Diagnosis, Evaluation, and Management of Ascites, Spontaneous Bacterial Peritonitis and Hepatorenal Syndrome: 2021 Practice Guidance by the American Association for the Study of Liver Diseases

This is a comprehensive guidance on the diagnosis, evaluation, and management of ascites and hepatorenal syndrome (HRS) in patients with chronic liver disease from the American Association for the Study of Liver Diseases (AASLD). It replaces the prior AASLD guideline on the same topic published in 2012 (Table 1).(1) Because this guidance represents an update covering nearly a decade, numerous changes are made. Instead of enumerating the individual changes, the following list represents noticeable revisions: This AASLD Guidance provides a data-supported approach to the management of ascites and HRS. It differs from the AASLD Guidelines, which are supported by systematic reviews of the literature, formal rating of the quality of the evidence, and strength of the recommendations. In contrast, this Guidance was developed by consensus of an expert panel and provides guidance statements based on comprehensive review and analysis of the literature on the topics, with oversight provided by the AASLD Practice Guidelines Committee. The AASLD Practice Guidelines Committee chose to perform a Guidance on this topic because a sufficient number of randomized controlled trials were not available to support meaningful systematic reviews and meta-analyses. Hepatic decompensation, defined by ascites, hepatic encephalopathy, and portal hypertensive gastrointestinal bleeding, is an important landmark in the natural history of cirrhosis.(2) Ascites is commonly the first decompensation-defining event, with 5%-10% of patients with compensated cirrhosis developing ascites per year.(3) The development of ascites is associated with a reduction in 5-year survival from 80% to 30%,(4) which is due in part to patients with ascites being prone to additional complications, such as bacterial infections, electrolyte abnormalities, HRS, and nutritional imbalances, and, consequently, further clinical decline.(5) Patients with cirrhosis who develop clinically significant ascites and related complications should be considered for referral for liver transplantation (LT) evaluation and, when appropriate, palliative care.(6) HRS is a late complication of cirrhosis that accounted for 3.2% of all hospital discharges related to cirrhosis according to a 2012 study based on a large inpatient health care database of patients representative of community hospitals in the United States.(4) Moreover, the number of HRS discharges in the United States has increased significantly in the past 2 decades.(7) HRS was also associated with high inpatient mortality (~46%) as well as longer lengths of stay and higher costs of hospitalizations compared with cirrhosis discharges without HRS. Figure 1 summarizes the key steps in the pathogenesis of ascites and related complications discussed in this document. From the perspective of the management of ascites, pathogenetic events of importance are renal sodium retention, arterial underfilling, and portal hypertension, which may be mitigated by diuretics, albumin infusion, and portal decompressive procedures, respectively.(8, 9) More recently, the advent of vasopressin receptor antagonists provided further insights on the contribution of water retention in the pathogenesis of ascites.(10) Recent reviews provide more detailed discussion of the pathogenesis of ascites.(11-13) HRS is a functional renal failure resulting from hemodynamic changes occurring in patients with ascites and portal hypertension.(14) The primary pathophysiologic mechanism of HRS is reduced renal perfusion secondary to renal vasoconstriction mediated by increased activities of the sympathetic, renin-angiotensin-aldosterone, and vasopressin systems,(5) which may be further aggravated by decreased cardiac output in patients with cirrhosis-associated cardiomyopathy. In addition, systemic inflammation that is common among patients with decompensated cirrhosis may trigger immune-mediated renal injury.(15) Finally, emerging evidence suggests that renal autoregulation, a natural defense mechanism to maintain renal blood flow, is impaired in patients with cirrhosis, predisposing them to additional direct hemodynamic renal injury.(16) Together, structural kidney damage can follow severe and/or repeated episodes of such renal events.(17, 18) Although cirrhosis is the most common cause of ascites in the Western world, other potential causes should be considered, including malignancy, heart failure, tuberculosis, and pancreatic disease. The initial evaluation of ascites should include history, physical examination, abdominal doppler ultrasound, laboratory assessment of liver and renal function, serum and urine electrolytes, and a diagnostic paracentesis for analysis of the ascitic fluid (Fig. 2; Tables 2-4).(19, 20) In evaluating the etiology of ascites, the serum albumin ascites gradient is calculated by subtracting the ascitic fluid albumin from the serum albumin in simultaneously obtained samples.(21) A serum albumin ascites gradient ≥1.1 g/dL is highly suggestive of portal hypertension, usually caused by liver disease with an accuracy of approximately 97%, whereas a serum albumin ascites gradient <1.1 g/dL suggests other causes of ascites (Table 4). In contrast, a high ascitic fluid protein (>2.5 g/dL) supports a cardiac source for ascites.(22) Other tests of the ascitic fluid, such as amylase, cytology, or culture for mycobacteria, are not routinely indicated but should be guided by the patient's clinical context. In patients with cirrhosis, ascites can be graded according to the amount of fluid accumulated in the abdominal cavity and classified according to response to treatment (Table 5).(19) No treatment is recommended for grade 1 ascites, as there is no evidence that it improves patient outcomes. Response to therapy and subsequent outcome in patients with grade 2 or 3 ascites depends on several factors such as the underlying cause of cirrhosis; feasibility and effectiveness of therapy to alter the natural course of cirrhosis; presence of superimposed complications such as renal failure, hyponatremia, and spontaneous bacterial peritonitis (SBP); and adherence of the patient to dietary sodium restriction and diuretics. Moderate dietary sodium restriction (2 g or 90 mmol/day) should be prescribed to achieve a negative sodium balance and net fluid loss. Fluid restriction is not indicated unless hyponatremia is present. Patient education for sodium restriction is essential to maximize adherence while avoiding malnutrition and sarcopenia.(23-25) Instructions about a sodium-restricted diet should include advice on sodium contents of preprepared meals, avoiding adding salt to cooked meals, and guarding against nutritional deficiency.(23) A formal consultation with a dietician should be considered. In most patients with cirrhosis presenting with ascites, dietary sodium restriction alone is insufficient and diuretic therapy is necessary. The patient should be made aware that daily monitoring of body weight, preferably at the same time of the day, is essential in assessing the efficacy of diuretics and preventing their adverse effects. The peritoneal membrane's ability to reabsorb ascites from the abdominal cavity is limited to approximately 500 mL per day. Thus, in a patient without peripheral edema, weight loss exceeding 0.5 kg per day may result in plasma volume contraction, predisposing the patient to renal failure and hyponatremia. In those with edema, weight loss up to 1 kg/day may be tolerated.(19, 26) In addition, patients should understand the need for laboratory monitoring (e.g., serum electrolyte concentrations), particularly during the first weeks of treatment. Assessment of 24-hour urinary sodium excretion may be useful to guide therapy; in the absence of renal dysfunction, sodium excretion lower than the intake (e.g., 80 mmol/day) indicates an insufficient diuretic dose. Persistent ascites despite adequate urinary sodium excretion indicates dietary indiscretion. When a 24-hour urine collection is not feasible, a random "spot" urine sodium concentration that is greater than the potassium (K) concentration correlates well with 24-hour urine sodium excretion.(27, 28) When the spot urine sodium (Na)/K ratio is >1, the patient should be losing fluid weight,(28) and, if not, dietary noncompliance should be suspected. If the spot urine Na/K ratio is ≤1, there is insufficient natriuresis, and an increase in diuretics should be considered. Aldosterone antagonists (e.g., spironolactone) and loop diuretics (e.g., furosemide, torsemide, bumetanide) are the mainstay of diuretic treatment of cirrhotic ascites.(29, 30) Two studies addressing the best way to use these diuretics showed that for the first episode of ascites, treatment with aldosterone antagonists alone generated an adequate response with few side effects,(29, 30) whereas those with long-standing ascites responded better to a combined diuretic treatment.(31) The recommended initial dose of spironolactone is 100 mg/day, which can be progressively increased up to 400 mg/day. Spironolactone and its active metabolites have a long half-life; the full effect of a dose change may not be seen for up to 3 days. When the dose is increased, it should be done cautiously and in a stepwise fashion, with an interval of at least 72 hours. The dose of furosemide (initially 40 mg/day) may be progressively increased, according to the response and tolerability toward 160 mg/day, which is the generally accepted threshold to determine medical treatment refractoriness.(19, 26) Torsemide or bumetanide may improve natriuresis in patients with a suboptimal response to furosemide.(32) Patients with chronic kidney disease (CKD) in general are treated with higher doses of loop diuretics and lower doses of aldosterone antagonists. When ascites is adequately mobilized, attempts should be made to taper the diuretics to the lowest dosages to maintain minimal or no ascites. Adverse effects of diuretic therapy may occur in 20% and 40% of patients with cirrhosis and ascites (Table 6).(23) Painful gynecomastia can be caused or exacerbated by spironolactone, which may respond to switching to amiloride or eplerenone(33, 34); see Table 6 for conversion doses. Muscle cramps are common in patients with liver disease, particularly in patients on diuretic treatment for ascites, and adversely influence the quality of life.(35) The exact mechanisms by which they occur remain unclear; however, besides the correction of electrolyte alterations (e.g., hypokalemia and hypomagnesemia), muscle cramps may respond to medications, such as baclofen (10 mg/day, with a weekly increase of 10 mg/day up to 30 mg/day)(36) and albumin (20-40 g/week).(35) Other drugs such as orphenadrine(37) and methocarbamol(38) have been proposed for muscle cramps in patients with cirrhosis. Finally, quinidine at a dose of 400 mg/day for 4 weeks in patients with cirrhosis was more effective than placebo against painful muscle cramps; however, toxicities such as diarrhea in about one-third of cases requiring treatment withdrawal may limit its use.(39) For patients presenting with tense ascites, large-volume paracentesis (LVP) combined with hyperoncotic human albumin is the initial treatment of choice, even in the presence of hyponatremia.(40, 41) Patients with massive peripheral edema may require a second paracentesis shortly after the first because a rapid shift of fluid may occur from interstitial tissue to the abdominal cavity.(19, 26, 40, 42) After LVP and a significant reduction in the intra-abdominal pressure, diuretics can be instituted, which may eliminate or reduce the frequency of paracentesis.(43) More detailed discussion about LVP is found in the section on refractory ascites (RA). Given the hemodynamic abnormalities in patients with cirrhosis and ascites, medications that may further reduce effective arterial volume and renal perfusion should be avoided. The most commonly encountered example is nonsteroidal anti-inflammatory drugs, which may precipitate hyponatremia, diuretic refractoriness, and acute kidney injury (AKI).(44) The angiotensin-converting enzyme inhibitors and angiotensin II receptor antagonists, α1-adrenergic blockers, and dipyridamole should also be avoided.(45-48) Similarly, all potential nephrotoxins should be avoided in patients with cirrhosis and ascites. Aminoglycoside antibiotics should be avoided whenever possible in the treatment of bacterial infections.(49) Finally, in patients with cirrhosis and ascites, the use of IV contrast media is not contraindicated(50); however, caution needs to be exercised in patients with impaired renal function. Albumin, the most abundant serum protein, is the main component that generates the oncotic pressure. In addition, albumin has a multitude of other functions, including ligand binding, anti-inflammatory, antioxidant, and endothelial stabilizing effects.(51-53) Recently, long-term albumin administration to patients with decompensated cirrhosis has been studied.(54, 55) In the ANSWER study, 431 patients with diuretic-responsive ascites were randomized to either standard medical treatment or standard medical treatment plus 40 g of albumin twice a week for the initial 2 weeks and then 40 g once a week for 18 months. A significantly better overall survival was seen in patients receiving albumin, with a 38% reduction in mortality.(54) In the MACTH study, 173 patients with ascites listed for LT were randomized to receive standard medical treatment plus 40 g of albumin every 15 days and an α1-receptor agonist, midodrine (15-30 mg/day depending on the response), or standard medical treatment plus placebo. Despite some improvement in parameters reflecting improved effective plasma volume, no difference was observed in the complication rates or death during 12 months of follow-up.(55) Thus, the discrepant results between the two trials point to the need for further studies to address the role of albumin as well as cost-effectiveness(56) in the management of ascites. Given the complexity of medical care of patients with cirrhosis and ascites, the use of a multidisciplinary team is likely beneficial but has not been studied extensively. A model of specialized care has been proposed: an integrated team including hepatologists, dedicated nurses, physicians in training, and diagnostic facilities improved 12-month survival and reduced the rate of hospitalization for liver-related complications in outpatients with cirrhosis and ascites compared with standard practice.(57) RA occurs in approximately 5%-10% of all patients with cirrhosis and ascites and is associated with poor survival of 50% at 6 months.(58) RA is defined as ascites that cannot be mobilized or recurs after LVP despite dietary sodium restriction and diuretic therapy.(19) Thus, RA is further divided into (1) diuretic resistant (i.e., persistent ascites despite maximal doses of diuretics) and (2) diuretic intractable, in which side effects of diuretics preclude the use of maximum doses (Table 7).(59) Recurrent ascites, which is defined as ascites that recurs at least three times within 1 year despite dietary sodium restriction and diuretic therapy, may be a forerunner of RA.(59) Figure 3 outlines the suggested treatment algorithm for RA management. Diuretic-resistant ascites Because of the lack of response to dietary sodium restriction and maximal doses of diuretics Diuretic-intractable ascites Because of the development of diuretic-induced complications* that precludes the use of effective doses of diuretics Fails sodium restriction Fails maximum doses of diuretics Both for at least 1 week Lack of treatment response Early recurrence of ascites *Diuretic-induced complications Dietary sodium restriction is important in the management of patients at all stages of ascites, including those with recurrent or refractory ascites, as it lowers the rate of ascites accumulation. Frequent review of a food diary can help identify high-sodium food items if the patient is reaccumulating ascites rapidly. Some patients who have been labeled as having RA may reduce their ascites once they adhere to a low-sodium diet. This is especially true in patients who excrete approximately 80 mmol of sodium in their urine per day.(28) Fluid restriction in a patient with cirrhosis and RA is difficult to enforce and is often impractical. These patients' daily urine output is usually less than 1 L, making it virtually impossible to achieve a negative fluid balance by restricting fluid intake to less than the urine output. The serum sodium concentration at which fluid restriction should be instituted has not been well defined(60) but is recommended when serum sodium is ≤125 mmol/L or its onset is rapid (see the section on hyponatremia). In patients who have diuretic-resistant ascites, the continued use of diuretics is ineffective while predisposing patients to complications, especially renal impairment. Furthermore, loop diuretics have a sigmoidal dose-response curve, which means that once the ceiling dose is reached, further increase in doses will not increase renal sodium excretion. For patients with liver cirrhosis, this ceiling dose is reduced compared with healthy controls.(61) In patients with diuretic intractable ascites, there are no data as to whether diuretic doses lower than those that have produced side effects should be used once the side effects have abated. Chronic albumin infusion in patients with cirrhosis and RA was evaluated in a cohort of 70 participants, 45 of whom received 20 g of albumin twice weekly.(62) There was a significant reduction in the 24-month hospital admissions for complications of cirrhosis and mortality.(62) These results suggest that the use of albumin is generally safe and may be beneficial in patients with RA, but randomized controlled trials are needed to support these findings. The dose of albumin used may be critical in achieving positive results.(63) LVP, arbitrarily defined as a paracentesis of >5 L, has been shown to be safe and effective in the management of RA. When done repeatedly, LVP has a lower incidence of electrolyte abnormalities, renal dysfunction, and hemodynamic disturbance with similar survival compared with continued diuretic use.(40) In patients undergoing LVP, the use of albumin is crucial to prevent a further reduction of effective arterial blood volume, which may precipitate postparacentesis circulatory dysfunction (PPCD). The clinical manifestations of PPCD include renal impairment, including HRS, dilutional hyponatremia, hepatic encephalopathy, and death.(64, 65) Albumin infusion is particularly important if more than 5 L of ascites are removed to prevent the development of PPCD.(28, 66) Paracenteses of a smaller volume are not associated with significant hemodynamic changes,(67) and albumin infusion may not be required. Although there has not been a dose-response study on albumin use with LVP, the administration of 6-8 g of albumin per liter of ascites removed has been recommended.(19) For example, after the fifth liter, approximately 40 g of albumin should be infused, and after 8 L removal, the amount of albumin given should be approximately 64 g. It has been held that there is no limit for the amount of ascites that can be removed in a single session, provided an appropriate amount of albumin is administered. However, the risk of PPCD increases with >8 L of fluid evacuated in one single session. A recent study showed that by limiting the LVP volume to <8 L per session and providing a higher than recommended dose of albumin (9.0 ± 2.5 g per liter of ascites removed), renal function and survival may be better preserved over a mean period of 2 years despite the development of PPCD in 40% of patients.(68) In patients with hemodynamic instability (systolic blood hyponatremia sodium and/or the presence of albumin infusion should be considered for paracentesis of a smaller LVP is a safe even in the presence of In a study that patients with an ratio of and a of of patients minimal after time or is not a for is of factors or may include patients with or and In the may be considered, particularly if there is history of prior Given its ability to reduce the portal in patients with RA has been shown to be better than repeated LVP in the of with in patients with RA is in recent including a This may be especially true for patients with for Liver those who received a smaller and those who a response to with of reduction of portal with of the volume to the systemic the the effective blood In there is of the over at which a significant occurs with of it is important to patients' that the of ascites is not and patients should be on a sodium-restricted diet ascites is adequately is recommended about the use of diuretics as diuretics reduce the volume, which may the of the effective arterial blood volume and the volume effects of ascites approximately 80% of patients will their ascites with Patients who to despite a at 12 months should be for LT of may be related to the the or the presence of a which are discussed in in the AASLD guidance on the In patients with RA undergoing with have the incidence of dysfunction The of in the management of depends on the of the function after the is of the in patients with a has however, long-term has been suggested in patients who received for dysfunction and in patients with a as studies may should be considered in patients with persistent or recurrent ascites even if the is Patient and for is of critical importance for a In patients with high of are poor to receive a risk factors (e.g., and patients to more complications and hepatic per may not survival after for with a smaller than have been associated with lower incidence of hepatic without the efficacy on ascites A recent study suggests that at an of natural history as those with recurrent result in side effects and improved survival when compared with The survival of was significantly better than in patients who received LVP, albumin, and diuretics. There was also no difference in the incidence of hepatic during However, this of will need to be in a randomized controlled it can be For patients who are not the and efficacy of peritoneal remain to be The studies published are of in which the bacterial rate was The risk and are even less for for whom LVP a treatment The ascites is an that ascites from the peritoneal cavity into the the of ascites by of an was to reduce paracentesis with improvement in quality of and nutritional the is not available in Patients who have RA and significant liver dysfunction that precludes should be considered for Patients who have RA but preserved liver function may be the as patients with ascites may an additional mortality risk to especially in patients is patients with RA also have hyponatremia, which is by the the hemodynamic abnormalities of decompensated cirrhosis will weeks to months to Patients may to have ascites for some time in the period and will need to stay on a sodium-restricted diet of ascites. are the standard of care for the of in patients with cirrhosis and portal More recently, the use of was found to be associated with a higher of and survival in decompensated cirrhosis, including patients with and Other that showed no of use on or on even in patients with severe liver dysfunction and those with liver These results to the of the that were useful during a of period in the natural history of that use be It is important to that of the studies are randomized controlled In the randomized controlled in patients with compensated cirrhosis, the use of was associated with a reduced incidence of ascites, that the use of in the of cirrhosis is the adequately randomized controlled studies such as survival are needed in patients with decompensated cirrhosis. For can caution the use of in patients with RA, especially in those with hemodynamic abnormalities as indicated by blood hyponatremia with serum sodium or serum of be if circulatory dysfunction improves with improvement of these defined as a serum concentration is in nearly of patients with cirrhosis and ascites, with over a fifth having serum patients with cirrhosis, ascites, and hyponatremia have however, and hyponatremia should be considered. hyponatremia can occur because of poor intake or from urinary or gastrointestinal related to an of diuretic or hyponatremia is among patients with cirrhosis unless there is a such as syndrome of medications (e.g., and severe or of hyponatremia, in patients with cirrhosis, from muscle and to and in hyponatremia is associated with reduced edema and improved quality of and The of hyponatremia with cirrhosis is graded as and severe hyponatremia often not require management from monitoring and water however, patients with hyponatremia, or severe hyponatremia, and LT may require management. of hemodynamic as cirrhosis (Fig. Patients with cirrhosis and serum are at increased risk for developing hepatic HRS and and they have a higher and patients with hyponatremia may be at increased risk of these This the of serum into the liver in the United States in to LT for patients with of hyponatremia in cirrhotic ascites depends on