CLINICAL PRACTICE GUIDELINES FOR MANAGEMENT OF ASCITES, SBP AND HRS Dr. Perihan Salem Assistant Professor of Hepatology Internal Medicine Department

Ascites is the most common complication of cirrhosis, and up to 60% of cirrhotic patients develop ascites during the course of their disease. Also, development of ascites correlates with impaired quality of life and poor prognosis

Management of uncomplicated ascites: Ascites without complications as RA, SBP or HRS. Grades: Grade 1 Mild detected only by US No treatment with bed rest Grade 2 Moderate with symmetrical distention of the abdomen Restriction of Na intake Diuretics Grade 3 Large with marked abdominal distention Frequent large volume paracentesis

Management of uncomplicated ascites: Bed rest: Large number of studies proved that the upright posture activates Na retaining systems and slightly impairs renal perfusion.

Management of uncomplicated ascites: Na Restriction: In cirrhotic pts renal Na excretion is LOW relative to the intake due to increased Na reabsorption from both proximal & distal renal tubules, leading to Na retention. Treatment aimed at counteracting renal Na retention and achieving –ve Na balance by reducing Na intake (80-120 mmol/day=4.6-6.9 g/day this is equivalent to a NO added salt diet with avoidance of pre-prepared meals) & enhancing renal Na excretion by administration of diuretics..

Management of uncomplicated ascites: Diuretics: Renal Na retention in cirrhotic pts with ascites is due to increased Na reabsorption from both proximal & distal renal tubules. The mediators for enhanced proximal tubular reabsorption of Na haven’t been known completely. While, increased reabsorption of Na along the distal tubules is related to hyperaldosteronism. Thus, aldosteron antagonists are the diuretics of choice.

Management of uncomplicated ascites: Regimens: Pts with 1st episode of ascites should be treated initially ONLY with aldosteron antagonist in a starting dose of 100mg/day & a stepwise increase of the dose by 100mg/week till reaching a maximum dose of 400mg/day. Only in pts NOT responding to high doses of aldosteron antagonists, we should start loop diuretics (Frusemide) in a starting dose of 40mg/day with a stepwise increase till reaching a maximum dose of 160mg/day. Pts with recurrent ascites should be treated with combined therapy of aldosteron antagonists & frusemide from the beginning of treatment with the same starting doses, stepwise increase till the maximum doses.

Management of uncomplicated ascites: Target of diuretic therapy: In pts without peripheral edema: wt loss of 0.5 kg/day. In pts with peripheral edema: wt loss of 1 kg/day. Then diuretics should be reduced to the lowest effective dose that maintain the pt with minimal or no ascites. Complications of diuretics: *RF due to renal hypoperfusion. *HE mostly due to electrolyte disturbance. *Gynecomasta. *Muscle cramps. *Electrolyte disturbance (hyponatremia <120-125 mmol/L is an indication to reduce/stop diuretics temporary). Thus, frequent measurement of kidney function, Na, K, Mg should be performed during the 1st month of treatment.

Management of uncomplicated ascites: Large volume paracentesis (LVP): Treatment of choice in grade 3 large ascites, together with Na restriction and diuretics. LVP is more effective than diuretics alone & significantly shortens the duration of hospital stay. LVP is safe & the incidence of local complications (as Hg & bowel perforation) are extremely low. The most important complication of LVP is post paracentesis circulatory dysfunction (PPCD), due to removal of large volume of ascitic fluid & reduction of the effective circulating blood volume.

Management of uncomplicated ascites: Sequale of PPCD: 1- PPCD is associated with rapid reaccumulation of ascites. 2- Up to 20% of these pts develop HRS &/or water retention leading to dilutional hyponatremia. 3- Portal pressure increases with increased intrahepatic resistance due to the action of vasoconstrictor systems on the hepatic vascular bed. 4- PPCD is associated with shortened survival. The most effective method to prevent PPCD after LVP is: administration of albumin if the amount of ascitic fluid removed >5L (8 g/L removed) administration of volume expanders (colloids as plasma and dextran or even crystalloids) is not preferred.

Management of uncomplicated ascites: In patients undergoing LVP of less than 5 L of ascites, the risk of developing PPCD is low. However, it is generally agreed that these patients should still be treated with albumin because of concerns about use of alternative plasma expanders The latest health economic analysis suggested that it is more cost effective to use albumin after LVP compared with alternative cheaper plasma expanders since the administration of albumin is associated with lower number of liver related complications.

Management of Refractory ascites: Ascites which can’t be mobilized or early recurrence after LVP. Also, it can’t be prevented by medical therapy. (according to International Ascites Club) Types: *Diuretic resistant: Ascites can’t be mobilized or early recurrence which can’t be prevented because of lack of response to Na restriction & diuretics. *Diuretic intractable: Ascites can’t be mobilized or early recurrence which can’t be prevented because of the development of diuretic induced complications which interfere with the use of an effective diuretic dose.

Management of Refractory ascites: Refractory ascites is associated with poor prognosis & shortening of survival (6 months). Treatment included: *Frequent LVP with albumin infusion together with continuing salt restriction & diuretic therapy (only if urinary Na excretion is greater than 30 mmol/day and in the absence of diuretic-induced complications). *TIPS with possible complications of HE (30-50%), stent stenosis & thrombosis. TIPS cannot be recommended in patients with severe liver failure (serum bilirubin >5 mg/dl, INR >2 or Child-Pugh score >11, current hepatic encephalopathy ≥ grade 2 or chronic hepatic encephalopathy), concomitant active infection, progressive renal failure, or severe cardiopulmonary diseases. *LT.

Management of SBP: SBP is a very common bacterial infection in patients with cirrhosis and ascites, its prevalence in outpatients is 1.5–3.5% and 10% in hospitalized patients with up to 20% mortality rate. Diagnosis of SBP: 1-Clinically: asymptomatic, abdominal pain & tenderness, vomiting, diarrhea, ileus, hyperthermia, chills, tachycardia &/or tachypnea, worsening of liver function with altered white blood cell count, hepatic encephalopathy, shock, renal failure and gastrointestinal bleeding. 2-Ascitic fluid analysis: neutrophil count ≥250 cells/mm3. 3-Ascitic fluid culture: -ve in up to 60% of patients.

Management of SBP: Regimen: I) Empirical antibiotics: should be started immediately following the diagnosis of SBP without waiting culture results with 3rd generation cephalosporins in a dose of 2g/8 hours and 5-day therapy is as effective as a 10-day therapy. Alternative options include amoxicillin/clavulanic acid and quinolones such as ciprofloxacin or ofloxacin. However, the use of quinolones shouldn’t be considered in patients who are taking these drugs for prophylaxis against SBP. A second paracentesis after 48 h of starting treatment may help guide the effect of antibiotic therapy. Failure of antibiotic therapy should be suspected if there is worsening of clinical signs and symptoms and/or no marked reduction or even increase in ascitic fluid neutrophil count compared to levels at diagnosis. Failure of antibiotic therapy is usually due to resistant bacteria or secondary bacterial peritonitis. Thus, antibiotics should be changed.

Management of SBP: In cases with fungal infection: - Positive ascitic fluid culture (Candida spp) regardless PMN count. - Fluconazole (Diflucan) is the drug of choice in a dose of 100 mg/day for 5-10 days. - No requirement to adjust the dose when given to subjects with mild to moderate hepatic impairment.

Management of SBP: II) IV albumin: *Administration of IV albumin to patients with SBP reduced the incidence of renal impairment (10% vs 33%) and hospital mortality (10% vs 29%). *AASLD guidelines recommended that patients with SBP who benefit most from IV albumin are those with creatinine >1mg/dl, blood urea nitrogen >30mg/dl and serum bilirubin >4mg/dl. *EASL guidelines recommended that all patients who develop SBP should be treated with broad spectrum antibiotics and intravenous albumin. *Recommended dose: 1.5g/kg body weight at diagnosis and 1g/kg on day 3. III) Liver transplantation: SBP is an indication to LT particularly if recurrent.

Management of SBP: Prophylaxis of SBP: *Long term antibiotic prophylaxis will lead to the emergence of resistant bacteria. Therefore, only patients with high risk for development of SBP should receive antibiotic prophylaxis. *High risk patients are: (1) Patients with acute gastrointestinal hemorrhage. (2) Patients with low protein content in ascitic fluid (less than 1-1.5gm/dl) and no prior history of SBP (primary prophylaxis). (3) Patients with a previous history of SBP, with recurrence rate at 1 year is approximately 70% (secondary prophylaxis).

Management of SBP: In GIT bleeding: Norfloxacin 400 mg/12 hours for 7 days. In patients with GIT bleeding and advanced cirrhosis (at least 2 of the following: severe malnutrition, encephalopathy, or bilirubin >3 mg/dl), 3rd generation cephalosporins was more effective than Norfloxacin in the prevention of SBP. In patients with low ascitic fluid protein content (less than 1-1.5gm/dl without prior SBP: -In patients with severe liver disease: Norfloxacin 400 mg/day for long periods. (creatinine ≥1.2, BUN ≥25, serum Na ≤130, Child score ≥9 and bilirubin ≥3) according AASLD. -In patients with moderate liver disease: The efficacy of Quinolones in preventing SBP or improving survival is not clearly established. Studies are needed in this field with no consensus of prophylactic antibiotics among these patients. In patients with a previous attack of SBP: Norfloxacin (400 mg/day) is the treatment of choice which reduces the risk of recurrent SBP (70% vs 20%). Alternative antibiotics include ciprofloxacin (750 mg once weekly, orally) or co-trimoxazole (800 mg sulfamethoxazole and 160 mg trimethoprim daily, orally), but evidence is not as strong as that with Norfloxacin.

Management of HRS: Monitoring: Patients with HRS should be monitored carefully. Parameters to be monitored include urine output, fluid balance to prevent volume overload, vital signs, kidney & liver functions and electrolytes. Screening for sepsis: Bacterial infection should be identified early by doing blood, urine and ascitic fluid cultures, and treated with the proper antibiotics. Patients who do not have signs of infection should continue taking prophylactic antibiotics, if previously prescribed. There are NO data on the use of antibiotics as empirical treatment for unproven infection in patients presenting with HRS.

Management of HRS: Terlipressin/Glypressin (1 mg/4–6 hs IV) in combination with albumin (1 gm/kg in the 1st day after diagnosis of HRS with a maximum dose of 100 gm/day, then 20-40 gm/day) is the first line of therapy in HRS. The aim of therapy is to improve renal function & decrease serum creatinine to less than 1.5 mg/dl (complete response). If serum creatinine does not decrease at least 25% after 3 days, the dose of terlipressin/glypressin should be increased in a stepwise manner up to a maximum dose of 2 mg/4-6 hs. For patients with partial or no response treatment should be discontinued within 14 days. Patients on terlipressin/glypressin should be carefully monitored for development of cardiac arrhythmias/ischemia, signs of splanchnic or digital ischemia and treatment should be modified or stopped accordingly.

Management of HRS: Potential alternative therapy to terlipressin include norepinephrine or midodrine plus octreotide, in association with albumin. TIPS: data are insufficient to support the use of TIPS in patients with HRS. Renal replacement therapy (hemodialysis or continuous venous hemofiltration): data are insufficient but it may be useful in patients who do not respond to vasoconstrictor therapy, and who fulfill criteria for renal support. Liver transplantation: with low survival rates (up to 65%) compared to patients with cirrhosis without HRS due to the fact that renal failure is a major predictor of poor outcome after transplantation.

Management of HRS: Use of beta-blockers: There are no data on whether it is better to stop or continue with beta-blockers in patients with type 1 HRS who are taking these drugs for prophylaxis against variceal bleeding. Use of paracentesis: There are few data on the use of paracentesis in patients with type 1 HRS. However, if patients have tense ascites, paracentesis with albumin infusion is useful in relieving patients’ discomfort. Use of diuretics: There are no data to support the use of diuretics in patients with ongoing type 1 HRS. However, frusemide may be useful to maintain urine output and treat central volume overload. While, spironolactone is contraindicated because of high risk of life-threatening hyperkalemia.

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