Paracentesis

With ongoing disease severity acites becomes intractable or refractory to the dietary and diuretic therapy requiring additional measures. Large volume paracentesis (LVP) relieves symptoms rapidly and has few technical complications.7 However, it does not correct the underlying problem leading to ascites formation and, therefore, ascites reappears in almost all patients requiring serial use of paracenteses.

LVP has haemodynamic side effects. Shortly after LVP the cardiac output increases and the mean arterial blood pressure decreases by 8–10 mm Hg17 18 together with a further decline of the peripheral and splanchnic vascular resistance.19 Consequently, paracentesis may lead to a further increase in splanchnic blood flow and portal pressure causing an increased filtration rate and rapid ascites re-accumulation.19 In addition, paracentesis aggravates central vascular underfilling with a further activation of the renin–aldosterone and sympathetic nervous systems leading to renal dysfunction and eventually to the hepatorenal syndrome.20 21 This complication is termed as ‘postparacentesis circulatory dysfunction’ which limits the use of LVP in patients with unstable renal function. The infusion of albumin during or shortly after the paracentesis reduces the incidence of postparacentesis circulatory dysfunction from about 50% to 15%.21 22

TIPS

The rationale for TIPS is to decrease the portal pressure and the filtration into the peritoneal space to a level which can be drained by the lymphatic system. Thus, in contrast to diuretics and paracentesis, TIPS may counteract the mechanisms leading to ascites formation.

Within 4 weeks after TIPS urinary sodium excretion and serum creatinine improve significantly and, in combination with diuretics, can normalise within 6–12 months (figure 2).23–38 This is associated with a gradual increase in urinary volume and glomerular filtration rate.25 37 In addition, serum sodium concentration increases gradually.25 28 33 As shown in figure 3, the plasma renin activity, aldosteron and noradrenalin concentrations decreased significantly during 4–6 months of follow-up by 80%, 80% and 31%, respectively.25 26 28 32 33 36 37 This indicates an improvement of the circulatory dysfunction which is demonstrated in figure 4. Opening of the shunt leads to a sudden increase of the cardiac preload with an increase of the central venous pressure by 100% from an average of 5.7–11.6 mm Hg.39 40 This is accompanied by a major increase of the cardiac output from 7.8–11.5 l/min and a decrease in the total systemic vascular resistance by 35%.39

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Figure 2

Effects of a transjugular intrahepatic portosystemic shunt (TIPS) on urinary sodium excretion and creatinine concentration. Data are extracted from 16 studies.23–38

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Figure 3

Effects of a transjugular intrahepatic portosystemic shunt (TIPS) on plasma renin activity, aldosterone and noradrenalin concentrations. Data are obtained from eight studies.23 25 26 28 32 33 36 37

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Figure 4

Effects of a transjugular intrahepatic portosystemic shunt (TIPS) on systemic hemodynamics. Data are obtained from nine studies.39–45

After a few hours, the haemodynamic changes return towards pre-TIPS conditions with a mild persisting increase in the cardiac output by about 1 l/min and a decreased total vascular resistance by about 20% for the following months.39–44 As demonstrated in two studies with 12 months follow-up37 40 cardiac output and peripheral vascular resistance return to the pre-TIPS levels.

The effect of TIPS on renal haemodynamics has been investigated in six studies 28 29 32 33 37 45 showing normalisation after a follow-up of 12 months. Recently46 it was demonstrated that TIPS results in an improved renal blood flow together with an upward and leftward shift of the renal blood flow/renal perfusion pressure relationship curve which represents the renal autoregulation by the sympathetic nervous system. Accordingly, a significant reduction in norepinephrine levels was observed. It was, however, not normalised and was significantly higher than normal and similar to that in patients with diuretic-responsive ascites. The effect on the norepinephrine concentration and renal blood flow was directly related to the portosystemic pressure gradient. These results support a previous study of the same group showing that opening and occlusion of the TIPS channel exerts a rapid effect on renal blood flow.31 The authors concluded that the findings support the existence of a previously postulated hepato- or porto-renal reflex.47

With respect to the hepatic blood flow, TIPS leads to a reduction in the portal perfusion of the liver, dependent on the shunt diameter and the degree of the portal pressure reduction. In most patients a reduction of the portal pressure by about 50% results in a complete loss of the hepatic portal blood flow seen at angiography. Accordingly, duplex sonography after the TIPS commonly shows retrograde flow direction or stagnant flow in the intrahepatic portal branches indicating an abolished portal perfusion of the liver. This is counter-balanced by an immediate increase in the arterial blood flow as demonstrated by Duplex sonography48 and endoluminal flow measurements during the TIPS procedure.49 The calculated average arterial liver perfusion per minute increased from 599±100 ml/min before to 749±161 ml/min after TIPS. The effect occurred within seconds after opening the shunt and disappeared also within seconds after its balloon occlusion.

With respect to other complications related to portal hypertension a meta-analysis50 comparing TIPS with paracentesis investigated three frequent complications which occurred during the follow-up: gastrointestinal bleeding, spontaneous bacterial peritonitis (SBP) and HRS. Among patients allocated to TIPS gastrointestinal bleeding occurred in 13 subjects (8%), SBP in three (2%), and HRS in seven (4.6%), respectively. Among patients allocated to paracentesis, gastrointestinal bleeding occurred in 20 subjects (12.7%), SBP in five (3%), and HRS in 20 (12.7%), respectively. The overall rate of portal hypertension-related complications was significantly lower in the TIPS group than in the paracentesis group (23/149, 15% vs 45/156, 28%; p=0.005).

TIPS may also have a positive effect on quality of life. One study including 21 patients with refractory or recidivant ascites rated quality of life, fatigue and physical performance on a scale (range 0–100) before and 3 and 6 months after TIPS implantation.51 In addition, quality of life was determined by the QoL index (range 0–10) introduced by Spitzer. Patients' ratings on the self-assessment scale increased significantly from 35±25 to 64±28. Similarly, the Spitzer index significantly improved from 6.9±2.0 to 8.3±2.1. However, a randomised study on refractory ascites did not show a difference of quality of life between the TIPS and the paracentesis groups.52

Malnutrition and protein wasting is seen in most patients with cirrhosis and refractory ascites and has a negative effect on survival.53 54 In contrast to paracentesis, which leads to a protein loss of about 200 g per 10 litres ascites removed, TIPS improves the protein metabolism and nutrition. Three studies show a significant improvement in dry weight, total body nitrogen, total body fat and total body protein55–57 (figure 5). This is in agreement with our findings of an increase in body weight despite resolution of ascites.58 The reasons for the positive effects of TIPS on nutrition are not known. One reason may be an increase in the systemic insulin concentration bypassing now the liver. Another reason may lie in the disappearance of the ascites which may lead to an improved appetite and absorption of nutrients.

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Figure 5

Effects of a transjugular intrahepatic portosystemic shunt (TIPS) on nutrition.56 Twenty-one patients were studied before and 6 months after TIPS. Body weight, muscle mass, body cell mass, resting energy expenditure and energy intake increased significantly while fat mass did not change significantly. In a subgroup of 16 patients followed over a 12-month period the parameters further improved (not demonstrated).

The drawbacks of TIPS are an increased incidence of hepatic encephalopathy (HE) and the negative effect on liver function. HE occurs in about 30% of patients after TIPS.59 60 Factors associated with the development of encephalopathy that can be used for patient selection are advanced age, liver or renal failure, and a history of encephalopathy before TIPS insertion.61–63 Encephalopathy usually becomes clinically apparent 2–3 weeks after TIPS insertion and then declines (as measured by the portosystemic encephalopathy index) at 6 months in bare but not in covered stents.59 60 63 Thus, shunt stenosis with time may reduce the incidence of HE.

As demonstrated in a meta-analysis of individual patient data50 the cumulative probability of developing a first episode of HE during follow-up was not different between TIPS and paracentesis groups (p=0.36 by log-rank) and a similar result was found for the development of severe HE (p=0.46 by log-rank). By contrast, when the average number of episodes-per-patient was considered, patients allocated to TIPS had significantly more episodes of HE with regard to both, total number of episodes (1.13±1.93 vs 0.63±1.18, p=0.006) and number of severe episodes (0.68±1.0 vs 0.24±0.50, p=0.008). Independent predictors of post-TIPS HE were baseline mean arterial pressure (MAP) (HR 0.93, CI 0.89–0.98; p=0.004), model of end stage liver disease (MELD) score at baseline (HR 1.068, CI 1.006 to 1.13; p=0.032), and post-TIPS porto-systemic pressure gradient (HR 0.93, CI 0.87 to 0.99; p=0.048). An explanation for the correlation of baseline MAP with HE may be that a low MAP reflects poor liver and brain perfusion together with advanced disease. This is confirmed by the finding that the increase in hepatic arterial blood flow after TIPS has a potential predictive value of postprocedural HE and mortality.64 With respect to the MELD score, the INR and bilirubin concentration reflect liver function and the creatinine concentration the haemodynamic impact of the liver disease similar to the MAP. Theoretically, the combination of bilirubin and MAP or the MELD score may both be promising predictors for HE in patients with cirrhosis with and without a TIPS. Unfortunately, the study by Salerno50 does not provide thresholds with lower or higher probabilities of HE after TIPS. However, with a mean MAP of 87 mm Hg and a mean MELD score of 12.5 values of <80 mm Hg or above 15 may be regarded as risk indicators for HE.

The TIPS diameter, which can be adjusted during the TIPS intervention, correlates inversely with the portosystemic pressure gradient after TIPS, the remaining portal liver perfusion and the liver function. In patients at risk for HE according to the parameters mentioned, a smaller shunt diameter may be less harm and should therefore be preferred.

Treatment of HE is medical in most of the cases and consists of controlling any precipitating factor, lactulose and non-absorbable antibiotics (neomycin or rifaximin).60 62 If medical therapy fails, the TIPS diameter can be reduced or the shunt occluded.65–67 In this situation one should be assured that the patient's quality of life benefits more from improving HE than it worsens by the re-accumulation of ascites. Fortunately, in a series of 1000 patients, the need for shunt reduction for debilitating HE was only 3%.68

Deterioration of liver function after TIPS is indicated by an increase of serum bilirubin concentration.42 69 Its magnitude depends on the baseline liver function. As demonstrated, a bilirubin concentration of >3 mg/dl was closely correlated with mortality (RR: 5.4, 95% CI: 1.4 to 10.2).70 The finding is confirmed by showing that an elevated pre-TIPS bilirubin is a powerful independent predictor of 30-day mortality after TIPS creation with a 40% increased risk of death for each 1 mg/dl increase above 3.0 mg/dl.71 Therefore, a bilirubin concentration above 3 mg/dl can be regarded as a relative and above 5 mg/dl as an absolute contraindication for TIPS implantation for refactory ascites.72

To prevent both deterioration of liver function and HE the shunt diameter and the degree of reduction of the portosystemic pressure gradient should be moderate. As demonstrated recently, 25 of 27 patients who developed hepatic encephalopathy after TIPS implantation had a pressure gradient of <12 mm Hg.73 Thus, in patients with a higher risk of HE and poor liver function (ie, bilirubin concentration above 3 mg/dl) the portosystemic pressure gradient should be decreased with great caution.

Complications

Although many serious complications have been reported and summarised,74 no prospective study on technical complications has been published so far. The estimated technical success rate is reported in the range of 93–100% and procedure-related mortality is very low (<1%) and mainly due to intra-abdominal bleeding.74 Technical complications comprise mispuncture of the carotid artery (2%), the hepatic artery and the bile ducts (6% each), and rupture of the liver capsule (6%).10 Clinical consequences of these technical complications are rare. Many interventional radiologists consider TIPS insertion more difficult and possibly accompanied by more complications in patients with refractory ascites. This, however, is not our experience.10 To avoid procedural problems, as much ascites as possible should be removed before TIPS. This facilitates the access to a suitable hepatic vein and improves the patient's respiratory function.

Temporary cardiac complications such as arrhythmia if the catheter enters the right atrium or right ventricle are often seen but rarely serious. In the presence of cirrhotic cardiomyopathy the haemodynamic changes upon TIPS may lead to manifest cardiac dysfunction seen in a few patients after TIPS insertion.75 Therefore an ejection fraction below 50% has been regarded as a relative and below 40% as an absolute contraindication for TIPS. Since the ejection fraction of patients with cirrhosis is usually greater than 60%76 only few patients will be precluded from TIPS. As shown recently, cardiac diastolic dysfunction may also play a role in a patient's survival after TIPS.77 In particular, a reduced E/A ratio predicted a poorer survival after TIPS.

A complication which was encountered mainly in the early 1990s is anaemia due to haemolysis. It is probably due to mechanical damage of erythrocytes when passing with a high velocity of up to 2 m/s through the wire mesh of the stent.74 The complication is now rare and limited possibly because of improved stents. This is also true for the stent migration into the right heart or lungs which is almost abandoned by the use of self-expandable nitinol stents.

As with any intravenous intervention, systemic infection or septicaemia may not be avoided completely. In the experience of the authors and based on previous studies74 antibiotics are not needed in general. They may, however, be indicated after complicated and long-lasting procedures with a great number of guide wire and catheter exchanges.

Shunt failure

Shunt insufficiency is frequent with bare stents and occurs in 50–80% during 1 year of follow-up.74 In many cases it may be due to bile duct involvement which may lead to ‘endotipsitis’ followed by intimal proliferation and thrombosis. It can be prevented by introducing covered stents and reduced by subcutaneous low molecular weight heparin for 4 weeks possibly together with trapidil and ticlopidin for 12 months.78 Our present practical approach in patients receiving bare stents is the adapted application of up to 2000 U of heparin intravenously during stent implantation followed by low molecular weight heparin subcutaneously during the index hospitalisation and a platelet aggregation inhibitor (eg, acetyl salicylic acid 100 mg/day for at least 6 months) in patients with platelet count >100 000/μl.

Shunt insufficiency does not necessarily indicate the need for shunt revision. Shunt revision is indicated in patients who fail initial response or who have recurrence of ascites. With the availability of stents covered with polytetrafluoroethylene (Goretex), long-term patency rates of 80–90% have been described.79 80

Shunt diameter, type of stent

The diameter of the shunt is crucial for effects and side effects.50 73 The decision of the individual shunt diameter ranging between 7 and 12 mm needs consideration of all aspects of the liver disease and the patient's biomedical characteristics. It should therefore be the result of a clinical judgement before the intervention. As demonstrated in patients with variceal bleeding,81 the reduction of the pressure gradient must not always reach the 12 mm Hg threshold. The same is possibly true for the treatment of ascites. As ascites formation begins within a wide range of porto-systemic pressure gradient ranging from about 12–40 mm Hg (mean of 24 mm Hg),24 the therapeutic reduction to below 12 mm Hg which is almost always efficient,73 is not always necessary.82 A smaller reduction of the gradient by about 25–50% fits better to the individual requirements and showed promising results with a 1-year response rate of 93%.82 Thus, in most patients it may be advisable to implant a 10 mm stent but dilate it to only 6–8 mm. In cases of insufficient response further dilatation can be performed.

As for the shunt diameter, the choice of the stent type is also a decision with clinical relevance which should be discussed before the intervention. In a patient with a higher risk of shunt-related complications such as age over 60 years, bilirubin around 3 mg/dl, presence of some degree of encephalopathy or with a poor prognosis, uncovered stents may be preferred because they allow spontaneous narrowing in case of worsening of liver function or HE. In contrast, patients with a low risk of complications or with Budd–Chiari syndrome may have a covered stent a priori to avoid unnecessary revisions. A randomised study including patients with varices and ascites found a better survival with the covered stent graft.83 This may, however, not apply to ascites patients who did not show a correlation between shunt failure and survival.50 In patients with Budd–Chiari syndrome covered stents can provide better results.84 85 The effects and side effects of the treatments are summarised in box 1.

Survival

Five randomised studies from France,29 Germany,58 Spain/USA,86 USA/Canada,52 and Italy87 have been published which showed poorer, similar or improved survival with TIPS (table 1). Several reasons could be identified to explain these variations including differences in technical skills, patient selection and data analysis.

Table 2 summarises three technical quality parameters of the TIPS procedure: success rate of the TIPS intervention, reduction of the portosystemic pressure gradient and rate of secondary patency. The first study published in 199629 differs considerably with respect to technical success (77%), reduction in pressure gradient (6 mm Hg), and the rate of secondary TIPS patency (46%). As demonstrated by D'Amico et al88 the technical variables correspond to the ORs for mortality suggesting that technical disability was the reason for the poor outcome of TIPS in the French study.29 Therefore, the French study should be regarded as an outlier. It should be borne in mind that this was the first study, and therefore the experience with TIPS was limited.

Second, selection of patients may have influenced the results. About 40–60% of patients screened were included in the trials with the exception of the American study52 which included only 21% of the source population.89 Selection also depends on inclusion and exclusion criteria. It can be biased due to unbalanced criteria favouring one of the two treatment arms. Thus, the use of different inclusion and exclusion thresholds for the bilirubin and creatinine concentrations may be a source of bias (table 3). Both parameters are equally important as markers for liver or kidney function. Since the TIPS may worsen liver function (but improve kidney function) and the paracentesis worsens kidney function (but has no effect on liver function) one should request similar concentrations of bilirubin and creatinine to provide equal chances for the treatment arms and to avoid a selection bias. As shown in table 3 all studies disfavoured the TIPS groups by including patients with much higher bilrubin than creatinine concentrations. The Spanish study86 allowed inclusion of patients with a bilirubin concentration as high as 10 mg/dl, which is a clear contraindication for a portosystemic shunt. On the other hand, in the American study52 inclusion and exclusion conditions selected patients with an almost normal renal function but with severe liver dysfunction, a fine condition for the paracentesis arm but a clear disadvantage for the TIPS arm.90

Third, survival analysis in all studies was performed according to the method described by Kaplan and Meier. However, studies differ in providing transplant-free survival. This is of particular importance when the time to transplantation differs between the groups. In the two studies providing the time to transplantation,52 87 TIPS patients had a much longer time to transplantation than did paracentesis patients. Unfortunately, the American study52 did not present a transplant-free survival analysis although this trial included the highest proportion of transplanted patients.

Four meta-analyses of these five studies88 91–93 have been published and are summarised in table 4. Surprisingly, they show different results although the calculations were done on an identical body of data.

The first study91 lacks sophisticated statistical evaluation and calculation of heterogeneity. The second analysis92 provides relative risks which are not identical to the commonly used ORs and thus is difficult to compare. Considering survival, heterogeneity between the studies was found but authors made no effort to investigate and eliminate its source. A meta-analysis by the Cochrane Institute93 is hampered by incorporating incorrect data of the Italian publication.87 This is why their OR for survival differs from the other meta-analyses. The best meta-analysis was performed by D'Amico.88 It identified the French study as the source of heterogeneity of survival probabilities. After eliminating this study as an outlier, heterogeneity disappeared. Actuarial rates of survival were clearly different between groups favouring TIPS (POR 0.74).

Finally, the inappropriate survival analysis in the American study52 was overcome by Salerno et al50 who analysed individual patient data. Their findings with respect to survival/mortality are summarised in table 5. After excluding the French study and analysing transplant-free survival, TIPS patients were found to live significantly longer than the patients treated with paracentesis. TIPS also improved the estimated transplant-free survival in patients with MELD scores between 10 and 20 suggesting that even patients with severe disease may benefit from TIPS. In a multivariate analysis, factors predicting mortality were older age (HR 0.61, 95% CI 0.41 to 0.91, p=0.015), high bilirubin levels (HR 1.22, 95% CI 1.029 to 1.048, p=0.022), low sodium concentration (HR 0.95, 95% CI 0.92 to 0.99, p=0.03), and TIPS (HR 0.61, 95% CI 0.41 to 0.91, p=0.015).

Treatment efficacy

A recent analysis of the literature on TIPS for refractory ascites including 16 studies showed a complete response in 51%, complete and partial response not requiring paracenteses in 68% of the patients.94 The five randomised studies discussed before29 52 58 86 87 show a mean response to TIPS in 76% of patients. As shown in the meta-analysis by Salerno50 recurrence of tense ascites occurred in 42% of patients allocated to TIPS and 89% of patients allocated to paracentesis (p<0.0001). Recurrence is mostly due to shunt insufficiency and can be effectively treated by TIPS revision. Accordingly, the average number of paracenteses-per-patient was significantly lower in patients allocated to TIPS (1.6±3.5 vs 7.1±8.8; p<0.0001) whereas allocation to paracentesis resulted in an independent association to recurrence of ascites (OR 11.67, 95% CI 6.2 to 21.9).

Vasoconstrictor therapy

Terlipressin in combination with albumin is the most widely studied pharmacological treatment for patients with type 1 HRS. Complete response occurs in approximately 40% of patients treated for a maximum of 15 days with terlipressin and albumin and is associated with improved survival.4 95

TIPS

Numerous studies in patients with refractory ascites including the five randomised studies show that TIPS improves renal function and haemodynamic variables. Even patients with cirrhosis and parenchymal kidney disease may benefit from TIPS.35 Many patients with HRS type 1, however, suffer from advanced hepatocellular insufficiency with serum bilirubin exceeding 5 mg/dl, a clear contraindication for TIPS. However, mortality after liver transplantation is higher in patients transplanted with HRS than in those without HRS.96This may argue in favour for TIPS in transplantation candidates. A recent study confirms this contention.97 It showed that TIPS improves post-transplant graft and patient survival significantly possibly due to an improved pre-transplant renal function and portal blood supply of the graft.

Only a few studies have assessed the role of TIPS for the treatment of HRS in a total of 61 patients.33 36 38 98 Brensing et al36 treated 31 non-transplantable patients (14 type 1 and 17 type 2) and found that renal function improved following TIPS. One- and 2-year survival rates were 20% for type 1 and 70% and 45%, respectively, for type 2 HRS. However, due to a bilirubin cut-off of 10 mg/dl, nine patients had to be excluded from TIPS. Liver failure was one of the most frequent causes of death following TIPS. Guevara et al33 reported on seven patients with type 1 HRS showing a significant improvement in serum creatinine, blood urea nitrogen, glomerular filtration rate and renal plasma flow by TIPS. Three patients survived by more than 3 months. As shown by Wong et al98 TIPS may also have a role in maintaining patients who initially respond to vasoconstrictor treatment. Fourteen patients with type 1 HRS were treated using a combination of midodrine, octreotide and albumin. Medical therapy for 14 days improved renal function in 10/14 patients with mean serum creatinine significantly decreasing from 233 μmol/l to 112 μmol/l. Five responders were then treated with TIPS and showed further improvement in renal function (mean glomerular filtration rate: 96±20 ml/min at 12 months). Testino et al38 reported the effects of TIPS in 18 patients with type 2 HRS and a Child–Pugh score of 10–12 awaiting transplantation. All patients improved with respect to ascites and renal function.

These beneficial effects of TIPS on renal function are difficult to reconcile with the findings by Malinchoc et al99 who observed a (negative) correlation between the creatinine concentration before TIPS and survival after TIPS, a fact which was well recognised in the MELD scoring system. Accordingly, an elevated creatinine concentration should be a negative predictive factor for the survival after TIPS. However, numerous studies24 58 including the meta-analysis by Salerno,50 failed to show a correlation between the pre-TIPS creatinine concentration and post-TIPS survival. The positive effect of TIPS on renal function explains that the MELD score underestimates survival following TIPS for refractory ascites.100

In summary, TIPS can improve renal function in type 1 and 2 HRS and eliminate ascites. However, the data are limited and survival may not be improved in patients with poor liver function. Thus, TIPS is indicated in selected patients with HRS and/or in candidates for liver transplantation.