Austrian consensus guidelines on the management and treatment of portal hypertension (Billroth III)

Summary The Billroth III guidelines were developed during a consensus meeting of the Austrian Society of Gastroenterology and Hepatology (ÖGGH) and the Austrian Society of Interventional Radiology (ÖGIR) held on 18 February 2017 in Vienna. Based on international guidelines and considering recent landmark studies, the Billroth III recommendations aim to help physicians in guiding diagnostic and therapeutic strategies in patients with portal hypertension.


I.
Definitions of portal hypertension II. Diagnosis and screening of portal hypertension III. Preprimary prophylaxis and prevention of decompensation IV. Primary prophylaxis of variceal bleeding V.
Acute variceal bleeding VI. Secondary prophylaxis of variceal bleeding VII. Measurement of the hepatic venous pressure gradient (HVPG) VIII. Portal hypertensive gastropathy IX. Gastric varices X.
Management of ascites XI. Spontaneous bacterial peritonitis (SBP) The strength of the underlying evidence and the recommendations were based on a modified version of the GRADE system (Table 1) I. Definitions of portal hypertension 1. The term compensated advanced chronic liver disease (cACLD) may be used similar to cirrhosis and is defined as confirmed liver stiffness >15 kPa on transient elastography [2]. Diagnosis of cACLD should trigger screening for clinically significant portal hypertension (CSPH) [3]. (A1) 2. CSPH is defined as an increase of the hepatovenous pressure gradient (HVPG) to values of ≥10 mm Hg. (A1) [3] 3. Normal portal pressure is defined as HVPG of ≤5 mm Hg, while subclinical portal hypertension is defined as HVPG 6-9 mm Hg. (A1) 4. CSPH might already be present in compensated patients (without ascites, without varices). (A1) 5. The presence of gastroesophageal varices (GOVs), variceal hemorrhage, ascites (in the absence of significant cardiac, malignant, peritoneal or renal comorbidities) and/or the presence of large portosystemic collaterals on imaging studies are indicative of the presence of CSPH [3]. (A1) 6. Assessing the four Baveno stages of portal hypertension is clinically useful to quickly assess the prognosis of patients with liver cirrhosis: Baveno-I compensated, no varices, Baveno-II compensated, presence of GOVs, Baveno-III decompensated with ascites and Baveno-IV decompensated, history of variceal bleeding [3,4]. (B1)  1. Patients with cirrhosis (or cACLD) should be screened for CSPH [3] (see Billroth-III screening algorithm in Fig. 1). (A2) 2. After the initial diagnosis of cirrhosis (or cACLD) screening endoscopy may be performed at least once if the patient never had an upper GI endoscopy before. (C1) 3. In cirrhotic patients with a platelet count >150 G/L and liver stiffness <15 kPa on transient elastography screening endoscopy can be safely deferred [5][6][7]. (B1) 4. Esophageal varices (EV) should be graded as absent, small (<5 mm of diameter), or large (≥5 mm).
The presence of red spots should be indicated for risk stratification. (A2) 5. Gastric varices should be described as GOV-1 (continued varices on minor curvature), GOV-2 (continued varices on larger curvature extending to the fundus) or isolated gastric varices (IGV-1) isolated fundal varices or IGV-2 ectopic varices in the stomach. The presence of red spots should be indicated for risk stratification [8]. (B2) 6. In patients without varices, endoscopy should be repeated every 2 years in the case of compensated cirrhosis and every year in the case of decompensated cirrhosis [3]. (C1) 7. Patients with low-risk varices should receive nonselective beta blockers (NSBBs). (C1) 8. In compensated patients with varices (EV or GOV) receiving NSBBs there is no indication for endoscopic monitoring of the varices [3]. (C1) 9. If HVPG is measured as ≥10 mm Hg, endoscopy should be repeated every year in order to screen for the presence of varices, since CSPH is predictive of the formation of esophagogastric varices [3]. (A1) 10. There is no indication for subsequent endoscopic surveillance once large EVs or gastric varices (≥5 mm) are detected, unless endoscopic treatment is performed for primary or secondary prophylaxis of variceal bleeding [3]. (B1)

III. Preprimary prophylaxis and prevention of decompensation
The effectiveness of NSBBs in the setting of preprimary prophylaxis (prevention of the development of varices and variceal bleeding in patients with compensated cirrhosis; cACLD) has been addressed in a landmark study which randomly assigned patients with cirrhosis and portal hypertension (defined by HVPG ≥6 mm Hg; 63% had CSPH) to timolol or placebo [9]. After a median follow-up of nearly 5 years, approximately 40% of patients in both groups met the composite primary endpoint of development of varices or variceal bleeding. Thus, in general, there is no indication for NSBBs treatment in patients who have not developed varices; however, NSBBs might be indicated for extrahepatic comorbidities (e. g. arterial hypertension, coronary heart disease, and heart failure). In the aforementioned study, patients who had a relative HVPG decrease of >10% after 1 year showed a lower incidence of the primary endpoint [9]; however, relevant HVPG decreases during NSBBs treatment are only observed in patients with CSPH [10]. In a recent randomized controlled trial (RCT) restricted to patients with CSPH, preprimary prophylaxis (44%) or small varices without red spot signs (56%), propranolol/carvedilol decreased the risk of S136 Austrian consensus guidelines on the management and treatment of portal hypertension (Billroth III) K original article hepatic decompensation, mostly by decreasing the incidence of ascites [11]. Thus, future studies should address the potential benefits of early initiation of NSBBs (especially carvedilol) treatment in the subgroup of patients with CSPH.
1. Preprimary prophylaxis defines the prevention of the development of varices and variceal bleeding in patients with compensated cirrhosis (cACLD) who do not have varices. (A1) 2. In general, there is no indication for NSBBs treatment in patients with cACLD who have not yet developed varices. Nevertheless, NSBBs might be indicated for extrahepatic comorbidities (e. g. arterial hypertension, coronary heart disease, and heart failure). (A1) 3. Preprimary prophylaxis with NSBBs can be considered in patients with CSPH since it may reduce the risk of developing ascites. (B2)

Indications for primary prophylaxis
This chapter addresses primary prophylaxis in patients with esophageal varices (EV) and recommendations for the management of gastric varices is discussed in Chap. IX (gastric varices). Choice of treatment for primary prophylaxis 2. Patients with small EVs with risk factors (red spot signs and/or with decompensated cirrhosis Child-Pugh class B or C) should receive NSBBs since they reduce the risk of bleeding in this setting [12]. (A1) 3. Patients with small EV without risk factors should also receive NSBBs prophylaxis, since NSBBs may reduce the incidence of variceal bleeding in this setting. (C1) 4. If monitoring of HVPG is available, treatment with NSBBs should be preferred, since achieving a hemodynamic response defines an excellent long-term prognosis [13]. (B1) 5. Hemodynamic response to NSBBs is defined as a reduction in HVPG ≤ 12 mm Hg or at least ≥10% from baseline. This is not only associated with a lower risk of first variceal bleeding but also with a lower incidence of ascites and death [14][15][16]. (A1) 6. The lack of access to HVPG measurement should not prevent physicians from using NSBBs for primary prophylaxis, since bleeding rates in primary prophylaxis are low even in hemodynamic nonresponders to NSBBs. (B1) 7. Propranolol or carvedilol should be used for prophylactic pharmacological treatment of patients with varices. Carvedilol is more effective than propranolol in primary prophylaxis of variceal bleeding [17,18]. (B1) 8. In patients with contraindications to NSBBs therapy, NSBBs intolerance, non-adherence to NSBBs or non-responders to NSBBs, EVL should be used.
Endoscopic treatment 9. Use of EVL in primary prophylaxis should be performed in 2-6-week intervals until variceal eradication. A first follow-up endoscopy after variceal eradication should be performed after 6 months and then every 12 months. If EVL must be restarted the intervals are similar to first EVL [19]. (B1)

Pharmacological treatment with NSBBs
10. There is no need for follow-up endoscopy in patients on pharmacological therapy. (B1) 11. The initial dose of propranolol is 20-40 mg twice daily with a maximum dosage of 160 mg/day in patients without and 80 mg/day with ascites. The initial dose of carvedilol is 6.25 mg once daily with a maximum dosage of 12.5 mg/day [16]. (B1) 12. The dose of NSBBs should be increased to achieve a resting heart rate of 55-60 beats per minute (bpm). The systolic blood pressure should not decrease below 90 mm Hg. (B1) 13. There is no relationship between reduction in portal pressure or protection from variceal bleeding and the reduction in resting heart rate or in blood pressure. There is no consensus on whether NSBBs treatment should be continued in patients without a hemodynamic response to NSBBs treatment; however, the benefit of NSBBs treatment may go beyond the portal pressure reducing effect and may also reduce the incidence of ascites, infections, decompensation and death [14,15]. (B1) 14. In patients with severe or refractory ascites NSBBs should be discontinued during spontaneous bacterial peritonitis (SBP), a decline of systolic blood pressure <90 mm Hg or hyponatremia Na < 125 mmol/l or in the presence of acute kidney injury [20][21][22]. (C2) 15. Isosorbide mononitrate (ISMN) (alone or combined with NSBBs) is not recommended for primary prophylaxis, since it is not more effective in preventing first bleeding but increases side effects [23,24]. (B1) 16. The combination of endoscopic treatment and NSBBs treatment does not further decrease the incidence of bleeding or death but is associated K Austrian consensus guidelines on the management and treatment of portal hypertension (Billroth III) S137 with a higher number of side effects and cannot be recommended for primary prophylaxis [25]. (A1) 17. The presence of varices does not represent an indication for proton pump inhibitors (PPIs); however, a short course of PPI post-variceal ligation reduces ulcer size and early bleeding risk [26,27]. (C1) 18. Transjugular intrahepatic portosystemic shunt (TIPS) placement is not recommended for prevention of first variceal hemorrhage [28]. (C1)

V. Acute variceal bleeding
The Billroth-III algorithm for treatment of acute variceal bleeding is summarized in Fig. 2 Definition 1. Acute variceal bleeding (AVB) is diagnosed in cases of: (a) active bleeding at endoscopy or (b) signs of upper GI bleeding (hematemesis, blood or coagulated blood, melena) in patients with varices in the absence of any other source of bleeding.

Blood products
2. Blood volume restitution should be done conservatively using packed red cells to maintain a Hb level of 7-8 g/dl (unless comorbidities/active bleeding necessitate more aggressive substitution), and substitution of fluids to maintain hemodynamic stability [29] Antibiotic prophylaxis 6. Antibiotic prophylaxis is an integral part of the therapy of variceal bleeding and should be started at admission with i. v. broad spectrum antibiotics which can be de-escalated according to culture results. In the absence of overt infections and successful control of AVB, antibiotic prophylaxis can be stopped after 5-7 days [30]. Prognosis 24. Active bleeding at endoscopy (under vasoactive therapy) is a poor prognostic sign regarding successful control of bleeding for the short-term period after variceal bleeding [33]. (B1) 25. An HVPG of ≥20 mm Hg, active bleeding at endoscopy and a Child-Pugh class C are associated with an increased failure to control bleeding and early mortality [34]. (B1) Failure to control bleeding 26  (C1) 11. EVL to prevent rebleeding in secondary prophylaxis should be continued at 2-4-week intervals until eradication of varices (small residual varices can be tolerated) and should then be repeated after 6 months and 12 months. If EVL must be restarted the intervals are similar to the first EVL. 12. Patients with advanced stage liver disease should be evaluated for liver transplantation. In these patients, endoscopic and/or medicinal therapy should be continued until liver transplantation. (C2) 13. EVL is the therapy of choice for variceal rebleeding (or insufficient decrease in HVPG on NSBBs), although EVL may have only moderate beneficial effects especially in these patients (B2). 14. TIPS is indicated in patients with failure of secondary prophylaxis and should be preferred over surgical shunts. (B1) 15. BRTO and surgical devasculariziation are a rescue therapy in patients with failure of secondary prophylaxis with NSBBs and EVL combination therapy if neither a TIPS nor shunt surgery is feasible.
16. TIPS should be considered for secondary prophylaxis in patients with severe/refractory concomitant ascites and/or in patients with NSBBs intolerance or non-response. (C1) 17. In patients with severe or refractory ascites NSBBs should be discontinued during SBP, a decline of systolic blood pressure <90 mm Hg or hyponatremia Na < 125 mmol/L or in cases of acute kidney injury (AKI).

VII. Measurement of hepatic venous pressure gradient (HVPG)
1. Portal pressure, assessed by the hepatic venous pressure gradient (HVPG) drives the development of liver-related complications and mortality in patients with (compensated) advanced chronic liver disease (cACLD) [38,39]. (A1) 2. HVPG measurements are indicated for assessing the prognosis and monitoring the response to etiologic and HVPG-lowering treatment [38,39]. (A2) 3. The number needed to treat (NNT) for NSBBs for preventing variceal bleeding ranges from 5 (secondary prophylaxis) to 10 (primary prophylaxis) [40], underlining the need for methods to assess the expected benefits of NSBBs treatment in the individual patient [21]. (B2) 4. HVPG response is the only established surrogate for the effectiveness of NSBBs in preventing (recurrent) variceal bleeding. If HVPG decreases to a value of <12 mm Hg or is reduced by ≥20% during NSBBs treatment, patients are protected from variceal bleeding and survival is increased [41,42].
(A1) 5. The assessment of acute HVPG response to intravenous propranolol (0.15 mg/kg given as 15 min infusion) provides a valuable alternative to chronic response assessment (separate measurements). An HVPG reduction by >10% or to <12 mm Hg (measured after the 15 min infusion) is sufficient in the acute setting [14,43]. (A1) 6. Several studies support the use of HVPG-guided therapy. Thus, in centers with sufficient experience, HVPG response should be assessed to guide treatment decisions [11,16,[44][45][46][47]. (A2) 7. HVPG measurements should be performed in fasting conditions. Since the procedure is generally well tolerated [48], ideally no sedation, or if necessary only low doses of midazolam (maximum 0.02 mg/kg) should be used [49,50]. (A1) 8. HVPG measurements should be performed using a balloon catheter ensuring a sufficient wedge position and in order to maximize the assessed amount of liver parenchyma [51][52][53]. (A1) 9. Free hepatic venous pressure (FHVP) should be measured in a liver vein 2 cm from the inferior vena cava (stable values are usually obtained after 15 s) [54]. A difference between the inferior vena S140 Austrian consensus guidelines on the management and treatment of portal hypertension (Billroth III)

VIII. Portal hypertensive gastropathy
1. Portal hypertensive gastropathy (PHG) is defined as a macroscopically visible mosaic-like pattern of the gastric mucosa (usually fundus or corpus) and can be found in 35-80% of cirrhotic patients, correlates with the Child-Pugh score and the degree of portal hypertension (PHT) [55]. A summary for the management of PHT is shown in Fig. 3. (A1) 2. PHG should be differentiated into mild PHG (without signs of bleeding) and severe PHG (red marks or active bleeding). (A1) 3. Gastric antral vascular ectasia (GAVE) is a distinct entity that is endoscopically characterized by tortuous columns of erythematous (mild) or hemorrhagic (severe) lesions in a "watermelon" or diffuse pattern (in the latter case histology may help to confirm diagnosis). GAVE may be present without cirrhosis and is associated with PHT in only 30% of cases [56]. (A1) 4. The incidence of acute PHG bleeding is 2-20% (mostly in severe PHG) [57]. (B2) 5. The incidence of chronic PHG bleeding is around 3-26% and is defined by a >2 g/dl decrease in Hb or by the presence of anemia together with positive faecal occult blood tests [57]. (B2) 6. If PHG is associated with iron deficiency anemia, iron substitution and in severe cases (Hb < 7 g/dL) transfusion should be considered. (B1) 7. There is no evidence for PHG screening or primary bleeding prophylaxis, yet the use of NSBBs for other indications is not discouraged. (C2) 8. Acute bleeding should be pharmacologically treated as AVB. Emergency gastroscopy should rule out other causes for GI bleeding and help to manage endoscopically treatable bleeding [58,59]. (A1) 9. PHG with chronic bleeding should be treated with NSBBs [55,57]. (B1) 10. In cases of refractory PHG bleeding TIPS, shunt surgery, argon-plasma coagulation (APC) or even liver transplantation represent rescue therapies. (B2) 11. GAVE bleeding should be treated by APC or Nd:YAG laser coagulation but multiple treatment sessions might be necessary [60]. (A1) 12. In severe or treatment resistant GAVE, band ligation, cryotherapy, radiofrequency ablation or surgical antrectomy represent potential salvage therapies [60]. Acute variceal bleeding from gastric varices 8. Initial management of patients with acute variceal bleeding from gastric varices is similar to bleeding from EVs, including vasoactive drugs, restrictive transfusion policy and antibiotic prophylaxis. (B1) 9. Cyanoacrylate glue injection is the treatment of choice for acute variceal bleeding from cardiofundal varices (GOV2, IGV1) and may be also used for GOV1 and IGV2 [63]. (A1) 10. A single injection should consist of maximum 1.0 ml of a cyanoacrylate/lipiodol mixture (1:1)

X. Management of ascites
30% of patients with compensated cirrhosis develop ascites within 5 years of follow-up [68]. Occurrence of ascites significantly impairs prognosis of liver cirrhosis, with a mortality of 15-20% within 1 year and 44% within 5 years [4,69]. Treatment of ascites has not yet resulted in significant improvements in survival; however, treating ascites is important because it improves the quality of life of cirrhotic patients and the occurrence of SBP is unlikely in patients without ascites. Important definitions, grading and treatment are summarized in Table 2.

Diagnostic approach in patients with ascites
1. Ascites should be graded according to the International Ascites Club guidelines into uncomplicated (grade 1: only visible on ultrasound, grade 2: moderate ascites, grade 3: massive ascites), and refractory ascites (not responsive or intolerant to diuretic therapy even after paracentesis) [70]. (A1) 2. Diagnostic paracentesis is indicated in (i) all cirrhotic patients presenting with ascites for the first time, (ii) cirrhotic patients with ascites with unscheduled admission to hospital regardless of the reason, and (iii) cirrhotic patients with ascites with signs of clinical deterioration (such as fever, hepatic encephalopathy, leucocytosis, abdominal pain, upper gastrointestinal bleeding or deterioration in renal function). Substitution of coagulation factors or platelets is not indicated even in patients with severe coagulopathy, because paracentesis rarely leads to serious bleeding complications [71,72]. (B1) 3. Investigation of ascites should include at least determination of ascitic neutrophil count, protein concentration, and the serum-ascites albumin gradient (SAAG). Uncomplicated ascites due to portal hypertension is expected to show a neutrophil count <250/µl, a SAAG >1.1 g/dl [73] and a protein level <2.5 g/dl. The SAAG is calculated by subtracting the ascitic fluid albumin level from the serum albumin level (both determined on the same day). (B1) 4. Additionally, aerobic and anaerobic blood culture bottles should be inoculated with ascitic fluid for bacteriological diagnosis of SBP or bacterascites (neutrophil count <250/µl but positive ascites fluid culture). (B1) Therapy of uncomplicated ascites 5. Initial therapy of patients with cirrhosis and ascites consists of moderate sodium restriction (90 mmol NaCl/day, corresponding to 5.2 g NaCl/day), and diuretic therapy. Sodium restriction to less than 5 g NaCl/day is not recommended due to the risk of aggravating malnutrition that is usually present in these patients [74]. (B1) 6. Diuretic therapy should be started with spironolactone 100 mg and furosemide 40 mg [75,76]. In the case of insufficient ascites control or lack of effectiveness, doses of spironolactone and furosemide can be increased by 100 mg and 40 mg every 3-5 days. The daily dose of 400 mg spironolactone and 160 mg furosemide should not be exceeded. (A1) 7. Furosemide should not be administered intravenously as a bolus in cirrhotic patients because of risk of deterioration in the glomerular filtration rate (GFR) [77]. (B1) 8. The use of spironolactone or amiloride as single agents or combined with thiazides may have a role for outpatients or previously untreated patients due to a lesser need for dose adjustments [78,79] (B1) 9. Eplerenone is an alternative for men with gynecomastia, but has not been compared to spironolactone or furosemide in the setting of portal hypertensive ascites [80]. 100 mg of spironolactone is considered equivalent to 50 mg of eplerenone. Furthermore, amiloride as single agent or combined with thiazides may have a role in patients who are intolerant or develop side effects to spironolactone or furosemide [81]. (B2) 10. Vaptans are not beneficial for the long-term management of portal hypertensive ascites [82]. (A1) 11. Rapid weight loss during diuretic therapy might increase the risk of hypovolemia, AKI and hepatic encephalopathy and thus, weight loss during diuretic therapy should not exceed 1 kg/day or 4 kg/ week. (B2) 12. In patients with tense ascites (grade 3), paracentesis is the treatment of choice and should be followed by diuretic therapy. Total paracentesis should be carried out as a single procedure, even when a large volume of ascites is present, as long as it is hemodynamically tolerated by the patient. (B1) 13. Plasma volume expansion using albumin is recommended in all patients undergoing paracentesis if more than 5 l of ascites have been removed, for prevention of hypovolemia and circulatory dysfunction [83]. Albumin at a dose of 8 g/l of ascites removed should be administered (i. e. 100ml 20% albumin per 2.5 l ascites removed). Removal of less than 5 l does not appear to have hemodynamic consequences [84]. (A1) K Austrian consensus guidelines on the management and treatment of portal hypertension (Billroth III) S143 original article 14. Patients responsive to diuretics should primarily be treated with sodium restriction and diuretics and should not undergo serial paracentesis. (B1) 15. In cirrhotic patients with severe hyponatremia (plasma sodium levels <125 mmol/l) fluid restriction is recommended since the underlying pathophysiology is usually dilutional/hypervolemic hyponatremia. (A1) 16. In severe hyponatremia diuretics should be stopped, since at these levels diuretics are ineffective and worsen hyponatremia. Substitution with concentrated NaCl solutions should be avoided [85].
(C2) 17. If hyponatremia occurs together with hepatic encephalopathy or with AKI, plasma volume expansion with saline and/or albumin should be considered. (C2) 18. Patients with moderate to severe ascites should be evaluated for liver transplantation. (B1) 19. The administration of non-steroidal anti-inflammatory drugs (NSAIDs) in patients with decompensated cirrhosis and ascites can lead to renal failure and therefore should be avoided [86]. The same is true for angiotensin receptor blockers and angiotensin converting enzyme inhibitors [87,88]. Aminoglycosides should only be used in cases where infections cannot be otherwise treated [89,90]. (A1) 20. In the absence of strong indications, proton pump inhibitors (PPIs) should not be used in patients with ascites since PPIs might be associated with a higher risk of infections [91]. (A2) 21. Ascites per se is not a contraindication for NSBBs, but they should be used with caution. Carvedilol should not be used in patients with severe or refractory ascites due to induction of hypotension [92]. In patients with severe or refractory ascites, high doses of propranolol (>80 mg/day) should be avoided [93]. (C2)

Refractory ascites
Only less than 10% of patients with cirrhosis and ascites are refractory to treatment regimens consisting of sodium restriction and oral diuretics [94].

Refractory ascites is defined by the International Ascites Club [70] (A1):
-as ascites that cannot be mobilized by intensive diuretic therapy (up to a maximum of 400 mg spironolactone and 160 mg furosemide per day) and confirmed dietary sodium restriction (diuretic-resistant ascites), -or as ascites that rapidly reaccumulates after therapeutic paracentesis (within 4 weeks), -or as the situation, where the maximum dose of diuretics cannot be administered due to side effects, such as electrolyte imbalance, renal fail-ure, and encephalopathy (diuretic-intolerant ascites). 23. Refractory ascites can develop secondary to hepatocellular carcinoma or portal vein thrombosis; therefore, ultrasound examination should be performed to exclude these complications of cirrhosis. (B1) 24. A characteristic feature of refractory ascites is impaired urinary sodium excretion despite maximum tolerated doses of diuretics [95]. Since urine collection for 24 h is cumbersome, a spot urinary sodium/potassium ratio <2.5 is a reasonable surrogate for diuretic-resistant ascites [96]. Diuretic treatment should be continued only when urinary sodium excretion under diuretic therapy is greater than 30 mmol/day [97]. (B2) 25. Due to the poor prognosis of patients with refractory ascites liver transplantation must be considered. (A1) 26. Patients with refractory ascites should be evaluated for TIPS, since TIPS is associated with improved survival [98][99][100][101]. (A1) 27. If TIPS is contraindicated or refused by the patient, repetitive large volume paracentesis in combination with albumin substitution, sodium restriction and diuretic therapy should be performed. (B1) 28. The efficacy and safety of low-flow pump systems to remove ascites from the peritoneal cavity into the bladder in patients with refractory ascites remains to be established [102,103]. (C2) 29. In patients with severe/refractory ascites NSBBs should be discontinued during SBP [20], a decline of systolic blood pressure <90 mmHg, hyponatremia <125 mmol/L or in the presence of AKI.
Hepatic hydrothorax 30. Hepatic hydrothorax represents a (usually a rightsided) pleural effusion in patients with cirrhosis and ascites in the absence of any other pleural or pulmonary disease [104]. (A1) 31. Diagnostic pleuracentesis of hepatic hydrothorax should be performed at first diagnosis and include similar testing as for ascitic fluid. (B1) 32. The absolute neutrophil count is usually higher than in the ascitic fluid and thus, the diagnosis of bacterial infection of the pleural effusion should mainly be based on culture results [105]. (C2) 33. Hepatic hydrothorax should be primarily treated with salt restriction and diuretics [106]. (B1) 34. TIPS should be considered for recurrent hepatic hydrothorax not responsive to diuretic therapy [107,108]. (B1) 35. Other treatment modalities including pleurodesis [109] or permanent drainage systems [110] cannot be recommended for treatment of hepatic S144 Austrian consensus guidelines on the management and treatment of portal hypertension (Billroth III) K original article hydrothorax. The role of novel indwelling pleural catheters is not yet clear [111]. (B2) 36. Patients with recurrent hepatic hydrothorax should be evaluated for liver transplantation [112]. (A1)

XI. Spontaneous bacterial peritonitis (SBP)
1. All patients presenting with ascites for the first time, with recurrence of ascites, or deterioration of ascites, evidence of systemic infection, GI bleeding, worsening liver or renal function, or hepatic encephalopathy should undergo paracentesis to screen for SBP [97]. (A1) 2. Ascitic fluid and blood cultures should be performed using blood culture bottles. Even in culture-negative SBP, positive blood cultures might hint at the responsible organism [97]. (A1) 3. In patients with an ascitic fluid absolute neutrophil count >250/µl or a positive ascitic fluid culture, antibiotic therapy with gram-negative coverage (e. g. aminopenicillin/beta-lactamase inhibitor, third generation cephalosporin, or quinolone) should be started immediately. (A1) 4. Chinolones should not be used to treat SBP in patients who were on norfloxacin prophylaxis [97]. (B1) 5. In selected high-risk patients (e. g. nosocomial SBP as defined by onset of signs and symptoms of infection after 72 h from hospitalization and/or patients with sepsis), the use of combination regimens as initial therapy might be warranted [113]. (A2) 6. To prevent the development of hepatorenal syndrome (HRS) type of AKI, 1.5 g/kg bodyweight albumin should be administered in patients with SBP at the time of diagnosis, plus 1 g/kg body weight on day three [114]. (A1) 7. Blood pressure should be carefully monitored in patients with SBP and NSBBs should be discontinued in the case of systolic blood pressure <90 mm Hg, hyponatremia Na < 125 mmol/L, or AKI [21,22]. (C2) 8. In the case of an ascitic fluid neutrophil count <250/µL but clinical evidence of infection, similar antibiotic therapy should be initiated and continued until culture results are available [97]. (B1) 9. A second paracentesis should be performed 48 h after initiation of the antibiotic therapy to demonstrate a decrease of the ascitic absolute neutrophil count by 25% of the initial value [115]. (A1) 10. A smaller drop is highly suggestive of failure of the antibiotic regimen. In these patients, antibiotic therapy should be adopted based on culture results and susceptibility testing [97]. (A1) 11. If culture-negative, antibiotic therapy should be changed to cover gaps in the antibacterial spectrum of the initial therapy, as well as relevant multidrug-resistant gram-negative and gram-positive bacteria (e. g. meropenem plus daptomycin) [113]. (B1) 12. Due to the poor prognosis of patients who recovered from SBP, liver transplantation should be considered in these patients [97]. (A1) 13. All patients with a history of SPB should be treated continuously with secondary prophylaxis using norfloxacin 400 mg/day or alternatively co-trimoxazole (800 mg/160 mg/day) [97]. (A1) 14. Given the inevitable risk of antibiotic resistance, the use of prophylactic antibiotics in patients without a history of SBP should be restricted to patients at high risk for SBP: low ascites protein (<15 g/l) with advanced liver failure (Child-Pugh score ≥9 points with serum bilirubin ≥3 mg/dL) or impaired renal function (serum creatinine sCr ≥ 1.2 mg/dL, blood urea nitrogen ≥25 mg/dl, or serum sodium ≤130 mmol/L) [116,117]. (C1) 15. In patients with Child-Pugh C10-15 norfloxacin prophylaxis seems to decrease 6-months mortality. (B1) [118] 16. Based on the currently available evidence, rifaximin cannot be used as a substitute for norfloxacin/co-trimoxazole [119][120][121][122][123][124].

XII. Management of acute kidney injury and hepatorenal syndrome (HRS-AKI)
Acute kidney injury (AKI) is a common complication of cirrhosis with a significant prognostic impact [125,126]. As a consequence of systemic and splanchnic arterial vasodilatation, renal perfusion is critical in patients with advanced cirrhosis and CSPH [127]. AKI is commonly triggered by precipitating events leading to further circulatory compromise including overdose of diuretics, large volume paracentesis without albumin replacement, GI blood loss, and infections (e. g. SBP) [128].

Diagnosis and definitions
The traditional diagnostic criteria of renal failure in cirrhosis (percentage increase in sCr, ≥50% to a final value ≥1.5 mg/dl) [129] were replaced by the Kidney Disease Improving Global Outcome (KDIGO) criteria to diagnose AKI [130] and adapted for patients with cirrhosis by the International Club of Ascites (ICA) in 2015 [131]. One of the main modifications of the ICA-AKI criteria is the abandonment of a threshold of sCr ≥ K Austrian consensus guidelines on the management and treatment of portal hypertension (Billroth III) S145 • Continuous infusion (initial dose 0.5 mg/h; max. studied in RCTs 3 mg/hour) • Complete response is defined by a decrease in sCr to a value within 0.3 mg/dL of the baseline value. • Partial response is defined by a regression of at least one AKI stage • The vasoconstrictor dose should be increased if there is no response after 3 days of treatment • In non-responders, treatment should be discontinued after 14 days

Other considerations for HRS-AKI
• RRT should be restricted to patients eligible for liver transplantation • TIPS should be considered in patients with severe/refractory ascites • Patients with HRS-AKI associated with SBP should receive secondary antibiotic prophylaxis • Patients should be evaluated for liver transplantation Normal renal 1.5 mg/dl to diagnose AKI in cirrhosis, since smaller rises in sCr have also been shown to have a negative prognostic impact in these patients [126,132].
A detailed algorithm for diagnosis and treatment of AKI in patients with cirrhosis is shown in Fig. 4.

Diagnosis and definitions
1. AKI in cirrhosis should be diagnosed according to the ICA-AKI criteria [131]. (B1): -Increase in sCr ≥ 0.3 mg/dl within 48 h or -Increase in sCr ≥ 50% from a baseline value that is known or presumed to have occurred in the past 7 days.
-A baseline sCr value obtained in the previous 3 months should be used. If no previous sCr value is available, the sCr on admission should be used.
In cases of impairment of renal function (sCr ≥ 1.5 mg/dl) at time of admission and a clearly identifiable precipitating event, it is reasonable to assume AKI based on clinical judgement. -The use of a reduction in urine output as part of the diagnostic criteria was eliminated in the new ICA criteria for the diagnosis of AKI because many patients with cirrhosis and ascites are oliguric as part of the sodium and water retention syndrome and yet maintain a nearly normal GFR [131,134]. Based on that only the changes in sCr should be S146 Austrian consensus guidelines on the management and treatment of portal hypertension (Billroth III) K original article used to diagnose AKI in patients with cirrhosis (B1). 2. AKI in cirrhosis should be staged according to the ICA-AKI criteria [131]: (B1) -ICA-AKI stage 1: increase in sCr ≥ 0.3 mg/dl or ≥1.5 to 2-fold from baseline -ICA-AKI stage 2: increase in sCr > 2 to 3-fold from baseline -ICA-AKI stage 3: increase in sCr > 3-fold from baseline or ≥4 mg/dl with an acute increase ≥0.3 mg/dl or need for renal replacement therapy (RRT) 3. The hepatorenal syndrome type of AKI (HRS-AKI, formerly known as HRS type 1) is defined as ≥ stage 2 ICA-AKI fulfilling all other diagnostic criteria of HRS-AKI [131]: (A1) -Presence of ascites -No improvement in sCr after 2 consecutive days of withdrawal of diuretics and plasma volume expansion with albumin (1 g/kg, max.100 g/day) -Absence of shock -Exclusion of nephrotoxic agents (e. g. NSAIDs, aminoglycosides, contrast media) -Exclusion of parenchymal kidney disease (proteinuria <500 mg/day, <50 red blood cells per high power field, normal renal ultrasound) 4. Hepatorenal syndrome type 2 is defined as slowly progressive impairment of renal function (sCr > 1.5 mg/dl) [135,136] fulfilling the abovementioned diagnostic criteria of HRS-AKI and is usually associated with refractory ascites [125,126] (A1).

Management of AKI and HRS-AKI in cirrhosis
The initial management of AKI should focus on identification and correction of precipitating factors that further exaggerate the already disturbed hemodynamics in advanced cirrhosis [131,137,138].
5. The following measures should be taken in cirrhotic patients with initial ICA-AKI stage 1. (A1) -Review of all medications (including over the counter drugs) -Reduction or withdrawal of diuretic therapy and/ or lactulose for patients who are volume-depleted from diuretics or excess lactulose use -Withdrawal of all potentially nephrotoxic agents (e. g. NSAIDs) -Careful assessment of ongoing use of drugs potentially inducing/aggravating hypotension (e. g. NSBBs) [93,139] -Plasma volume expansion with crystalloids or albumin in patients with clinically suspected hypovolemia -Blood transfusion in patients with AKI after GI blood loss -Screening for bacterial infections (e. g. SBP) and early or empiric antibiotic treatment if an infection is diagnosed or strongly suspected [140] 6. In the case of response (return of sCr to a value within 0.3 mg/dl of the baseline value), patients should be followed closely for early identification of potential new episodes of AKI [131,141]. (B2) -Assessment of sCr every 2-4 days during hospitalization -Assessment of sCr every 2-4 weeks during the first 6 months after discharge 7. In the case of stage 2 or 3 ICA-AKI or progression of stage 1 ICA-AKI to a higher stage, patients need to be assessed for the presence of HRS-AKI in addition to the following measures [131]. (B1): -Administration of the same general measures as described for patients with ICA-AKI stage 1, -Withdrawal of diuretics if not withdrawn already, -Plasma volume expansion with albumin for two consecutive days (1 g/kg body weight, maximum 100 g/day).

Treatment of HRS-AKI
8. Patients with HRS-AKI should be treated with vasoconstrictors (terlipressin or norepinephrine) in combination with albumin (40 g/day) [131]. (A1). 9. Patients with ICA-AKI stage 1 and sCr < 1.5 mg/dl fulfilling the diagnostic criteria of HRS-AKI can be treated the same way on a case-by-case basis [131]. (C2). 10. Patients with HRS type 2 can be treated similarly [142][143][144]. (A1). original article 17. Patients should be monitored for hyponatremia, which more commonly occurs in patients with less advanced liver disease and (near) normal baseline serum sodium levels [146]. (A1). 18. Continuous infusion (initial dose of 2 mg/day; maximum 12 mg/day) decreases the rate of adverse events, the mean effective terlipressin dose and, thus, might also decrease costs as compared to bolus administration (initial dose of 0.5 mg every 4 h; maximum 2 mg every 4 h). Continuous infusion might be preferred over bolus administration [147]. (A1) 19. Although terlipressin has been consistently shown to improve renal function, its impact on survival is less clear [148]. (A1) 20. Terlipressin is particularly beneficial in patients with systemic inflammatory response or sepsis and might also prevent variceal bleeding during the period of discontinuation of NSBBs [149]. (B2) Norepinephrine 21. Norepinephrine (initial dose of 0.5 mg/h; maximum dose studied in RCTs: 3 mg/h) is an equally effective and inexpensive alternative to terlipressin [150].

(A1)
Response to treatment and considerations for follow-up 22. Complete response to treatment is defined by a decrease in sCr to a value within 0.3 mg/dl of the baseline value, while a regression of at least one AKI stage is considered as partial response. (B1) 23 4. Patients with acute PVT should receive anticoagulation for at least 6 months to prevent extension to mesenteric veins and intestinal ischemia and in order to achieve recanalization [178][179][180]. (A1) 5. For acute PVT, LMWH should be initiated and shifted to oral anticoagulation after stabilization of the patient. (A1) 6. In symptomatic patients with acute, non-cirrhotic PVT (i. e. ascites and/or risk of intestinal infarction) a TIPS combined with local clot fragmentation/aspiration should be considered [181]. (B1) 7. Lifelong anticoagulation should be given to PVT patients with a permanent prothrombotic condition. (A1) 8. Long-term anticoagulation is also recommended in patients without identifcation of (prothrombotic) risk factor or thrombus extension into the mesenteric/splenic vein. Malignant PVT (regardless of cirrhotic/non-cirrhotic PVT) 19. In general, anticoagulation is not indicated for malignant PVT [178]. (C2) 20. Anticoagulation may be considered for symptomatic and progressive malignant PVT. (C1) 21. TIPS should not be used for treatment of malignant PVT. (C1) Acute cirrhotic, non-malignant PVT 22. Anticoagulation is indicated in cirrhotic patients with acute PVT with progression to mesenteric/ splenic vein or signs of intestinal ischemia [178]. (A1) 23. Anticoagulation should be considered in all candidates for liver transplantation with PVT [178,182].