Scandinavian Journal of Gastroenterology, 2009; 44: 902911

REVIEW ARTICLE

Ascites: Pathogenesis and therapeutic principles

SREN MLLER1, JENS H. HENRIKSEN1 & FLEMMING BENDTSEN2

1

Department of Clinical Physiology 239, and 2Department of Medical Gastroenterology 439, Hvidovre Hospital, Faculty of Health Sciences, University of Copenhagen, Hvidovre, Denmark

Scand J Gastroenterol Downloaded from informahealthcare.com by HINARI on 02/13/11 For personal use only.

Abstract Ascites is a classic complication of advanced cirrhosis and it often marks the first sign of hepatic decompensation. Ascites occurs in more than 50% of patients with cirrhosis, worsens the course of the disease, and reduces survival substantially. Portal hypertension, splanchnic vasodilatation, liver insufficiency, and cardiovascular dysfunction are major pathophysiological hallmarks. Modern treatment of ascites is based on this recognition and includes modest salt restriction and stepwise diuretic therapy with spironolactone and loop-diuretics. Tense and refractory ascites should be treated with large volume paracentesis followed by plasma volume expansion or transjugular intrahepatic portosystemic shunt. Ascites complicated by spontaneous bacterial peritonitis requires adequate treatment with antibiotics. New potential treatment strategies include the use of vasopressin V2-receptor antagonists and vasoconstrictors. Since formation of ascites is associated with a poor prognosis, and treatment of fluid retention does not substantially improve survival, such patients should always be considered for liver transplantation.

Key Words: Ascites, hepatobiliary-clinical, portal-hypertension

Introduction The genesis and perpetuation of ascites is a common complication, occurring in more than 50% of patients within 10 years of the diagnosis of cirrhosis [1]. Ascites is defined as more than 25 ml fluid in the peritoneal cavity and can be seen in various diseases, but is most frequently caused by cirrhosis with portal hypertension and by peritoneal carcinomatosis. Less common aetiologies of ascites are hepatocellular carcinoma, Budd-Chiari syndrome, congestive heart failure, pancreatitis, and tuberculosis. The normal hepatosplanchnic lymph formation is about 1 ml/min. In patients with cirrhosis, this rate can increase up to 10 ml/min [2,3]. When the production of lymphatic fluid exceeds the lymphatic transport capacity, ascites develops. According to the amount of ascites, this can be divided into grades 03 [4]. Grade 3 represents the gross and tense ascites with vast discomfort to the patient (Table I). However, the presence of even lower

grades of ascites is not just a cosmetic problem since it is associated with poor survival with a 50% mortality rate within 3 years [5,6]. In these patients, survival depends mainly on the degree of portal hypertension, liver insufficiency, and circulatory dysfunction. In about 25% of patients, bacterial translocation leads to the development of spontaneous bacterial peritonitis (SBP), which further worsens the prognosis [7]. A substantial number of patients with ascites caused by advanced cirrhosis also develop hepatic nephropathy, which carries a very poor prognosis despite new treatment modalities [1,810]. Contemporary treatments range from diuretics, the use of new therapeutic principles such as aquaretics and vasoconstrictors, large volume paracentesis, transjugular intrahepatic portosystemic shunts (TIPS), liver-supporting devices, antibiotics, and, at the end stage, liver transplantation. In this paper we summarize the most recent advances in our understanding of the formation of ascites and modern aspects of treatment.

Correspondence: Sren Mller, MD, DMSc, Associate Professor, Department of Clinical Physiology 239, Hvidovre Hospital, DK-2650 Hvidovre, Denmark. Tel: '45 3632 3568. Fax: '45 3632 3750. E-mail: soeren.moeller@hvh.regionh.dk

(Received 28 January 2009; accepted 18 March 2009)

ISSN 0036-5521 print/ISSN 1502-7708 online # 2009 Informa UK Ltd. DOI: 10.1080/00365520902912555

Treatment of ascites
Table I. Grades of ascites according to the International Club of Ascites [4]. Grade of ascites Grade 0 Grade 1 Grade 2 Grade 3 Explanation No detectable ascites Mild ascites that is only detectable by ultrasound examination Moderate ascites with moderate distension of the abdomen Large or tense ascites with marked distension of the abdomen

903

Portal hypertension In cirrhosis, portal and sinusoidal hypertension is a prerequisite for the development of ascites. The hydrostatic pressure within the hepatic sinusoids favours transudation of fluid into hepatic lymphatics and the peritoneal cavity [2,13]. The topographic site of the lesion is therefore important. Patients with post-hepatic portal hypertension with hepatic vein thrombosis, as in Budd-Chiari syndrome, often develop ascites which is difficult to treat [14]. On the other hand, development of ascites is considered a late-phase manifestation in patients with portal hypertension due to portal vein thrombosis, and ascites in these patients is usually easy to control [15]. The hepatic vascular resistance and portal venous inflow together with the development of portosystemic collaterals determine the height of the portal pressure. Factors that determine hepatic vascular resistance include both structural and dynamic components [16]. Among the structural components are fibrosis and regeneration nodules. Dynamic structures include hepatic stellate cells, myofibroblasts, and other cells with contractile properties. A preferential sinusoidal constriction in the liver seems to be attributed to a defective nitric oxide (NO) production but also to endogenous vasoconstrictors like endothelin-1 (ET-1), angiotensin II, catecholamines, and leukotrienes may all increase the hepatic sinusoidal resistance [1618]. The haemodynamic imbalance with a predominant sinusoidal constriction contributes significantly to the development of portal hypertension and thereby is an important target for treatment. Moreover, the formation of ascites depends on the balance between the increased local transvascular filtration and augmented lymph drainage [2]. Thus, the amount of ascitic fluid produced is governed by increased transsinusoidal filtration of protein and fluid and by accelerated transperitoneal hydrostatic and oncotic dynamics. However, in contrast to earlier assumptions, the decreased plasma oncotic pressure may be of minor importance for the generation of ascites and low plasma concentrations of albumin have little influence on the rate of ascites formation (Figure 2) [2,19,20]. In this context, the increased hydrostatic pressure in the sinusoids and intestinal capillaries is critical, and ascites rarely develops in patients with a hepatic venous pressure gradient below 12 mmHg [21]. Pathophysiology of arterial vasodilatation and neurohumoral activation The pathophysiological coupling between early portal hypertension and the development of the systemic and splanchnic vasodilatation and the hyperdynamic

Pathogenesis and perpetuation of the ascites syndrome

Scand J Gastroenterol Downloaded from informahealthcare.com by HINARI on 02/13/11 For personal use only.

Major factors involved in the complex pathogenesis of ascites are portal and sinusoidal hypertension, arterial vasodilatation, and neurohumoral activation, all leading to sodium and water retention [10,11]. According to the peripheral arterial vasodilatation theory, development of systemic and splanchnic vasodilatation results in a decrease in the effective arterial blood volume and a hyperdynamic circulation [12]. This theory has lately been modified into what has been termed the forward theory of ascites formation (Figure 1) which combines arterial underfilling with a forward increase in splanchnic capillary pressure and filtration with increased lymph formation [3].

Cirrhosis and liver dysfunction Portal hypertension TIPS -adrenergic blockers

Increased splanchnic capillary pressure

Increased production of vasodilators

Increased lymph formation

Splanchnicarteriolar vasodilatation

Ascites

Paracentesis plasma Volume expansion

V1 receptor agonists

Central hypovolaemia Arterial hypotension Deloadingof arterial baroreceptors

-1agonist
Plasma volume expansion

-adrenergic blockers
Loopdiuretics Sodium and water retention

Activation of SNS Activation of RAAS Activation of vasopressin Aldosterone antagonists V2 receptor antagonists

Figure 1. Pathophysiology of the development of ascites in cirrhosis and potential targets for treatment. SNS 0 sympathetic nervous system; RAAS 0 renin-angiotensin-aldosterone system; AVP 0 arginine vasopressin.

S. Mller et al.

Hepatocytes Space of Disse with stellate cellsse

Scand J Gastroenterol Downloaded from informahealthcare.com by HINARI on 02/13/11 For personal use only.

Total splanchnic lymph flow:

Peritoneal spill-over:

Figure 2. Hydrostatic pressures and transperitoneal uid dynamics in cirrhosis: An increased hepatic venous pressure gradient (HVPG) generates increased transsinusoidal uid ltration with an overall increased hepatosplanchnic lymph ow of 10 25 l/24 h. As long as the transsinusoidal ltration keeps pace with lymphatic drainage, no surplus protein-rich uid willspill over into the peritoneal cavity. When ltration exceeds the lymphatic drainage, protein-rich uid will accumulate in the peritoneal cavity as ascites. However, this spillover fraction (0.5 l/24 h) is relatively small compared to the overall transsinusoidal ltration and lymphatic drainage. WHVP wedged hepatic venous pressure; FHVP free hepatic venous pressure.

syndrome is still obscure. It may be brought about either by overproduction of circulating vasodilators induced by shear stress in the splanchnic circulation or by direct neurohumoral signals from the liver to the brain [18,22]. Several findings indicate that the splanchnic vasodilatation precedes renal sodium and water retention [23]. In experimental as well as in human portal hypertension, splanchnic vasodilatation leads to reduced systemic vascular resistance, decreased effective blood volume, and a reduction in arterial blood pressure with activation of potent vasoconstricting systems such as the sympathetic nervous system (SNS), the renin-angiotensin-aldosterone system (RAAS), and non-osmotic release of vasopressin [3,11,18]. The haemodynamic consequences of the development of a hyperdynamic circulation with an increased heart rate and cardiac output have previously been described as a mediator of the effective blood volume, and underfilling of the arterial circulation occurs in these patients as a result of diminished systemic vascular resistance [12]. However, at a much later stage of the disease, underfilling of the arterial circulation may also occur secondary to a reduction of the increased cardiac output, as described in patients with renal failure and SBP [24]. NO is among the vasodilators that have been implicated in the systemic vasodilatation, and is

primarily synthesized in the systemic vascular endothelium by NO synthase [25,26]. In portal hypertension, there seems to be a diminished release of NO from sinusoidal endothelial cells in the cirrhotic liver, whereas in the systemic circulation there is evidence of an up-regulation of the NO synthesis [27]. Calcitonin gene-related peptide (CGRP) and adrenomedulin are potent vasodilatating neuropeptides, which have been found increased especially in patients with ascites and the hepatorenal syndrome (HRS) [18,23]. The increase in circulating vasoactive substances is mainly due to increased production and, to a lesser extent, to a decrease in hepatic clearance [28]. It is likely that these peptides play a role as neurotransmitters, both in the initiation of the haemodynamic changes and in the perpetuation of the hyperdynamic circulation and the formation of ascites. Systemic vasodilatation has also been related to resistance to pressor substances, such as noradrenaline, angiotensin II, and vasopressin. An impaired response to these vasoconstrictors is most likely related to changes in receptor affinity, down-regulation of receptors, and to post-receptor defects related to increased NO expression [18,29,30]. Recently, alterations in arterial and total vascular compliance have also been considered [31,32].

Treatment of ascites Although the pathophysiology and the role of arterial vasodilatation are complex, there is definite experimental and clinical evidence to show that it precedes the counter-regulatory neurohumoral activation and the renal sodium and water retention in cirrhosis. Renal dysfunction In the early phases of cirrhotic portal hypertension, the renal sodium excretion capacity is impaired, with reduced natriuretic response to acute administration of sodium chloride or to changes in posture [33,34]. These early events are seen before the development of ascites, but in most of the patients they represent the initiation of a more pronounced renal dysfunction. This includes progressively increased sodium and water reabsorption and decreases in renal perfusion and the glomerular filtration rate (GFR) often in parallel with reduced liver function [35]. In healthy individuals on a normal intake of sodium chloride, the free water clearance approximates 10 ml/min [36]. In particular decompensated cirrhotic patients, the free water clearance is often less than 1 ml/min, equivalent to an intake of 1.5 l/day before accumulation of fluid begins. The consequences are the development of dilutional hyponatraemia (serum sodium concentration of less than 130 mmol/l) [37]. At later stages, there is a progressive fall in GFR and renal blood flow (RBF) [8]. According to the sequence of the development of the functional renal abnormalities, genesis of ascites has been divided into successive pathophysiological phases (Table II). The early phase 1 is also called the pre-ascitic phase, because ascites is not present, but the renal metabolism of sodium is impaired, despite normal RBF, GFR, and free water clearance [38,39]. From a haemodynamic point of view, these patients often exhibit an increased plasma volume, supporting the presence of a period with increased sodium and water retention and adaptation between the vascular capacitance and the circulating medium [38]. The second phase denotes a negative sodium balance despite

905

Scand J Gastroenterol Downloaded from informahealthcare.com by HINARI on 02/13/11 For personal use only.

decreased urinary sodium excretion, and the absence of ascites in this phase can be achieved by reducing the dietary intake of sodium. At this stage there is only activation of the RAAS and SNS in some patients, and the GFR and RBF may be normal [40]. In phase 3, sodium excretion is often below 10 mmol/day and there is immense activation of the RAAS and SNS, but the RBF and GFR are still normal or low normal [41,42]. The arterial blood pressure is often low or low normal, despite activation of RAAS and SNS, and therefore these patients are highly susceptible to the hypotensive effects of angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor inhibitors, and V1-vasopressin antagonist [8]. Phases 4 and 5 ascites denote the development of the HRS type 2 and type 1, respectively. Type-2 HRS is characterized by moderate renal failure with a slow progressive course and it is typically associated with refractory ascites. Type1 HRS is characterized by a rapid decrease in renal function which is often precipitated by SBP [43]. The new diagnostic criteria for HRS according to The International Club of Ascites are presented in Table III [43].

Principles of ascites therapy Diagnostic investigations The presence of ascites should be confirmed by abdominal ultrasonography. In the case of identification of ascitic fluid, diagnostic paracentesis should, as a minimum, include measurement of albumin or protein concentrations, a neutrophil count, and aerobic and anaerobic cultures of the ascitic fluid. Presence of SBP, defined as a neutrophil count 250 cells/ml, is seen in about 15% of patients with ascites [20,44]. Determination of the serumascites albumin gradient may be helpful in distinguishing between ascites caused by cirrhosis, cardiac failure, and primary renal diseases from ascites caused by pancreatic and malignant diseases. Thus, a serum-ascites albumin gradient 11 g/l favours a hepatic, cardiac, or renal aetiology [20]. Ascitic fluid

Table II. Pathophysiological phases in the development of ascites and the hepatorenal syndrome. Term Pre-ascitic cirrhosis Mildmoderate ascites Moderatetense ascites HRS type 2 HRS type 1 Phase Phase Phase Phase Phase Phase 1 2 3 4 5 Sodium and water retention No/Yes Yes Yes Yes Yes Activated RAAS and SNS No No/Yes Yes Yes Yes Impaired RBF and GFR No No No/Yes Yes Yes

Abbreviations: RAAS 0renin-angiotensin-aldosterone system; SNS 0sympathetic nervous system; RBF 0renal blood flow; GFR 0 glomerular filtration rate; HRS 0hepatorenal syndrome. Modified from Arroyo et al. [3].

906

S. Mller et al. Medical treatment. A strategy for the treatment of ascites is presented in Table IV. Diuretics have been used for the treatment of fluid retention for more than 60 years. The diuretic treatment of ascites should be initiated with an aldosterone antagonist that acts mainly on the distal tubules in order to increase natriuresis, since, if furosemide is administered alone, its natriuretic effects on the loop of Henle will be counteracted by sodium reabsorbed in the distal tubules, because of activation of aldosterone. The initial prescription in mild to moderate ascites should be 100 mg/day, a dose that can be gradually increased up to 400 mg/day [3,4]. But, to avoid hyperkalaemia, it is often necessary to give a loop diuretic supplement before the full aldosterone antagonist dose. The full effect of diuretic treatment is normally seen after 35 days. Body-weight should be checked daily and serum sodium, potassium, and creatinine concentrations monitored. A daily weight loss of no more than 500 800 g is recommended to prevent intravascular volume depletion [1]. In the case of massive peripheral oedema, higher weight losses can be accepted. When this is insufficient, a loop diuretic should be added, usually furosemide, as it may induce marked diuresis and natriuresis. The initial recommended dose is 40 mg/day and can be increased to 160 mg/day with a stepwise increase every 23 days [4]. Additional diuresis can sometimes be achieved with the supplementation of other diuretics such as amiloride or a thiazide, but side effects are common. The main purpose of the treatment is to keep the patient free of ascites. When the ascites has been resolved,
Table IV. Suggestions for a progressive strategy in the treatment of sodium and uid retention and renal complications in cirrhosis. Clinical condition Pre-ascitic cirrhosis Mild ascites Moderatetense ascites Refractory ascites Hyponatraemia Treatment

Table III. New diagnostic criteria of the hepatorenal syndrome (HRS) according to The International Club of Ascites [43]. Cirrhosis with ascites. Serum creatinine 133 mmol/l (1.5 mg/dl) No improvement of serum creatinine (decrease to a level of 5133 mmol/l) after at least 2 days with diuretic withdrawal and volume expansion with albumin. The recommended dose of albumin is 1 g/kg body weight per day up to a maximum of 100 g/day Absence of shock No current or recent treatment with nephrotoxic drugs Absence of parenchymal kidney disease as indicated by proteinuria 500 mg/day, microhaematuria ( 50 red blood cells per high-power field) and/or abnormal renal ultrasonography

Scand J Gastroenterol Downloaded from informahealthcare.com by HINARI on 02/13/11 For personal use only.

amylase should be measured on clinical suspicion of pancreatic disease. Analyses of cytology should be carried if malignancy is suspected [45]. Treatment of non-complicated ascites Para-medical treatment. Previous studies have shown that the supine position ameliorates the RBF and GFR and improves sodium and water excretion [46]. A less activated RAAS and SNS and a more favourable diuretic response in the supine patient have led to the assumption that bedrest would benefit the treatment of ascites. However, severe side effects of prolonged bedrest, for example an increased risk of thromboembolic complications, decalcification of the bones, and muscular atrophy, imply that bedrest in general cannot be recommended for the treatment of ascites [20]. Reduced salt intake will counteract the sodium imbalance in patients with fluid retention and may create a negative sodium balance in some of the patients; therefore a low salt diet should be part of the basic treatment of ascites. However, a rigorous low salt diet is usually unacceptable to the patient and thus a no-salt-added diet of 80120 mmol NaCl per day is recommended. In patients with dilutional hyponatraemia in particular, water restriction (1.0 1.5 l/day) has been used, but the effectiveness of this treatment to increase the serum sodium concentration more than 5 mmol/l is limited and ranges from 0% to 26% [47]. Moreover, water restriction has a limited effect on improving serum sodium, because the daily fluid intake cannot be reduced to less than one litre per day, which is insufficient to ensure a negative fluid balance [48]. Water restriction should be reserved only for patients who are clinically hypervolaemic with severe hyponatraemia and decreased free water clearance. Thus, for practical purposes, water can only be restricted in very few (if any) patients.

No treatment Modest salt restriction (80120 mmol/day) Salt restriction Stepwise spironolactone (100400 mg/day) Salt restriction Spironolactone Stepwise furosemide (40160 mg/day) Large volume paracentesis and plasma volume substitution and diuretics TIPS Serum sodium B125 mmol/l: diuretics discontinued Serum sodium B120 mmol/l: plasma volume expansion Hyper/euvolaemia: modest water restriction Experimental vasopressin V2 receptor antagonists

Abbreviation: TIPS 0transjugular intrahepatic portosystemic shunt.

Treatment of ascites
Table V. Denition of and diagnostic criteria for refractory ascites in cirrhosis according to a consensus report from the International Club of Ascites [4].

907

Diuretic-resistant ascites Ascites that cannot be mobilized or the early recurrence of which cannot be prevented, because of a lack of response to sodium restriction and diuretic treatment Diuretic-intractable ascites Ascites that cannot be mobilized or the early recurrence of which cannot be prevented, because of the development of diuretic-induced complications that preclude the use of an effective diuretic dose Conditions 1. Treatment duration: Patients must be on intensive diuretic therapy (spironolactone 400 mg/day and furosemide 160 mg/ day) for at least 1 week and a salt-restricted diet of less than 90 mmol/day or 5.2 g salt per day 2. Lack of response: Mean weight loss B0.8 kg over 4 days and urinary sodium output less than the sodium intake 3. Early ascites recurrence: Reappearance of grades 2 or 3 ascites within 4 weeks of initial mobilization 4. Diuretic-induced complications: Diuretic-induced hepatic encephalopathy is the development of encephalopathy in the absence of any other precipitating factors. Diuretic-induced renal impairment is an increase of serum creatinine by  100% to a value 2 mg/dl (177 mmol/l) in patients with ascites responding to treatment. Diuretic-induced hyponatraemia is defined as a decrease in serum sodium by 10 mol/l to B125 mmol/l. Diuretic-induced hypo- or hyperkalaemia is defined as a change in serum potassium to B3 mol/l or 6 mmol/l, despite appropriate measures Adopted from Moore et al. The management of ascites in cirrhosis: Report on the consensus conference of the International Club of Ascites [4].

the diuretic dose should be reduced to the minimum and, if possible, discontinued. Non-steroidal antiinflammatory drugs (NSAIDs) enhance sodium retention and formation of ascites, and are associated with the development of renal failure, hyponatraemia and resistance to diuretics and, for these reasons, should be avoided [20]. Drugs that can induce arterial hypotension and interfere with renal function, such as ACE inhibitors, angiotensin II antagonists, and a1adrenergic blockers, should be used cautiously and only when weight loss, blood pressure, serum creatinine, and clinical status are monitored. Treatment of refractory ascites Ten percent of patients with ascites become refractory to medical treatment and paracentesis, and so other treatment modalities are necessary [20]. Refractory ascites is defined as diuretic-resistant ascites which cannot be mobilized by intensive diuretic therapy and a low salt diet (weight loss less than 200 g/day over 4 days) (Table V). Diuretic-intractable ascites is characterized by the presence of diuretic-induced compl

ications, such as encephalopathy and hyponatraemia [4]. The response to diuretics and the salt diet should be validated only in stable patients without bleeding or infection, since such conditions affect the ability to excrete salt and water. Ascites recurs in as much as 90% of patients particularly in those with post-sinusoidal alcoholic cirrhosis after therapeutic paracentesis, and supplementation with a minimum dose of diuretics is therefore essential [49]. Therapeutic paracentesis should be done in a single session and should always be combined with plasma volume expansion. The intra-abdominal, right atrial, and pulmonary capillary wedge pressures decrease after large volume paracentesis [31]. Cardiac output increases after 23 h and the mean arterial blood pressure decreases by an average of 810 mmHg [50,51]. Large volume paracentesis without adequate volume substitution may result in the development of post-paracentesisinduced circulatory dysfunction (PICD) in up to 75% of patients [52]. This condition is characterized by pronounced activation of the RAAS and SNS, which reflects central hypovolaemia. PICD is mainly caused by paracentesis-induced splanchnic arteriolar vasodilatation and brings about a further reduction in systemic vascular resistance and an increase in portal pressure [53]. Several randomized, controlled trials of albumin versus synthetic plasma expanders, such as dextran, collagen-based colloids, and starch, have shown equal effectiveness as synthetic plasma expanders and albumin in the prevention of postparacentesis-induced complications after small volume paracentesis [5457]. After paracentesis of large volume ascites (5 l), albumin (8 g/l) seems to be more effective than polygeline in preventing the paracentesis-induced increase in RAAS and liverrelated complications [58,59]. Intravenous albumin may therefore prevent the development of complications caused by circulatory dysfunction, such as HRS and rapid recurrence of ascites, and may also improve survival [52,53]. For these reasons alternative plasma expanders should be avoided for the prevention of PICD after large volume paracentesis. In the case of tense ascites, which may cause the patient abdominal discomfort and haemodynamic or respiratory dysfunction, therapeutic paracentesis should be preferred because of fewer complications and a shorter hospital stay compared to intensive diuretic treatment [3]. Recent studies have shown that administration of vasoconstrictors such as terlipressin, midodrine, or noradrenaline may also be effective, either alone or in combination with albumin [6062]. In a recent study, the vasoconstrictor midodrine was as effective as albumin in preventing PICD, and at a lower cost [63]. This has, however, been questioned in a newer pilot study of

Scand J Gastroenterol Downloaded from informahealthcare.com by HINARI on 02/13/11 For personal use only.

908

S. Mller et al. of reduced excretion of AQP2 [72,73]. Clinical use of V2-receptor antagonists, known as the vaptans, may prove to be effective in the treatment of dilutional hyponatraemia. Up to the present time, data on the long-term effects are needed but randomized trials are currently in progress [47,74]. Diuretics should be discontinued if serum sodium is lower than 120 mmol/l. Spontaneous bacterial peritonitis (SBP) As mentioned above, SBP is defined as 250 neutrophil cells/ml. Culture from ascitic fluid often discloses bacterial species, such as Escherichia coli and Streptococcus [44]. Antibiotic treatment of SBP significantly improves survival and third-generation cephalosporins should be considered, such as cefotaxime 2 g twice a day for up to two weeks. Alternatively, amoxicillin/clavolanic acid can be considered. Fluoroquinolones are also effective. Other recommended antibiotics are ceftizoxime, cefonicid, ceftriaxone, and ceftazidime. In patients with ascites and a history of SBP, prophylactic treatment with, for example, ciprofloxacin 250 mg/day orally is recommended, especially in the case of low ascites protein [4,20,48,75]. Prophylactic treatment of patients with SBP with antibiotics alone or in combination with albumin has significantly reduced the risk of development of type-1 HRS [76,77]. Aminoglycosides should not be used, because of their nephrotoxic side effects. Summary and conclusions Ascites and its complications, including HRS, are still conditions associated with a poor prognosis despite treatment. However, our knowledge of the pathophysiology underlying these severe complications has improved considerably and novel medical treatments combined with different pharmacological approaches may improve prognosis. The future approach will probably be to attack various aspects in the pathophysiological process. A multitarget strategy should seek efficiently to counteract the splanchnic vasodilatation, central hypovolaemia, and arterial hypotension by administration of potent vasoconstrictors, such as midodrine or terlipressin, combined with plasma expanders such as albumin. Development of long-acting systemic vasoconstrictors should be encouraged. Aquaporins may have a future, especially in the treatment of dilutional hyponatraemia. TIPS or beta-blockers should be applied to reduce portal pressure, whereas nitrates, COX-inhibitors and nephrotoxic antibiotics should be used with caution. Cardiac function should be

Scand J Gastroenterol Downloaded from informahealthcare.com by HINARI on 02/13/11 For personal use only.

24 patients [64]. PICD is an example of a complication attributable to further vasodilatation and reduction in effective blood volume, which can be prevented by specific volume support and vasoconstriction. The use of specific vasoconstrictors such as midodrine or terlipressin may potentially play a role in the future strategy of treatment. In the case of recurrent ascites, insertion of a TIPS should be considered. In experienced centres the technical success rate is usually high, at about 95% [65]. Control of ascites is achieved in 8090%, with complete resolution in 75%. TIPS is now considered more effective than large volume paracentesis for the control of ascites [6668]. A major problem with insertion of TIPS is the relatively high frequency of hepatic encephalopathy, and, although patients often report a better quality of life, no significant effect on survival has been demonstrated after TIPS insertion [69]. However, improved survival after TIPS for refractory ascites has been demonstrated in a metaanalysis based on individual patient data from three large randomized trials [68]. The use of polytetrafluoroethylene-covered stents improves shunt patency and may contribute to enhance the overall efficacy of this procedure [70]. Risk factors and relative contraindications for TIPS insertion include serum bilirubin 85 mmol/l, INR 2, episodic or chronic encephalopathy greater than grade 2, and bacterial infections and renal, cardiac, and respiratory failure [71]. Although TIPS is more effective in removing ascites compared with large volume paracentesis, it is at the cost of a higher frequency of hepatic encephalopathy and it may not significantly affect transplant-free survival. Large volume paracentesis with plasma expander infusion should therefore continue to be the first-line treatment for refractory ascites. TIPS should be regarded as a second-choice treatment in patients with preserved liver function and recurrence of ascites [48]. Hyponatraemia Hyponatraemia in cirrhosis is defined as a reduction in serum sodium below 130 mmol/l [48]. Hyponatraemia often develops in cirrhosis, preferentially because of immense release of vasopressin. In the presence of plasma volume expansion, this is hypervolaemic or dilutional hyponatraemia [48]. Vasopressin acts on V2 receptors (G protein coupled with cyclic AMP as second messenger) in the collecting ducts and is responsible for the vasopressin-induced reabsorption of water [48]. This effect is mediated through aquaporins (AQPs), which are selective water channels, AQP2 being the most important [72]. Activation of AQPs increases water permeability and in patients with ascites there is evidence

Treatment of ascites supported, especially in the presence of simultaneous infections.

909

References
[1] Gines P, Cardenas A, Arroyo V, Rodes J. Management of cirrhosis and ascites. N Engl J Med 2004;350:164654. [2] Henriksen JH, Mller S. Alterations of hepatic and splanchnic microvascular exchange in cirrhosis: local factors in the formation of ascites. In: Gines P, Arroyo V, Rodes J , Schrier RW, editors. Ascites and renal dysfunction in liver disease. Malden: Blackwell; 2005. pp 17485. [3] Arroyo V, Colmenero J. Ascites and hepatorenal syndrome in cirrhosis: pathophysiological basis of therapy and current management. J Hepatol 2003;38(Suppl 1):S6989. [4] Moore KP, Wong F, Gines P, Bernardi M, Ochs A, Salerno F, et al. The management of ascites in cirrhosis: report on the consensus conference of the International Ascites Club. Hepatology 2003;38:25866. [5] Fernandez-Esparrach G, Sanchez-Fueyo A, Gines P, Uriz J, Quinto L, Ventura PJ, et al. A prognostic model for predicting survival in cirrhosis with ascites. J Hepatol 2001; 34:4652. [6] Guevara M, Cardenas A, Gine s P. Prognosis of patients with cirrhosis and ascites. In: Gine s P, Arroyo V, Rodes J, Schrier RW, editors. Ascites and renal dysfunction in liver disease. Malden: Blackwell; 2005. pp 26070. [7] Wiest R, Garcia-Tsao G. Bacterial translocation (BT) in cirrhosis. Hepatology 2005;41:42233. [8] Arroyo V, Terra C, Gines P. Advances in the pathogenesis and treatment of type-1 and type-2 hepatorenal syndrome. J Hepatol 2007;46:93546. [9] Dagher L, Moore K. The hepatorenal syndrome. Gut 2001; 49:72937. [10] Gentilini P, Vizzutti F, Gentilini A, Zipoli M, Foschi M, Romanelli RG. Update on ascites and hepatorenal syndrome. Dig Liver Dis 2002;34:592605. [11] Bernardi M, Caraceni P. Pathogenesis of ascites and hepatorenal syndrome: altered haemodynamics and neurohumoral systems. In: Gerbes AL, Beuers U, Jungst D, Pape G, Sackmann M, Sauerbruch T, editors. Hepatology 2000. Falk symposium 117. Dordrecht: Kluwer Academic Publishers; 2001. pp 185203. [12] Schrier RW. Decreased effective blood volume in edematous disorders: what does this mean? J Am Soc Nephrol 2007;18: 202831. [13] Kravetz D, Bildozola M, Argonz J, Romero G, Korula J, Munoz A, et al. Patients with ascites have higher variceal pressure and wall tension than patients without ascites. Am J Gastroenterol 2000;95:17705. [14] Plessier A, Valla DC. Budd-Chiari syndrome. Semin Liver Dis 2008;28:25969. [15] Garcia-Pagan JC, Hernandez-Guerra M, Bosch J. Extrahepatic portal vein thrombosis. Semin Liver Dis 2008;28: 28292. [16] Bosch J, Abraldes JG, Groszmann R. Current management of portal hypertension. J Hepatol 2003;38:S5468. [17] Iwakiri Y, Groszmann RJ. The hyperdynamic circulation of chronic liver diseases: from the patient to the molecule. Hepatology 2006;43:S12131. [18] Mller S, Henriksen JH. The systemic circulation in cirrhosis. In: Gines P, Arroyo V, Rodes J, Schrier RW, editors. Ascites and renal dysfunction in liver disease. Malden: Blackwell; 2005. pp 13955.
/ / / / / / / / / / / / / / / / / / / / / / / / / / / /

[19] Henriksen JH, Siemssen O, Krintel JJ, Malchow-Moller A, Bendtsen F, Ring-Larsen H. Dynamics of albumin in plasma and ascitic uid in patients with cirrhosis. J Hepatol 2001;34: 5360. [20] Moore KP, Aithal GP. Guidelines on the management of ascites in cirrhosis. Gut 2006;55 Suppl 6:vi1vi12. [21] Casado M, Bosch J, Garcia-Pagan JC, Bru C, Banares R, Bandi JC, et al. Clinical events after transjugular intrahepatic portosystemic shunt: correlation with hemodynamic ndings. Gastroenterology 1998;114:1296303. [22] Liu H, Schuelert N, McDougall JJ, Lee SS. Central neural activation of hyperdynamic circulation in portal hypertensive rats depends on vagal afferent nerves. Gut 2008;57:96673. [23] Wiest R. Splanchnic and systemic vasodilation: the experimental models. J Clin Gastroenterol 2007;41:S27287. [24] Ruiz-Del-Arbol L, Monescillo A, Arocena C, Valer P, Gines P, Moreira V, et al. Circulatory function and hepatorenal syndrome in cirrhosis. Hepatology 2005;42:43947. [25] Ferguson JW, Dover A, Chia S, Cruden N, Hayes PC, Newby D. Inducible nitric oxide synthase activity contributes to the regulation of peripheral vascular tone in patients with cirrhosis and ascites. Gut 2005;55:5426. [26] Iwakiri Y, Groszmann RJ. Vascular endothelial dysfunction in cirrhosis. J Hepatol 2007;46:92734. [27] Wiest R, Groszmann RJ. The paradox of nitric oxide in cirrhosis and portal hypertension: too much, not enough. Hepatology 2002;35:47891. [28] Henriksen JH, Mller S. Hemodynamics, distribution of blood volume, and kinetics of vasoactive substances in cirrhosis. In: Epstein M, editor. The kidney in liver disease. Philadelphia: Hanley and Belfus; 1996. pp 24158. [29] Farzaneh-Far R, Moore K. Nitric oxide and the liver. Liver 2001;21:16174. [30] Helmy A, Newby DE, Jalan R, Johnston NR, Hayes PC, Webb DJ. Nitric oxide mediates the reduced vasoconstrictor response to angiotensin II in patients with preascitic cirrhosis. J Hepatol 2003;38:44050. [31] Mller S, Henriksen JH. Cardiovascular complications of cirrhosis. Gut 2008;57:26878. [32] Henriksen JH, Mller S, Schifter S, Abrahamsen J, Becker U. High arterial compliance in cirrhosis is related to elevated circulating calcitonin gene-related peptide (CGRP) and low adrenaline, but not to activated vasoconstrictor systems. Gut 2001;49:1128. [33] La Villa G, Salmeron JM, Arroyo V, Bosch J, Gines P, Garcia-Pagan JC, et al. Mineralocorticoid escape in patients with compensated cirrhosis and portal hypertension. Gastroenterology 1992;102:21149. [34] Bernardi M, Li BS, Arienti V, de Collibus C, Scialpi C, Boriani L, et al. Systemic and regional hemodynamics in preascitic cirrhosis: effects of posture. J Hepatol 2003;39:5028. [35] Wensing G, Lotterer E, Link I, Hahn EG, Fleig WE. Urinary sodium balance in patients with cirrhosis: relationship to quantitative parameters of liver function. Hepatology 1997; 26:114955. [36] Mller S, Henriksen JH. Pathogenesis and pathophysiology of hepatorenal syndrome: is there scope for prevention? Aliment Pharmacol Ther 2004;20(Suppl 3):3141. [37] Angeli P, Wong F, Watson H, Gines P. Hyponatremia in cirrhosis: results of a patient population survey. Hepatology 2006;44:153542. [38] Bernardi M, Matco CD, Trevisani F, Collibus CD, Fornale L, Baraldini M, et al. The hemodynamic status of preascitic cirrhosis: an evaluation under steady-state conditions and after postural change. Hepatology 1992;16:3416.
/ / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / /

Scand J Gastroenterol Downloaded from informahealthcare.com by HINARI on 02/13/11 For personal use only.

910

S. Mller et al.
starch versus albumin as a plasma expander in cirrhotic patients with tense ascites treated with paracentesis. Eur J Gastroenterol Hepatol 1998;10:510. Planas R, Gines P, Arroyo V, Llach J, Panes J, Vargas V et al. Dextran-70 versus albumin as plasma expanders in cirrhotic patients with tense ascites treated with total paracentesis. Gastroenterology 1990;99:173644. Gines A, Fernandez-Esparrach G, Monescillo A, Vila C, Domenech E, Abecasis R, et al. Randomized trial comparing albumin, dextran 70, and polygeline in cirrhotic patients with ascites treated by paracentesis. Gastroenterology 1996; 111:100210. Moreau R, Valla DC, Durand-Zaleski I, Bronowicki JP, Durand F, Chaput JC, et al. Comparison of outcome in patients with cirrhosis and ascites following treatment with albumin or a synthetic colloid: a randomised controlled pilot trail. Liver Int 2006;26:4654. Moreau R, Asselah T, Condat B, de Kerguenec C, Pessione F, Bernard B, et al. Comparison of the effect of terlipressin and albumin on arterial blood volume in patients with cirrhosis and tense ascites treated by paracentesis: a randomised pilot study. Gut 2002;50:904. Singh V, Kumar B, Nain CK, Singh B, Sharma N, Bhalla A, et al. Noradrenaline and albumin in paracentesis-induced circulatory dysfunction in cirrhosis: a randomized pilot study. J Intern Med 2006;260:628. Krag A, Mller S, Henriksen JH, Holstein-Rathlou NH, Larsen FS, Bendtsen F. Terlipressin improves renal function in patients with cirrhosis and ascites without hepatorenal syndrome. Hepatology 2007;46:186371. Singh V, Dheerendra PC, Singh B, Nain CK, Chawla D, Sharma N, et al. Midodrine versus albumin in the prevention of paracentesis-induced circulatory dysfunction in cirrhotics: a randomized pilot study. Am J Gastroenterol 2008;103: 1399405. Appenrodt B, Wolf A, Grunhage F, Trebicka J, Schepke M, Rabe C, et al. Prevention of paracentesis-induced circulatory dysfunction: midodrine vs albumin. A randomized pilot study. Liver Int 2008;28:101925. Damico G, Luca A, Morabito A, Miraglia R, DAmico M. Uncovered transjugular intrahepatic portosystemic shunt for refractory ascites: a meta-analysis. Gastroenterology 2005; 129:128293. Ro ssle M, Ochs A, Gulberg V, Siegerstetter V, Holl J, Deibert P, et al. A comparison of paracentesis and transjugular intrahepatic portosystemic shunting in patients with ascites. N Engl J Med 2000;342:17017. Gines P, Uriz J, Calahorra B, Garcia-Tsao G, Kamath PS, del Arbol LR, et al. Transjugular intrahepatic portosystemic shunting versus paracentesis plus albumin for refractory ascites in cirrhosis. Gastroenterology 2002;123:183947. Salerno F, Camma C, Enea M, Rossle M, Wong F. Transjugular intrahepatic portosystemic shunt for refractory ascites: a meta-analysis of individual patient data. Gastroenterology 2007;133:82534. Saab S, Nieto JM, Lewis SK, Runyon BA. TIPS versus paracentesis for cirrhotic patients with refractory ascites. Cochrane Database Syst Rev 2006;CD004889. Bureau C, Garcia-Pagan JC, Otal P, Pomier-Layrargues G, Chabbert V, Cortez C, et al. Improved clinical outcome using polytetrauoroethylene-coated stents for TIPS: results of a randomized study. Gastroenterology 2004;126:46975. Arroyo V, Fernandez J, Gines P. Pathogenesis and treatment of hepatorenal syndrome. Semin Liver Dis 2008;28:8195. Esteva-Font C, Baccaro ME, Fernandez-Llama P, Sans L, Guevara M, Ars E, et al. Aquaporin-1 and aquaporin-2
/ / / / / / / / / / / / / / / / / / / / / / / / / / / / / /

[39] Sansoe G, Ferrari A, Baraldi E, Castellana CN, De Santis MC, Manenti F. Renal distal tubular handling of sodium in central uid volume homoeostasis in preascitic cirrhosis. Gut 1999;45:7505. [40] Claria J, Rodes J. Renal sodium handling in preascitic cirrhosis. Gut 2001;48:7401. [41] Pozzi M, Grassi G, Redaelli E, DellOro R, Ratti L, Redaelli A, et al. Patterns of regional sympathetic nerve trafc in preascitic and ascitic cirrhosis. Hepatology 2001;34:11138. [42] Bernardi M, Domenicali M. The renin-angiotensin-aldosterone system in cirrhosis. In: Gine s P, Arroyo V, Rodes J, Schrier RW, editors. Ascites and renal dysfunction in liver disease. Malden: Blackwell Publishing; 2005. Pp 4354. [43] Salerno F, Gerbes A, Gines P, Wong F, Arroyo V. Diagnosis, prevention and treatment of the hepatorenal syndrome in cirrhosis. A consensus workshop of the International Ascites Club. Gut 2007;56:13108. [44] Tandon P, Garcia-Tsao G. Bacterial infections, sepsis, and multiorgan failure in cirrhosis. Semin Liver Dis 2008;28: 2642. [45] Salerno F, Restelli B, Incerti P, Annoni G, Capozza L, Badalamenti S, et al. Utility of ascitic uid analysis in patients with malignancy-related ascites. Scand J Gastroenterol 1990;25:2516. [46] Ring-Larsen H, Henriksen JH, Wilken C, Clausen J, Pals H, Christensen NJ. Diuretic treatment in decompensated cirrhosis and congestive heart failure: effect of posture. Br Med J 1986;292:13513. [47] Gerbes AL, Gulberg V, Gines P, Decaux G, Gross P, Gandjini H, et al. Therapy of hyponatremia in cirrhosis with a vasopressin receptor antagonist: A randomized double-blind multicenter trial. Gastroenterology 2003;124: 9339. [48] Gines P, Cardenas A. The management of ascites and hyponatremia in cirrhosis. Semin Liver Dis 2008;28:4358. [49] Fernandez-Esparrach G, Guevara M, Sort P, Pardo A, Jimenez W, Gines P, et al. Diuretic requirements after therapeutic paracentesis in non-azotemic patients with cirrhosis. A randomized double-blind trial of spironolactone versus placebo. J Hepatol 1997;26:61420. [50] Cabrera J, Falcon L, Gorriz E, Pardo MD, Granados R, Quinones A, et al. Abdominal decompression plays a major role in early postparacentesis haemodynamic changes in cirrhotic patients with tense ascites. Gut 2001;48:3849. [51] Pozzi M, Ratti L, Redaelli E, Guidi C, Mancia G. Cardiovascular abnormalities in special conditions of advanced cirrhosis. The circulatory adaptative changes to specic therapeutic procedures for the management of refractory ascites. Gastroenterol Hepatol 2006;29:26372. [52] Gines P, Guevara M, De Las HD, Arroyo V. Review article: albumin for circulatory support in patients with cirrhosis. Aliment Pharmacol Ther ;16 Suppl 2002;5:2431. [53] Sola-Vera J, Minana J, Ricart E, Planella M, Gonzalez B, Torras X, et al. Randomized trial comparing albumin and saline in the prevention of paracentesis-induced circulatory dysfunction in cirrhotic patients with ascites. Hepatology 2003;37:114753. [54] Salerno F, Badalamenti S, Lorenzano E, Moser P, Incerti P. Randomized comparative study of hemaccel vs. albumin infusion after total paracentesis in cirrhotic patients with refractory ascites. Hepatology 1991;13:70713. [55] Fassio E, Terg R, Landeira G, Abecasis R, Salemne M, Podesta A, et al. Paracentesis with Dextran 70 vs. paracentesis with albumin in cirrhosis with tense ascites. Results of a randomized study. J Hepatol 1992;14:3106. [56] Altman C, Bernard B, Roulot D, Vitte RL, Ink O. Randomized comparative multicenter study of hydroxyethyl
/ / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / /

[57]

[58]

[59]

[60]

Scand J Gastroenterol Downloaded from informahealthcare.com by HINARI on 02/13/11 For personal use only.

[61]

[62]

[63]

[64]

[65]

[66]

[67]

[68]

[69]

[70]

[71] [72]

Treatment of ascites
urinary excretion in cirrhosis: relationship with ascites and hepatorenal syndrome. Hepatology 2006;44:155563. [73] Krag A, Bendtsen F, Pedersen EB, Holstein-Rathlou NH, Mller S. Effects of terlipressin on the aquaretic system: evidence of antidiuretic effects. Am J Physiol Renal Physiol 2008;295:F1295300. [74] Gines P. Vaptans: A promising therapy in the management of advanced cirrhosis. J Hepatol 2007;46:11502. [75] Gerbes AL, Gulberg V. Progress in treatment of massive ascites and hepatorenal syndrome. World J Gastroenterol 2006;12:5169.
/ / / / / / / /

911

[76] Sort P, Navasa M, Arroyo V, Aldeguer X, Planas R, RuizDel-Arbol L, et al. Effect of intravenous albumin on renal impairment and mortality in patients with cirrhosis and spontaneous bacterial peritonitis. N Engl J Med 1999;341: 4039. [77] Fernandez J, Navasa M, Planas R, Montoliu S, Monfort D, Soriano G, et al. Primary prophylaxis of spontaneous bacterial peritonitis delays hepatorenal syndrome and improves survival in cirrhosis. Gastroenterology 2007;133: 81824.
/ / / /

Scand J Gastroenterol Downloaded from informahealthcare.com by HINARI on 02/13/11 For personal use only.