Management of refractory ascites in cirrhosis: Are we out of date?

Table 1 Studies evaluating large-volume paracentesis with albumin infusion and diuretic therapy in hospitalized patients with cirrhosis and refractory ascites

Ref.	Study design	Results	Conclusions/comments
Quintero et al[9], 1985	Total n: 72 Group 1: LVP and albumin - n of 38 Group 2: Diuretic therapy - n of 34	LVP with albumin had worse outcomes that diuretic therapy with adverse effects on hemodynamics, renal function, readmission, mortality	Diuretic therapy is better that LVP
Kao et al[10], 1985	Total n: 18 underwent LVP of exactly 5 L Exclusion criteria: Cardiac disease chronic renal disease active intestinal bleed encephalopathy 500 mg/d Na and 1 L/d fluid restriction Diuretic discontinued 3 d prior	No untoward effects LVP of 5 L No symptomatic hypotension or hyponatremia No worsening or acute renal failure No encephalopathy Improved pitting edema	LVP is safe in patients with peripheral edema due to mobilization of fluid to intravascular space
Salerno et al[11], 1987	Total n: 41 patients randomized into 2 groups Group A: Paracentesis + IV albumin: 20 patients Group B: Paracentesis + diuretics: 21 patients Exclusion criteria: Urinary sodium excretion rate > 20 mEq/d on a sodium-restricted diet and without diuretics Presence of cancer, encephalopathy, active gastrointestinal bleeding, renal failure, diabetes, infection, or primary cardiac disorders Hemoglobin < 9 g/dL Total bilirubin > 6 mg/dL Aminotransferases > 200 U/L Serum urea > 60 mg/dL Serum creatinine > 1.5 mg/dL	Deaths: Group A: 2/20 Group B: 3/21 Complications (encephalopathy, renal failure, and gastrointestinal bleeding): Group A: 3/20 patients Group B: 4/21 patients Group A: Satisfactory mobilization for ascites for 19/20 patients 4/20 patients did not reaccumulate ascites while 15/20 patients did reaccumulate ascites Group B: Resolution of ascites in 19/21 patients Diuretic treatment was unsuccessful for 2/21 Group B patients who were receiving the highest doses of diuretic therapy Group A: Mean body weight significantly reduced at all times after paracentesis, slight decrease in heart rate and urine osmolality (day 10). Increase noted in PAC (days 5 and 10) and urine flow rates (days 5, 10, and 15). Increased urine flow rates in 14 patients who also had significantly lower baseline urine excretions than the other 5 responsive Group A patients In the 19/21 responsive Group B patients, significant body weight reductions observed on days 10 and 15. Mean blood pressure and heart rate did not change. Significant increases noted in urine flow rate, sodium and potassium excretion, plasma albumin and potassium concentrations. Significant decrease in urine osmolality	LVP is faster and equally effective alternative to diuretic therapy and suggested that LVP might be used to decrease hospital length of stay without additional risk
Ginès et al[12], 1988	105 patients randomized into 2 groups Group A: Paracentesis + IV albumin: 52 patients Group B: paracentesis without fluid replacement: 53 patients Exclusion criteria: Similar to study by Salerno[10]	Died in hospital: Group A: 2/52 Group B: 2/53 Deaths at 1 yr: Group A: 20/52 Group B: 16/53	These findings indicated that, aside from systemic hemodynamics, there are likely multiple factors, such as renal production of vasodilators or ADH antagonists, which contribute to the development of renal failure
		Complications of hyponatremia, renal impairment, encephalopathy, gastrointestinal hemorrhage, and severe infection: Group A 9/52 Group B 16/53 Group A: Significant increase in serum albumin, GFR, free water clearance
		Group B: No change in serum albumin, significant increase in BUN, PRA, PAC, significant decrease in serum sodium
		PRA significant increase at 48 h and 5 d post LVP Group B 23/24 and 9/24 respectively Group A had none Readmission: Group A 29/52 Group B 36/53 Renal impairment: Group A: None Group B: 11/53
Ginès et al[5], 1996	289 patients randomized into 3 groups Group A: Paracentesis + IV albumin: 97 patients Group B: Paracentesis + Dextran 70: 93 patients Group C: Paracentesis + Polygeline: 99 patients Exclusion criteria: Similar to study by Salerno[10]	Deaths: Group A 2/97 Group B 4/93 Group C 6/99 PICD (based on 280 patients who developed dysfunction and had PRA measured at baseline and 6 d after the procedure): Total 85/289 Group A 17/892 Group B 31/90 Group C 37/98 PRA > 50% increase (at 2 d after LVP) if PICD occurred: 47/85 PICD associated with shorter survival Complications of hyponatremia, renal impairment, hepatic encephalopathy, gastrointestinal bleeding, bacterial infection Group A: 28/97 patients, 30 complications Group B: 28/93 patients, 43 complications Group C: 30/99 patients, 39 complications Incidence of death with PICD: 5/85 Incidence of death without PICD: 6/195	PICD found to not be spontaneously reversible and persists during follow-up PICD associated with faster reaccumulation of ascites and impaired prognosis The authors suggest that albumin is more effective than dextran 70 or polygeline at preventing postparacentesis circulatory dysfunction and is the volume expander of choice for cirrhotics who undergo paracentesis with > 5 L of ascites removed The authors discussed the pathophysiology of PICD, theorizing that PICD was most likely secondary to variable changes in neurohormonal responses, which accelerate the disease and lead to decreased long-term survival. They felt that PICD was unlikely due to a more advanced disease state, as patients with and without PICD did not differ in their degree of liver, renal, or hemodynamic function after paracentesis

LVP: Large-volume paracentesis; IV: Intravenous; PICD: Paracentesis induced circulatory dysfunction; ADH: Antidiuretic hormone.

Table 2 Randomized control studies evaluating transhepatic portosystemic shunts vs paracentesis in patients with cirrhosis and refractory ascites

Ref.	Study design	Results	Conclusions/comments
Lebrec et al[30], 1996	Total of 25 13 TIPS 12 LVP Excluded: Age > 70 Severe diseases other than liver Pulmonary hypertension Hepatocellular carcinoma Hepatic encephalopathy Sepsis/spontaneous bacterial peritonitis Severe alcoholic hepatitis Portal/hepatic vein obstruction/thrombosis Obstruction of biliary tract or hepatic artery Plasma creatinine > 150 mmol/L	Deaths: TIPS - 9/13 LVP - 4/12 3/13 TIPS unsuccessful, of the remaining 10/13 TIPS patients: 8 required a second shunt and 2 required 3 shunts 1/12 LVP patients received liver transplant Survival at 2 yr with "intention to treat" analysis 29% ± 13% for TIPS and 60% ± 16% for LVP Survival at 2 yr with "per protocol" analysis was 38% ± 16% for TIPS and 70% ± 15% for LVP	The authors concluded that intrahepatic shunts were selectively effective in patients with Childs-Pugh class B, although they did not improve survival, and actually decreased survival in class C patients compared to LVP. They believed that the prominent factor is ascites management were dependent on both neurohormonal factors which control natriuresis and the hepatic sinusoidal pressures
Rössle et al[31], 2000	Total of 60 patients Randomized to 2 groups: TIPS 29/60 LVP 31/60 Excluded: Hepatic encephalopathy > Grade 2 Serum bilirubin > 5 mg/dL Serum creatinine > 3 mg/dL Portal-vein thrombosis Hepatic hydrothorax Advanced cancer Continual ascites after paracentesis or multiple paracentesis within 1 wk	Deaths: TIPS - 15/29 LVP - 23/31 13/29 patients had shunt insufficiency, 11/29 underwent reestablishment of the shunt after 10 ± 16 mo and 5 of these patients required a second reestablishment 1/29 TIPS patients received liver transplant 2/31 LVP patients received liver transplant These patients were alive 60 mo following transplant Of the patients assigned to paracentesis in whom this procedure was unsuccessful, 10 received a transjugular shunt a mean of 5.5 ± 4 mo after randomization; 4 had a response to this rescue treatment Estimated probability of survival without transplant: TIPS: 69% and 58% at 1 and 2 yr; LVP: 52% and 32% at 1 and 2 yr In a multivariate analysis, treatment with transjugular shunting was independently associated with survival without the need for transplantation (P = 0.02) At three mo, 61% of the patients in the shunt group and 18% of those in the paracentesis group had no ascites (P = 0.006) Age > 60 yr, female sex, bilirubin > 3 mg/dL, and serum sodium < 125 mmol/L significantly decreased survival in the TIPS group	In comparison with large-volume paracentesis, the creation of a transjugular intrahepatic portosystemic shunt can improve the chance of survival without liver transplantation in patients with refractory or recurrent ascites
Ginès et al[32], 2002	Total of 70 patients randomized into 2 groups TIPS: 35 LVP + Albumin (8 g/L ascites removed): 35 Primary endpoint: Survival without liver transplantation Secondary endpoints: Complications of cirrhosis and cost Excluded: < 18/> 75 yesrs old Serum bilirubin > 10 mg/dL Prothrombin time < 40% Platelet count < 40000/mm³ Serum creatinine > 3 mg/dL Hepatocellular carcinoma Complete portal vein thrombosis Cardiac/respiratory failure Organic renal failure Bacterial infection Hormonal measurements (plasma renin	Deaths: TIPS 20/35 LVP 18/35 Transplanted: TIPS 7/35 LVP 7/35 1 TIPS patient required repeat LVP’s 3 LVP patients required TIPS placement Ascites recurrence: TIPS - 17 patients developed 60 episodes of ascites (30 episodes attributed to 1 patient who experienced a total occlusion of their shunt), LVP - 29 patients developed 341 episodes of ascites Median time of the first recurrence of ascites: TIPS - 171 d LVP - 20 d 13 TIPS patients experienced shunt dysfunction	They concluded that TIPS lowers the rate of ascites recurrence and the risk of developing hepatorenal syndrome, but does not improve survival and has increased occurrence of encephalopathy and higher cost that LVP
	activity, aldosterone, norepinephrine, and atrial natriuretic peptide) were measured at 1 wk, 1 mo and 6 mo in 18 TIPS patients and 23 LVP patients	Total costs for TIPS patients (calculated separately in United States dollars on intention-to-treat basis from Spanish and then United States hospitals that participated in the study) demonstrated that total costs and costs per patient were greater in the TIPS group TIPS $693460, or $19813 per patient. LVP patients were $341760, or $9765 per patient
Sanyal et al[33], 2003	109 patients with refractory ascites were randomized into 2 groups 52 patients received TIPS with medical therapy (low sodium diets, diuretics, and LVP) 57 patients received medical therapy without TIPS Excluded: Similar criteria to prior studies All patients placed on low Na diets and diuretics All patients placed on low Na diets and diuretics Diuretics stopped 5 d prior to LVP Albumin infusion followed LVP at 6-8 g/L removed TIPS patients received shunts Some patients from both groups received repeat LVP’s plus Albumin for tense, symptomatic ascites with weight gain > 10 pounds	Deaths: TIPS - 21/52 LVP 21/57 Failed Treatments: TIPS 3/52 unsuccessful LVP 2/57 patients required TIPS Failed treatments in the first year after randomization requiring repeat LVP for tense ascites: TIPS - 22/52 LVP 48/57 Average rate of LVP per patient in the first year after randomization: for TIPS - 1.69 LVP - 6.11 Transplants: TIPS 16/52 LVP 17/57	Although TIPS plus medical therapy is superior to medical therapy alone for the control of ascites, it does not improve survival, affect hospitalization rates, or improve quality of life
Salerno et al[34], 2004	66 patients randomized into 2 groups TIPS group: 33 LVP + Albumin group: 33 Excluded: Similar criteria to prior studies Diuretic doses continued throughout the study and doses adjusted for each patient’s clinical needs All patients on low Na diets (80 mg/d) TIPS placed LVP patients received Albumin replacements at 8 g/L ascites removed Patients discharged and followed at 1, 3 and 6 mo, then every 3-6 mo or as clinically necessary Mean follow up time was 18.2 ± 2.3 mo	Deaths: TIPS - 13/33 LVP - 20/33 Failed treatments: TIPS - 3/33 Initial LVP - 0/33 reported Estimated probability of survival at 1 yr: TIPS - 77% LVP - 52% Estimated probability of survival at 2 yr: TIPS 59% LVP 29% Transplanted: TIPS 4/33 LVP 4/33 Cox proportional hazard model indicated that treatment assigned and MELD scores were independent predictors of mortality Failure of treatment noted in 7/33 TIPS patients: 2 patients received LeVeen Shunts and 5 LVP’s Failure of treatment noted in 19/33 LVP patients: 1 received a LeVeen Shunt, 11 received TIPS, and 7 elected to continue with LVP treatment	Treatment failure was more frequent in patients assigned to paracentesis, whereas severe episodes of hepatic encephalopathy occurred more frequently in patients assigned to TIPS The number and duration of re-hospitalizations were similar in the two groups Compared to large-volume paracentesis plus albumin, TIPS improves survival without liver transplantation in patients with refractory ascites

LVP: Large-volume paracentesis; TIPS: Transhepatic portosystemic shunts; MELD: Model for end-stage liver disease.