Please select the eligibility criteria that correspond to the clinical trial below.
Title: Role of Midodrine and Tolvaptan in Patients With Cirrhosis With Refractory or Recurrent Ascites
Brief Summary: The development of ascites in the natural history of cirrhosis heralds a worsening of the prognosis to 50% survival at 2 years, and this deteriorates to 30-50% at 1 year when the ascites becomes refractory to medical therapy. Hemodynamic alterations and their relation to neurohumoral systems are essential in pathophysiology of ascites formation. The theory that best explain the ascites formation and sodium retention in cirrhotics is portal hypertension leading to splanchnic arterial vasodilatation leading to underfilling of arterial circulation which is sensed by the arterial and the cardiopulmonary receptors leading to sympathetic nervous system activation and activation of the anti-natriuretic factors (RAAS and arginine vasopressin), resulting in sodium and water retention. The therapeutic options available for patients with refractory ascites are serial therapeutic paracentesis, liver transplantation and transjugular intrahepatic portosystemic shunts.Vasopressin V2 receptor antagonists antagonize the antidiuretic effects of vasopressin at the V2 receptor located in the renal collecting duct, they increase free water clearance, and thus may be helpful in mobilizing excess water in conditions associated with water retention including cirrhosis. The use of V2 receptor antagonists in cirrhosis with ascites has been shown to be safe and efficacious. Midodrine, an alpha adreno receptor agonist by causing splanchnic vasoconstriction has been used in hepatorenal syndrome (HRS) and for control of ascites in patients with refractory or recurrent ascites. It is possible that vasoconstrictors and aquaretics (V2 receptor antagonists) by acting at different sites in combination may reverse some of the pathogenic events that results in refractory or recurrent ascites.There are no reports on the use of combination of midodrine and tolvaptan in the patients with cirrhosis with ascites. Therefore, we plan to study the role of midodrine, tolvaptan and their combination on systemic hemodynamics, renal functions and control of ascites in patients with cirrhosis and refractory or recurrent ascites.


Options:
A: Inclusion criteria

* Diagnosis of liver cirrhosis (based on clinical, laboratory, endoscopic and ultrasonographic features) and uncomplicated ascites according to the criteria of the International Ascites Club (1).
* Ongoing diuretic treatment with an anti-mineralocorticoid drug at a dose of 200 mg/day and furosemide of 25 mg/day, stable for at least 4 days prior enrollment, not inducing response (defined according to the criteria of the International Ascites Club as body weight reduction ≥ 800 grams in the 4 days prior enrollment). With this limitation, we aim to identify a fairly homogeneous population with a relatively advanced stage of the disease that will likely have more benefit from albumin administration, as also suggested by Gentilini at al. (17).
* Ongoing diuretic treatment with an anti-mineralocorticoid drug at a dose \> 200 mg/day and furosemide \> 25mg/day, independent of response to treatment.
* EGDS performed in the last 12 months, abdominal ultrasonography performed in the last 30 days, and laboratory tests required by the protocol in the last 7 days.

Exclusion criteria

* Age lower than 18 years
* No written informed consent
* Inability to follow written consent
* Established diagnosis of refractory ascites, as defined by the IAC (1)
* Need of 2 or more paracentesis during the last month
* Serum creatinine \> 1.5 mg/dl
* Organic nephropathy, as defined by the IAC (1)
* Hepatorenal syndrome type 1 in the last 15 days
* Gastrointestinal bleeding in the last 15 days
* Ongoing endoscopic eradication after a recent gastro-esophageal variceal bleeding
* Bacterial or fungal infection, including spontaneous bacterial peritonitis, in the last 7 days
* Hepatic encephalopathy grade III/IV
* Budd-Chiari Syndrome
* Patients with TIPS or other surgical porto-caval shunts
* Known and suspected active hepatocellular carcinoma or other malignancies
* Previous liver transplantation
* Ongoing alcohol abuse (patients should be abstinent for at least three months)
* Antiviral therapy for hepatitis B started in the last 6 months
* Heart failure
* Respiratory failure as defined as PO2 \<60 mmHg
* Known or suspected hypersensitivity to albumin
* Previous albumin administration given for the treatment of ascites in the last 30 days
* Patients enrolled in other clinical study for the treatment of ascites
* Use of experimental drugs for the last 2 months prior the inclusion in the present study
* Pregnancy and breast-feeding
* Females of child-bearing potential are excluded unless they meet one of the following criteria:

  * Post-menopausal for 6 months or more, and if post-menopausal for less than 2 years, a negative pregnancy test
  * Surgical sterilisation for more than one month duration and a negative pregnancy test
  * Intrauterine device in combination with a secondary barrier (e.g. diaphragm, condom or spermicide) and a negative pregnancy test
B: Inclusion Criteria:

* Cirrhosis of any etiology
* Age 18-80 years
* Moderate to severe ascites

Exclusion Criteria:

* No or small ascites
* Severe hepatic hydrothorax
* Recent GI (gastrointestinal) hemorrhage
* Active bacterial infection
* Cardiac failure
* Organic renal disease
* Hepatocellular carcinoma
* Severe comorbidity (advanced neoplasia)
* Serum creatinine \> 3 mg/dl
* Pregnancy
C: Inclusion Criteria:60 consecutive patients with cirrhosis and refractory or recurrent ascites with stable renal function ( creatinine level \<1.5mg/dl for at least 7 days ).

Exclusion Criteria:

* Presence of gastrointestinal bleeding, HRS, hepatic encephalopathy of grade 2 or higher or infection within 1 month preceding the study or during the study, presence of diabetes, intrinsic renal or cardiovascular disease or arterial hypertension on history and physical examination, abnormal urine analysis, chest radiograph or electrocardiogram, presence of hepatocellular carcinoma or portal vein thrombosis or treatment with drugs with known effects on systemic and renal hemodynamics within 7 days of inclusion .
D: Inclusion Criteria:

* patients of both sexes, with cirrhosis, as documented by previous liver-biopsy or usual clinical and biochemical stigmata
* with refractory or recurrent ascites as defined in chapter IV
* who signed the informed consent form

Exclusion Criteria:

* patients not fulfilling inclusion criteria
* patients having needed more than 6 paracenteses within the last 3 months
* patients expected to be transplanted within the next 6 months
* usual contra-indication for TIPS : congestive heart failure NYHA\>III or medical history of pulmonary hypertension, portal vein thrombosis, hepatic polycystosis, intra-hepatic bile ducts dilatation, spontaneous clinical recurrent hepatic encephalopathy
* hepatocarcinoma on the expected tract of the shunt
* severe liver failure as defined by : Prothrombin index \< 35 % or total bilirubin \> 100 micromol/l or Child Pugh Score \>12
* serum creatinine \> 250 micromol/l
* uncontrolled sepsis
* known allergy to albumin
* pregnant or breast feeding women
* refusal to participate or patient unable to receive informations or to sign written informed consent

Answer: C