Metabolic Effects of Furosemide +HSS in Refractory Ascites
Condition: Ascites; Cirrhosis
MeSH terms: Fibrosis; Ascites
Study type: Interventional
Phase: Phase 2

Summary: 
      Introduction: Patients with chronic liver diseases are usually thin as a result of
      hypermetabolism and malnutrition expressed by reduced levels of leptin and impairment of
      other adyponectins such as visfatin.

      Aims: To evaluate the metabolic and inflammatory effects of intravenous high-dose furosemide
      plus hypertonic saline solutions (HSS) compared with repeated paracentesis and a standard
      oral diuretic schedule, in patients with cirrhosis and refractory ascites.

      Methods; All consecutive cirrhotic patients with refractory ascites unresponsive to
      outpatient treatment will be enrolled . Enrolled subjects will be randomized to treatment
      with intravenous infusion of furosemide (125-250mg⁄bid) plus small volumes of HSS from the
      first day after admission until 3 days before discharge (Group A ), or repeated paracentesis
      from the first day after admission until 3 days before discharge (Group B, ).

      Plasma levels of ANP, BNP, Leptin, visfatin, IL-1β, TNF-a, IL-6 were measured before and
      after the two type of treatment.
    

Detailed description: 
      Cirrhosis and congestive heart failure (CHF) are major clinical disease states characterized
      by renal sodium and water retention with edema formation. Abnormalities of circulatory and
      volume homeostasis in these diseases elicit neuro-hormonal responses influencing renal
      function and leading to retention of sodium and water.Cytokines constitute a complex network
      of molecules involved in the regulation of the inflammatory response and the homeostasis of
      organ functions. Moreover cytokines coordinate physiologic and pathologic processes in the
      liver, such as liver growth and regeneration, as well as inflammatory processes including
      viral liver disease, liver fibrosis and cirrhosis .

      Furthermore, patients with chronic liver diseases are usually thin as a result of
      hypermetabolism, diminished food intake, and malnutrition, and leptin is thought to be
      involved in this process. Furthermore, other adipocytokines play an important role in lipid
      metabolism and liver disease progression. Visfatin a 52-kDa protein that has been cloned as
      pre-B cell colony-enhancing factor (PBEF), and liver and muscle have been reported to be the
      tissues with the highest expression levels of this protein. Recently, visfatin has also been
      proposed as an adipokine secreted by adipose tissue.

      A recent study reported that patients with chronic HBV infection have significantly higher
      serum levels of adiponectin and visfatin, but lower leptin levels than healthy controls, and
      that serum adipocytokine levels independently correlate with HBV viremia, HBsAg levels, and
      liver fibrosis stages.

      Another recent study reported that in subjects with alcoholic cirrhosis following adjustment
      for fat mass, visfatin levels were significantly higher from Child-Pugh Class A to Class C.
      Furthermore, leptin, the first described adipokine, interplays with hepatic metabolism, and
      data from a small study suggest that recombinant leptin administration has a possibly
      beneficial effect on steatosis, but not fibrosis, in NAFLD patients with hypo-leptinemia and
      a very recent study reported that in non-alcoholic steatohepatitis (NASH), leptin is
      upregulated, and promotes liver fibrosis by directly activating hepatic stellate cells (HSC)
      via the hedgehog pathway and the hedgehog-regulated osteopontin (OPN).

      Nevertheless, to the best of knowledge, no study has addressed the effectiveness of treatment
      of complications of cirrhosis such as ascites and fluid overload on these inflammatory and
      metabolic abnormalities.

      According to the International Ascites Club, refractory ascites is defined by the lack of
      response to high doses of diuretics (spironolactone 400mg⁄day and furosemide 160mg⁄day) or
      the development of adverse effects (hyperkalemia, hyponatremia, hepatic encephalopathy or
      renal failure) that prohibit further use of diuretics.

      A recent clinical trial reported that intravenous hypertonic saline solutions (HSS) plus
      high-dose furosemide is a safe and effective alternative to repeated paracentesis when
      treating hospitalized patients with cirrhosis and refractory ascites.

      Specific objective and hypothesis:

      On this basis, the hypothesis of this trial was that the clinical effectiveness of high dose
      furosemide + HSS could be accomplished by parallel effects on inflammatory, natriuretic and
      metabolic pathways expressed by changes of cytokines, natriuretic peptides, leptin and
      visfatin serum levels after treatment.

      Thus the aim of this trial will be to evalute the metabolic and inflammatory effects of
      intravenous high-dose furosemide plus HSS compared with repeated paracentesis and a standard
      oral diuretic schedule, in patients with cirrhosis and refractory ascites, evaluating their
      effects on a panel of serum biomarkers such as some inflammatory cytokines, ANP/BNP, leptin
      and visfatin serum levels by means of analysis of differences of their serum levels before
      and after treatment with high dose furosemide + HSS.

      Materials and methods All consecutive cirrhotic patients presenting with ascites unresponsive
      to ambulatory treatment at Palermo University Hospital (Azienda Ospedaliera Policlinico
      'Paolo Giaccone') who will be admitted to the Internal Medicine Ward from December 2013 to
      December 2015 will be offered enrolment in the study protocol after a diagnosis of ascites
      had been made and all potential contraindications excluded.

      Refractory ascites was defined according to the International Ascites Club criteria 1 as
      either: (a) diuretic-resistant refractory ascites: <1.5kg ⁄week weight loss while being
      treated with furosemide (160mg⁄day) and spironolactone (400mg⁄day) or an equivalent dose of a
      loop-acting and distal-acting diuretic; or (b) diuretic-intractable refractory ascites:
      <1.5kg⁄week weight loss as a result of the inability to use an effective dose of diuretic
      because of development of diuretic-induced hyponatremia (sodium level <125mEq⁄ L),
      hyperkalemia (potassium level >5.5mEq⁄L), renal failure (doubling of serum creatinine or
      values >2.5g⁄dL) or encephalopathy; (c) previous dietary restriction of sodium between
      50-66mEq ⁄day.

      Exclusion criteria were: inability to obtain informed consent, possible non-cirrhotic
      ascites, congestive heart failure (defined by clinical exam and echocardiogram), acute renal
      failure, hepatocellular carcinoma based on the Barcelona Clinic liver Cancer (BCLC) criteria
      , complete portal vein thrombosis, active sepsis or other incurable cancers. The study was
      approved by the institutional Ethics Committee and written informed consent was obtained for
      all patients.

      Daily clinical and laboratory evaluation Treatment protocol Group A: treatment with
      intravenous infusion of furosemide (doses 125-250mg⁄ bid) plus small volumes of HSS (150mL
      1.4-4.6% NaCl), from the first day after admission until 3 days before discharge ( 8 days of
      treatment) , with water restriction and a normal sodium diet.

      Group B: repeated paracentesis (4-6L daily) from the first day after admission until 3 days
      before discharge with albumin reinfusion at a rate of 5-8g⁄ L of removed ascites. The last
      paracentesis (at 3 days from admission after 8 days was a total paracentesis (8.1±2.7L) plus
      iv albumin infusion (8g per liter of ascitic fluid removed) following a method previously
      described.

      Blood sample collection Blood samples from each subject enrolled wil, be drawn after at least
      30 minutes of bed rest in a supine position, within 24h of admission and after 8 days of
      active treatment. Blood samples were centrifuged (10,000g) and the resulting supernatant was
      immediately frozen at -80°C until analysis was completed.

      Metabolic and immune-inflammatory biochemical evaluation Will be evaluate plasma levels of
      ANP, BNP, Leptin, visfatin, and IL-1β, TNF-a, IL-6 that will be measured using a sandwich
      ELISA (Human IL-1β, TNF-a, IL-6 6 Diaclone). ANP and BNP plasma concentration was measured in
      duplicate by a solid phase sandwich immune-radiometric assay for human BNP (IRMA, ANP and
      BNP, Shering cis bio int). The minimum detectable concentrations for the diagnostic tests
      are: TNF-a: 8pg/mL; IL-1β: <1pg/mL; IL-6: <0.81pg/mL; ANP: 3.1pg/mL; BNP: 5pg/mL.

      Leptin and visfatin will be measured by ELISA Sandwich (leptin Mediagnost and visfatin
      Phoenix Pharmaceticals Inc); the minimum detectable concentration for these diagnostic teste
      were: leptin 0.8ng/ml; visfatin: 1.8ng/ml.
    

Intervention name(s): intravenous furosemide; Hypertonic saline solutions; Seriated paracentesis
Intervention type(s): Drug; Drug; Procedure
Intervention description(s): treatment with intravenous infusion of furosemide (doses 125-250mg⁄ bid) plus small volumes of HSS (150mL 1.4-4.6% NaCl), from the first day after admission until 3 days before discharge, with water restriction and a normal sodium diet.; Intravenous small volumes of HSS (150mL 1.4-4.6% NaCl), plus treatment with intravenous infusion of furosemide (doses 125-250mg⁄ bid) from the first day after admission until 3 days before discharge, with water restriction and a normal sodium diet.; repeated paracentesis from the first day after admission until 3 days before discharge
Other intervention name(s): furosemide +HSS; HSS; paracentesis
Intervention MeSH terms: Furosemide
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: cirrhosis; ascites; immunology; inflammation; nutrition