Clinical trial: high-dose furosemide plus small-volume hypertonic saline solutions vs. repeated paracentesis as treatment of refractory ascites

Alimentary Pharmacology & Therapeutics Clinical Trial: High-dose furosemide plus small-volumehypertonic saline solutions vs. repeated paracentesis astreatment of refractory ascitesG. LICATA*,1, A. TUTTOLOMONDO*,1, A. LICATA–, G. PARRINELLO*, D. DI RAIMONDO§,R. DI SCIACCA*, C. CAMMA`–, A. CRAXI`–, S. PATERNAà & A. PINTO§ e Cardio-Angiologia, DipartimentoBiomedico di Medicina Interna e Specialistica, Di.Bi.M.I.S, University of In patients with cirrhosis, ascites is defined as refractory when it cannot be mobilized or recurs early in standard diuretic therapy.
ativa di Gastroenterologia, Diparti-mento Biomedico di Medicina Internae Specialistica, Di.Bi.M.I.S, University To compare the safety and efficacy of intravenous high-dose furosemide + hypertonic saline solutions (HSS) with repeated paracentesis in patients with cirrhosis and refractory ascites.
Interna e Specialistica, Di.Bi.M.I.S,University of Palermo, Palermo, Italy;§Unita` Operativa di Fisiopatogia Eighty-four subjects (59 ⁄ 25 M ⁄ F) with cirrhosis, mostly of viral aetiol- ogy, admitted for refractory ascites, were randomly assigned to receive furosemide (250–1000 mg ⁄ bid i.v.) plus HSS (150 mL H 1.4–4.6% or 239–187 mEq ⁄ L) (60 patients, Group A) or to repeated paracentesis and a standard diuretic schedule (24 patients, Group B).
Dr A. Tuttolomondo, Cattedra diMedicina Interna, Di.Bi.M.I.S., P.zza (1605 Æ 131 mL vs. 532 Æ 124 mL than Group B patients; P < 0.001)and a greater loss of weight at discharge ()8.8 Æ 4.8 kg vs. )4.5 Æ 3.8 kg, P < 0.00). Control of ascites, pleural effusions and ⁄ or leg oedema was deemed significantly better in Group A.
This randomized pilot study suggests that HHS plus high-dose furose- mide is a safe and effective alternative to repeated paracentesis when treating hospitalized patients with cirrhosis and refractory ascites.
Accepted 7 May 2009Epub Accepted Article 12 May 2009 Larger studies will be needed to evaluate long-term outcomes such asreadmission and mortality.
increase in intravascular volume,14 reduction in tissue oedema (shifting of tissue water along the osmotic According to the International Ascites Club,1 refrac- gradient), increased renal blood flow and reduced tory ascites is defined by the lack of response to high sympathetic tone.15 All of these mechanisms are doses of diuretics (spironolactone 400 mg ⁄ day and potentially relevant to the treatment of refractory furosemide 160 mg ⁄ day) or the development of adverse effects (hyperkalemia, hyponatremia, hepatic A few years ago, our group performed a randomized encephalopathy or renal failure) that prohibit further study16 to evaluate the effects of the combination of use of diuretics. Few studies have compared paracente- high-dose furosemide and small-volume HSS in the sis and diuretics in the treatment of tense or refractory treatment of refractory CHF. One hundred seven patients ascites. Quintero et al.2 randomly assigned patients with refractory CHF were randomized to receive an IV with tense ascites to treatment with either paracentesis infusion of furosemide (500–1000 mg) plus HSS plus intravenous albumin infusion or diuretics, show- (150 mL of 1.4–4.6% NACl) in 30 min twice a day or ing similar outcomes. Salerno et al.3 confirmed furosemide alone (500–1000 mg) twice a day over 6 to that repeated paracentesis with human albumin 12 days, on a normosodic diet. A significant increase in replacement was safe, effective and more rapid than daily diuresis and natriuresis was observed in both traditional diuretic therapy in treating tense ascites.
groups, but it was more significant in the group receiv- Paracentesis poses, however, a number of issues in ing HSS, in which the serum Na level also increased.
patient management and alternative treatments to High-dose furosemide plus HSS was effective and well- overcome the limitations of diuretic therapy and tolerated, leading to improvement in the quality of life repeated paracenteses are certainly needed.4, 5 measurements of CHF. It also reduced mortality after Cirrhosis and congestive heart failure (CHF) are discharge (survival 55% vs. 13% at 1 year).
major clinical disease states characterized by renal On the basis of our former experience,16 we have sodium and water retention with oedema formation. In designed a study aiming to evaluate the safety and these diseases, abnormalities of circulatory and volume efficacy of intravenous high-dose furosemide plus HSS homeostasis elicit neuro-hormonal responses influenc- compared with repeated paracentesis and a standard ing renal function and leading to retention of sodium oral diuretic schedule, in patients with cirrhosis and and water.6 Furthermore, prior observations in human subjects and in experimental animals with eithercirrhosis7–10 or CHF indicate that an increase in effer- ent renal sympathetic nerve activity (ERSNA), whichserved to antagonize the diuretic and natriuretic All consecutive cirrhotic patients presenting between effects of atrial natriuretic peptides, is present and January 2002 and December 2007 with refractory contributes to the renal sodium and water retention.
ascites unresponsive to ambulatory treatment at Paler- The model of refractory congestive heart failure, on mo’s University Hospital (Azienda Ospedaliera Policli- the basis of these similarities and taking into account nico ‘Paolo Giaccone’) who were admitted to two Units other pathophysiological differences between these two (Internal Medicine; Emergency Medicine) of the ‘Dipar- syndromes, may be helpful when exploring possible timento Biomedico di Medicina Interna e Specialistica’ innovative treatments for refractory ascites in cirrhosis.
of University of Palermo were offered enrolment in When diuretic resistance occurs in CHF, proposed the study protocol after a diagnosis of refractory therapeutic options include higher doses of furosemide ascites had been made and all potential contraindica- or constant furosemide infusion.11 Several studies have demonstrated the efficacy of hypertonic saline solution Refractory ascites was defined according to the (HSS) infusion when regional organ blood flow is International Ascites Club criteria1 as either: (a) diure- impaired.12 HSS was first applied in this way for the tic-resistant refractory ascites: <1.5 kg ⁄ week weight loss while being treated with furosemide (160 mg ⁄ day) traumatic shock and this therapy promptly restored and spironolactone (400 mg ⁄ day) or an equivalent central hemodynamics and peripheral blood flow.12 dose of a loop-acting and distal-acting diuretic; or (b) The suggested mechanisms were direct myocardial diuretic-intractable refractory ascites: <1.5 kg ⁄ week stimulation with high cardiac output maintenance,12, 13 weight loss as a result of the inability to use an Aliment Pharmacol Ther 30, 227–235ª 2009 Blackwell Publishing Ltd H I G H - D O S E F U R O S E M I D E I N R E F R A C T O R Y A S C I T E S 229 effective dose of diuretic because of development of day after admission until 3 days before discharge, with diuretic-induced hyponatremia (sodium level <125 water restriction and a normal sodium diet.
mEq ⁄ L), hyperkalemia (potassium level >5.5 mEq ⁄ L), (ii) Group B: repeated paracentesis (4 to 6 L daily) renal failure (doubling of serum creatinine or values from the first day after admission until 3 days before >2.5 g ⁄ dL) or encephalopathy; (c) previous dietary discharge with albumin reinfusion at a rate of 5 to restriction of sodium between 50 and 66 mEq ⁄ day.
8 g ⁄ L of removed ascites. The last paracentesis (at The ascites was considered symptomatic if it had 3 days from admission) was a total paracentesis necessitated removal of at least 10 L of ascites in (8.7 Æ 2.5 L) plus i.v. albumin infusion (8 g per litre the 2 months preceding randomization for relief of of ascitic fluid removed) following a method previ- ously described.1 After last mobilization of ascites, The study was approved by the institutional Ethics patients were assigned to receive diuretic therapy with Committee and written informed consent was obtained oral furosemide (increasing doses up to a maximum of 160 mg ⁄ day) and oral spironolactone (400 mg ⁄ day) Exclusionary criteria were: inability to obtain was given. Water restriction and a normal sodium diet were given throughout the in-hospital stay.
congestive heart failure (defined by clinical exam and Dosing of furosemide in Group A patients was gov- echocardiogram), acute renal failure, hepatocellular erned by clinical parameters such as blood pressure carcinoma [based on the Barcelona Clinic liver Cancer and severity of ascites, while the concentration of (BCLC) criteria],13 complete portal vein thrombosis, hypertonic saline solution was calculated as a serum active sepsis or other incurable cancers.
sodium value according to the following criteria: Each patient was assessed daily from admission until (i) For serum sodium £125 mEq ⁄ L hypertonic sal- discharge with a complete objective examination, ine solution at 4.6%. (787.2 mEq ⁄ L NaCl).
assessment of ascites grade [evaluated by International (ii) For serum sodium between 126 and 135 mEq ⁄ L Ascites Club criteria1 defining three grades: grade I hypertonic saline solution at 3.5% (599 mEq ⁄ L NaCl).
ascites, fluid detected only by ultrasound; grade II, (iii) For serum sodium ‡136 mEq ⁄ L hypertonic moderate ascites with symmetrical distension of the saline solution between 1.4% and 2.4% (239.6– abdomen; grade III, large or tense ascites with marked abdominal distension], assessment of Child-Pugh Daily dosage of furosemide was reassessed according score, measurement of blood pressure, heart rate, to diuresis, blood pressure and potassium levels.
diuresis and body weight, clinical assessment of (i) reduction in body weight (D body weight) at Blood samples were obtained every 3 days to deter- mine serum electrolytes (sodium, potassium, chlorine), (ii) relief of overt ascites at discharge 3 days after albumin, uric acid, urea, creatinine, prothrombin the end of diuretic treatment period or after last para- activity, activated partial thromboplastin time, fibrino- centesis (ascites graded at admission and at discharge gen, full blood counts, glucose and ammonia. Urine according to International Ascites Club criteria); samples were collected to determine sodium and (iii) improvement in Child Pugh score at discharge; potassium excretion at admission and at discharge. All (iv) improvement in any co-existing fluid overload patients underwent a chest X-ray at admission and at (leg oedema; pleural effusion) at discharge; (pleural discharge, a twelve derivation electrocardiogram at effusion was evaluated clinically and by chest X-ray admission, while an abdominal echo-tomography was performed both at admission and at discharge to In Group A, achievement of these endpoints at 3 days from discharge determined the end of intrave- Patients were randomly assigned by the use of nous therapy and switching to oral furosemide (range sequentially numbered boxes (prepared before starting 200–500 mg ⁄ die) and spironolactone (400 mg ⁄ day), while Group B continued therapy until discharge.
(i) Group A: treatment with intravenous infusion of (i) new onset hepatic encephalopathy (HE);18 furosemide (doses 250–1000 mg ⁄ bid) plus small vol- (ii) new onset spontaneous bacterial peritonitis umes of HSS (150 mL 1.4–4.6% NaCl), from the first Aliment Pharmacol Ther 30, 227–235ª 2009 Blackwell Publishing Ltd (iii) acute renal failure in patients without renal In Group A, 42 patients (70%) had Hepatitis C (HCV) impairment at admission, diagnosed by a serum creati- cirrhosis; four patients (6.6%) had Hepatitis B virus nine level increasing by more than 50% over the base- (HBV) cirrhosis; two (3.3%) had combined HCV ⁄ HBV cirrhosis; 11 (18.3%) had alcohol cirrhosis without (iv) impairment of pre-existing renal failure in viral infection and one patient had idiopathic cirrhosis.
patients with pre-existing renal impairment, diagnosed In Group B, 14 patients (58.3%) had HCV cirrhosis; by serum creatinine increasing by more than 50% three patients (12.5%) had HBV cirrhosis; five (20.8%) had combined HCV ⁄ HBV cirrhosis and two (8.3%) had (v) incidence of hepatorenal syndrome (HRS);19 (vi) incidence of gastrointestinal (GI) bleedings. Gas- In Group B, the mean number of paracentesis trointestinal bleeding refers to any bleeding that starts performed in the whole group was 2.7 Æ 0.95 (range in the gastrointestinal tract, i.e. from the mouth to the 1–4), the mean volume of ascites removed was 4.4 (1) Upper GI bleeding: between the mouth and At discharge, patients of Group A showed signifi- outflow tract of the stomach; (2) Lower GI bleeding: cantly higher diuresis and sodium plasma levels and from the outflow tract of the stomach to the anus significantly lower body weight and leg oedema and pleural effusion prevalence and median Child Pughscore; the median change in Child-Pugh score at dis-charge was significantly higher in Group A compared with Group B ()1.7 vs.)0.9; P < 0.05) (see Tables 2 Results are presented as means Æ s.d. Analyses of the data were performed using the unpaired Student’s t At discharge, 14 subjects (23.3%) in Group A had test and the nonparametric test of Mann–Whitney.
ascites (detected clinically or by ultrasound) vs. 11 The chi-square test was used for comparing distribu- tions and frequency of complications. All reported P No other significant difference was observed in values less than 0.05 were considered statistically terms of other laboratory and clinical variables between the two groups (ammonium, potassium To calculate the number of patients to be enrolled, plasma levels, new onset episodes of HE, incidence of we defined as meaningful a significant difference in detectable ascites frequency at discharge between the pre-existing renal failure progression, hepatorenal two groups, with a beta error of 20% and a power of syndrome). There was no difference in hospital mortal- 0.80. To the estimated sample size of 80 patients (60 ity between the two groups (see Table 3).
in Group A and 20 in Group B), we added four more In Group A, no significant difference was observed patients to compensate for possible drop outs; the final between patients with the two subtypes of refractory sample, therefore, comprised 84 patients.
ascites, diuretic-resistant and diuretic-intractable asci-tes.
We recruited 108 subjects with refractory ascites (73with diuretic-resistant refractory ascites and 35 with Our pilot study showed how treatment with high-dose diuretic-intractable refractory ascites). Twenty subjects furosemide plus small-volume of HSS is safe and more were excluded on the basis of exclusion criteria and effective compared with repeated paracentesis plus four patients refused to participate in the study.
diuretic treatment in subjects with refractory ascites.
Eighty-four patients (59 men and 25 women) (58 with At the time of discharge, patients in Group A dem- diuretic-resistant refractory ascites and 26 with diure- onstrated significantly greater diuresis, higher plasma tic-intractable refractory ascites) agreed to participate sodium levels, lower body weight, less leg oedema and in the study and were randomized: 60 were assigned smaller volume pleural effusion than Group B patients.
to Group A and 24 to Group B. The mean age was This could be because of a more stable maintenance of 64 Æ 13.6 years in Group A and 64.8 Æ 8.06 years in volume reduction with high-dose diuretic treatment compared with repeated paracentesis.
Aliment Pharmacol Ther 30, 227–235ª 2009 Blackwell Publishing Ltd H I G H - D O S E F U R O S E M I D E I N R E F R A C T O R Y A S C I T E S 231 Diuretic-resistant refractory ascites, n (%) Diuretic-intractable refractory ascites, n (%) Oesophageal varices (F1 ⁄ F2 ⁄ F3); n (%) Demographic and clinical data are expressed as number (percentage). Laboratoryvariables are expressed as mean Æ s.d. HBV, hepatitis B virus; HCV, hepatitis C virus;Pre-treatment drugs, drugs used immediately prior to hospitalization or studyenrolment.
Changes in body weight and urinary sodium deter- treated with diuretics. More recently, Salerno et al.28 minations reflect response to treatment and represent compared the effects of large-volume paracentesis and a key outcome in patients with ascites. Our findings, transjugular intrahepatic portosystemic shunt (TIPS) in through the evaluation of body weight, provide a cirrhotic patients with refractory ascites and showed direct outcome evaluation about the higher efficacy of that TIPS significantly improves ascites recurrence-free high-dose furosemide + HSS treatment compared with survival of cirrhotic patients with refractory ascites, although the cumulative probability of developing the Quintero et al.2 analysed 72 cirrhotics with tense first episode of HE was similar between the groups.
ascites randomly assigned to treatment with either However, there are some disadvantages in repeated paracentesis plus intravenous albumin infusion or paracentesis. Ascitic fluid opsonic activity and ascitic diuretics and showed that paracentesis was not associ- fluid C3 concentrations are important protective fac- ated with significant changes in renal function. Gines tors against spontaneous bacterial peritonitis. Ljubicic et al.26 showed how paracentesis was effective in elim- et al.27 compared the effect of diuretic administration inating the ascites and did not induce significant alone vs. single large-volume therapeutic paracentesis changes in renal and hepatic function, plasma volume, followed by administration of diuretics on ascitic fluid cardiac index, peripheral resistance and plasma renin opsonic activity on ascites and serum immunoglobulin activity (plasma norepinephrine, antidiuretic hormone and complement concentrations in patients with alco- concentration and urinary excretion of prostaglandin holic cirrhosis and tense ascites. These authors showed E2 and 6-keto-prostaglandin F1a). They also reported that the ascitic fluid opsonic activity increased signifi- a significantly higher incidence of HE, renal impair- cantly in patients treated with diuretics alone, whereas ment and electrolyte disturbances occurring in patients in the group of patients treated with therapeutic Aliment Pharmacol Ther 30, 227–235ª 2009 Blackwell Publishing Ltd Table 2. Clinical and laboratory variables before (at admission) and after treatment with high-dose furosemide + HSS(Group A) or after seriated paracentesis (Group B) Demographic and clinical data are expressed as number (percentage). Laboratory variables are expressed as mean Æ s.d.
HE, hepatic encephalopathy; SBP, spontaneous bacterial peritonitis; ascites grade was evaluated by Ascites InternationalClub criteria.5 paracentesis followed by diuretics, the ascites opsonic suggesting possible use in refractory ascites. The activity remained stable. In our patients, we observed formation of ascites in cirrhosis is the final conse- no case of SBP among those treated with high-dose quence of a combination of abnormalities in the furosemide + HSS and two cases of SBP among splanchnic and systemic circulation as well as renal patients who underwent repeated paracentesis.
function abnormalities that bring about the accumula- Cirrhotic patients with ascites refractory to diuretics tion of fluid in the peritoneal cavity (forward theory).
also have blunted response to marked elevation of The pathophysiological basis of higher efficacy of plasma atrial natriuretic factor levels alone or to mod- treatment with furosemide + HSS could be because of erate intravascular volume expansion by head-out both volume expansion and improved reduction in water immersion. Wong et al.29 reported that massive sinusoidal portal pressure resulting in a fall in the (as opposed to moderate) volume expansion or greatly plasma renin activity and serum aldosterone levels, a elevated levels of plasma atrial natriuretic factor rise in renal blood flow and glomerular filtration rate associated with moderate volume expansion can associated with improved natriuresis. This effect occurs improve blunted atrial natriuretic factor responsiveness despite a possible exacerbation of the hyper-dynamic in cirrhotic patients with refractory ascites. Thus, circulation, with a further fall in systemic vascular volume expansion could represent a way to improve resistance and further increase in cardiac output. Nev- natriuretic response in patients with refractory ascites.
ertheless, it is possible that in our patients treated with A recent study by our group30 showed that in patients furosemide + HSS, the HSS-related volume expansion with refractory congestive heart failure, treatment with served to compensate the ‘underfilling’ mechanisms HSS plus i.v. high-dose furosemide was associated that characterize ascitic cirrhosis. Small-volume HSS with a significant reduction in BNP levels, thus clearly induces an increase in the extracellular Aliment Pharmacol Ther 30, 227–235ª 2009 Blackwell Publishing Ltd H I G H - D O S E F U R O S E M I D E I N R E F R A C T O R Y A S C I T E S 233 high-dose furosemide + HSS(Group A) or with seriate para- Demographic and clinical data are expressed as number (percentage). Laboratoryvariables are expressed as mean Æ s.d.
D weight: body weight difference (body weight at admission – body weight aftertreatment with high-dose furosemide + HSS or seriate paracentesis); D Child Pughscore: Child pugh score change (Child Pugh score at admission – Child Pugh score atdischarge).
* Ascites grade was evaluated by Ascites International Club criteria.5HE, hepatic encephalopathy; SBP, spontaneous bacterial peritonitis; HRS, HepathorenalSyndrome; GI bleedings, Gastrointestinal bleedings; Ascites at discharge, grade ofascites evaluated 3 days after end of diuretic treatment period or last paracentesis.
circulating concentration of NaCl with consequent in natriuresis.14, 15 Another mechanism involved in the increment in the osmotic pressure and in the plasmatic effectiveness of the HSS seems to be the restoration of volume determining the fast redistribution of fluid in normal production of renal E2 prostaglandin with the vascular compartment with consequential increase restoration of the normal medullar tonicity usually in renal plasmatic flow.12, 14, 17 Such fast expansion of altered by the chronic assumption of furosemide.31, 32 the extracellular volume is also the cause of the reduc- Our findings emphasize the treatment with intravenous tion in the peritubular oncotic pressure that in combi- high-dose furosemide plus small volumes of HSS as nation with the increment of the hydrostatic pressure effective and safe in patients with refractory ascites.
reduces the proximal reabsorption of the Na.14, 15 HSS An interesting finding is a slight, but not statistically can determine an increase in the diuretic efficiency significant, reduction in the creatinine levels (1.45 Æ because HSS expands the arterial circulating volume 0.3 mg ⁄ dL vs. 1.7 Æ 0.5 mg ⁄ dL) in Group A patients, and increases the distribution of the sodium after the probably attributable to the benefits brought by this proximal nephron until the thin portion of the ascend- ing branch of the Henle loop, determining an increase renal perfusion, but requiring ulterior evaluation in Aliment Pharmacol Ther 30, 227–235ª 2009 Blackwell Publishing Ltd prospective long-term studies. Nevertheless, although paracentesis to achieve relief of ascites in patients with statistically insignificant, a potentially important find- refractory ascites with a higher change of Child-Pugh ing of our study is that high-dose furosemide diuresis Score and no significant differences between the two may not be as injurious to the kidney as high volume paracentesis and this finding contrasts with what has This is a pilot study conducted on consecutive patients with refractory ascites. Further studies are In contrast to previous studies,20, 21, 22, 23–26 we did needed to confirm our findings and to evaluate hemo- not observe a higher rate of hepatic encephalopathy dynamic and neurohormonal changes after treatment (HE) in the group treated with high-dose furosemide. A with high-dose furosemide + small-volume HSS and combined derangement of cellular osmolarity coupled the possible relationship between these changes with cerebral hyperaemia can explain the development and therapeutic effectiveness of this type of treatment.
of brain oedema in HE.33 It is possible that HSS infusion Further studies are needed to test the effectiveness of may influence cellular osmolarity to avoid increased this treatment protocol on a longer-term follow-up incidence of HE in patients treated with high-dose furo- semide, but future studies should evaluate this issue.
Our study showed that treatment with high-dose i.v furosemide + small-volume of hypertonic salinesolutions is more effective compared with repeated Declaration of personal and funding interests: None.
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