- Email: [email protected]
Treatment of patients with cirrhosis and refractory ascites using LeVeen shunt with titanium tip: Comparison with therapeutic paracentesis
Treatment of Patients With Cirrhosis and Refractory Ascites Using LeVeen Shunt With Titanium Tip" Comparison With Therapeutic Paracentesis ANGELS GINES,1 RAMON PLANAS,2 PAOLO ANGELI,3 CARLOS GUARNER,4 FRANCESCO SALERNO,5 PERE GINES,1 JOAN SALO,1 NIVARDO RODRIGUEZ,2 EUGENI DOMI~NECH,2 GERM~3q SORIANO,4 LUIS ANIBARRO,~ MIGUEL ANGEL GASSULL,2 ANGELO GATTA,3 VICENTE ARROYO,1AND JUAN ROD]~S1
the m a n a g e m e n t of cirrhotic patients with refractory ascites. (HEPATOLOGY1995;22:124-131.)
It has recently b e e n suggested that insertion of a titan i u m tip at the v e n o u s e n d of the LeVeen shunt drastically reduces the rate of shunt obstruction. To assess w h e t h e r the LeVeen shunt w i t h titanium tip i m p r o v e s the results obtained w i t h therapeutic paracentesis, 81 patients with cirrhosis and refractory ascites w e r e rand o m l y assigned to therapy with paracentesis plus intrav e n o u s albumin (42 patients) or LeVeen shunt with titan i u m tip (39 patients). If patients w e r e readmitted for ascites during follow-up, those in the first group w e r e treated with paracentesis, and those in the LeVeen shunt group by the insertion of a n e w valve or a n e w shunt if obstruction was demonstrated. During first hospitalization, both treatments w e r e equally effective in r e m o v i n g ascites. Complications w e r e similar in both groups except for a higher rate of severe bacterial infection in the LeVeen shunt group. The m e a n duration of hospitalization w a s shorter in the paracentesis group than in the shunt group. During follow-up, the total number of readmissions and the n u m b e r of readmissions for ascites w e r e higher in the paracentesis group than in the shunt group (252 vs. 99, P < .001; and 193 vs. 43, P < .001, respectively). The total time in hospital, h o w e v e r , was similar (38 + 38 vs. 39 -+ 43 days, P = NS). Three patients had obstruction of the shunt during first hospitalization and 14 patients had a total'~of 22 obstructions during follow-up. Long-term survival was similar in b o t h groups. The insertion of a titanium tip at the v e n o u s end of the LeVeen shunt does not prevent obstruction. The LeVeen shunt with titanium tip does not provide significant i m p r o v e m e n t o v e r therapeutic paracentesis in
From the ~Liver Unit, Department of Medicine, Hospital Clinic i Provincial, Barcelona, the 2Gastroenterology Unit, Hospital Germans Trias i Pujol, Badalona, 8Istituto di Medicina Clinica, Padova, the 4Liver Unit, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain, and 5Istituto di Medicina Interna, Milano, Italy. Received July 2, 1994; accepted February 17, 1995. Supported by grants from Fondo de Investigaciones Sanitarias de la Seguridad Social (FISS 93/0610) and DirecciSn General de InvestigaciSn Cientifica y T~cnica (DGICYT PM 91-0216). A. Gin,s and J. Sal5 were granted by FISS (91/5549 and 93/0610, respectively). Address reprint requests to: Vicente Arroyo, MD, Liver Unit, Hospital Clinic i Provincial, Villarroel, 170, 08036 Barcelona, Spain. Copyright © 1995 by the American Association for the Study of Liver Diseases. 0270-9139/95/2201-001953.00/0
A recent randomized controlled trial I showed t h a t peritoneovenous shunting with the LeVeen prosthesis is more effective t h a n therapeutic paracentesis associated with intravenous albumin infusion for the treatment of refractory ascites in cirrhosis because it markedly reduces the time to recurrence of tense ascites, number of readmissions for ascites, and diuretic requirements. These beneficial effects, however, did not result in significant improvement in the long-term m a n a g e m e n t of the patients or in reduction in the total time spent in hospital during follow-up because of a very high rate of shunt obstruction requiring reoperation, which approached 40% during the first postoperative year. Such a high incidence of s h u n t obstruction has also been reported by other investigators. 2 The probability of survival Was identical in the two therapeutic groups. 1 Based on this trial, therapeutic paracentesis has been proposed as an alternative t r e a t m e n t to peritoneovenous shunting for the m a n a g e m e n t of refractory ascites in cirrhosis. Recently, data have been presented suggesting t h a t the insertion of a 3-cm-long t i t a n i u m tip into the venous end of the LeVeen shunt prevents thrombotic obstruction of the venous limb of the prosthesis and the development of superior vena cava thrombosis. 3'4 Using this approach, Hillaire et al 5 have reported a cumulative rate of shunt obstruction of 6% at 1 year and 12% at 2 years in 56 patients with cirrhosis and refractory ascites. The beneficial effects of this specifically designed t i t a n i u m tip on s h u n t patency is attributed to the thromboresistant properties of t i t a n i u m and to the shape of the tip, providing gradual, streamlined-flow convergence of ascites and blood-limiting endothelial damage and mural thrombus formation in the superior vena cava. These studies prompted us to assess whether this modified approach of peritoneovenous shunting improves the results obtained with therapeutic paracentesis in the m a n a g e m e n t of cirrhotic patients with refractory ascites. The current article reports the results of a multicenter randomized
124
HEPATOLOGYVol. 22, No. 1, 1995
GIN]~S ET AL 125
controlled trial a i m e d at c o m p a r i n g L e V e e n s h u n t w i t h t i t a n i u m tip v e r s u s total t h e r a p e u t i c p a r a c e n t e s i s plus i n t r a v e n o u s a l b u m i n in t h e s e patients. MATERIALS A N D METHODS The study was approved by the Investigation and Ethics Committee of each hospital participating in the trial and all patients gave informed consent. Eighty-one patients with cirrhosis admitted to five hospitals for the treatment of refractory ascites were included. The number of patients studied at the various hospitals ranged from 12 (at the Istituto di Medicina Interna, Milano) to 22 (at the Hospital Germans Trias i Pujol, Badalona). All these hospitals have a high degree of expertise in the management of patients with ascites and have been involved in several multicenter therapeutic trials in these p a t i e n t s Y 1° The diagnosis of cirrhosis was based on liver histology in 65 patients and on the following clinical and laboratory findings in 16 cases: signs of chronic liver disease, prolonged prothrombin time, hypoalbuminemia, hypergammaglobulinemia, ultrasonographic findings compatible with the diagnosis of cirrhosis, and esophageal varices on endoscopy. The cause of cirrhosis was alcohol related in 41 patients, associated with hepatitis C antibodies in 24, associated with hepatitis B surface antigen in 8, cryptogenic in 7, and hemochromatotic in 1. Patients meeting one of the two following criteria were considered to have refractory ascites: (1) no response, defined as loss of body weight less than 200 g per day together with urinary sodium excretion less than 50 mEq/day, to a restriction of sodium intake (<50 mEq/day), and to maximal doses of diuretic therapy for 5 days during hospitalization in which the dosage of diuretic agents was increased stepwise every 5 days from 40 to 120 mg furosemide per day and from 100 to 300 mg spirono]actone per day; or (2) three or more episodes of tense ascites requiring hospitalization within a 9-month period before the inclusion in the study, despite adequate diuretic treatment and sodium restriction. Patients meeting the second criterion were entered in the trial without assessment of response to diuretic treatment in the hospital. Patients with hepatocellular carcinoma, cardiac, respiratory, or renal disease, serum bilirubin > 10 mg/dL, prothrombin time <40%, platelet count <40 × 109/L, or serum creatinine >3 mg/dL were not included in the trial. Patients with spontaneous bacterial peritonitis, gastrointestinal hemorrhage, or hepatic encephalopathy were considered as candidates for the trial after they had recovered from these complications. Patients were studied after 5 days on a 50 mEq sodium diet without diuretics. On the sixth day, 24-hour urine volume was carefully collected to measure urinary sodium excretion. Blood samples were taken on the morning of the seventh day to measure standard liver and renal function tests. Patients were then randomly assigned to two groups with the use of sealed envelopes. One group consisted of 42 patients who were treated with total paracentesis (complete mobilization of the ascitic fluid in only one session) associated with intravenous albumin infusion (8 g/L ascitic fluid removed) administered during and immediately after the procedure. The second group consisted of 39 patients who were treated with LeVeen peritoneovenous shunt with a titanium tip inserted at the venous end of the prosthesis. Randomization was independent in each hospital. To ensure homogeneous distribution into the two therapeutic groups, patients were randomized separately according to the criterion used to define refractory ascites. Insertion of the LeVeen shunt (Becton Dickinson, Fairfield, NJ) was performed as previously de-
FIG. 1. LeVeenshunt with the titanium tip. scribed. 11 Most ascitic fluid was removed during the operation, before the insertion of the shunt. The correct placement of the venous tip (the superior vena cava just before the atrium) was checked roentgenographically in the operating room. Prophylactic cloxacillin (1 g immediately before surgery and 1 g every 6 hours during 2 days after the operation) was given to all patients. This prophylactic antibiotic regimen was also administered whenever a patient with LeVeen shunt required invasive maneuvers. The titanium tip 3-~ was supplied by France M~dical Conseil (Saint Germain en Laye, France) and consists of a cylinder of 1.4 g in weight and 30 mm in length, which comprises two parts: the neck (12-mm length), which is inserted within the venous catheter of the LeVeen prosthesis, and the main part (18-mm length) (Fig. 1). The external diameter of the main part (5.7 mm) terminares with an apex whose wall becomes thinner toward its end in such a way that the internal and external surfaces join together at an annular edge with a thin, smooth, rounded profile. At the opposite end of the apex, the neck terminates in a collar with a slightly larger diameter. Before the insertion into the venous end of the LeVeen shunt, the neck of the titanium tip was covered with a thin layer of sterilized adhesive (080118; Medtronic, Minneapolis, MN). Special care was taken to ensure that the external surface of the main part of the tip and the external surface of the venous catheter were aligned. Total paracentesis was performed as described elsewhere.12 Diuretics were started immediately after treatment in both groups. Patients in the paracentesis group were given furosemide (80 mg/day) and spironolactone (200 mg/day), and those in the peritoneovenous shunt group received furosemide (80 rag/day) intravenously for 2 days and furosemide (80 mg/ day) and spironolactone (200 mg/day) orally thereafter. The dosage of diuretics was subsequently adjusted according to individual response. Patients in the paracentesis group were discharged 3 days after the mobilization of ascites, and those in the peritoneovenous shunt group 5 days after operation, unless continued hospitalization was required for diagnostic or therapeutic purposes. When needed, patients in the paracentesis group requiring long hospitalizations were treated by a second therapeutic paracentesis. Standard liver and renal function tests were performed 2 to 7 days after treatment in all patients. The duration of first hospitalization was calculated from the day of entry into the study. The follow-up period started at the end of the first hospitalization. Patients were controlled in the outpatient clinic weekly for 1 month, monthly for the next 2 months, and bimonthly thereafter. Patients of the paracentesis group developing tense ascites during follow-up were treated by total paracentesis plus intravenous albumin infusion. In patients of the LeVeen shunt group developing tense ascites during follow-up, the patency of the shunt was checked by Doppler u]trasonography. When the shunt was obstructed, a shuntogram was performed after the injection of contrast medium into the proximal subcutaneous limb of the shunt to identify the site of obstruction. Venacavography by digital angiogra-
126
GIN]~S ET AL
HEPATOLOGYJuly 1995
phy was performed in patients with obstruction at the venous limb of the shunt to rule out thrombosis of the superior vena cava. Patients without shunt obstruction were treated with diuretics, those with occlusion of the valve by replacement of only the valve and the intraperitoneal tubing, and those with occlusion of the venous segment of the shunt by replacement of the entire shunt with the titanium tip. In patients developing superior vena cava thrombosis, the shunt was removed. Because patients recovering from this complication are at great risk of developing recurrent superior vena cava thrombosis after reinsertion of the prosthesis, 13 they were subsequently treated with diuretics and, when necessary, paracentesis. Renal impairment was defined as an increase in serum creatinine concentration of more than 50% from the pretreatment value, to a level greater than 1.5 mg/dL. Hyponatremia during first hospitalization was defined as a decrease in the serum sodium concentration greater than 5 mEq/L, to a level below 130 mEq/L. Patients with serum sodium concentration below 130 mEq/L before treatment with decreases of more than 5 mEq/L in this parameter were also included among the patients in whom hyponatremia developed. Follow-up readmissions to the hospital were grouped according to five causes: ascites, hepatic encephalopathy, severe bacterial infections, gastrointestinal hemorrhage, and other complications. When two of these causes were present, the following criteria were arbitrarily used to define the cause of readmission: (1) when tense ascites was associated with gastrointestinal hemorrhage, severe bacterial infection, grades 2 to 4 hepatic encephalopathy, or some other complication requiring emergency treatment, the associated condition was considered to be the cause ofreadmission; (2) when tense ascites was associated with grade 1 hepatic encephalopathy or another condition not requiring emergency treatment, ascites was considered to be the cause; (3) when hepatic encephalopathy was associated with severe bacterial infection or gastrointestinal bleeding it was considered to be secondary; and (4) when patients had gastrointestinal bleeding and bacterial infection, hemorrhage was considered to be the cause of readmission. These criteria were also used to define the cause of readmission in the few cases who had three complications at entry into the hospital. Statistical analysis of the results was performed using the BMDP statistical package. 14 Categorical data were compared by the X2 test or by Fisher's exact test when the number in a cell was 5 or less. Continuous data were compared using paired and unpaired Student's t-tests and the nonparametric test of Mann-Whitney. Probability curves were constructed by the Kaplan-Meier method and compared with the MantelCox test. The results are presented as mean _+SD. Statistical significance was considered when the P value was .05 or less. RESULTS
Characteristics of the Patients at Entry Into the Trial. B y chance, t h e age of t h e p a t i e n t s t r e a t e d w i t h p a r a c e n t e s i s was slightly h i g h e r t h a n t h a t of p a t i e n t s t r e a t e d w i t h L e V e e n s h u n t (P < .02). However, t h e r e were no significant differences b e t w e e n g r o u p s in a n y of t h e r e m a i n i n g clinical d a t a c o n s i d e r e d or in s t a n d a r d liver a n d r e n a l f u n c t i o n tests, C h i l d - P u g h score, 1~ a n d m e a n a r t e r i a l p r e s s u r e (Table 1). B o t h t h e r a p e u t i c g r o u p s were also similar w i t h r e s p e c t to the n u m b e r of p a t i e n t s w i t h previous episodes of ascites (42 a n d 38 p a t i e n t s , respectively), h e p a t i c e n c e p h a l o p a t h y (16 a n d
TABLE 1. B a s e l i n e C l i n i c a l a n d L a b o r a t o r y D a t a i n t h e T w o Groups of Patients With Cirrhosis and Refractory Ascites
Age Sex (M/F) No. with alcohol-induced cirrhosis No. with peripheral edema No. with renal failure* Serum bilirubin (mg/dL) Prothrombin time (%) Serum albumin (g/L) Serum creatinine (mg/dL) Serum sodium (mEq/L) Urinary sodium (mEq/day) Mean arterial pressure (mm Hg) Child-Pugh scorer
Paracentesis (n = 42)
Leveen Shunt (n = 39)
P
63 (37-80) 20/22
58 (37-69) 25/14
.02 NS
19
22
NS
21 21 2.0 _+ 1.5 58 _+ 16 31.8 _+ 5
24 17 1.9 _+ 1 59 _+ 12 31.6 _+ 5
NS NS NS NS NS
1.3 _+0.6 132 _+ 6
1.3 _+0.6 132 _+ 5
NS NS
4 _+ 5
3 _+ 2
NS
82 _+ 13 9 _+ 1
84 _+ 10 9 _+ 1
NS NS
Abbreviation: NS: P > .05. * Renal failure was defined as serum creatinine concentration >1.5 mg/dL. t The Child-Pugh score (range, 5 to 15) was calculated on the basis of the presence and degree of hepatic encephalopathy, the presence and degree of ascites, serum bilirubin concentration, serum albumin concentration, and prothrombin time. 1°
12), g a s t r o i n t e s t i n a l bleeding (18 a n d 11), a n d severe bacterial infections (14 a n d 9). The n u m b e r of p a t i e n t s included in the trial b e c a u s e of lack of r e s p o n s e to maxim a l diuretic t h e r a p y d u r i n g h o s p i t a l i z a t i o n (criterion 1, 16 in the p a r a c e n t e s i s g r o u p a n d 18 in t h e L e V e e n s h u n t group) a n d r e c i d i v a n t ascites before a d m i s s i o n (criterion 2, 26 a n d 21 patients, respectively) was comp a r a b l e in t h e two groups.
Effectiveness, Complications, Shunt Obstruction, and Mortality During First Hospitalization. T h e r a peutic p a r a c e n t e s i s a n d p e r i t o n e o v e n o u s s h u n t i n g were e q u a l l y effective in relieving ascites. A m o n g 42 p a t i e n t s included in the p a r a c e n t e s i s group, 40 were d i s c h a r g e d from h o s p i t a l w i t h m i n i m a l or no ascites. I n one p a t i e n t ascites w a s u n c o m p l e t e l y mobilized bec a u s e of i n t r a a b d o m i n a l c o m p a r t m e n t a l i z a t i o n of ascitic fluid. The p a t i e n t was d i s c h a r g e d from hospital w i t h diuretic t h e r a p y . The r e m a i n i n g p a t i e n t died in h o s p i t a l of liver failure a n d progressive r e n a l failure. I n the L e V e e n s h u n t g r o u p 34 p a t i e n t s of t h e 39 were d i s c h a r g e d w i t h m i n i m a l or no ascites. One of t h e s e 34 p a t i e n t s h a d to be r e o p e r a t e d on d u r i n g t h e first h o s p i t a l i z a t i o n b e c a u s e of s h u n t o b s t r u c t i o n located in the valve. I n a second p a t i e n t in w h o m s h u n t obstruction developed a t the v e n o u s end of t h e prosthesis, obs t r u c t i o n w a s resolved a f t e r t h e injection of c o n t r a s t m e d i a d u r i n g s h u n t o g r a p h y . Two p a t i e n t s were disc h a r g e d w i t h m o d e r a t e ascites despite s h u n t p e r m e ability. The r e m a i n i n g t h r e e p a t i e n t s died d u r i n g
HEPATOLOGY Vol. 22, No. 1, 1995
GIN]~S ET AL
127
TABLE 2. T e s t s o f L i v e r a n d R e n a l F u n c t i o n a n d M e a n A r t e r i a l P r e s s u r e B e f o r e a n d A f t e r T r e a t m e n t i n t h e T w o G r o u p s Paracentesis (n = 42) Before
Serum bilirubin (mg/dL) Serum albumin (g/L) Prothrombin time (%) Serum creatinine (mg/dL) Serum sodium (mEq/L) Mean arterial pressure (mm Hg)
2.0 31.8 58 1.3 132 82
-- 1.5 _+ 5 _+ 16 +_ 0.6 + 6 _+ 13
After 2.0 33.5 60 1.4 131 80
_+ 1.5 _+ 5 _+ 14 _+ 0.6 _+ 6 _+ 14
LeVeen Shunt (n = 38*)
P Value NS .01 NS NS NS NS
Before
1.9 31.6 59 1.3 132 84
_+ 1 _+ 5 _+ 12 _+ 0.6 _+ 5 +_ 10
After
2.0 30.4 54 1.3 134 79
_+ 1.4 _+ 5 _+ 15 _+ 0.7 _+ 4 _+ 11
P Value
NS NS .007 NS NS 0.02
Abbreviation: NS: P > .05. * One patient in this group died 4 days after insertion of the s h u n t and is not included.
hospitalization, with severe bacterial infection (pneumonia and sepsis) being the cause of death in two. The third case developed acute superior vena cava thrombosis and superior vena cava syndrome and died despite removal of the shunt and thrombolitic treatment. The volume of ascitic fluid removed, as estimated by the loss of body weight during hospitalization in the survivors, was comparable in the two groups (9.8 _+ 3.2 kg in the paracentesis group and 10.2 _+ 4.5 kg in the LeVeen shunt group). The mean duration of the first hospitalization was 11.6 _+ 10.3 days in the paracentesis group and 29.1 _+ 15.2 days in the LeVeen shunt group (P < .001). Table 2 shows the standard liver and renal function tests and mean arterial pressure before and after treatment in the two groups. Serum albumin concentration increased significantly in patients treated by paracentesis. Patients treated by LeVeen shunt had a significant decrease in prothrombin time and mean arterial pressure. There was no significant change in any of the remaining parameters evaluated. Complications during first hospital stay are shown in Table 3. Eleven (26%) patients in the paracentesis TABLE 3. C o m p l i c a t i o n s D u r i n g t h e F i r s t H o s p i t a l S t a y i n the Two Groups Paracentesis (n = 42)
LeVeen Shunt (n = 39)
Patients (%)
Patients with complications Encephalopathy Gastrointestinal bleeding Renal impairment Severe bacterial infection Hyponatremia Severe abdominal pain Symptomatic disseminated intravascular coagulation Superior vena cava thrombosis
P Value
11 (26) 4 (9)
15 (38) 3 (8)
NS NS
2 (5) 5 (12)
2 (5) 4 (10)
NS NS
2 (5) 2 (5)
9 (23) 1 (3)
.01 NS
0
3 (8)
NS
0
3 (8)
NS
0
1 (3)
NS
group, and 15 (38%) in the LeVeen shunt group developed a total of 15 and 26 complications, respectively, during first hospitalization. In both groups, complications were equally distributed among the five participating hospitals. Severe bacterial infections occurred with a significantly higher frequency in the LeVeen group than in the paracentesis group. Nine patients in this group developed severe bacterial infections (bacterial peritonitis in 3, pneumonia in 3, sepsis in 2, and bacterial peritonitis plus pneumonia in 1) as compared with two patients in the paracentesis group (spontaneous bacterial peritonitis and cellulitis). The remaining complications (hepatic encephalopathy, gastrointestinal hemorrhage, renal impairment, and hyponatremia) occurred with a similar frequency in both groups. Seven patients in the LeVeen shunt group had complications related with the prosthesis (symptomatic disseminated intravascular coagulation in three, severe abdominal pain in three, and superior vena cava thrombosis causing superior vena cava syndrome in one). As indicated above, one patient in the paracentesis group and three in the LeVeen shunt group died during first hospitalization. Effectiveness and Complications During Followu p . Of the 77 cases surviving first hospitalization only i from the paracentesis group was lost to follow-up 7 months after discharge from hospital. The mean followup period was 287 _+ 213 days in the paracentesis group and 336 _+ 248 days in the LeVeen shunt group. Of the 38 patients with alcohoMnduced cirrhosis discharged from hospital (19 in the paracentesis group and 19 in the LeVeen shunt group), 14 (8 in the paracentesis group and 6 in the LeVeen shunt group) continued drinking alcohol during follow-up. Thirty-seven of the 41 patients discharged from hospital in the paracentesis group and 28 of the 36 patients discharged from hospital in the LeVeen shunt group required one or more readmissions to the hospital during follow-up. Twenty-nine (71%) patients treated with paracentesis and 15 (42%) treated with LeVeen shunt were readmitted for ascites at least once during followup (P = .02). Other major reasons for readmission were encephatopathy, bacterial infection, and gastrointestinal hemorrhage, which were responsible for readmission in 22%, 22%, and 22% of the patients in the paracentesis group and 17%, 28%, and 11% of the patients
128
HEPATOLOGYJuly 1995
GINI~S ET AL
TABLE 4. Read_missions to H o s p i t a l D u r i n g F o l l o w - u p i n t h e Two Groups Paracentesis (n = 41)
Number of readmissions Cause Ascites Encephalopathy Bacterial infection Gastrointestinal bleeding Other
! r . . . . . . .
Leveen Shunt (n = 36)
252*
0.8
t I-
>-
99
193" 17 9 8 25
PARACENTESIS
1.0I
,
,
J
0.6 < CO O 0.4 EC fl-
43 13 12 6 25
-
.'
'
LEVEEN SHUNT
r~
/
p=0.01
0.2
*P < .0Ol for the comparison with the peritoneovenous shunt group.
0.0 0
in the LeVeen s h u n t group, respectively. Of the four cases not requiring readmission in the paracentesis group, three were alive and well at the time of analysis of the results after a follow-up period of 240, 300, and 810 days, respectively. The fourth case died at home of liver failure 1 month after discharge. Of the eight patients not requiring readmission in the LeVeen s h u n t group, six were alive and well after a mean follow-up period of 535 +_ 150 days (range, 391 to 749 days). The remaining two cases died at home 150 and 272 days after discharge because of gastrointestinal hemorrhage and cerebral hemorrhage, respectively. The number and causes ofreadmissions to the hospital during follow-up are shown in Table 4. Overall, there were 252 readmissions in patients of the paracentesis group and 99 in patients of the LeVeen shunt group (P < .001). Readmission was caused by a single complication on 245 occasions in the paracentesis group and 85 in the LeVeen shunt group. The higher frequency of hospitalization during follow-up in the paracentesis group was attributable exclusively to a higher number ofreadmissions for ascites. The number of readmissions for other causes were comparable in
1.0
0
o.4-
the two groups. Figure 2 shows t h a t the time to first readmission for ascites during follow-up was significantly shorter in the paracentesis group t h a n in the LeVeen shunt group (median time: 2 _+ 6.4 and 11.9 _+ 12 months, P < .001, respectively). The differences were less pronounced when the time to first readmission for any complication was considered (1.2 _+ 1.9 vs. 3.7 _+ 6 months, P = .01, respectively) (Fig. 3). The mean need for diuretics during follow-up was significantly higher (P < .001) in the paracentesis group (furosemide 75 _+ 53 mg/day; spironolactone 233 _ 99 mg/day) t h a n in the LeVeen shunt group (34 _+ 36 mg/day and 133 _+ 92 mg/day, respectively). Figure 4 shows t h a t the probability of developing renal impairment during follow-up was similar in the two groups. Despite the significantly higher frequency of readmissions in the paracentesis group, the total time spent
0.8
I
>-
IJ
;
r ! I
t
LEVEEN SHUNT
P
!
0_
.J
[
p=0.001
i
_/
0.2-
PARACENTESIS
0.6
< m 0.4 0 rr 13.. 0.2
oo : C 0
12
18
24 MONTHS
FIG. 2. Probabilityof readmission to the hospital during followup for ascites in patients in the two study groups,
........ I
I . . . . . . . . . -
j,
0.0 6
24
F~G.3. Probabilityof readmission to the hospital during followup for any complicationin patients in the two study groups.
I I
_1
0.6
18
1.0
>J co <
12
MONTHS
PARACENTESIS
0.8
6
0
,~--I
'
I
LEVEEN SHUNT
S
i
i
i
i
6
12
18
24 MONTHS
FIG. 4. Probability of developing renal impairment after entry into the study in the two study groups.
GINES ET AL 129
HEPATOLOGYVol. 22, No. 1, 1995 TABLE 5. Mean Time i n H o s p i t a l D u r i n g F o l l o w - u p i n t h e Two G r o u p s Paracentesis (n = 41) (number
Duration of follow-up Time in hospital Total For ascites For other reasons Mean duration hospital admissions Total For ascites For other reasons
LeVeen Shunt (n = 36)
287 _+ 213
336 _+ 248
38 + 38 16 _+26 22 _+27
39 + 43 14 _+ 25 25 +_ 34
_n
m ,<
-
0.6
I
LEVEEN SHUNT
! I
-
--
-
',
0.4 0 rr Q..
I L --I
PARACENTESIS
0.2
6 _+ 7 3 _+4 15 _+ 10
16 _+ 13" 13 +_ 11" 17 _+ 15
1.00.8-
0.6m <
H rr-r-_
0.2-
I ',. . . . . . . . . . . . . . . . .
!
0.0 6
12
18
0.0 0
6
12
18
24 MONTHS
in hospital d u r i n g follow-up a n d the t i m e s p e n t for the t r e a t m e n t of ascites or o t h e r complications was similar in t h e two groups (Table 5). This was b e c a u s e of t h e significantly lower m e a n d u r a t i o n of hospital stays during follow-up in t h e p a r a c e n t e s i s group, p a r t i c u l a r l y w h e n ascites was t h e cause of r e a d m i s s i o n (Table 5). T h e total t i m e s p e n t in hospital a f t e r e n t r y into t h e s t u d y (first h o s p i t a l i z a t i o n a n d follow-up) was lower in the p a r a c e n t e s i s group (50 _+ 37 days) t h a n in t h e L e V e e n s h u n t group (68 _+ 46 days) (P = .05). Shunt Obstruction During Follow-up. Of the 43 readmissions for ascites in t h e L e V e e n s h u n t group, t h e s h u n t was o b s t r u c t e d in 22 r e a d m i s s i o n s in 14 p a t i e n t s . In the r e m a i n i n g 21 r e a d m i s s i o n s for ascites, the s h u n t was p a t e n t , a n d t h e cause of ascites was r e l a t e d to e i t h e r a b a n d o n m e n t of t r e a t m e n t , i m p a i r m e n t of r e n a l function, or was u n k n o w n . In p a t i e n t s w i t h o b s t r u c t e d shunts, t h e site of o b s t r u c t i o n was t h e valve in 14 readmissions a n d t h e v e n o u s t u b e in 6. In two r e a d m i s s i o n s
0
1 I
0.8
of days)
* P < .001 for the comparison with the paracentesis group.
0 0.4n.," fl.
1.0
24 MONTHS
FIG. 5. Global probability of shunt obstruction due to clotting at the valve or at the venous end (continuous line) and probability of shunt obstruction due to clotting at the venous end (dotted line).
FIG. 6. Probability of survival after entry into the study in the two groups.
s h u n t obstruction occurred in the setting of a superior v e n a cava t h r o m b o s i s with p a r t i a l occlusion of the superior v e n a cava. T h e s h u n t was replaced on seven occasions in six patients. In one p a t i e n t s h u n t obstruction was resolved on two occasions a f t e r t h e injection of the c o n t r a s t m e d i a d u r i n g s h u n t o g r a p h y . In the rem a i n i n g 13 readmissions, the L e V e e n s h u n t was not replaced because t h e p a t i e n t was t e r m i n a l l y ill (five patients), r e s p o n d e d to diuretic t h e r a p y (two patients), rejected the i n s e r t i o n of a n e w p r o s t h e s i s (four patients), or because the cause of the obstruction was s u p e r i o r v e n a cava t h r o m b o s i s (two patients). In two o t h e r p a t i e n t s , t h e s h u n t was r e m o v e d d u r i n g followu p because of s p o n t a n e o u s b a c t e r i a l peritonitis. Obs t r u c t i o n s of t h e s h u n t occurred w i t h a similar freq u e n c y in the different centers involved in the study. F i g u r e 5 shows t h e global probability of s h u n t obstruction, including all cases w i t h obstruction located e i t h e r a t the valve or a t the v e n o u s end, a n d t h a t c a u s e d by clotting a t the v e n o u s end. The 1- a n d 2-year probabilities of obstruction w e r e 43% a n d 60% a n d 19% a n d 26%, respectively. Because the p a t e n c y of the s h u n t was only checked in p a t i e n t s developing ascites d u r i n g follow-up, t h e s e figures m a y u n d e r e s t i m a t e the actual risk of obstruction of t h e L e V e e n s h u n t . Mortality During Follow-up. T w e n t y - t h r e e p a t i e n t s in the p a r a c e n t e s i s group (56%) a n d 17 in the L e V e e n s h u n t group (47%) died d u r i n g follow-up. As w i t h complications, m o r t a l i t y in b o t h groups was equally distribu t e d a m o n g the different hospitals p a r t i c i p a t i n g in the study. T h e cause of d e a t h was liver failure in 12 pat i e n t s in the p a r a c e n t e s i s group a n d in 9 in t h e L e V e e n s h u n t group; g a s t r o i n t e s t i n a l h e m o r r h a g e in 4 a n d 2 patients, respectively; bacterial infection in 4 a n d 5 p a t i e n t s , respectively; a n d a n o t h e r cause in 3 a n d 1 p a t i e n t s , respectively. F i g u r e 6 shows t h a t t h e r e was no significant difference in t h e probability of survival a f t e r e n t r y into the s t u d y b e t w e e n the two groups.
130 GINES ET AL
HEPATOLOGYJuly 1995 DISCUSSION
The design of the current trial was identical to that of a previous investigation comparing therapeutic paracentesis versus LeVeen shunt in patients with refractory ascites, 1 with two exceptions. First, in the current study patients included in the paracentesis group were treated by total paracentesis, whereas in the previous trial they were treated by repeated large-volume paracentesis. Total paracentesis associated with intravenous albumin infusion has been shown to be as safe as repeated large-volume paracentesis plus albumin infusion in the treatment of tense ascites in cirrhosis because it is not associated with significant changes in renal and hepatic function and effective circulating blood volume, as estimated by the plasma levels of renin and aldosterone. 12 Second, in the current trial a titanium tip was inserted at the venous end of the LeVeen shunt. The decision to compare LeVeen shunt with titanium tip versus therapeutic paracentesis was based on several features: first, patients with refractory ascites and relatively preserved hepatic and renal function are very infrequent; therefore, a trial with three arms (therapeutic paracentesis and LeVeen shunt with and without titanium tip) is difficult to organize. Second, the inclusion criteria, surgical technique to insert the LeVeen prosthesis and methodology to assess shunt patency in this trial are identical to those in the previous trial; 1 therefore, the effect of the titanium tip on shunt obstruction and superior vena cava thrombosis can be inferred by comparing the results of the two studies. Finally, a trial comparing LeVeen shunt plus titanium tip and total paracentesis can provide important information concerning the management of refractory ascites because it deals with the two most widely used treatments for this complication. 16 The main result of the current trial is that peritoneovenous shunting with the LeVeen prosthesis modifled by the insertion of a titanium tip at the venous end of the shunt is associated with a high rate of shunt obstruction. The 1- and 2-year probabilities of shunt obstruction observed (43% and 60%, respectively) are similar to those observed in the previous trial comparing LeVeen shunt without titanium tip with therapeutic paracentesis (40% and 52%, respectively). 1 These data are not consistent with the suggestion that the insertion of a titanium tip at the venous end of the LeVeen shunt decreases the rate of shunt obstruction. 3-5 In the previous trial 60% of obstructions occurred in the valve, 20% in the venous tube, and 20% were secondary to superior vena cava thrombosis. ~ The corresponding figures in the current study are 60%, 28%, and 12%, respectively. Because the titanium tip does not affect the deposition of fibrin and cell debris in the valve, and, in our experience, the valve is the main site of shunt obstruction, the lack of effect of the titanium tip on shunt patency is not surprising. Moreover, our results also indicate that the titanium tip prevents neither thrombotic obstruction of the venous
limb of the prosthesis nor superior vena cava thrombosis. In fact, the 1- and two-year probabilities of obstruction attributable to clotting at the venous end of the shunt in the current study (19% and 26%, respectively) are very similar to the figures observed in the previous study without the titanium tip (17% and 28%, respectively). The results of the current study confirm that peritoneovenous shunting is more effective than therapeutic paracentesis in the treatment of refractory ascites in cirrhosis because it markedly increased the time to first readmission for ascites, decreased the number of readmissions for ascites, and lowered diuretic requirements. However, as in the previous trial, these beneficial effects did not result in a reduction of total hospital stay. The duration of first hospitalization was almost three times longer in the peritoneovenous shunt group than in the paracentesis group. This was in part related to the higher incidence of bacterial infections requiring intensive antibiotic treatment in the former group of patients. Conversely, although the number of readmissions during follow-up was 1.5-fold higher in patients treated by paracentesis, the mean duration of readmissions in this group was 1.5-fold shorter; thus, the time spent in hospital during follow-up by the patients was similar in the two groups. The total time spent in hospital after entry into the study was significantly higher in the LeVeen shunt group than in the paracentesis group. It may be difficult to evaluate differences between treatments based on the comparison of hospital stays, which may be subjected to a great variability. Nevertheless, the differences in the duration of hospitalizations found in the current study are so marked that they can hardly be ascribed to reasons other than the different treatments used. As in the previous trial, treatment of refractory ascites by peritoneovenous shunting with titanium tip did not result in improved prognosis. The 1-year probabilities of survival in the current study (51% in the paracentesis group and 57% in the LeVeen shunt group) were similar to those in the previous trial (56% and 43%, respectively). Moreover, in the current trial, peritoneovenous shunting did not result in a reduction in the probability of developing renal impairment. In summary, the results of the study indicate that the insertion of a titanium tip at the venous end of the LeVeen shunt does not reduce the incidence of shunt obstruction or prevent thrombotic occlusion of the venous tube or superior vena cava thrombosis in cirrhotic patients with refractory ascites. Our findings also indicate, in agreement with a previous trial in patients with refractory ascites, that although peritoneovenous shunting is more effective than paracentesis in the long-term control of refractory ascites, it does not result in a substantial improvement in the quality of life, because it does not reduce hospitalization requirements or prolong survival and requires frequent reoperation because of shunt obstruction.
Acknowledgment: We are indebted to Drs Victor Vargas, Sergio Boccia, Jean-Pierre Vinel, Joan Manuel SalmerSn, and Alessandra Maggi for their participa-
HEPATOLOGYVol. 22, No. 1, 1995
GINt~S ET AL
tion in the study and to Dr Antoni Castells for his statistical support. The authors thank Raquel Cela, Mariana Roman, and the nursing staffofthe Liver Unit of Hospital Clinic i Provincial of Barcelona for their help, and E. de Belza for secretarial assistance.
8.
REFERENCES
9.
1. Gin,s P, Arroyo V, Vargas V, Planas R, Casafont F, Pan~s J, Hoyos M, et al. Paracentesis with intravenous infusion of albumin as compared with peritoneovenous shunting in cirrhosis with refractory ascites. N Engl J Med 1991;325:829-835. 2. Ring-Larsen H, Siemsen O, Krintell JJ, Stadager C, Henriksen JH. Diuretic resistant ascites in cirrhosis treated with peritoneovenous shunt: a randomized controlled trial. HEPATOLOGY
1988;8:$86. 3. Franco D, Labianca M, Smajda C, Fragoso J, Halabi S. Titanium catheter tip for peritoneovenous shunts. Artif Organs 1988; 12: 81-82. 4. Hillaire S, Labianca M, Smajda C, Grange D, Franco D. D~rivation p~riton~o-veineuse dans l'ascite irr~ductible de la cirrhose: r~sultats d'une ~tude prospective sur les facteurs d'am61ioration du pronostic. Gastroenterol Clin Biol 1988; 12:681-686. 5. Hillaire S, Labianca M, Borgonovo G, Smajda C, Grange D, Franco D. Peritoneovenous shunting of intractable ascites in patients with cirrhosis: improving results and predictive factors of failure. Surgery 1993;113:373-379. 6. Gin, s P, Arroyo V, Quintero E, Planas R, Bory F, Cabrera J, Rimola A, et al. Comparison of paracentesis and diuretics in the treatment of cirrhotics with tense ascites: results of a randomized study. Gastroenterology 1987;93:234-241. 7. Gin, s P, Tit6 L1, Arroyo V, Planas R, Pan~s J, Viver J, Torres M,
10.
11. 12.
13. 14. 15. 16.
131
et al. Randomized comparative study of therapeutic paracentesis with and without intravenous albumin in cirrhosis. Gastroenterology 1988;94:1493-1502. Planas R, Gin, s P, Arroyo V, Llach J, Pan~s J, Vargas V, Salmer6n JM, et al. Dextran-70 versus albumin as plasma expanders in cirrhotic patients with tense ascites treated with total paracentesis: results of a randomized study. Gastroenterology 1990;99:1736~1744. Salerno F, Badalamenti S, Lorenzano E, Moser P, Incerti P. Randomized comparative study ofhemaccel vs. albumin infusion after total paracentesis in cirrhotic patients with refractory ascites. HEPATOLOGY1991;4:707-713. Angeli P, Pria M, Bei E, Albino G, Caregaro L, Merkel C, Ceolotto G, et al. Randomized clinical study of the efficacy of amiloride and potassium canreonate in nonazotemic cirrhotic patients with ascites. HEPATOLOGY1994; 19:72-79. Smajda C, Franco D. The LeVeen shunt in the elective treatment of intractable ascites in cirrhosis: a prospective study in 140 patients. Ann Surg 1985;201:488-493. Tit5 L1, Gin,s P, Arroyo V, Planas R, Pan~s J, Rimola A, Llach J, et al. Total paracentesis associated with intravenous albumin management of patients with cirrhosis and ascites. Gastroenterology 1990;98:146-151. Smajda C, Tridard D, Franco D. Recurrent ascites due to central venous thrombosis after peritoneojugular (LeVeen) shunt. Surgery 1986; 100:535-541. Dixon WJ, ed. BMDP statistical software. Berkeley: University of California Press, 1985. Pugh RNH, Murray-Lyon M, Dawson JL, Pietroni MC, Williams R. Transection of the esophagus for bleeding oesophageal varices. Br J Surg 1973;60:646-649. Arroyo V, Epstein M, Gallus G, Gentilini P, Ring-Larsen H, Salerno F. Refractory ascites in cirrhosis: mechanism and treatment. Gastroenterology International 1989;2:195-207.
the m a n a g e m e n t of cirrhotic patients with refractory ascites. (HEPATOLOGY1995;22:124-131.)
It has recently b e e n suggested that insertion of a titan i u m tip at the v e n o u s e n d of the LeVeen shunt drastically reduces the rate of shunt obstruction. To assess w h e t h e r the LeVeen shunt w i t h titanium tip i m p r o v e s the results obtained w i t h therapeutic paracentesis, 81 patients with cirrhosis and refractory ascites w e r e rand o m l y assigned to therapy with paracentesis plus intrav e n o u s albumin (42 patients) or LeVeen shunt with titan i u m tip (39 patients). If patients w e r e readmitted for ascites during follow-up, those in the first group w e r e treated with paracentesis, and those in the LeVeen shunt group by the insertion of a n e w valve or a n e w shunt if obstruction was demonstrated. During first hospitalization, both treatments w e r e equally effective in r e m o v i n g ascites. Complications w e r e similar in both groups except for a higher rate of severe bacterial infection in the LeVeen shunt group. The m e a n duration of hospitalization w a s shorter in the paracentesis group than in the shunt group. During follow-up, the total number of readmissions and the n u m b e r of readmissions for ascites w e r e higher in the paracentesis group than in the shunt group (252 vs. 99, P < .001; and 193 vs. 43, P < .001, respectively). The total time in hospital, h o w e v e r , was similar (38 + 38 vs. 39 -+ 43 days, P = NS). Three patients had obstruction of the shunt during first hospitalization and 14 patients had a total'~of 22 obstructions during follow-up. Long-term survival was similar in b o t h groups. The insertion of a titanium tip at the v e n o u s end of the LeVeen shunt does not prevent obstruction. The LeVeen shunt with titanium tip does not provide significant i m p r o v e m e n t o v e r therapeutic paracentesis in
From the ~Liver Unit, Department of Medicine, Hospital Clinic i Provincial, Barcelona, the 2Gastroenterology Unit, Hospital Germans Trias i Pujol, Badalona, 8Istituto di Medicina Clinica, Padova, the 4Liver Unit, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain, and 5Istituto di Medicina Interna, Milano, Italy. Received July 2, 1994; accepted February 17, 1995. Supported by grants from Fondo de Investigaciones Sanitarias de la Seguridad Social (FISS 93/0610) and DirecciSn General de InvestigaciSn Cientifica y T~cnica (DGICYT PM 91-0216). A. Gin,s and J. Sal5 were granted by FISS (91/5549 and 93/0610, respectively). Address reprint requests to: Vicente Arroyo, MD, Liver Unit, Hospital Clinic i Provincial, Villarroel, 170, 08036 Barcelona, Spain. Copyright © 1995 by the American Association for the Study of Liver Diseases. 0270-9139/95/2201-001953.00/0
A recent randomized controlled trial I showed t h a t peritoneovenous shunting with the LeVeen prosthesis is more effective t h a n therapeutic paracentesis associated with intravenous albumin infusion for the treatment of refractory ascites in cirrhosis because it markedly reduces the time to recurrence of tense ascites, number of readmissions for ascites, and diuretic requirements. These beneficial effects, however, did not result in significant improvement in the long-term m a n a g e m e n t of the patients or in reduction in the total time spent in hospital during follow-up because of a very high rate of shunt obstruction requiring reoperation, which approached 40% during the first postoperative year. Such a high incidence of s h u n t obstruction has also been reported by other investigators. 2 The probability of survival Was identical in the two therapeutic groups. 1 Based on this trial, therapeutic paracentesis has been proposed as an alternative t r e a t m e n t to peritoneovenous shunting for the m a n a g e m e n t of refractory ascites in cirrhosis. Recently, data have been presented suggesting t h a t the insertion of a 3-cm-long t i t a n i u m tip into the venous end of the LeVeen shunt prevents thrombotic obstruction of the venous limb of the prosthesis and the development of superior vena cava thrombosis. 3'4 Using this approach, Hillaire et al 5 have reported a cumulative rate of shunt obstruction of 6% at 1 year and 12% at 2 years in 56 patients with cirrhosis and refractory ascites. The beneficial effects of this specifically designed t i t a n i u m tip on s h u n t patency is attributed to the thromboresistant properties of t i t a n i u m and to the shape of the tip, providing gradual, streamlined-flow convergence of ascites and blood-limiting endothelial damage and mural thrombus formation in the superior vena cava. These studies prompted us to assess whether this modified approach of peritoneovenous shunting improves the results obtained with therapeutic paracentesis in the m a n a g e m e n t of cirrhotic patients with refractory ascites. The current article reports the results of a multicenter randomized
124
HEPATOLOGYVol. 22, No. 1, 1995
GIN]~S ET AL 125
controlled trial a i m e d at c o m p a r i n g L e V e e n s h u n t w i t h t i t a n i u m tip v e r s u s total t h e r a p e u t i c p a r a c e n t e s i s plus i n t r a v e n o u s a l b u m i n in t h e s e patients. MATERIALS A N D METHODS The study was approved by the Investigation and Ethics Committee of each hospital participating in the trial and all patients gave informed consent. Eighty-one patients with cirrhosis admitted to five hospitals for the treatment of refractory ascites were included. The number of patients studied at the various hospitals ranged from 12 (at the Istituto di Medicina Interna, Milano) to 22 (at the Hospital Germans Trias i Pujol, Badalona). All these hospitals have a high degree of expertise in the management of patients with ascites and have been involved in several multicenter therapeutic trials in these p a t i e n t s Y 1° The diagnosis of cirrhosis was based on liver histology in 65 patients and on the following clinical and laboratory findings in 16 cases: signs of chronic liver disease, prolonged prothrombin time, hypoalbuminemia, hypergammaglobulinemia, ultrasonographic findings compatible with the diagnosis of cirrhosis, and esophageal varices on endoscopy. The cause of cirrhosis was alcohol related in 41 patients, associated with hepatitis C antibodies in 24, associated with hepatitis B surface antigen in 8, cryptogenic in 7, and hemochromatotic in 1. Patients meeting one of the two following criteria were considered to have refractory ascites: (1) no response, defined as loss of body weight less than 200 g per day together with urinary sodium excretion less than 50 mEq/day, to a restriction of sodium intake (<50 mEq/day), and to maximal doses of diuretic therapy for 5 days during hospitalization in which the dosage of diuretic agents was increased stepwise every 5 days from 40 to 120 mg furosemide per day and from 100 to 300 mg spirono]actone per day; or (2) three or more episodes of tense ascites requiring hospitalization within a 9-month period before the inclusion in the study, despite adequate diuretic treatment and sodium restriction. Patients meeting the second criterion were entered in the trial without assessment of response to diuretic treatment in the hospital. Patients with hepatocellular carcinoma, cardiac, respiratory, or renal disease, serum bilirubin > 10 mg/dL, prothrombin time <40%, platelet count <40 × 109/L, or serum creatinine >3 mg/dL were not included in the trial. Patients with spontaneous bacterial peritonitis, gastrointestinal hemorrhage, or hepatic encephalopathy were considered as candidates for the trial after they had recovered from these complications. Patients were studied after 5 days on a 50 mEq sodium diet without diuretics. On the sixth day, 24-hour urine volume was carefully collected to measure urinary sodium excretion. Blood samples were taken on the morning of the seventh day to measure standard liver and renal function tests. Patients were then randomly assigned to two groups with the use of sealed envelopes. One group consisted of 42 patients who were treated with total paracentesis (complete mobilization of the ascitic fluid in only one session) associated with intravenous albumin infusion (8 g/L ascitic fluid removed) administered during and immediately after the procedure. The second group consisted of 39 patients who were treated with LeVeen peritoneovenous shunt with a titanium tip inserted at the venous end of the prosthesis. Randomization was independent in each hospital. To ensure homogeneous distribution into the two therapeutic groups, patients were randomized separately according to the criterion used to define refractory ascites. Insertion of the LeVeen shunt (Becton Dickinson, Fairfield, NJ) was performed as previously de-
FIG. 1. LeVeenshunt with the titanium tip. scribed. 11 Most ascitic fluid was removed during the operation, before the insertion of the shunt. The correct placement of the venous tip (the superior vena cava just before the atrium) was checked roentgenographically in the operating room. Prophylactic cloxacillin (1 g immediately before surgery and 1 g every 6 hours during 2 days after the operation) was given to all patients. This prophylactic antibiotic regimen was also administered whenever a patient with LeVeen shunt required invasive maneuvers. The titanium tip 3-~ was supplied by France M~dical Conseil (Saint Germain en Laye, France) and consists of a cylinder of 1.4 g in weight and 30 mm in length, which comprises two parts: the neck (12-mm length), which is inserted within the venous catheter of the LeVeen prosthesis, and the main part (18-mm length) (Fig. 1). The external diameter of the main part (5.7 mm) terminares with an apex whose wall becomes thinner toward its end in such a way that the internal and external surfaces join together at an annular edge with a thin, smooth, rounded profile. At the opposite end of the apex, the neck terminates in a collar with a slightly larger diameter. Before the insertion into the venous end of the LeVeen shunt, the neck of the titanium tip was covered with a thin layer of sterilized adhesive (080118; Medtronic, Minneapolis, MN). Special care was taken to ensure that the external surface of the main part of the tip and the external surface of the venous catheter were aligned. Total paracentesis was performed as described elsewhere.12 Diuretics were started immediately after treatment in both groups. Patients in the paracentesis group were given furosemide (80 mg/day) and spironolactone (200 mg/day), and those in the peritoneovenous shunt group received furosemide (80 rag/day) intravenously for 2 days and furosemide (80 mg/ day) and spironolactone (200 mg/day) orally thereafter. The dosage of diuretics was subsequently adjusted according to individual response. Patients in the paracentesis group were discharged 3 days after the mobilization of ascites, and those in the peritoneovenous shunt group 5 days after operation, unless continued hospitalization was required for diagnostic or therapeutic purposes. When needed, patients in the paracentesis group requiring long hospitalizations were treated by a second therapeutic paracentesis. Standard liver and renal function tests were performed 2 to 7 days after treatment in all patients. The duration of first hospitalization was calculated from the day of entry into the study. The follow-up period started at the end of the first hospitalization. Patients were controlled in the outpatient clinic weekly for 1 month, monthly for the next 2 months, and bimonthly thereafter. Patients of the paracentesis group developing tense ascites during follow-up were treated by total paracentesis plus intravenous albumin infusion. In patients of the LeVeen shunt group developing tense ascites during follow-up, the patency of the shunt was checked by Doppler u]trasonography. When the shunt was obstructed, a shuntogram was performed after the injection of contrast medium into the proximal subcutaneous limb of the shunt to identify the site of obstruction. Venacavography by digital angiogra-
126
GIN]~S ET AL
HEPATOLOGYJuly 1995
phy was performed in patients with obstruction at the venous limb of the shunt to rule out thrombosis of the superior vena cava. Patients without shunt obstruction were treated with diuretics, those with occlusion of the valve by replacement of only the valve and the intraperitoneal tubing, and those with occlusion of the venous segment of the shunt by replacement of the entire shunt with the titanium tip. In patients developing superior vena cava thrombosis, the shunt was removed. Because patients recovering from this complication are at great risk of developing recurrent superior vena cava thrombosis after reinsertion of the prosthesis, 13 they were subsequently treated with diuretics and, when necessary, paracentesis. Renal impairment was defined as an increase in serum creatinine concentration of more than 50% from the pretreatment value, to a level greater than 1.5 mg/dL. Hyponatremia during first hospitalization was defined as a decrease in the serum sodium concentration greater than 5 mEq/L, to a level below 130 mEq/L. Patients with serum sodium concentration below 130 mEq/L before treatment with decreases of more than 5 mEq/L in this parameter were also included among the patients in whom hyponatremia developed. Follow-up readmissions to the hospital were grouped according to five causes: ascites, hepatic encephalopathy, severe bacterial infections, gastrointestinal hemorrhage, and other complications. When two of these causes were present, the following criteria were arbitrarily used to define the cause of readmission: (1) when tense ascites was associated with gastrointestinal hemorrhage, severe bacterial infection, grades 2 to 4 hepatic encephalopathy, or some other complication requiring emergency treatment, the associated condition was considered to be the cause ofreadmission; (2) when tense ascites was associated with grade 1 hepatic encephalopathy or another condition not requiring emergency treatment, ascites was considered to be the cause; (3) when hepatic encephalopathy was associated with severe bacterial infection or gastrointestinal bleeding it was considered to be secondary; and (4) when patients had gastrointestinal bleeding and bacterial infection, hemorrhage was considered to be the cause of readmission. These criteria were also used to define the cause of readmission in the few cases who had three complications at entry into the hospital. Statistical analysis of the results was performed using the BMDP statistical package. 14 Categorical data were compared by the X2 test or by Fisher's exact test when the number in a cell was 5 or less. Continuous data were compared using paired and unpaired Student's t-tests and the nonparametric test of Mann-Whitney. Probability curves were constructed by the Kaplan-Meier method and compared with the MantelCox test. The results are presented as mean _+SD. Statistical significance was considered when the P value was .05 or less. RESULTS
Characteristics of the Patients at Entry Into the Trial. B y chance, t h e age of t h e p a t i e n t s t r e a t e d w i t h p a r a c e n t e s i s was slightly h i g h e r t h a n t h a t of p a t i e n t s t r e a t e d w i t h L e V e e n s h u n t (P < .02). However, t h e r e were no significant differences b e t w e e n g r o u p s in a n y of t h e r e m a i n i n g clinical d a t a c o n s i d e r e d or in s t a n d a r d liver a n d r e n a l f u n c t i o n tests, C h i l d - P u g h score, 1~ a n d m e a n a r t e r i a l p r e s s u r e (Table 1). B o t h t h e r a p e u t i c g r o u p s were also similar w i t h r e s p e c t to the n u m b e r of p a t i e n t s w i t h previous episodes of ascites (42 a n d 38 p a t i e n t s , respectively), h e p a t i c e n c e p h a l o p a t h y (16 a n d
TABLE 1. B a s e l i n e C l i n i c a l a n d L a b o r a t o r y D a t a i n t h e T w o Groups of Patients With Cirrhosis and Refractory Ascites
Age Sex (M/F) No. with alcohol-induced cirrhosis No. with peripheral edema No. with renal failure* Serum bilirubin (mg/dL) Prothrombin time (%) Serum albumin (g/L) Serum creatinine (mg/dL) Serum sodium (mEq/L) Urinary sodium (mEq/day) Mean arterial pressure (mm Hg) Child-Pugh scorer
Paracentesis (n = 42)
Leveen Shunt (n = 39)
P
63 (37-80) 20/22
58 (37-69) 25/14
.02 NS
19
22
NS
21 21 2.0 _+ 1.5 58 _+ 16 31.8 _+ 5
24 17 1.9 _+ 1 59 _+ 12 31.6 _+ 5
NS NS NS NS NS
1.3 _+0.6 132 _+ 6
1.3 _+0.6 132 _+ 5
NS NS
4 _+ 5
3 _+ 2
NS
82 _+ 13 9 _+ 1
84 _+ 10 9 _+ 1
NS NS
Abbreviation: NS: P > .05. * Renal failure was defined as serum creatinine concentration >1.5 mg/dL. t The Child-Pugh score (range, 5 to 15) was calculated on the basis of the presence and degree of hepatic encephalopathy, the presence and degree of ascites, serum bilirubin concentration, serum albumin concentration, and prothrombin time. 1°
12), g a s t r o i n t e s t i n a l bleeding (18 a n d 11), a n d severe bacterial infections (14 a n d 9). The n u m b e r of p a t i e n t s included in the trial b e c a u s e of lack of r e s p o n s e to maxim a l diuretic t h e r a p y d u r i n g h o s p i t a l i z a t i o n (criterion 1, 16 in the p a r a c e n t e s i s g r o u p a n d 18 in t h e L e V e e n s h u n t group) a n d r e c i d i v a n t ascites before a d m i s s i o n (criterion 2, 26 a n d 21 patients, respectively) was comp a r a b l e in t h e two groups.
Effectiveness, Complications, Shunt Obstruction, and Mortality During First Hospitalization. T h e r a peutic p a r a c e n t e s i s a n d p e r i t o n e o v e n o u s s h u n t i n g were e q u a l l y effective in relieving ascites. A m o n g 42 p a t i e n t s included in the p a r a c e n t e s i s group, 40 were d i s c h a r g e d from h o s p i t a l w i t h m i n i m a l or no ascites. I n one p a t i e n t ascites w a s u n c o m p l e t e l y mobilized bec a u s e of i n t r a a b d o m i n a l c o m p a r t m e n t a l i z a t i o n of ascitic fluid. The p a t i e n t was d i s c h a r g e d from hospital w i t h diuretic t h e r a p y . The r e m a i n i n g p a t i e n t died in h o s p i t a l of liver failure a n d progressive r e n a l failure. I n the L e V e e n s h u n t g r o u p 34 p a t i e n t s of t h e 39 were d i s c h a r g e d w i t h m i n i m a l or no ascites. One of t h e s e 34 p a t i e n t s h a d to be r e o p e r a t e d on d u r i n g t h e first h o s p i t a l i z a t i o n b e c a u s e of s h u n t o b s t r u c t i o n located in the valve. I n a second p a t i e n t in w h o m s h u n t obstruction developed a t the v e n o u s end of t h e prosthesis, obs t r u c t i o n w a s resolved a f t e r t h e injection of c o n t r a s t m e d i a d u r i n g s h u n t o g r a p h y . Two p a t i e n t s were disc h a r g e d w i t h m o d e r a t e ascites despite s h u n t p e r m e ability. The r e m a i n i n g t h r e e p a t i e n t s died d u r i n g
HEPATOLOGY Vol. 22, No. 1, 1995
GIN]~S ET AL
127
TABLE 2. T e s t s o f L i v e r a n d R e n a l F u n c t i o n a n d M e a n A r t e r i a l P r e s s u r e B e f o r e a n d A f t e r T r e a t m e n t i n t h e T w o G r o u p s Paracentesis (n = 42) Before
Serum bilirubin (mg/dL) Serum albumin (g/L) Prothrombin time (%) Serum creatinine (mg/dL) Serum sodium (mEq/L) Mean arterial pressure (mm Hg)
2.0 31.8 58 1.3 132 82
-- 1.5 _+ 5 _+ 16 +_ 0.6 + 6 _+ 13
After 2.0 33.5 60 1.4 131 80
_+ 1.5 _+ 5 _+ 14 _+ 0.6 _+ 6 _+ 14
LeVeen Shunt (n = 38*)
P Value NS .01 NS NS NS NS
Before
1.9 31.6 59 1.3 132 84
_+ 1 _+ 5 _+ 12 _+ 0.6 _+ 5 +_ 10
After
2.0 30.4 54 1.3 134 79
_+ 1.4 _+ 5 _+ 15 _+ 0.7 _+ 4 _+ 11
P Value
NS NS .007 NS NS 0.02
Abbreviation: NS: P > .05. * One patient in this group died 4 days after insertion of the s h u n t and is not included.
hospitalization, with severe bacterial infection (pneumonia and sepsis) being the cause of death in two. The third case developed acute superior vena cava thrombosis and superior vena cava syndrome and died despite removal of the shunt and thrombolitic treatment. The volume of ascitic fluid removed, as estimated by the loss of body weight during hospitalization in the survivors, was comparable in the two groups (9.8 _+ 3.2 kg in the paracentesis group and 10.2 _+ 4.5 kg in the LeVeen shunt group). The mean duration of the first hospitalization was 11.6 _+ 10.3 days in the paracentesis group and 29.1 _+ 15.2 days in the LeVeen shunt group (P < .001). Table 2 shows the standard liver and renal function tests and mean arterial pressure before and after treatment in the two groups. Serum albumin concentration increased significantly in patients treated by paracentesis. Patients treated by LeVeen shunt had a significant decrease in prothrombin time and mean arterial pressure. There was no significant change in any of the remaining parameters evaluated. Complications during first hospital stay are shown in Table 3. Eleven (26%) patients in the paracentesis TABLE 3. C o m p l i c a t i o n s D u r i n g t h e F i r s t H o s p i t a l S t a y i n the Two Groups Paracentesis (n = 42)
LeVeen Shunt (n = 39)
Patients (%)
Patients with complications Encephalopathy Gastrointestinal bleeding Renal impairment Severe bacterial infection Hyponatremia Severe abdominal pain Symptomatic disseminated intravascular coagulation Superior vena cava thrombosis
P Value
11 (26) 4 (9)
15 (38) 3 (8)
NS NS
2 (5) 5 (12)
2 (5) 4 (10)
NS NS
2 (5) 2 (5)
9 (23) 1 (3)
.01 NS
0
3 (8)
NS
0
3 (8)
NS
0
1 (3)
NS
group, and 15 (38%) in the LeVeen shunt group developed a total of 15 and 26 complications, respectively, during first hospitalization. In both groups, complications were equally distributed among the five participating hospitals. Severe bacterial infections occurred with a significantly higher frequency in the LeVeen group than in the paracentesis group. Nine patients in this group developed severe bacterial infections (bacterial peritonitis in 3, pneumonia in 3, sepsis in 2, and bacterial peritonitis plus pneumonia in 1) as compared with two patients in the paracentesis group (spontaneous bacterial peritonitis and cellulitis). The remaining complications (hepatic encephalopathy, gastrointestinal hemorrhage, renal impairment, and hyponatremia) occurred with a similar frequency in both groups. Seven patients in the LeVeen shunt group had complications related with the prosthesis (symptomatic disseminated intravascular coagulation in three, severe abdominal pain in three, and superior vena cava thrombosis causing superior vena cava syndrome in one). As indicated above, one patient in the paracentesis group and three in the LeVeen shunt group died during first hospitalization. Effectiveness and Complications During Followu p . Of the 77 cases surviving first hospitalization only i from the paracentesis group was lost to follow-up 7 months after discharge from hospital. The mean followup period was 287 _+ 213 days in the paracentesis group and 336 _+ 248 days in the LeVeen shunt group. Of the 38 patients with alcohoMnduced cirrhosis discharged from hospital (19 in the paracentesis group and 19 in the LeVeen shunt group), 14 (8 in the paracentesis group and 6 in the LeVeen shunt group) continued drinking alcohol during follow-up. Thirty-seven of the 41 patients discharged from hospital in the paracentesis group and 28 of the 36 patients discharged from hospital in the LeVeen shunt group required one or more readmissions to the hospital during follow-up. Twenty-nine (71%) patients treated with paracentesis and 15 (42%) treated with LeVeen shunt were readmitted for ascites at least once during followup (P = .02). Other major reasons for readmission were encephatopathy, bacterial infection, and gastrointestinal hemorrhage, which were responsible for readmission in 22%, 22%, and 22% of the patients in the paracentesis group and 17%, 28%, and 11% of the patients
128
HEPATOLOGYJuly 1995
GINI~S ET AL
TABLE 4. Read_missions to H o s p i t a l D u r i n g F o l l o w - u p i n t h e Two Groups Paracentesis (n = 41)
Number of readmissions Cause Ascites Encephalopathy Bacterial infection Gastrointestinal bleeding Other
! r . . . . . . .
Leveen Shunt (n = 36)
252*
0.8
t I-
>-
99
193" 17 9 8 25
PARACENTESIS
1.0I
,
,
J
0.6 < CO O 0.4 EC fl-
43 13 12 6 25
-
.'
'
LEVEEN SHUNT
r~
/
p=0.01
0.2
*P < .0Ol for the comparison with the peritoneovenous shunt group.
0.0 0
in the LeVeen s h u n t group, respectively. Of the four cases not requiring readmission in the paracentesis group, three were alive and well at the time of analysis of the results after a follow-up period of 240, 300, and 810 days, respectively. The fourth case died at home of liver failure 1 month after discharge. Of the eight patients not requiring readmission in the LeVeen s h u n t group, six were alive and well after a mean follow-up period of 535 +_ 150 days (range, 391 to 749 days). The remaining two cases died at home 150 and 272 days after discharge because of gastrointestinal hemorrhage and cerebral hemorrhage, respectively. The number and causes ofreadmissions to the hospital during follow-up are shown in Table 4. Overall, there were 252 readmissions in patients of the paracentesis group and 99 in patients of the LeVeen shunt group (P < .001). Readmission was caused by a single complication on 245 occasions in the paracentesis group and 85 in the LeVeen shunt group. The higher frequency of hospitalization during follow-up in the paracentesis group was attributable exclusively to a higher number ofreadmissions for ascites. The number of readmissions for other causes were comparable in
1.0
0
o.4-
the two groups. Figure 2 shows t h a t the time to first readmission for ascites during follow-up was significantly shorter in the paracentesis group t h a n in the LeVeen shunt group (median time: 2 _+ 6.4 and 11.9 _+ 12 months, P < .001, respectively). The differences were less pronounced when the time to first readmission for any complication was considered (1.2 _+ 1.9 vs. 3.7 _+ 6 months, P = .01, respectively) (Fig. 3). The mean need for diuretics during follow-up was significantly higher (P < .001) in the paracentesis group (furosemide 75 _+ 53 mg/day; spironolactone 233 _ 99 mg/day) t h a n in the LeVeen shunt group (34 _+ 36 mg/day and 133 _+ 92 mg/day, respectively). Figure 4 shows t h a t the probability of developing renal impairment during follow-up was similar in the two groups. Despite the significantly higher frequency of readmissions in the paracentesis group, the total time spent
0.8
I
>-
IJ
;
r ! I
t
LEVEEN SHUNT
P
!
0_
.J
[
p=0.001
i
_/
0.2-
PARACENTESIS
0.6
< m 0.4 0 rr 13.. 0.2
oo : C 0
12
18
24 MONTHS
FIG. 2. Probabilityof readmission to the hospital during followup for ascites in patients in the two study groups,
........ I
I . . . . . . . . . -
j,
0.0 6
24
F~G.3. Probabilityof readmission to the hospital during followup for any complicationin patients in the two study groups.
I I
_1
0.6
18
1.0
>J co <
12
MONTHS
PARACENTESIS
0.8
6
0
,~--I
'
I
LEVEEN SHUNT
S
i
i
i
i
6
12
18
24 MONTHS
FIG. 4. Probability of developing renal impairment after entry into the study in the two study groups.
GINES ET AL 129
HEPATOLOGYVol. 22, No. 1, 1995 TABLE 5. Mean Time i n H o s p i t a l D u r i n g F o l l o w - u p i n t h e Two G r o u p s Paracentesis (n = 41) (number
Duration of follow-up Time in hospital Total For ascites For other reasons Mean duration hospital admissions Total For ascites For other reasons
LeVeen Shunt (n = 36)
287 _+ 213
336 _+ 248
38 + 38 16 _+26 22 _+27
39 + 43 14 _+ 25 25 +_ 34
_n
m ,<
-
0.6
I
LEVEEN SHUNT
! I
-
--
-
',
0.4 0 rr Q..
I L --I
PARACENTESIS
0.2
6 _+ 7 3 _+4 15 _+ 10
16 _+ 13" 13 +_ 11" 17 _+ 15
1.00.8-
0.6m <
H rr-r-_
0.2-
I ',. . . . . . . . . . . . . . . . .
!
0.0 6
12
18
0.0 0
6
12
18
24 MONTHS
in hospital d u r i n g follow-up a n d the t i m e s p e n t for the t r e a t m e n t of ascites or o t h e r complications was similar in t h e two groups (Table 5). This was b e c a u s e of t h e significantly lower m e a n d u r a t i o n of hospital stays during follow-up in t h e p a r a c e n t e s i s group, p a r t i c u l a r l y w h e n ascites was t h e cause of r e a d m i s s i o n (Table 5). T h e total t i m e s p e n t in hospital a f t e r e n t r y into t h e s t u d y (first h o s p i t a l i z a t i o n a n d follow-up) was lower in the p a r a c e n t e s i s group (50 _+ 37 days) t h a n in t h e L e V e e n s h u n t group (68 _+ 46 days) (P = .05). Shunt Obstruction During Follow-up. Of the 43 readmissions for ascites in t h e L e V e e n s h u n t group, t h e s h u n t was o b s t r u c t e d in 22 r e a d m i s s i o n s in 14 p a t i e n t s . In the r e m a i n i n g 21 r e a d m i s s i o n s for ascites, the s h u n t was p a t e n t , a n d t h e cause of ascites was r e l a t e d to e i t h e r a b a n d o n m e n t of t r e a t m e n t , i m p a i r m e n t of r e n a l function, or was u n k n o w n . In p a t i e n t s w i t h o b s t r u c t e d shunts, t h e site of o b s t r u c t i o n was t h e valve in 14 readmissions a n d t h e v e n o u s t u b e in 6. In two r e a d m i s s i o n s
0
1 I
0.8
of days)
* P < .001 for the comparison with the paracentesis group.
0 0.4n.," fl.
1.0
24 MONTHS
FIG. 5. Global probability of shunt obstruction due to clotting at the valve or at the venous end (continuous line) and probability of shunt obstruction due to clotting at the venous end (dotted line).
FIG. 6. Probability of survival after entry into the study in the two groups.
s h u n t obstruction occurred in the setting of a superior v e n a cava t h r o m b o s i s with p a r t i a l occlusion of the superior v e n a cava. T h e s h u n t was replaced on seven occasions in six patients. In one p a t i e n t s h u n t obstruction was resolved on two occasions a f t e r t h e injection of the c o n t r a s t m e d i a d u r i n g s h u n t o g r a p h y . In the rem a i n i n g 13 readmissions, the L e V e e n s h u n t was not replaced because t h e p a t i e n t was t e r m i n a l l y ill (five patients), r e s p o n d e d to diuretic t h e r a p y (two patients), rejected the i n s e r t i o n of a n e w p r o s t h e s i s (four patients), or because the cause of the obstruction was s u p e r i o r v e n a cava t h r o m b o s i s (two patients). In two o t h e r p a t i e n t s , t h e s h u n t was r e m o v e d d u r i n g followu p because of s p o n t a n e o u s b a c t e r i a l peritonitis. Obs t r u c t i o n s of t h e s h u n t occurred w i t h a similar freq u e n c y in the different centers involved in the study. F i g u r e 5 shows t h e global probability of s h u n t obstruction, including all cases w i t h obstruction located e i t h e r a t the valve or a t the v e n o u s end, a n d t h a t c a u s e d by clotting a t the v e n o u s end. The 1- a n d 2-year probabilities of obstruction w e r e 43% a n d 60% a n d 19% a n d 26%, respectively. Because the p a t e n c y of the s h u n t was only checked in p a t i e n t s developing ascites d u r i n g follow-up, t h e s e figures m a y u n d e r e s t i m a t e the actual risk of obstruction of t h e L e V e e n s h u n t . Mortality During Follow-up. T w e n t y - t h r e e p a t i e n t s in the p a r a c e n t e s i s group (56%) a n d 17 in the L e V e e n s h u n t group (47%) died d u r i n g follow-up. As w i t h complications, m o r t a l i t y in b o t h groups was equally distribu t e d a m o n g the different hospitals p a r t i c i p a t i n g in the study. T h e cause of d e a t h was liver failure in 12 pat i e n t s in the p a r a c e n t e s i s group a n d in 9 in t h e L e V e e n s h u n t group; g a s t r o i n t e s t i n a l h e m o r r h a g e in 4 a n d 2 patients, respectively; bacterial infection in 4 a n d 5 p a t i e n t s , respectively; a n d a n o t h e r cause in 3 a n d 1 p a t i e n t s , respectively. F i g u r e 6 shows t h a t t h e r e was no significant difference in t h e probability of survival a f t e r e n t r y into the s t u d y b e t w e e n the two groups.
130 GINES ET AL
HEPATOLOGYJuly 1995 DISCUSSION
The design of the current trial was identical to that of a previous investigation comparing therapeutic paracentesis versus LeVeen shunt in patients with refractory ascites, 1 with two exceptions. First, in the current study patients included in the paracentesis group were treated by total paracentesis, whereas in the previous trial they were treated by repeated large-volume paracentesis. Total paracentesis associated with intravenous albumin infusion has been shown to be as safe as repeated large-volume paracentesis plus albumin infusion in the treatment of tense ascites in cirrhosis because it is not associated with significant changes in renal and hepatic function and effective circulating blood volume, as estimated by the plasma levels of renin and aldosterone. 12 Second, in the current trial a titanium tip was inserted at the venous end of the LeVeen shunt. The decision to compare LeVeen shunt with titanium tip versus therapeutic paracentesis was based on several features: first, patients with refractory ascites and relatively preserved hepatic and renal function are very infrequent; therefore, a trial with three arms (therapeutic paracentesis and LeVeen shunt with and without titanium tip) is difficult to organize. Second, the inclusion criteria, surgical technique to insert the LeVeen prosthesis and methodology to assess shunt patency in this trial are identical to those in the previous trial; 1 therefore, the effect of the titanium tip on shunt obstruction and superior vena cava thrombosis can be inferred by comparing the results of the two studies. Finally, a trial comparing LeVeen shunt plus titanium tip and total paracentesis can provide important information concerning the management of refractory ascites because it deals with the two most widely used treatments for this complication. 16 The main result of the current trial is that peritoneovenous shunting with the LeVeen prosthesis modifled by the insertion of a titanium tip at the venous end of the shunt is associated with a high rate of shunt obstruction. The 1- and 2-year probabilities of shunt obstruction observed (43% and 60%, respectively) are similar to those observed in the previous trial comparing LeVeen shunt without titanium tip with therapeutic paracentesis (40% and 52%, respectively). 1 These data are not consistent with the suggestion that the insertion of a titanium tip at the venous end of the LeVeen shunt decreases the rate of shunt obstruction. 3-5 In the previous trial 60% of obstructions occurred in the valve, 20% in the venous tube, and 20% were secondary to superior vena cava thrombosis. ~ The corresponding figures in the current study are 60%, 28%, and 12%, respectively. Because the titanium tip does not affect the deposition of fibrin and cell debris in the valve, and, in our experience, the valve is the main site of shunt obstruction, the lack of effect of the titanium tip on shunt patency is not surprising. Moreover, our results also indicate that the titanium tip prevents neither thrombotic obstruction of the venous
limb of the prosthesis nor superior vena cava thrombosis. In fact, the 1- and two-year probabilities of obstruction attributable to clotting at the venous end of the shunt in the current study (19% and 26%, respectively) are very similar to the figures observed in the previous study without the titanium tip (17% and 28%, respectively). The results of the current study confirm that peritoneovenous shunting is more effective than therapeutic paracentesis in the treatment of refractory ascites in cirrhosis because it markedly increased the time to first readmission for ascites, decreased the number of readmissions for ascites, and lowered diuretic requirements. However, as in the previous trial, these beneficial effects did not result in a reduction of total hospital stay. The duration of first hospitalization was almost three times longer in the peritoneovenous shunt group than in the paracentesis group. This was in part related to the higher incidence of bacterial infections requiring intensive antibiotic treatment in the former group of patients. Conversely, although the number of readmissions during follow-up was 1.5-fold higher in patients treated by paracentesis, the mean duration of readmissions in this group was 1.5-fold shorter; thus, the time spent in hospital during follow-up by the patients was similar in the two groups. The total time spent in hospital after entry into the study was significantly higher in the LeVeen shunt group than in the paracentesis group. It may be difficult to evaluate differences between treatments based on the comparison of hospital stays, which may be subjected to a great variability. Nevertheless, the differences in the duration of hospitalizations found in the current study are so marked that they can hardly be ascribed to reasons other than the different treatments used. As in the previous trial, treatment of refractory ascites by peritoneovenous shunting with titanium tip did not result in improved prognosis. The 1-year probabilities of survival in the current study (51% in the paracentesis group and 57% in the LeVeen shunt group) were similar to those in the previous trial (56% and 43%, respectively). Moreover, in the current trial, peritoneovenous shunting did not result in a reduction in the probability of developing renal impairment. In summary, the results of the study indicate that the insertion of a titanium tip at the venous end of the LeVeen shunt does not reduce the incidence of shunt obstruction or prevent thrombotic occlusion of the venous tube or superior vena cava thrombosis in cirrhotic patients with refractory ascites. Our findings also indicate, in agreement with a previous trial in patients with refractory ascites, that although peritoneovenous shunting is more effective than paracentesis in the long-term control of refractory ascites, it does not result in a substantial improvement in the quality of life, because it does not reduce hospitalization requirements or prolong survival and requires frequent reoperation because of shunt obstruction.
Acknowledgment: We are indebted to Drs Victor Vargas, Sergio Boccia, Jean-Pierre Vinel, Joan Manuel SalmerSn, and Alessandra Maggi for their participa-
HEPATOLOGYVol. 22, No. 1, 1995
GINt~S ET AL
tion in the study and to Dr Antoni Castells for his statistical support. The authors thank Raquel Cela, Mariana Roman, and the nursing staffofthe Liver Unit of Hospital Clinic i Provincial of Barcelona for their help, and E. de Belza for secretarial assistance.
8.
REFERENCES
9.
1. Gin,s P, Arroyo V, Vargas V, Planas R, Casafont F, Pan~s J, Hoyos M, et al. Paracentesis with intravenous infusion of albumin as compared with peritoneovenous shunting in cirrhosis with refractory ascites. N Engl J Med 1991;325:829-835. 2. Ring-Larsen H, Siemsen O, Krintell JJ, Stadager C, Henriksen JH. Diuretic resistant ascites in cirrhosis treated with peritoneovenous shunt: a randomized controlled trial. HEPATOLOGY
1988;8:$86. 3. Franco D, Labianca M, Smajda C, Fragoso J, Halabi S. Titanium catheter tip for peritoneovenous shunts. Artif Organs 1988; 12: 81-82. 4. Hillaire S, Labianca M, Smajda C, Grange D, Franco D. D~rivation p~riton~o-veineuse dans l'ascite irr~ductible de la cirrhose: r~sultats d'une ~tude prospective sur les facteurs d'am61ioration du pronostic. Gastroenterol Clin Biol 1988; 12:681-686. 5. Hillaire S, Labianca M, Borgonovo G, Smajda C, Grange D, Franco D. Peritoneovenous shunting of intractable ascites in patients with cirrhosis: improving results and predictive factors of failure. Surgery 1993;113:373-379. 6. Gin, s P, Arroyo V, Quintero E, Planas R, Bory F, Cabrera J, Rimola A, et al. Comparison of paracentesis and diuretics in the treatment of cirrhotics with tense ascites: results of a randomized study. Gastroenterology 1987;93:234-241. 7. Gin, s P, Tit6 L1, Arroyo V, Planas R, Pan~s J, Viver J, Torres M,
10.
11. 12.
13. 14. 15. 16.
131
et al. Randomized comparative study of therapeutic paracentesis with and without intravenous albumin in cirrhosis. Gastroenterology 1988;94:1493-1502. Planas R, Gin, s P, Arroyo V, Llach J, Pan~s J, Vargas V, Salmer6n JM, et al. Dextran-70 versus albumin as plasma expanders in cirrhotic patients with tense ascites treated with total paracentesis: results of a randomized study. Gastroenterology 1990;99:1736~1744. Salerno F, Badalamenti S, Lorenzano E, Moser P, Incerti P. Randomized comparative study ofhemaccel vs. albumin infusion after total paracentesis in cirrhotic patients with refractory ascites. HEPATOLOGY1991;4:707-713. Angeli P, Pria M, Bei E, Albino G, Caregaro L, Merkel C, Ceolotto G, et al. Randomized clinical study of the efficacy of amiloride and potassium canreonate in nonazotemic cirrhotic patients with ascites. HEPATOLOGY1994; 19:72-79. Smajda C, Franco D. The LeVeen shunt in the elective treatment of intractable ascites in cirrhosis: a prospective study in 140 patients. Ann Surg 1985;201:488-493. Tit5 L1, Gin,s P, Arroyo V, Planas R, Pan~s J, Rimola A, Llach J, et al. Total paracentesis associated with intravenous albumin management of patients with cirrhosis and ascites. Gastroenterology 1990;98:146-151. Smajda C, Tridard D, Franco D. Recurrent ascites due to central venous thrombosis after peritoneojugular (LeVeen) shunt. Surgery 1986; 100:535-541. Dixon WJ, ed. BMDP statistical software. Berkeley: University of California Press, 1985. Pugh RNH, Murray-Lyon M, Dawson JL, Pietroni MC, Williams R. Transection of the esophagus for bleeding oesophageal varices. Br J Surg 1973;60:646-649. Arroyo V, Epstein M, Gallus G, Gentilini P, Ring-Larsen H, Salerno F. Refractory ascites in cirrhosis: mechanism and treatment. Gastroenterology International 1989;2:195-207.