantly, a shorter survival rate than patients who do not develop PCD.24 The pathogenesis of PCD is still pooriy understood, but it is likely to involve further reduction in EABV as the result of va~odilatation.~~ The use of plasma expanders, by increasing EABV, should therefore prevent the development of PCD. The administration of intravenous albumin as a plasma expander has been shown to reduce the incidence of PCD.24,49 Other types of plasma expanders have also been evaluated. In a study comparing albumin with the synthetic plasma expanders dextran-70 and polygeline it was found that for LVPs of less than 5 liters the incidence of PCD was similar in all patients, regardless of the type of plasma expander used. If more than 5 liters of ascites was removed, the incidence of PCD among patients who were given albumin was 1870,compared with 34% and 38% for patients given dextran-70 and polygeline, respectively. Albumin may be a more effective expander because of its longer half-life and greater oncotic property. In summary, LVP is a safe and effective means for management of ascites, provided that albumin is given for LVP of greater than 5 liters. The recommended dose is 6 to 8 grams of albumin for each liter of fluid removed. Large-volume paracentesis is recommended in patients with ascites that is refractory to diuretic treatment. It can also be used to provide temporary relief while awaiting an effect from diuretics. Al-
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though LVP can be associated with intraperit~neal~ or subcutaneous hemorrhage, its main complication is the development of PCD that can be minimized by the use of albumin. Synthetic crystalloids may be substituted for albumin if less than 5 liters of ascitic fluid are removed. In fact, the use of a plasma volume expander may not be necessary at all in this setting." Sodium restriction and diuretic therapy should be continued to minimize the recurrence of ascites after LVP. Portosystemic Shunts
Placement of a portosystemic shunt is another means of treating ascites. Because sinusoidal hypertension is one of the main forces driving ascites formation, the shunt chosen should relieve both portal pressure and sinusoidal pressure. End-to-side portacaval shunts are not effective in alleviating ascites, because this type of shunt does not reduce sinusoidal pressure. On the other hand, side-to-side portacaval shunts, mesocaVal shunts, and TIPS are effective because they relieve sinusoidal pressure. In addition to reducing pressure, portosystemic shunts also increase EABV, as evidenced by improvement in renal sodium handling.63,79, 87 Given the high morbidity and mortality rates of surgical shunts and the current availability of a nonsurgical shunt (i.e., TIPS), surgical shunts can no longer be recommended for the therapy of refractory ascites. As do surgical shunts, a TIPS reduces sinusoidal pressure and increases the EABV. Unlike conventional shunts, however, placement of a TIPS is less invasive and is performed by angiographic technique through a transjugular approach. Although a TIPS is effective in the treatment of ascites, its effect on survival remains under scrutiny. Two randomized, controlled trials comparing TIPS with LVP have been published. Both show that TIPS is superior with regards to resolution of ascites.44,70 This result is predictable, because LVP does not act on any of the mechanisms of ascites formation. In terms of survival, the results of these two studies are contradictory. One showed a higher mortality rate in patients treated with TIPS, particularly in Child class C patients, whereasM the other showed a tendency for a lower mortality rate in TIPS-treated patients.70 Neither of these trials routinely administered intravenous albumin with LVP. Interim results of two additional multicenter trials show no differences in survival rates between patients treated with TIPS and those treated with LVP plus albumin.83,84 As for any procedure that diverts blood away from the liver, the major complications of TIPS are portosystemic encephalopathy and liver failure. The balance between the reduction in portal pressure and the degree of shunting is quite precarious. The portal pressure gradient must be reduced below 12 mm Hg for ascites to disappear.13 With pressures below 10 mm Hg, however, the incidence of encephalopathy or liver failure increases.13,65 Patients with more severe liver dysfunction are at a higher risk of developing complications of TIPS; therefore, the procedure should be avoided in Child-Pugh class C patients. An addi-
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tional complication of TIPS is shunt stenosis or occlusion that occurs in up to 70% of the cases at 1year.I3Results of ongoing trials will establish the role of TIPS in the treatment of refractory ascites. At present, because of its unclear effect on survival, TIPS should be use as a bridge to liver transplantation in Child-Pugh class A and class B patients who develop refractory ascites and require frequent LVP. Other Treatments of Ascites
Peritoneovenous shunts (PVS) such as the Denver and Le Veen shunts act by transferring fluid from the peritoneal space directly into the systemic circulation. By removing intraperitoneal fluid and increasing the EABV, PVS has been shown to be as effective as LVP plus albumin in the treatment of ascites.26,30 The main drawback of PVS is the high incidence of shunt occlusion.26, 30, 37 Furthermore, the use of a jugular vein and the development of intra-abdominal adhesions may hinder future TIPS or transplant surgery, respectively. Vasoconstrictors have been used to counteract the vasodilatory state of cirrhosis and may be a therapeutic option for ascites in the future. Specifically, clinical investigations have used three vasoconstrictive agents, 0ctreotide7~ornipressin,46and m i d ~ d r i n eOctreotide, .~ a somatostatin analogue, was shown in one small study to suppress plasma renin activity and serum aldosterone level. There was no significant increase in natriuresis, however.73Intravenous ornipressin, a vasopressin analogue, was shown to improve systemic and renal hemodynamics as well as natri~resis.~~ The need for intravenous administration precludes its use in a routine outpatient setting. A single dose of midrodine, an oral a-adrenergic agonist, was shown to improve natriuresis and systemic hemodynamics in cirrhotic patients with ascites who had a normal renal f~nction.~ The effects of long-term administration have yet to be determined. In short, the use of vasoconstrictors for the treatment of ascites is at an experimental stage. Further investigations are needed before their role in ascites management can be defined. A step-wise scheme for the management of ascites is summarized in Figure 2. COMPLICATIONS OF ASCITES
The main morbidity caused by ascites is abdominal discomfort. In severe cases, tense ascites may interfere with respiratory function, ambulation, and other daily activities. Hyponatremia is another common complication seen in cirrhotic patients with ascites.6 Hyponatremia is defined as serum sodium concentration of less than 130 mmol/L. Hyponatremia in cirrhotics is usually dilutional and, as mentioned previously, results from impaired water handling caused by vasodilatation. Therapy
CLINICAL MANAGEMENT OF ASCITES A N D ITS COMPLICATIONS
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Sodium Restriction
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I
1.5-2 gm of sodiumiday
.1 I
Ascitss not controlled
I
Diuretic Therapy
Spironolactone100-400 rnglday f furosernide 40-160 rnglday
+ I
I
Ascites not controlled or complicationsof diuretics
Refractory Ascites**
I
7 7 LVP+alburnin***
TIPS
Peritoneovenousshunt
1I
Investigational Therapy
I
Vasoconstrictors LVP + vasoconstrictors
Figure 2. Step-wise management of ascites. *In patients with tense ascites, particularly if hospitalized, a single LVP albumin may be performed as the initial therapy; **Salt restriction and diuretics should be continued as tolerated; ***For paracentesis of less than 5 liters, synthetic plasma expanders may be considered. LVP = large volume paracentesis, TIPS = transjugular intrahepatic portosystemic shunt.
+
of hyponatremia is based on fluid restriction and adjustment of diuretic dosage. The use of aquaretics, drugs that preferentially promote renal water excretion, in the treatment of hyponatremia is currently being evaluated.lO, Severer complications of ascites are HRS and SBP. In the following sections the management of these two complications is described in more detail.
Hepatorenal Syndrome Hepatorenal syndrome represents an extreme end of the spectrum of hemodynamic abnormalities seen in cirrhosis. In this syndrome, vasodilatation and reduction of EABV are maximal, and so is the activation of the RAAS, resulting in extreme renal vasoconstriction and renal failure. Patients with ascites have probabilities of developing HRS of 27% and 40% at 1 and 5 years, respectivelyE Hepatorenal syndrome has been categorized as types I and 11, with type I being related to a more rapid
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deterioration of renal function. Hepatorenal syndrome type I also carries a much poorer prognosis, with a median survival of 2 weeks.25Further description and diagnostic criteria of HRS are available el~ewhere.~ Hepatorenal syndrome is a diagnosis of exclusion, and other possible causes of renal failure must be exhaustively ruled out. HRS is a functional renal failure associated with end-stage liver disease; that is, there are no anatomic renal abnormalities. At present, liver transplantation remains the standard therapy, and patients with HRS have a good long-term survival following tran~plantation.~~ Based on the theory that HRS results from extreme vasodilatation and reduction in EABV, ornipressin (a potent vasoconstrictor) in combination with albumin (a plasma expander) has been used with favorable results.40The use of TIPS, which, in addition to increasing the EABV, reduces sinusoidal pressure and thereby reduces ascites formation, has also shown promise.39,l1 Controlled trials involving a larger number of patients are required before either of these therapies can be recommended as a treatment for HRS. It is likely that in most cases these therapeutic maneuvers will be used as a bridge to liver transplantation. Because there are no effective specific therapies for HRS, efforts should be made to prevent its development. Although definite causes of HRS have not been identified, it seems wise to try to minimize maneuvers that will further decrease EABV in cirrhotic patients with ascites. For example, SBP should be treated promptly and possibly be accompanied by plasma volume expanders (as discussed later), and LVP or diuretics should be withheld in patients who exhibit signs of worsening renal function. Spontaneous Bacterial Peritonitis
Spontaneous bacterial peritonitis is defined as an infection of ascites in the absence of a contiguous source of infection such as an abdominal abscess or an intestinal perforation. Spontaneous bacterial peritonitis is common in hospitalized cirrhotic patients; the prevalence ranges between 10% and 30%. Although in earlier studies the in-hospital mortality rate of SBP was as high as 8O%, prompt institution of antibiotic therapy has reduced its mortality rate to around 30% in recent years. Early diagnosis of SBP is essential and requires a strong index of suspicion, because symptoms of SBP may be i n s i d i o ~ s Patients .~~ may not have any gastrointestinal complaints, or they may be asymptomatic. Worsening liver or renal function can often be the predominant features of SBP. As recommended in a recent consensus c~nference?~ a diagnostic paracentesis should be performed at the time of admission in every patient with ascites whether or not symptoms suggestive of SBP are present. Furthermore, a diagnostic tap should also be performed in hospitalized patients if they develop abdominal pain, signs of systemic infection, hepatic encephalopathy, worsening renal function without a clear precipitating factor, or gastrointestinal hemorrhage. In the last
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scenario, diagnostic paracentesis should be done before administration of prophylactic antibiotics. The diagnosis of SBP is established when the ascites polymorphonuclear leukocyte count (PMN) is greater than 250/mm3. In case of bloody ascites, 1 PMN should be subtracted for every 250 red blood cells (RBC). Ascites cultures (in blood culture bottles) and simultaneous blood cultures should be obtained in patients suspected of having SBP to increase the possibility of identifying a causative organism.67
Management of SBP Management of the acute infection. Once the diagnosis of SBP is made, empiric antibiotic therapy should be promptly instituted even before microbiologic results are available. The most common causative agents of SBP are gram-negative aerobic bacteria and nonenterococcal Streptococcus ~ p p . 2and ~ the empiric antibiotics should be selected accordingly. Randomized trials have demonstrated that cefotaxime, a thirdgeneration cephalosporin, is at least as effective as a p-lactam plus aminoglycoside combination and has a lower incidence of nephrotoxicity.16,52 Other cephalosporins (ceftriaxone, ceftizoxime, and cefonicid) More recently, seem to be equally effective in the treatment of SBP.34*53,69 the combination amoxicillin and clavulanic acid was shown to be as effective as cefotaxime." The recommended antibiotic dosage is that recommended for other severe infections; however, it has been shown that cefotaxime at a dose of 2 grams every 12 hours is as effective as more frequent dosings.68The use of readily absorbed quinolones such as ofloxacin may be considered in patients with uncomplicated SBP (creatinine < 3 g/dL and absence of shock, hemorrhage, ileus, or severe er~cephalopathy).~~ Aminoglycosides should be avoided because cirrhotic patients seem to be more susceptible to their nephrotoxic effect.22The duration of therapy can be determined by the ascites PMN count (i.e., therapy can be discontinued once ascites PMN count drops below 250/ mm3)19or when at least 5 days of therapy have been completed.72 The presence or development of renal failure constitutes the best It is postulated that infections predictor of death in patients with SBP.18,82 may worsen the vasodilatory physiology seen in cirrhotics, leading to a further decrease in EABV, renal vasoconstriction, and renal failure. Recent evidence suggests that the use of intravenous albumin as an adjuvant to antibiotic therapy can improve survival in patients with SBP.80 In this randomized study, patients who received albumin had a significantly lower incidence of renal failure (107'0 versus 33%), in-hospital mortality (loo/, versus 29%), and 3-month mortality rates (22% versus 41%) than patients who did not receive albumin. In this study, albumin was empirically given at the dose of 1.5 g/kg on the first day and 1 g/ kg on the third day of hospitalization. Patients who benefited more from adjuvant albumin therapy were those who had an abnormal renal function at baseline (blood urea nitrogen > 30 mg/dL or creatinine
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> 1.0 mg/dL) and those who had a serum bilirubin greater than 4 mg/ dL. Given the high cost and low availability of human albumin, future studies should further delineate subgroups of patients who will require this adjunctive therapy and determine the minimal effective dose. Maneuvers that can lead to a further decrease in EABV, such as LVP and diuretics, should be avoided in patients with SBP. Because of a high mortality rate in patients who do not respond to initial antibiotic therapy,19 it is important to identify treatment failure promptly. A follow-up diagnostic paracentesis is recommended after 48 hours of antibiotic therapy, particularly in patients who are asymptomatic at diagnosis or in whom no obvious clinical improvement is observed. Patients with an ascites PMN reduction of less than 25% from baseline have not responded to therapy and should be re-evaluated in terms of broadening or changing the antibiotic coverage and initiating investigations to rule out secondary p e r i t ~ n i t i sThere . ~ ~ is a subgroup of patients with SBP in whom cure and survival has been shown to occur in all patients kood prognosis SBP).56These are patients with communityacquired SBP, no encephalopathy, and no renal dysfunction at the time of diagnosis. In these patients and in those with obvious clinical improvement, a repeat paracentesis may not be necessary. In summary, it is important to diagnose SBP promptly. Intravenous cefotaxime and other third-generation cephalosporins and the combination of p-lactam plus p-lactamse seem to be equally effective. Oral ofloxacin may be considered in patients with uncomplicated SBP. Duration of treatment should be at least 5 days. Adjuvant albumin therapy should be given, at least to patients who exhibit abnormalities in renal function. A follow-up paracentesis is recommended after 48 hours of antibiotic treatment to assess response to therapy. Repeat paracentesis may not be necessary in the presence of marked clinical improvement or in patients with good-prognosis SBP. Prophylaxis for Spontaneous Bacterial Peritonitis. Two groups of patients clearly benefit from antibiotic prophylaxis. These are patients with a prior history of SBP and cirrhotic patients admitted with gastrointestinal hemorrhage. Whether or not a patient with ascites but no prior SBP should receive primary antibiotic prophylaxis is still under investigation. Patients with a previous episode of SBP are at a 40% to 70% risk of developing another episode within 1 year.81Gines et a1 demonstrated that the use of norfloxacin at a daily dose of 400 mg can reduce the risk of recurrent SBP from 68% to 27?'0.~*Because the mortality rate can be as high as 30% for each SBP episode, prophylaxis for this group of patients is justified. Additionally, because the median survival time of patients who have developed SBP is around 9 months, prophylaxis is not likely to be prolonged. Another group of patients who will benefit from antibiotic prophylaxis are cirrhotic patients who develop gastrointestinal hemorrhage. These patients, regardless of the presence of ascites, are at high risk of developing severe bacterial infections, including SBP.9,l4 As many as
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27% may already be infected at the time of admission, and another 50% will develop an infection during hospitalization. Five randomized, controlled trials showed a significant reduction in the probability of developing an infection with the use of prophylactic antibiotics.8,41, 58, 66, 78 A meta-analysis of these trials confirmed a significant reduction in the rate of infections and also showed a survival benefit from antibiotic pro phyla xi^.^ Norfloxacin (orally or by nasogastric tube) is the firstchoice antibiotic because it is only partially absorbed and hence effective in achieving selective intestinal decontamination. The recommended dose is 400 mg two times/day for a minimum of 7 days. Because patients may already be infected at the time of admission, it is important to obtain appropriate cultures before administration of prophylactic antibiotics. Unlike the two groups of patients already described, it is still unclear whether primary antibiotic prophylaxis is indicated in patients with ascites who are not experiencing gastrointestinal hemorrhage and who have no prior episodes of SBP.67Administration of prophylactic antibiotics will probably be more prolonged in these patients. Caution should always be exercised with the use of long-term antibiotics.60Concerns involve the emergence of quinolone-resistant organisms and also a change in the spectrum of organisms causing infection in cirrhosis (i.e., more infections caused by gram-positive organisms).l2.48 Several studies have been conducted to identify risk factors in the development of SBP. An ascites protein content above 1 g/dL is associated with a low incidence of SBP, with 1- and 3-year probabilities of developing SBP of 0% and 39'0, re~pectively,~~ provided that patients receive antibiotics during an acute hemorrhagic event. Prophylactic antibiotic therapy is therefore not recommended in this low-risk group. Patients who seem to be at a higher risk are those with low ascites protein, although the only placebo-controlled study performed in this group of patients did not show a significant benefit of prophylaxis with quinolones.36In addition to a low ascites protein, studies have identified a high serum bilirubin (> 2.5 or > 3.2 mg/dL)2,38 and a low platelet count (< 98,000/mm3)38as being independently associated with a higher risk of developing SBP. In the latter study, the l-year probability of developing the first episode of SBP in high-risk patients (low ascites protein, high bilirubin, low platelet count) was 55%, the highest reported so far.38Performance of placebo-controlled prophylactic trials in these patients will further clarify this issue. In summary, prophylactic antibiotic therapy should be used in patients who have prior history of SBP and in patients admitted with gastrointestinal hemorrhage. Because the objective of prophylaxis is to decontaminate the gut (the source of bacteria), prophylaxis with poorly absorbed antibiotics is ideal. In the first group, oral norfloxacin, 400 mg/day, is recommended, and therapy should continue indefinitely. In patients who are admitted with acute gastrointestinal hemorrhage, a 7day course of oral norfloxacin, 400 mg two times/day, is recommended. If administration by mouth or nasogastric tube is not feasible, intrave-
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nous quinolones can be used. Based on the currently available data, antibiotic prophylaxis cannot be recommended in other cirrhotic patients with ascites. More studies are needed to identify a high-risk group of patients who may benefit from primary antibiotic prophylaxis.
SUMMARY Development of ascites is a poor prognostic sign with a 1 year mortality rate of up to 50°/0. Cirrhotic patients who develop ascites should therefore be evaluated for liver transplantation. Even though current therapies of ascites are not associated with a survival benefit, the elimination of ascites will improve quality of life and prevent the development of lethal complications such as SBP and HRS. Therapy of ascites should be directed at correcting the pathophysiologic abnormalities that lead to ascites formation, namely sodium retention, reduced effective arterial blood volume, and sinusoidal hypertension.
References 1. Albillos A, Colombato LA, Groszmann RJ: Vasodilatation and sodium retention in prehepatic portal hypertension [see comments]. Gastroenterology 102:931-935, 1992 2. Andreu M, Sola R, Sitges-Serra A, et al: Risk factors for spontaneous peritonitis in cirrhotic patients with ascites. Gastroenterology 1041133-1138, 1993 3. Angeli P, Volpin R, Piovan D, et al: Acute effects of the oral administration of midodrine, an a-adrenergic agonist, on renal hemodynamics and renal function in cirrhotic patients with ascites. Hepatology 28:937-943, 1998 4. Arnold C, Haag K, Blum HE, et al: Acute hemoperitoneum after large-volume paracentesis. Gastroenterology 113:978-982, 1997 5. Arroyo V, Gines P, Gerbes AL, et al: Definition and diagnostic criteria of refractory ascites and hepatorenal syndrome in cirrhosis. Hepatology 233166176, 1996 6. Arroyo V, Rodes J, Gutierrez-Lizarraga MA, et al: Prognostic value of spontaneous hyponatremia in cirrhosis with ascites. American Journal of Digestive Diseases 21:249, 1976 7. Bernard B, Grange JD, Khac EN, et a1 Antibiotic prophylaxis for the prevention of bacterial infections in cirrhotic patients with gastrointestinal bleeding: A meta-analysis. Hepatology 29:1655-1661, 1999 8. Blaise M, Peterson D, Trinchet J-C, et a1 Systemic antibiotic therapy prevents bacterial infection in cirrhotic patients with gastrointestinal hemorrhage. Hepatology 20:34-38, 1994 9. Bleichner G, Boulanger R, Squara P, et al: Frequency of infections in cirrhotic patients presenting acute gastrointestinal hemorrhage. Br J Surg 73:724-726, 1986 10. Bosch-Marce M, Jinenez W, Angeli P, et al: Aquaretic effect of the kappa-opiod agonist RU 51599 in cirrhotics rats with ascites and water retention. Gastroenterology 109:217223, 1995 11. Brensing KA, Textor J, Perz J, et al: Long-term outcome after transjugular intrahepatic portosystemic shunt in non-transplant cirrhotics with hepatorenal syndrome: A phase I1 study. Gut 47288-295,2000 12. Campillo 8, Dupeyron C, Richardet JP, et al: Epidemiology of severe hospital-acquired infections in patients with liver cirrhosis: Effect of long-term administration of norfloxaxin. Clin Infect Dis 26:1066-1070,
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13. Casado M, Bosch J, Garcia-Pagan JC, et al: Clinical events after TIPS Correlation with hemodynamics findings. Gastroenterology 114:1296-1303, 1998 14. Deschenes M, ViLleneuve Jl? Risk factors for the development of bacterial infections in hospitalized patients with cirrhosis. Am J Gastroenterol942193-2197, 1999 15. DeFranchis R Updating consensus in portal hypertension: Report of the Baveno I11 Consensus Workshop on definitions, methodology and therapeutic strategies in portal hypertension. J Hepatol3384&852,2000 16. Felisart J, Rimola A, Arroyo V, et a1 Cefotaxime is more effective than ampicillintobramycin in cirrhotics with severe infections. Hepatology 5:457-462, 1985 17. Fogel MR, Sawhney VK, Neal A, et al: Diuresis in the ascitic patient: A randomized controlled trial of three regimens. J Clin Gastroenterol 3 (suppl 1):73-80, 1981 18. Follo A, Llovet JM, Navasa M, et al: Renal impairment after spontaneous bacterial peritonitis in cirrhosis: Incidence, clinical course, predictive factors and prognosis. Hepatology 20:1495-1501, 1994 19. Fong TL, Akriviadis EA, Runyon BA, et al: Polymorphonuclear cell count response and duration of antibiotic therapy in spontaneous bacterial peritonitis. Hepatology 9:423-426, 1989 20. Foms X, Gines A, Gines P, et al: The management of ascites and renal failure in cirrhosis. Semin Liver Dis 1482, 1994 21. Freedman AM, Sanyal AJ, Tisnado J, et al: Complications of transjugular intrahepatic portosystemic shunt: A comprehensive review. Radiographics 13:1185-1210, 1993 22. Garcia-Tsao G: Further evidence against the use of aminoglycosides in cirrhotic patients. Gastroenterology 114:612-613, 1998 23. Garcia-Tsao G: Spontaneous bacterial peritonitis. Gastroenterol Clin North Am 21257275, 1992 24. Gines A, Arroyo V, Monescillo A, et al: Randomized trial comparing albumin, dextran70 and polygeline in cirrhotic patients with ascites treated by paracentesis. Gastroenterology 111:1002, 1996 25. Gines A, Escorsell A, Gines P, et al: Incidence, predictive factors and prognosis of the hepatorenal syndrome in cirrhosis with ascites. Gastroenterology 105:229-236, 1993 26. Gines A, Planas R, Angeli P, et al: Treatment of patients with cirrhosis and refractory ascites by Le Veen shunt with titanium tip. Comparison with therapeutic paracentesis. Hepatology 22:124-131, 1995 27. Gines P, Arroyo V, Quintero E, et al: Comparison of paracentesis and diuretics in the treatment of cirrhotics with tense ascites. Results of a randomized study. Gastroenterology 93:234-241, 1987 28. Gines P, Arroyo V, Rodes J: Current guidelines for pharmacotherapy of ascites associated with cirrhosis. Drugs 43:316, 1992 29. Gines P, Arroyo V, Rodes J: Disorders of renal function in cirrhosis: Pathophysiology and clinical aspects. In Zakim D, Boyer TD (eds): Hepatology: A Textbook of Liver Disease, ed 3. Philadelphia, WB Saunders 1996, p 650 30. Gines P, Arroyo V, Vargas V, et a1 Paracentesis with intravenous infusion of albumin as compared with peritoneovenous shunting in cirrhosis with refractory ascites. N Engl J Med 325:829-835, 1991 31. Gines P, Berl T, Bernardi M, et al: Hyponatremia in cirrhosis: From pathogenesis to treatment. Hepatology 28:851-864, 1998 32. Gines P, Rimola A, Planas R, et al: Norfloxacin prevents spontaneous bacterial peritonitis recurrence in cirrhosis; results of double-blind, placebo-controlled trial. Hepatology 12:716-724, 1990 33. Gines P, Tito LI, Arroyo V, et al: Randomized comparative study of therapeutic paracentesis with and without intravenous albumin in cirrhosis. Gastroenterology 94:1493, 1988 34. Gomez-Jimknez J, Ribera E, Gasser J, et al: Randomized trial comparing ceftriaxone with cefonicid for treatment of spontaneous bacterial peritonitis in cirrhotic patients. Antimicrob Agents Chemother 371587-1592, 1993 35. Gonwa TA, Wilkinson AH: Liver transplantation and renal function: Results in patients with and without hepatorenal syndrome. In Epstein M (ed). The Kidney in Liver Disease, ed 4. Philadelphia, Hanley & Belfus, 1996, pp 529-542
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36. Grange JD, Roulot D, Pelletier G, et al: Norfloxacin primary prophylaxis of bacterial infections in cirrhotic patients with ascites-A double-blind randomized trial. J Hepatol 29:430436, 1998 37. Greig PD, Langer B, Blendis LM, et a1 Complications after peritoneovenous shunting. Am J Surg 139:125-131, 1980 38. Guamer C, Sola R, Soriano G, et al: Risk of a first community-acquired spontaneous bacterial peritonitis in cirrhotics with low ascitic fluid protein levels. Gastroenterology 117414-419, 1999 39. Guevara M, Gines P, Bandi JC, et al: Transjugular intrahepatic portosystemic shunt in hepatorenal syndrome: Effects of renal functions and vasoactive systems. Hepatology 28:41&422, 1998 40. Guevara M, Gines P, Fernandez-Esparrach G, et al: Reversibility of hepatorenal syndrome by prolonged administration of omipressin and plasma volume expansion. Hepatology 273541,1998 41. Hsieh W-J, Lin H-C, Hwang S-J, et al: The effect of ciprofloxacin in the prevention of bacterial infections in patients with cirrhosis after upper gastrointestinal bleeding. Am J Gastroenterol93:962-966, 1998 42. Inoue T, Ohnishi A, Matsuo A, et al: Therapeutic and diagnostic potential of a vasopressin-2 antagonist for impaired water handling in cirrhosis. Clin Pharmacol Ther 63:561-570, 1998 43 Kao HW, Rakov NE, Savage E, et al: The effect of large volume paracentesis on plasma volume-a cause of hypovolemia? Hepatology 5:403<07, 1985 44. Lebrec D, Giuily N, Hadengue A, et al: Transjugular intrahepatic portosystemic shunts: Comparison with paracentesis in patients with cirrhosis and refractory ascites: A randomized trial. J Hepatology 25:135-144, 1996 45. Lee FY, Colombato LA, Albillos A, et al: N omega-nitro-L-arginine administration corrects peripheral vasodilation and systemic capillary hypotension and ameliorates plasma volume expansion and sodium retention in portal hypertensive rats. Hepatology 1784-90, 1993 46. Lenz G, Hornatgl H, Drum1 W, et al: Omipressin in the treatment of functional renal failure in decompensated liver cirrhosis. Gastroenterology 101:1060-1067, 1991 47. Llach J, b o l a A, Navasa M, et al: Incidence and predictive factors of first episode of spontaneous bacterial peritonitis in cirrhosis with ascites: Relevance of ascitic fluid protein concentration. Hepatology 16724-727, 1992 48. Llovet JM, Rodriguez-Iglesias P, Moitinho E, et al:. Spontaneous bacterial peritonitis in patients with cirrhosis undergoing selective intestinal decontamination. A retrospective study of 229 spontaneous bacterial peritonitis episodes. J Hepatol 2688-95, 1997 49. Luca A, Garcia-Pagan JC, Bosch J, et al: Beneficial effects of intravenous albumin infusion on the hemodynamic and humoral changes after total paracentesis. Hepatology 22:753, 1995 50. Martin PY, Gines P, Schrier RW Nitric oxide as a mediator of hemodynamic abnormalities and sodium and water retention in cirrhosis. N Engl J Med 339:533-541, 1998 51. Martin PY, Ohara M, Gines P, et al: Nitric oxide synthase (NOS) inhibition for one week improves renal sodium and water excretion in cirrhotic rats with ascites. J Clin Invest 101:235-242, 1998 52. McCormick PA, Greenslade L, Kibbler CC, et al: A prospective randomized trial of ceftazidime versus nethylmicin plus mezlocillin in the empirical therapy of presumed sepsis in cirrhotic patients. Hepatology 252333436, 1997 53. Mercader J, Gomez J, Ruiz J, et al: Use of ceftriaxone in the treatment of bacterial infections in cirrhotic patients. Chemotherapy 35(suppl 2):23-26, 1989 54. Mirouze D, Zipser RD, Reynolds TB: Effects of inhibitors of prostaglandin synthesis on induced diuresis in cirrhosis. Hepatology 3:50-55, 1983 55. Morali GA, Sniderman KW, Deitel KM, et al: Is sinusoidal portal hypertension a necessary factor for the development of hepatic ascites? [letter]. J Hepatol 16:249-250, 1992 56. Navasa M, Follo A, Llovet JM, et a1 Randomized, comparative study of oral ofloxacin versus intravenous cefotaxime in spontaneous bacterial peritonitis. Gastroenterology 111:1011-1017, 1996
CLINICAL MANAGEMENT OF ASCITES AND ITS COMPLICATIONS
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57. Panos M Z , Moore K, Vlavianos P, et al: Single, total paracentesis for tense ascites: Sequential hemodynamic changes and right atrial size. Hepatology 11:662,1990 58. Pauwels A, Mostefa-Kara N, Debenes B, et al: Systemic antibiotic prophylaxis after gastrointestinal hemorrhage in cirrhotic patients with a high risk of infection. Hepatology 24802-806,1996 59. Perez-Ayuso RM, Arroyo V, Planas R, et al: Randomized comparative study of efficacy of furosemide versus spironolactone in nonazotemic cirrhosis with ascites. Relationship between the diuretic response and the activity of the renin-aldosterone system. Gastroenterology 84:961-968, 1983 60. Piddock LJV: Fluoroquinolone resistance. Overuse of fluoroquinolones in human and veterinary medicine can breed resistance. BMJ 3171029-1030, 1999 61. Pizcueta MP, Casamitjana R, Bosch J, et a1 Decreased systemic vascular sensitivity to norepinephrine in portal hypertensive rats: Role of hyperglucagonemia. Am J Physiol 258:G191-G195, 1995 62. Planas R, Arroyo V, Rimola A, et al: Acetylsalicylic acid suppresses the renal hemodynamic effect and reduces the diuretic action of furosemide in cirrhosis with ascites. Gastroenterology 84.247-252, 1983 63. Quiroga J, Sangro B, Nunez M, et al: Transjugular intrahepatic portosystemic shunt in the management of refractory ascites: Effect on clinical, renal, humoral and hemodynamic parameters. Hepatology 21:986, 1995 64. Ricart E, Soriano G, Novella MT, et al: Amoxicillin-clavulanic acid versus cefotaxime in the therapy of bacterial infections in cirrhotic patients. J Hepatol 32:596-602, 2000 65. Riggio 0, Merli M, Pedretti G, et a 1 Hepatic encephalopathy after transjugular intrahepatic portosystemic shunt: Incidence and risk factors. Dig Dis Sci 41:578-584, 1996 66. Rimola A, Bory F, Teres J, et a1 Oral, nonabsorbable antibiotics prevent infection in cirrhotics with gastrointestinal hemorrhage. Hepatology 5:463-467, 1985 67. Rimola A, Garcia-Tsao G, Navasa M, et al: Diagnosis, treatment and prophylaxis of spontaneous bacterial peritonitis: A consensus document. J Hepatol 32142-153,2000 68. b o l a A, Salmeron JM, Clemente G, et al: Two different dosages of cefotaxime in the treatment of spontaneous bacterial peritonitis: Results of a prospective, randomized, multicenter study. Hepatology 213674679, 1995 69. b o l a A, Tit6 L, Llach J, et al: Efficacy of ceftizoxime in the treatment of severe bacterial infections in patients with cirrhosis. Drug Invest 4 (suppl 1):35-37, 1992 70. Rossle M, Ochs M, Giilberg V, et al: A comparison of paracentesis and transjugular intrahepatic portosystemic shunting in patients with ascites. N Engl J Med 34217011707, 2000 71. Ruiz del Arbol L, Monescillo A, Jimenez W, et al: Paracentesis-induced circulatory dysfunction: Mechanism and effect on hepatic hemodynamics in cirrhosis. Gastroenterology 113~579-586,1997 72. Runyon BA, McHutchison JG, Antillon MR, et al: Short-course versus long-course antibiotic treatment of spontaneous bacterial peritonitis. Gastroenterology 100:17371742, 1991 73. Sabat M, Guamer C, Soriano G, et al: Effect of subcutaneous administration of octreotide on endogenous vasoactive systems and renal function in cirrhotic patient with ascites. Dig Dis Sci 4332184-2189, 1998 74. Schrier RW, Arroyo V, Bernardi M, et al: Peripheral arterial vasodilation hypothesis: A proposal for the initiation of renal sodium and water retention in cirrhosis. Hepatology 8:1151, 1988 75. Schrier RW, Neiderbeger M, Weigert A, et al: Peripheral arterial vasodilation: Determinant of functional spectrum of cirrhosis. Semin Liver Dis 1994; 14114, 1994 76. Simon DM, McCain JR, Bonkovsky HL, et al: Effects of therapeutic paracentesis on systemic and hepatic hemodynamics and on renal and hormonal function. Hepatology 7423, 1987 77. Sitzmann JV, Campbell KA, Wu Y, et al: Effect of portosystemic shunting on PgIZ and glucagon levels in humans. Ann Surg 217248-252,1993 78. Soriano G, Guamer C, Tomas A, et al: Norfloxacin prevents bacterial infection in cirrhotics with gastrointestinal hemorrhage. Gastroenterology 103:1267-1272, 1992 79. Somberg KA, Lake JR, Tomlanovich SJ, et al: Transjugular intrahepatic portosystemic
850
WONGCHARATRAWEE & GARCIA-TSAO
shunts for refractory ascites: Assessment of clinical and hormonal response and renal function. Hepatology 21:709-716, 1995 80. Sort P, Navasa M, Arroyo V, et al: Effect of intravenous albumin on renal impairment and mortality in patients with cirrhosis and spontaneous bacterial peritonitis. N Engl J Med 341:403409, 1999 81. Tito L, Rimola A, Gines P, et al: Recurrence of spontaneous bacterial peritonitis in cirrhosis: Frequency and predictive factors. Hepatology 8:27-31, 1988 82. Toledo C, Salmeron JM, Rimola A, et al: Spontaneous bacterial peritonitis in cirrhosis: Predictive factors of infection resolution and survival of patients treated with cefotaxime. Hepatology 17:251-257, 1993 83. Uriz J, Gines P and The International Group of Refractory Ascites: Randomized, multicenter, comparative study between TIPS and paracentesis with albumin in cirrhosis with refractory ascites. J Hepatol 2001; 34(suppll):A10 84. Valeriano V, Salerno F, Merli M, et al: TIPS versus paracentesis in the treatment of refractory ascites: Preliminary results of a randomized controlled trial [abstract]. Gastroenterology 118:A980, 2000 85. Wiest R, Das S, Cadelina G, et al: Bacterial translocation in cirrhotic rats stimulates eNOS-derived NO production and impairs mesenteric vascular contractility. J Clin Invest 104:1223-1233, 1999 86. Wong F, Liu P, Allidina Y, et al: Pattern of sodium handling and its consequences in patients with preascitic cirrhosis. Gastroenterology 108:1820-1827, 1995 87. Wong W, Liu P, Blendis L, et al: Long-term renal sodium handling in patients with cirrhosis treated with transjugular intrahepatic portosystemic shunts for refractory ascites. Am J Med 106:315-322, 1999
Address reprint requests to Guadalupe Garcia-Tsao, MD Yale University School of Medicine Section of Digestive Diseases P.O. Box 208019 333 Cedar St - 1080 LMP New Haven, CT 06520-8019 e-mail: [email protected]