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Shunt surgery versus endoscopic sclerotherapy for variceal hemorrhage: Late results of a randomized trial
Shunt Surgery Versus Endoscopic Sclerotherapy for Variceal Hemorrhage: Late Results of a Randomized Trial Layton F. Rikkers, MD, Gongliang Jin, MD, David A. Burnett, MD, Omaha,Nebraska, Kenneth N. Buchi, MD, Salt LakeCity,Utah, Robert A. Cormier, RN, Omaha,Nebraska
Between September 1982 and April 1988, 60 cirrhotic patients with prior variceal hemorrhage were randomized to undergo the placement of an elective shunt (distal splenorenah 26; nonselective: 4) or long-term endoscopic sclerotherapy (n = 3 0 ) . Eighty-six percent of patients had alcoholic cirrhosis, and 33% were classified as Child's class C. After a mean follow-up of 87 months, 60% of patients undergoing sclerotherapy and 17% of shunt patients experienced rebleeding (p < 0 . 0 0 1 ) . Shunt patients have survived longer than those who had selerotherapy (6-year survival rates of 53% and 26%, respectively; p < 0 . 0 5 ) . in part because of the wide geographic distribution of patients, only 4, of 13 patients in whom sclerotherapy failed (31%) could undergo salvage by shunt surgery. Although hepatic portal perfusion was better maintained after sclerotherapy, there were no major differences between the groups in terms of post-therapy hepatic or psychoneurologic function. In a predominantly alcoholic cirrhotic patient population (haft non-urban), the results of elective shunt surgery were superior to those of chronic endoscopic sclerotherapy with respect to the prevention of recurrent variceal hemorrhage and survival.
From the Departments of Surgery (LFR, GJ, RAC) and Medicine (DAB),Universityof Nebraska MedicalCenter,Omaha VeteransAdministration MedicalCenter,Omaha, Nebraska,and the Universityof Utah Schoolof Medicine(KNB),Salt LakeCity VeteransAdministration MedicalCenter,Salt LakeCity,Utah. Supportedby PublicHealth ServiceGrant #5 R01 DK35168and GeneralClinicalResearchCenter PublicHealth ServiceGrant #5M01RR00064: Requests for reprints should be addressed to Layton F. Rikkers, MD, Departmentof Surgery;UniversityOfNebraska MedicalCenter, 600 South42nd Street, Omaha, Nebraska68198-3280. Presentedat the 33rdAnnualMeetingof the Societyfor Surgeryof the AlimentaryTract, San Francisco,California,May 11-! 3, 1992.
" n 1982, we initiated a controlled trial comparing elecltherapy . tire shunt surgery with long-term endoscopic sclerofor the prevention of recurrent variceal hemorrhage in patients with cirrhosis and portal hypertension. Because the distal splenorenal shunt has the potential of preserving hepatic portal perfusion, it was selected for use in the majority of shunt patients. At the time of our preliminary report in 1987, after a mean follow-up in each group of 2 years, reblecding was more frequent after sclerotherapy, but survival curves for the two groups were similar [1]. One-year data revealed better preservation of hepatic portal perfusion by sclerotherapy, but no significant differences between groups with respect to functional hepatic reserve or the frequency of encephalopathy. Four other studies comparing the use of the elective shunt with scierotherapy have also found a higher incidence of rebleeding after sclerotherapy [2-5]. Survival has been similar after shunt placement and sclerotherapy in three of these investigations [3-5]. Endoscopic variceal sclerosis with surgical rescue of sclerotherapy failures has resulted in longer survival than the distal splenorenal shunt in the remaining trial [2]. The purpose of this report is to evaluate our long-term results. Patient accrual was terminated in April 1988 so all surviving patients were followed for a minimum of 4 years (range: 48 to 118 months), with a mean follow-up of over 7 years. PATIENTS AND M E T H O D S Sixty patients with cirrhosis and variceal hemorrhage were randomized to undergo either shunt surgery or 10ngterm endoscopic scler0therapy between September 1982 and April 1988. During the initial 2 years of the trial, patients were accrued from the University of Utah Medical Center (n = 19) and Salt Lake Veterans Administration Medical Center (n = 16). The principal investigator moved to the University of Nebraska Medical Center in August 1984, and since that time, patients have been selected from that institution (n ffi 9) and from the Omaha Veterans Administration Medical Center (n ffi 16). During the period of this investigation, 183 cirrhotic patients were treated for variceal bleeding at these institutions. To be considered for inclusion in the trial, patients had to meet several criteria:(1) portal hypertension secondary to cirrhosis; (2) endoscopic documentation of acute or recent esophageal variceal hemorrhage requiring a minimum transfusion of 3 U of blood; (3) residence within 500 miles of Salt Lake City or Omaha; (4) nonoperative control of acute variceal hemorrhage; and (5)
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TABLE I
Preoperative Comparison of S h u n t and Sclerotherapy Groups
Alcoholic cirrhosis Veterans Administration patients Non-urban Child's score Child's class C Galactose elimination capacity (mg/min) lndocyanine green (mg/kg/min) Effective hepatic blood flow (mL/min) Corrected sinuSoidal pressure (mm Hg) Prograde portal flow Encephalopathy Abnormal electroencephalOgram Abnormal number Connection test
Shunt Group (n = 30)
Sclerotherapy Group (n = 30)
25 16
27 16
17 6.6 -+ 0.4 10 266 -+ 18 (21)*
16 6.6 --- 0.4 10 265 • 16 (22)
0.20 -+ 0.03 (20)
0.19 -+ 0.03 (21)
1,369 -- 73 (23)
1.314 -+ 92- (22)
16.1 __ 0,9 (26)
16.6 +_ 1.2 (27)
29 9 10 (24)
26 (28) 8 4 (23)
t O (29)
7 (27)
*Parentheses denote number of patients tested if less than full group.
1
~ u
r
- -"
o
'
I
20
'
I
I
40
~
~"
I
80
....
'
~
- - -'~
I
SCLERO
'
120
1~
MONTHS
Figure 1. Kaplan-Meler survival <~urves for Shunt ( n ) and sclerol h e r a p y (Zl) groups. Shunt patients survived significantly longer than sclerottterapy patients (p < 0 . 0 5 ) .
TABLE II
Causes Of Death Shunt Group Bleeding Hepatic failure Hepatic failure with continued drinking Hepatoma Pneumonia Aneu~sm Esophageal cancer Myocardial infarction Accident Unknown Total
28
Sclerotherapy Group
1 5 5
8 4 5
1 0 1 0 1 0 1 15
1 2 0 1 0 1 1 23
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patency of splenic and portal veins documented by selective angiography. After the informed consent of the patients was obtained, patients were randomized using Efron's biased coin design [6] based on three liver function strata (modified Child's classification) and type of hospital (university or Veterans Administration). Thirtyone patients were randomized to shunt surgery, and 29 patients were randomized to endoscopic sclerotherapy. One patient who refused surgery was treated with endoscopic sclerotherapy and was included in that group for all subsequent analyses. Endoscopic sclerotherapy was performed using a flexible endoscope with intravariceal injections of either 0.75% sodium tetradecyl sulfate and 50% dextrose (first 2 years) or 5% sodium morrhuate (last 8 years). All variceal columns were injected just above and at 5 cm proximal to the esophagogastric jUnction. Balloons and overtubes were not used. Sclerotherapy was performed on a schedule of every 4 to 6 days until most varices were eradicated. The next session was scheduled for 1 month and then as necessary at 6-month intervals. The patients in the sclerotherapy group had 7.6 4- 0.9 endoscopic sclerosis treatments, with a range from 1 to 23 treatments. The only major complication other than rebleeding was esophageal stricture, which developed in three patients, all of whom were successfully managed by esophageal dilatation. One sclerotherapy patient was diagnosed with esophageal cancer 1 year after the initiation of sclerotherapy. Surgical variceal decompression was accomplished with a distal splenorenal shunt without splenopancreatic disconnection in 26 patients. Three patients with medically intractable ascites received either a side-to-side portacaval shunt (n = 1) or a Dacron graft interposition shunt (n = 2). One patient who experienced massive rebleeding soon after randomization underwent an emergency endt0-side portacaval shunt. All shunts were performed by a single surgeon (LFR). The failure of therapy was defined as shunt thrombosis for the shunt group and as death secondary to bleeding or the need for salvage surgery to control recurrent bleeding in the sclerotherapy group. The decision for surgical intervention was made by the referring gastroenterologist. Patient evaluation: All patients underwent a comprehensive evaluation of their hepatic hemodynamic status, functional hepatic reserve, and psychoneurologic status after randomization. In addition to intermittent clinic visits and contact by telephone, as many patients as possible returned for a comprehensive assessment at 3 months, 1 year, and 3 to 6 years after the initiation of therapy. The details of patient evaluation are included in the preliminary report of this trial [1]. Functional hepatic reserve was assessed by a modified Child's classification [7], galactose elimination capacity (GEC) [8], and the removal rate of a 5 mg/kg intravenous dose of indocyanine green [9]. Child's score was derived by totaling the grades (1 to 3) of four variables (serum albumin level, total bilirubin level, encephalopathy, and ascites: 4 to 5 -A, 6 t o 7 = B, 8 to 12 = C).
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Psychoneurologic status was assessed by clinical evaluation, electroencephalography (EEG), and psychometric testing. An episode of encephalopathy was defined as an incident of mental confusion related by the patient or a family member, or detection of disorientation on interview or asterixis on physical examination by a physician. Encephalopathy was considered mild if it was transient and did not require hospitalization and moderate when it required hospital care and/or prolonged treatment with lactulose and dietary protein restriction. Induced encephalopathy was defined as that occurring during gastrointestinal hemorrhage. The number connection test (NCT) was used for psychometric testing (normal: less than 50 seconds) [10]. Hepatic hemodynamic status was assessed by selective visceral angiography, measurement of corrected sinusoidal pressure (CSP), duplex ultrasonography, and quantitation of effective hepatic blood flow (EHBF) by a low-dose galactose clearance technique [11]. Hepatopetal (toward the liver) portal flow was considered to be present if the intrahepatic portal venous branches opacifled during the venous phase of the selective superior mesenteric angiography or prograde portal flow was detected by duplex ultrasonography. CSP was measured as hepatic venous wedge pressure minus free hepatic vein pressure during visceral angiography. Shunt patency status was determined by selective angiography. Statistical analysis: All results are expressed as mean 4- standard error of the mean. The Kaplan-Meier method was used to plot survival curves, which were statistically compared by the log likelihood ratio test. Shunt and sclerotherapy groups were compared at the various time points by X2 analysis and the unpaired Student's t-test. RESULTS Patient follow-up: As of April 1992, surviving sclerotherapy and shunt patients had been followed up for a mean of 92 • 7 months and 85 4- 5 months, respectively. All patients had been followed up for a minimum of 48 months, and the longest survivingpatienthad a follow-up of 118 months. Although the survivalstatusof allpatients was known, latepostoperativeevaluations were not possible for two patients in each group. Pretherapy comparisons: The two groups were comparable at randomization (Table I). Most patients had alcoholic cirrhosis,half were veterans, half lived in nonurban settings,and a third in each group were Child's classC. Except for one patientin each group with spontaneous encephalopathy, all episodes of preoperative encephalopathy were induced by gastrointestinalhemorrhage. Survival: There was a singleoperative death (3%) in the shunt group in an elderly patient (Child's class B) who underwent an emergency portacaval shunt when he experienced massive rebleeding the day afterrandomization. One sclcrotherapy patient died of uncontrolled bleeding after a single sclerosissession. All remaining patients survived for a minimum of 3 months after the initiationof treatment. Kaplan-Meier survival curves for the two groups of
TABLE lII
Quantitative Hepatic Function and Child's Score
Child's Score
Galactose Elimination Capacity (mg/min)
Indocyanine Green (mg/kg/min)
Shunt Preshunt Postshunt 3mo 1y 3-6 y
6.6 • 0.4 (30)*
266 • 18 (21)
0.20 _+ 0.03 (20)
6.3_+0.4(27) t 5.9 _+ 0.4 (21) 4.9 _+ 0.4 (11)
248_+23(20) 267 _+ 23 (17) 259 _+ 15 (6)
0.15_+0.02(17) 0.22 • 0.05 (15) 0.27 _+ 0.09 (5)
Sclerotherapy Presclero-
6.6 -+ 0.3 (30)
265 +- 16 (22)
0.19 • 0.03 (21)
5.3_+0.3(24) t 5.6 _+ 0.4 (19) 5.3 +_ 0.5 (12)
2 6 4 • 19 (22) 259 _+ 17 (17) 241 • 15 (6)
0.20• 0.20 • 0.03 (17) 0.17 • 0.05 (6)
therapy Postsclerotherapy 3mo 1y 3-6y
*Parentheses denote number of patients tested. tp <0.05.
TABLE IV
Hepatic Hemodynamic Data Prograde Portal Flow
Corrected Sinusoidal Pressure (ram Hg)
Effective Hepatic Blood Flow (mL/min)
29 (30)*
16.1 • 0.9 (26)
1,369 • 73 (23)
3 mo ly 3-6 y
22 (28) 6(12) t 4 (8)
18.2 • 1.5 (21) 9.9+_1.1 (7)t 8.5 • 2.0 (4)
1,176 _+ 85 (21) 1,113+_76(16) 1,293 • 82 (5)
Sclerotherapy Presclero-
26 (28)
16.6 • 1.2 (27)
1,313 -+ 92 (21)
12(13) 11 (12)* 3 (3)
17.1 • (8) 16.4 • 1.8 (8)* --
1,259-+68(22) 1,230 • 71 (17) 1,278 _+ 43 (2)
Shunt Preshunt
Postshunt
therapy Postsclerotherapy 3mo 1y 3-6 y
*Parentheses denote number of patients tested. tp <0.01.
patients as of April 1992 are shown in Figure 1. The survival of patients undergoing shunt surgery was significantly better than that of those receiving long-term sclerotherapy (p <0.05). The estimated 6-year survival rate in shunt patients was 53% as compared with 26% in sclerotherapy patients. Two of seven surviving sclerotherapy patients underwent salvage by shunt surgery. No preoperative variable predicted long-term survival in the sclerotherapy group. Both preoperative Child's score (alive: 5.9 • 0.5, dead: 7.3 4- 0.5, p <0.05) and GEC (alive: 300 4- 27, dead: 229 4- 27, p <0.05) were predictors of survival in the shunt group. A similar number of shunt and sclerotherapy patients died secondary to hepatic failure
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RIKKERS ET AL
TABLE V C u m u l a t i v e P s y c h o n e u r o l o g i c Data Shunt PrePostoperative operative Spontaneous PSE Mild Moderate Induced PSE Total PSE Abnormal electroencephalogram Abnormal NCT
Sclerotherapy PrePostoperative operative
0 1 7 8 10 (24)*
3 4 0 7 11 (24)
2 0 7 9 4 (23)
1 3 4 8 7 (24)
10 (29)
t 2 (24) t
7 (27)
5 (24) t
PSE = portal systemic encephalopathy; NCT = number connection test. *Parentheses denote number of tp < 0.05.
patients tested.
and to miscellaneous causes (Table H). The excess number of deaths in the sclerotherapy group was due to recurrent Needing. Of the 49 alcoholic cirrhotic patients who survived for longer than 3 months, 28 (57%) returned to alcoholism. However, alcoholic recidivism was not a predictive factor for long-term survival in either group. Reeurrent hemorrhage: The number of patients who experienced rebleeding (shunt: 5 [17%], sclerotherapy: 18 [60%], p <0.001), the number of rebleeding episodes (shunt: 5, sclerotherapy: 57, p <0.001), and the units of transfused blood required (shunt: 28, sclerotherapy: 314, p <0.001) were all greater in the sclerotherapy group. All episodes of recurrent hemorrhage were the result of varices or portal hypertensive gastropathy. Three patients (10%) developed shunt thrombosis (two distal splenorenal shunts; one interposition portacaval shunt), and all three experienced rebleeding of varices. During the early postoperative period, two patients with patent distal splenorenal shunts had rebleeding of esophageal varices and portal hypertensive gastropathy, respectively. Sixty percent of the 57 rebleeding episodes in the sclerotherapy group occurred during the first year after the initiation of treatment, 31% occurred between years 1 and 3, and 9% occurred after 3 years. Preoperative total bil/rubin levels (p = 0.006) and partial thromboplastin times (p ffi 0.02) were significantly higher in sclerotherapy patients who had rebleeding than in those who did not. All other preoperative variables were similar in these two subgroups. Therapy failm'e: Therapy failure (death as a result of bleeding or the need for salvage operation) developed in 3 shunt patients (10%) and in 13 sderotherapy patients (43%, p <0.01). The three shunt failures were all due to shunt thrombosis. Two of these patients had successful shunt reoperations (one end-to-side portacaval shunt and one interposition mesorenal shunt), and one died of persistent bleeding and hepatic failure after splenectomyand esophagogastrir devascularization. Mean time to sclerotherapy failure was 17 4- 4 months after an average of 2.5 4- 0.4 bleeding episodes 30
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and 7.8 4- 1.3 sclerotherapy treatments. Eight patients who had unsuccessful endoscopic variceal sclerosis bled to death before surgical salvage could be attempted. Five of these patients lived in non-urban areas, one refused further treatment, and one had massive rebleeding after the first sclerosis session. The remaining patient was judged to have terminal hepatic failure secondary to rebleeding by the time he was referred for surgery. Five patients in whom sclerotherapy failed underwent emergency salvage operations (four end-to-side portacaval shunts and one splenectomy plus esophagogastric devascularization), and four survived, for an overall salvage rate of 31%. Only one of these patients lived in a nonurban area. Esophageal varices were successfully eradicated in eight patients who had sclerotherapy failure (62%) with rebleeding from either gastric varices (n ffi 5) or portal hypertensive gastropathy (n = 3). The five remaining patients who experienced sclerotherapy failure had residual esophageal varices, but two patients also had prominent gastric varices, and the exact site of bleeding could not be determined. No pretherapy variables predicted those patients in whom sclerotherapy would ultimately fail. Quantitative hepatic function: With the exception of Child's score, which was lower (better hepatic function) in sclerotherapy patients at 3 months, there were no significant differences between groups at any time interval in the quantitative measures of hepatic function (Ta-
ble m). Hepatic hemodynamie data: All nonselective shunt patients in both groups lost portal flow immediately after surgery and were not further evaluated. Although portal perfusion was well maintained at all study intervals in sclerotherapy patients, only 50% of distal splenorenal shunt patients had continuing portal flow to the liver at 1 year and at 3 to 6 years after surgery (Table IV). CSP was also significantly lower in the shunt group at 1 year. Total EHBF was similar in both groups at aU study intervals. Eneephalopathy: The total incidence of clinically detectable encephalopathy was similar after shunt and sclerotherapy (Table V). Spontaneous episodes of encephalopathy tended to be more common in shunt patients, whereas encephalopathy that was induced by gastrointestinal bleeding occurred in the sclerotherapy group only. No patient in either group had severe, disabling encephalopathy. Subclinical encephalopathy, defined as at least one abnormal NCT at any time after the initiation of therapy, developed in significantly more shunt patients. More shunt patients than sclerotherapy patients had abnormal EEGs and NCTs on the preoperative evaluation, making them potentially more prone to abnormal tests postoperatively. COMMENTS Five randomized, controlled trials have compared elective shunt surgery with long-term endoscopic sclerotherapy for the prevention of recurrent variceal hemorrhage in patients with cirrhosis [1-5]. Four of these investigations, including the present one, have either exclusive-
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ly or predominantly utilized the selective distal splenorenal shunt in the surgical arm of the trial [1-4]. A common finding of all of these studies is the clear superiority of surgical portal decompression over long-term endoscopic variceal sclerosis for prevention of recurrent bleeding. The percentage of patients who experienced rebleeding ranged from 3% to 17% for the shunt groups and from 35% to 60% for those randomized to sclerotherapy. These relatively high rebleeding rates for patients receiving long-term sclerotherapy are consistent with the extensive experience reported in the literature for this treatment option [12]. The unique finding of the present study, which differs from our earlier preliminary report [1] and from the other published trials [2-5], is that survival was significantly prolonged in patients who underwent shunt placement. The survival advantage of the shunt patients was due to an excess of bleeding deaths in the sclerotherapy group. The numbers of patients who died of hepatic failure and of miscellaneous causes in the two treatment groups were nearly identical. Three controlled trials, all with follow-up of 2 years or less, have found no difference in survival between shunt and sclerotherapy groups [3-5]. The Atlanta investigation reported longer survival for sclerotherapy patients, a third of whom underwent surgical portal decompression when they could no longer be successfully managed by sclerotherapy [2]. This latter trial and our own contain several similarities and some important differences. Both investigations were nearly identical in design, were conducted in the United States, and had the longest available follow-up of the surviving patients. The Atlanta patients were followed for a median of 5 years, during which 59% of sclerotherapy patients had rebleeding. Thirty-five percent of sclerotherapy patients eventually experienced a failure of this treatment as defined by death secondary to hemorrhage or the necessity of undergoing a rescue operation to definitively control rebleeding. The mean patient follow-up in the present report exceeds 7 years, and the rebleeding and failure of therapy rates in the sclerotherapy group are 60% and 43%, respectively. The major difference in these two trials, which is most likely responsible for the conflicting survival results, is that nearly all patients who had failure of sclerotherapy (92%) in the Atlanta trial underwent successful salvage by shunt surgery, whereas nearly two thirds of our patients who had sclerotherapy failure bled to death before an operation could be performed. The percentage of patients who eventually had a failure of endoscopic sclerotherapy in the other trials with shorter lengths of follow-up were 5% [4], 20% [3], and 23% [5], respectively; salvage therapy was successful in fewer than half of these patients. Why was the salvage rate of sclerotherapy failure so much higher in the Atlanta investigation? Is a salvage rate of 92% for patients who continue to bleed despite repeated attempts at sclerotherapy a realistic goal for most institutions who treat patients with portal hypertension? Characteristics of the Atlanta patient population that might contribute to the good sclerotherapy results include residence within the Atlanta metropolitan area,
allowing rapid referral for surgery when recurrent hemorrhage developed, and a relatively high percentage (40%) of patients with nonalcoholic cirrhosis, increasing the likelihood of compliance with any treatment regimen [2]. In contrast, many of our patients were referred from small communities in the intermountain West and Great Plains, over half were derived from the Veterans Administration system, and most (87%) were alcoholic. Five of the eight sclerotherapy patients who bled to death lived in non-urban areas, and one Omaha patient refused further treatment when bleeding recurred. Based on the results of this trial, we have concluded that an elective portal-systemic shunt is a safer and more effective option than long-term sclerotherapy for patients with variceal bleeding who do not have tertiary medical care readily available to them. Patients who experience bleeding from gastric varices, which are generally ineffectively treated by sclerotherapy, and those who are unlikely to be compliant with respect to a long-term sclerotherapy schedule are also probably better served by a shunt placement. When patients have a failure of sclerotherapy, they often bleed from the stomach rather than the esophagus. As a result, nonoperative treatment options are limited, necessitating urgent or emergent surgical intervention in most cases. Many patients who bleed from varices in the United States are alcoholics, and the number of surgeons experienced in emergency shunt surgery is limited. Therefore, surgical rescue of less than 50% of sclerotherapy failures as was achieved in our trial is probably more realistic for most hospitals than the remarkable 92% salvage rate achieved by the Atlanta surgeons. Ideally, sclerotherapy failure would be predictable so that elective shunt surgery rather than long-term variceal sclerosis could be chosen for such patients. In the present study, one index of hepatic function (total serum bilirubin level) and one coagulation parameter (partial thromboplastin time) significantly differentiated sclerotherapy patients who had rebleeding episodes from those who did not, but the overlap between the groups was extensive, and no variable reliably predicted those patients in whom this therapeutic approach would ultimately fail. Both Child's class and GEC tended to be lower in patients in the Atlanta investigation who had unsuccessful sclerotherapy [2]. Other authors have also reported less success with endoscopic sclerotherapy in patients with limited functional hepatic reserve [13,14]. However, surgical morbidity and mortality rates are also higher in such patients. Hepatic transplantation, which was not widely available when our study and the Atlanta trial were initiated, is probably the best treatment option for many patients with variceal bleeding with advanced hepatic functional decompensation. The most frequently stated objections to shunt surgery as compared with long-term sclerotherapy are an increased early mortality rate, a higher likelihood of encephalopathy, and greater expense. In the five controlled trials of shunt versus sclerotherapy, early mortality (within 30 days) was similar in both groups [1-5]. Encephalopathy was more common after portacaval shunt in one
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RIKKERS ET AL
trial, but severe psychoneurologic dysfunction was infrequent in both arms of that investigation [5]. A significantly higher incidence of encephalopathy after the distal splenorenal shunt was observed in another study, but the retroperitoneal surgical approach used precluded ligation of the coronary vein and other collaterals, possibly leading to a more rapid attrition of hepatic portal perfusion than usually occurs after selective variceal decompression [3]. Although long-term sclerotherapy was more effective than the distal splenorenal shunt in preserving portal flow to the liver in our study as well as in the Atlanta investigation [2], over 50% of shunt patients maintained portal perfusion into the later postoperative interval. Clinical encephalopathy was no more common in the shunt groups than in the sclerotherapy arms of these two trials. The fairly high incidence of spontaneous encephalopathy in both groups of our trial (shunt: 23%, sclerotherapy: 13%) is most likely due to the length of followup. A higher percentage of our shunt patients developed subclinical encephalopathy as manifested by an abnormal score on a psychometric test. A greater number of shunt patients had abnormal EEGs and psychometric tests on the preoperative evaluation, although the difference was not statistically significant. In none of the trials in which it has been calculated has the total cost of treatment been greater after a shunt than after long-term sclerotherapy [1,5,15]. It has become increasingly apparent that no single therapy is ideal for all cirrhotic patients who experience variceal hemorrhage. In fact, in many cases, a sequence of treatments, e.g., sclerotherapy to shunt to transplant, may provide the best results [16]. In order to accrue sufficient numbers of patients, most controlled trials considering this problem have included patients with a variety of liver diseases and a wide spectrum of socioeconomic circumstances. In general, two therapeutic approaches have been compared. The present investigation is no exception. For the heterogenous population of patients included, selective variceal decompression was superior to long-term sclerotherapy with regard to both control of bleeding and long-term survival. However, two thirds of bleeding deaths in the sclerotherapy group were in either rural and/or noncompliant patients. As other investigators have reported, these two treatment modalities may be more equivalent when the study population consists of compliant urban patients, especially those with good hepatic function [2-5]. In such patients, a reasonable initial approach is sclerotherapy. When it is apparent that sclerotherapy is failing because of the frequency or severity of recurrent hemorrhage, those patients with good hepatic reserve should undergo prompt shunt surgery, whereas transplantation should be considered in patients with advanced liver dysfunction who are otherwise acceptable candidates. REFERENCES 1. Rikkers LF, Burnett DA, Volentine GD, Buchi KN, Cormier RA. Shunt surgery versus endoscopic sclerotherapy for long-term treatment of varieeal bleeding: early results of a randomized trial. Ann Surg 1987; 206: 261-71. 32
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2. Henderson JM, Kutner MH, Millikan WJ Jr, et al. Endoscopic variceal sclerosiscompared with distal splenorenal shunt to prevent recurrent variceal bleeding in cirrhosis: a prospective, randomized trial. Ann Intern Med 1990; 112: 262-9. 3. Teres J, Bordas JM, Bravo D, et al. Sclerotherapy vs. distal splenorenal shunt in the elective treatment of variceal hemorrhage: a randomized controlled trial. Hepatology 1987; 7: 430-6. 4. Spina GP, Santambrogio R, Opocher E, et al. Distal splenorenal shunt versus endoscopicsclerotherapy in the prevention of variceal rebleeding. Ann Surg 1990; 211: 178-86. 5. Planas R, Boix J, Broggi M, et al. Portacaval shunt versus endoscopic sclerotherapy in the electivetreatment of variceal hemorrhage. Gastroenterology 1991; 100: 1078-86. 6. Efron B. Biostatistics casebook. Miller RG, editor. New York: John Wiley and Sons, Inc., 1980: 19-30. 7. Campbell DP, Parker DE, Anagnostopoulos CE. Survival prediction in portacaval shunts: a computerized statistical analysis. Am J Surg 1973; 126: 748-51. 8. Tygstrup N. The galactose elimination capacity in control subjects and in patients with cirrhosis of the liver. Acta Med Scand 1964; 175: 281-9. 9. Moody FG, Rikkers LF, Aldrete JS. Estimation of the functional reserve of human liver. Ann Surg 1974; 180: 592-8. 10. Conn HO. Trailmaking and number connection tests in the assessment of mental state in portal-systemic encephalopathy. Am J Dig Dis 1977; 22: 541-50. 11. Henderson JM, Millikan WJ Jr, Wright L, et al. Quantitative estimation of metabolic and hemodynamic function: the effects of shunt surgery. Surg Gastroenterol 1982; 1: 77-85. 12. Burroughs AK, McCormick PA. Prevention of variceal rebleeding. Gastroenterol Clin North Am 1992; 21: 119-47. 13. Sauerbruch T, Weinziere M, Ansari H, et al. Injection sclerotherapy of oesophageal variceal hemorrhage: a prospective longterm follow-up study. Endoscopy 1987; 19: 181-6. 14. Van Hottegem P, Van BesienK, Broeckaert L, et al. Endoscopic sclerotherapy of esophageal varices. J Clin Gastroenterol 1988; 10: 368-73. 15. Cello JP, Grendell JH, Crass RA, Weber TE, Trunkey DD. Endoscopic sclerotherapy versus portacaval shunt in patients with severe cirrhosis and acute variceal hemorrhage: long-term followup. N Engl J Med 1987; 316: 11-5. 16. Rikkers LF. Definitivetherapy for variceal bleeding:a personal view. Am J Surg 1990; 160: 80-5.
DISCUSSION J. Henderson (Cleveland, OH): In our study, as you have pointed out, we had different results. After a followup of 9 years, our data remain the same as previously published. After 9 years, the survival rate in our randomized sclerotherapy group, one third of whom have required surgical rescue, is 50%, and in our shunt group, the survival rate is 30%. The survival curves remain parallel at 9 years, with a survival advantage to patients randomized to sclerotherapy. Our study was initiated 10 years ago. We concluded that sclerotherapy is a good management option for patients with acute variceal bleeding. How should we proceed with patients whose bleeding has stabilized? You conducted quantitative tests. Should these tests play a role in the selection of patients who are to undergo shunt surgery? How many patients would you now treat with transplantation rather than shunt surgery? There are other therapies on the horizon. We're going
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to hear a lot more about intrahepatic portal systemic shunts (TIPS) in the next few years. Is there a role for this procedure? Which patients are now considered for shunt surgery? I think sclerotherapy should be used to stabilize patients initially, giving us time to fully evaluate them and to prepare a treatment strategy in the event of rebleeding or when their varices appear to be high risk. Layton F. Rikkers: We have also performed quantitative tests of liver function. One of the few predictors of long-term survival in the shunt group was the galactose elimination capacity. Although we are not presently measuring this parameter in all patients with bleeding varices, I believe that we should do so. Those patients with low results should probably undergo transplantation. Currently, our major selection criterion is Child's classification. Patients who are Child's class A or B and have no other symptoms of liver disease other than variceal hemorrhage undergo either initial long-term sclerotherapy or shunt surgery. Patients who are Child's class C or who have significant symptoms of liver disease, such as fatigue, bone pain, or ascites, should undergo initial transplantation. At our institution, only patients who have access to tertiary medical and surgical care undergo longterm sclerotherapy. Those patients who live in remote geographic areas generally undergo an initial shunt operation if they are not considered to be immediate transplant candidates. Although I believe that TIPS will be an excellent bridge to transplantation for those patients who have a failure of acute sclerotherapy, we have no experience with the TIPS procedure. Whether this new shunt will be effective in the long-term remains to be proven. The effects of this procedure on hepatic portal perfusion and late shunt patency have not yet been determined. I. J. S a d e h (Irvine, CA): The rebleeding rate of 63% after long-term sclerotherapy seems to indicate that this modality has provided little, if any, protection from variceal hemorrhage, at least in the group of patients that you studied. We should remember that your patient population consisted mostly of alcoholics. As we and others have demonstrated, alcohol is extremely damaging to the portal hypertensive gastric mucosa. Moreover, D'Amico recently demonstrated that sclerotherapy increases the incidence and severity of congestive gastropathy. Was gastropathy a cause of rebleeding in your patients?
L a y t o n F. Rikkers: Sixty percent, not 63%, of our sclerotherapy patients experienced rebleeding during the follow-up period. The percentage of patients who had rebleeding during long-term sclerotherapy ranges from 40% to 60% in the literature. Since we had so few patients with nonalcoholic liver disease in our trial, I cannot determine whether sclerotherapy failure is more frequent in alcoholic patients than in those with nonalcoholic diseases. Approximately two thirds of our patients with sclerotherapy failure had bleeding of the stomach, either from gastric varices or portal hypertensive gastropathy. K. J. Paquet: (Bad Kissingen, Germany): Your conclusions have changed since your original publication in which you concluded that the two modalities are equal. Should patients classified as Child's C be included in this trial? Thirty-three percent of your patients were Child's C, and no modality seems to prolong survival in these patients. Are you able to perform a distal splenorenal shunt in a high percentage of patients with alcoholic disease, especially in those who have pancreatitis? In our trial, we were not able to perform distal splenorenal shunt in 20% of our patients and performed a narrow lumen mesocaval interposition shunt. After long-term follow-up, there was no difference in encephalopathy or shunt patency between these two shunts. Layton F. Rikkers: Patients with Child's C liver disease tend to do poorly with all palliative therapies. We prefer to perform transplantation in such patients whenever possible. Unfortunately, many Child's C patients are not candidates for transplantation because they are unreformed alcoholics or for other reasons. Although there is no good solution for these individuals, we initially treat them with long-term sclerotherapy and then perform the appropriate shunt procedure if the patient is still salvageable, when and if sclerotherapy fails to control their bleeding. If they have intractable ascites at that time, we perform some type of side-to-side shunt. Otherwise, we would prefer a distal splenorenal shunt. In contrast to your experience, we have seldom been prevented from doing a distal splenorenal shunt in an alcoholic cirrhotic patient because of prior pancreatitis. For unknown reasons, liver disease and chronic pancreatitis seldom coexist in alcoholic patients.
THE AMERICAN JOURNAL OF SURGERY VOLUME 165 JANUARY 1993 33
Between September 1982 and April 1988, 60 cirrhotic patients with prior variceal hemorrhage were randomized to undergo the placement of an elective shunt (distal splenorenah 26; nonselective: 4) or long-term endoscopic sclerotherapy (n = 3 0 ) . Eighty-six percent of patients had alcoholic cirrhosis, and 33% were classified as Child's class C. After a mean follow-up of 87 months, 60% of patients undergoing sclerotherapy and 17% of shunt patients experienced rebleeding (p < 0 . 0 0 1 ) . Shunt patients have survived longer than those who had selerotherapy (6-year survival rates of 53% and 26%, respectively; p < 0 . 0 5 ) . in part because of the wide geographic distribution of patients, only 4, of 13 patients in whom sclerotherapy failed (31%) could undergo salvage by shunt surgery. Although hepatic portal perfusion was better maintained after sclerotherapy, there were no major differences between the groups in terms of post-therapy hepatic or psychoneurologic function. In a predominantly alcoholic cirrhotic patient population (haft non-urban), the results of elective shunt surgery were superior to those of chronic endoscopic sclerotherapy with respect to the prevention of recurrent variceal hemorrhage and survival.
From the Departments of Surgery (LFR, GJ, RAC) and Medicine (DAB),Universityof Nebraska MedicalCenter,Omaha VeteransAdministration MedicalCenter,Omaha, Nebraska,and the Universityof Utah Schoolof Medicine(KNB),Salt LakeCity VeteransAdministration MedicalCenter,Salt LakeCity,Utah. Supportedby PublicHealth ServiceGrant #5 R01 DK35168and GeneralClinicalResearchCenter PublicHealth ServiceGrant #5M01RR00064: Requests for reprints should be addressed to Layton F. Rikkers, MD, Departmentof Surgery;UniversityOfNebraska MedicalCenter, 600 South42nd Street, Omaha, Nebraska68198-3280. Presentedat the 33rdAnnualMeetingof the Societyfor Surgeryof the AlimentaryTract, San Francisco,California,May 11-! 3, 1992.
" n 1982, we initiated a controlled trial comparing elecltherapy . tire shunt surgery with long-term endoscopic sclerofor the prevention of recurrent variceal hemorrhage in patients with cirrhosis and portal hypertension. Because the distal splenorenal shunt has the potential of preserving hepatic portal perfusion, it was selected for use in the majority of shunt patients. At the time of our preliminary report in 1987, after a mean follow-up in each group of 2 years, reblecding was more frequent after sclerotherapy, but survival curves for the two groups were similar [1]. One-year data revealed better preservation of hepatic portal perfusion by sclerotherapy, but no significant differences between groups with respect to functional hepatic reserve or the frequency of encephalopathy. Four other studies comparing the use of the elective shunt with scierotherapy have also found a higher incidence of rebleeding after sclerotherapy [2-5]. Survival has been similar after shunt placement and sclerotherapy in three of these investigations [3-5]. Endoscopic variceal sclerosis with surgical rescue of sclerotherapy failures has resulted in longer survival than the distal splenorenal shunt in the remaining trial [2]. The purpose of this report is to evaluate our long-term results. Patient accrual was terminated in April 1988 so all surviving patients were followed for a minimum of 4 years (range: 48 to 118 months), with a mean follow-up of over 7 years. PATIENTS AND M E T H O D S Sixty patients with cirrhosis and variceal hemorrhage were randomized to undergo either shunt surgery or 10ngterm endoscopic scler0therapy between September 1982 and April 1988. During the initial 2 years of the trial, patients were accrued from the University of Utah Medical Center (n = 19) and Salt Lake Veterans Administration Medical Center (n = 16). The principal investigator moved to the University of Nebraska Medical Center in August 1984, and since that time, patients have been selected from that institution (n ffi 9) and from the Omaha Veterans Administration Medical Center (n ffi 16). During the period of this investigation, 183 cirrhotic patients were treated for variceal bleeding at these institutions. To be considered for inclusion in the trial, patients had to meet several criteria:(1) portal hypertension secondary to cirrhosis; (2) endoscopic documentation of acute or recent esophageal variceal hemorrhage requiring a minimum transfusion of 3 U of blood; (3) residence within 500 miles of Salt Lake City or Omaha; (4) nonoperative control of acute variceal hemorrhage; and (5)
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TABLE I
Preoperative Comparison of S h u n t and Sclerotherapy Groups
Alcoholic cirrhosis Veterans Administration patients Non-urban Child's score Child's class C Galactose elimination capacity (mg/min) lndocyanine green (mg/kg/min) Effective hepatic blood flow (mL/min) Corrected sinuSoidal pressure (mm Hg) Prograde portal flow Encephalopathy Abnormal electroencephalOgram Abnormal number Connection test
Shunt Group (n = 30)
Sclerotherapy Group (n = 30)
25 16
27 16
17 6.6 -+ 0.4 10 266 -+ 18 (21)*
16 6.6 --- 0.4 10 265 • 16 (22)
0.20 -+ 0.03 (20)
0.19 -+ 0.03 (21)
1,369 -- 73 (23)
1.314 -+ 92- (22)
16.1 __ 0,9 (26)
16.6 +_ 1.2 (27)
29 9 10 (24)
26 (28) 8 4 (23)
t O (29)
7 (27)
*Parentheses denote number of patients tested if less than full group.
1
~ u
r
- -"
o
'
I
20
'
I
I
40
~
~"
I
80
....
'
~
- - -'~
I
SCLERO
'
120
1~
MONTHS
Figure 1. Kaplan-Meler survival <~urves for Shunt ( n ) and sclerol h e r a p y (Zl) groups. Shunt patients survived significantly longer than sclerottterapy patients (p < 0 . 0 5 ) .
TABLE II
Causes Of Death Shunt Group Bleeding Hepatic failure Hepatic failure with continued drinking Hepatoma Pneumonia Aneu~sm Esophageal cancer Myocardial infarction Accident Unknown Total
28
Sclerotherapy Group
1 5 5
8 4 5
1 0 1 0 1 0 1 15
1 2 0 1 0 1 1 23
THE AMERICAN JOURNAL OF SURGERY
patency of splenic and portal veins documented by selective angiography. After the informed consent of the patients was obtained, patients were randomized using Efron's biased coin design [6] based on three liver function strata (modified Child's classification) and type of hospital (university or Veterans Administration). Thirtyone patients were randomized to shunt surgery, and 29 patients were randomized to endoscopic sclerotherapy. One patient who refused surgery was treated with endoscopic sclerotherapy and was included in that group for all subsequent analyses. Endoscopic sclerotherapy was performed using a flexible endoscope with intravariceal injections of either 0.75% sodium tetradecyl sulfate and 50% dextrose (first 2 years) or 5% sodium morrhuate (last 8 years). All variceal columns were injected just above and at 5 cm proximal to the esophagogastric jUnction. Balloons and overtubes were not used. Sclerotherapy was performed on a schedule of every 4 to 6 days until most varices were eradicated. The next session was scheduled for 1 month and then as necessary at 6-month intervals. The patients in the sclerotherapy group had 7.6 4- 0.9 endoscopic sclerosis treatments, with a range from 1 to 23 treatments. The only major complication other than rebleeding was esophageal stricture, which developed in three patients, all of whom were successfully managed by esophageal dilatation. One sclerotherapy patient was diagnosed with esophageal cancer 1 year after the initiation of sclerotherapy. Surgical variceal decompression was accomplished with a distal splenorenal shunt without splenopancreatic disconnection in 26 patients. Three patients with medically intractable ascites received either a side-to-side portacaval shunt (n = 1) or a Dacron graft interposition shunt (n = 2). One patient who experienced massive rebleeding soon after randomization underwent an emergency endt0-side portacaval shunt. All shunts were performed by a single surgeon (LFR). The failure of therapy was defined as shunt thrombosis for the shunt group and as death secondary to bleeding or the need for salvage surgery to control recurrent bleeding in the sclerotherapy group. The decision for surgical intervention was made by the referring gastroenterologist. Patient evaluation: All patients underwent a comprehensive evaluation of their hepatic hemodynamic status, functional hepatic reserve, and psychoneurologic status after randomization. In addition to intermittent clinic visits and contact by telephone, as many patients as possible returned for a comprehensive assessment at 3 months, 1 year, and 3 to 6 years after the initiation of therapy. The details of patient evaluation are included in the preliminary report of this trial [1]. Functional hepatic reserve was assessed by a modified Child's classification [7], galactose elimination capacity (GEC) [8], and the removal rate of a 5 mg/kg intravenous dose of indocyanine green [9]. Child's score was derived by totaling the grades (1 to 3) of four variables (serum albumin level, total bilirubin level, encephalopathy, and ascites: 4 to 5 -A, 6 t o 7 = B, 8 to 12 = C).
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Psychoneurologic status was assessed by clinical evaluation, electroencephalography (EEG), and psychometric testing. An episode of encephalopathy was defined as an incident of mental confusion related by the patient or a family member, or detection of disorientation on interview or asterixis on physical examination by a physician. Encephalopathy was considered mild if it was transient and did not require hospitalization and moderate when it required hospital care and/or prolonged treatment with lactulose and dietary protein restriction. Induced encephalopathy was defined as that occurring during gastrointestinal hemorrhage. The number connection test (NCT) was used for psychometric testing (normal: less than 50 seconds) [10]. Hepatic hemodynamic status was assessed by selective visceral angiography, measurement of corrected sinusoidal pressure (CSP), duplex ultrasonography, and quantitation of effective hepatic blood flow (EHBF) by a low-dose galactose clearance technique [11]. Hepatopetal (toward the liver) portal flow was considered to be present if the intrahepatic portal venous branches opacifled during the venous phase of the selective superior mesenteric angiography or prograde portal flow was detected by duplex ultrasonography. CSP was measured as hepatic venous wedge pressure minus free hepatic vein pressure during visceral angiography. Shunt patency status was determined by selective angiography. Statistical analysis: All results are expressed as mean 4- standard error of the mean. The Kaplan-Meier method was used to plot survival curves, which were statistically compared by the log likelihood ratio test. Shunt and sclerotherapy groups were compared at the various time points by X2 analysis and the unpaired Student's t-test. RESULTS Patient follow-up: As of April 1992, surviving sclerotherapy and shunt patients had been followed up for a mean of 92 • 7 months and 85 4- 5 months, respectively. All patients had been followed up for a minimum of 48 months, and the longest survivingpatienthad a follow-up of 118 months. Although the survivalstatusof allpatients was known, latepostoperativeevaluations were not possible for two patients in each group. Pretherapy comparisons: The two groups were comparable at randomization (Table I). Most patients had alcoholic cirrhosis,half were veterans, half lived in nonurban settings,and a third in each group were Child's classC. Except for one patientin each group with spontaneous encephalopathy, all episodes of preoperative encephalopathy were induced by gastrointestinalhemorrhage. Survival: There was a singleoperative death (3%) in the shunt group in an elderly patient (Child's class B) who underwent an emergency portacaval shunt when he experienced massive rebleeding the day afterrandomization. One sclcrotherapy patient died of uncontrolled bleeding after a single sclerosissession. All remaining patients survived for a minimum of 3 months after the initiationof treatment. Kaplan-Meier survival curves for the two groups of
TABLE lII
Quantitative Hepatic Function and Child's Score
Child's Score
Galactose Elimination Capacity (mg/min)
Indocyanine Green (mg/kg/min)
Shunt Preshunt Postshunt 3mo 1y 3-6 y
6.6 • 0.4 (30)*
266 • 18 (21)
0.20 _+ 0.03 (20)
6.3_+0.4(27) t 5.9 _+ 0.4 (21) 4.9 _+ 0.4 (11)
248_+23(20) 267 _+ 23 (17) 259 _+ 15 (6)
0.15_+0.02(17) 0.22 • 0.05 (15) 0.27 _+ 0.09 (5)
Sclerotherapy Presclero-
6.6 -+ 0.3 (30)
265 +- 16 (22)
0.19 • 0.03 (21)
5.3_+0.3(24) t 5.6 _+ 0.4 (19) 5.3 +_ 0.5 (12)
2 6 4 • 19 (22) 259 _+ 17 (17) 241 • 15 (6)
0.20• 0.20 • 0.03 (17) 0.17 • 0.05 (6)
therapy Postsclerotherapy 3mo 1y 3-6y
*Parentheses denote number of patients tested. tp <0.05.
TABLE IV
Hepatic Hemodynamic Data Prograde Portal Flow
Corrected Sinusoidal Pressure (ram Hg)
Effective Hepatic Blood Flow (mL/min)
29 (30)*
16.1 • 0.9 (26)
1,369 • 73 (23)
3 mo ly 3-6 y
22 (28) 6(12) t 4 (8)
18.2 • 1.5 (21) 9.9+_1.1 (7)t 8.5 • 2.0 (4)
1,176 _+ 85 (21) 1,113+_76(16) 1,293 • 82 (5)
Sclerotherapy Presclero-
26 (28)
16.6 • 1.2 (27)
1,313 -+ 92 (21)
12(13) 11 (12)* 3 (3)
17.1 • (8) 16.4 • 1.8 (8)* --
1,259-+68(22) 1,230 • 71 (17) 1,278 _+ 43 (2)
Shunt Preshunt
Postshunt
therapy Postsclerotherapy 3mo 1y 3-6 y
*Parentheses denote number of patients tested. tp <0.01.
patients as of April 1992 are shown in Figure 1. The survival of patients undergoing shunt surgery was significantly better than that of those receiving long-term sclerotherapy (p <0.05). The estimated 6-year survival rate in shunt patients was 53% as compared with 26% in sclerotherapy patients. Two of seven surviving sclerotherapy patients underwent salvage by shunt surgery. No preoperative variable predicted long-term survival in the sclerotherapy group. Both preoperative Child's score (alive: 5.9 • 0.5, dead: 7.3 4- 0.5, p <0.05) and GEC (alive: 300 4- 27, dead: 229 4- 27, p <0.05) were predictors of survival in the shunt group. A similar number of shunt and sclerotherapy patients died secondary to hepatic failure
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RIKKERS ET AL
TABLE V C u m u l a t i v e P s y c h o n e u r o l o g i c Data Shunt PrePostoperative operative Spontaneous PSE Mild Moderate Induced PSE Total PSE Abnormal electroencephalogram Abnormal NCT
Sclerotherapy PrePostoperative operative
0 1 7 8 10 (24)*
3 4 0 7 11 (24)
2 0 7 9 4 (23)
1 3 4 8 7 (24)
10 (29)
t 2 (24) t
7 (27)
5 (24) t
PSE = portal systemic encephalopathy; NCT = number connection test. *Parentheses denote number of tp < 0.05.
patients tested.
and to miscellaneous causes (Table H). The excess number of deaths in the sclerotherapy group was due to recurrent Needing. Of the 49 alcoholic cirrhotic patients who survived for longer than 3 months, 28 (57%) returned to alcoholism. However, alcoholic recidivism was not a predictive factor for long-term survival in either group. Reeurrent hemorrhage: The number of patients who experienced rebleeding (shunt: 5 [17%], sclerotherapy: 18 [60%], p <0.001), the number of rebleeding episodes (shunt: 5, sclerotherapy: 57, p <0.001), and the units of transfused blood required (shunt: 28, sclerotherapy: 314, p <0.001) were all greater in the sclerotherapy group. All episodes of recurrent hemorrhage were the result of varices or portal hypertensive gastropathy. Three patients (10%) developed shunt thrombosis (two distal splenorenal shunts; one interposition portacaval shunt), and all three experienced rebleeding of varices. During the early postoperative period, two patients with patent distal splenorenal shunts had rebleeding of esophageal varices and portal hypertensive gastropathy, respectively. Sixty percent of the 57 rebleeding episodes in the sclerotherapy group occurred during the first year after the initiation of treatment, 31% occurred between years 1 and 3, and 9% occurred after 3 years. Preoperative total bil/rubin levels (p = 0.006) and partial thromboplastin times (p ffi 0.02) were significantly higher in sclerotherapy patients who had rebleeding than in those who did not. All other preoperative variables were similar in these two subgroups. Therapy failm'e: Therapy failure (death as a result of bleeding or the need for salvage operation) developed in 3 shunt patients (10%) and in 13 sderotherapy patients (43%, p <0.01). The three shunt failures were all due to shunt thrombosis. Two of these patients had successful shunt reoperations (one end-to-side portacaval shunt and one interposition mesorenal shunt), and one died of persistent bleeding and hepatic failure after splenectomyand esophagogastrir devascularization. Mean time to sclerotherapy failure was 17 4- 4 months after an average of 2.5 4- 0.4 bleeding episodes 30
THE AMERICAN JOURNAL OF SURGERY
and 7.8 4- 1.3 sclerotherapy treatments. Eight patients who had unsuccessful endoscopic variceal sclerosis bled to death before surgical salvage could be attempted. Five of these patients lived in non-urban areas, one refused further treatment, and one had massive rebleeding after the first sclerosis session. The remaining patient was judged to have terminal hepatic failure secondary to rebleeding by the time he was referred for surgery. Five patients in whom sclerotherapy failed underwent emergency salvage operations (four end-to-side portacaval shunts and one splenectomy plus esophagogastric devascularization), and four survived, for an overall salvage rate of 31%. Only one of these patients lived in a nonurban area. Esophageal varices were successfully eradicated in eight patients who had sclerotherapy failure (62%) with rebleeding from either gastric varices (n ffi 5) or portal hypertensive gastropathy (n = 3). The five remaining patients who experienced sclerotherapy failure had residual esophageal varices, but two patients also had prominent gastric varices, and the exact site of bleeding could not be determined. No pretherapy variables predicted those patients in whom sclerotherapy would ultimately fail. Quantitative hepatic function: With the exception of Child's score, which was lower (better hepatic function) in sclerotherapy patients at 3 months, there were no significant differences between groups at any time interval in the quantitative measures of hepatic function (Ta-
ble m). Hepatic hemodynamie data: All nonselective shunt patients in both groups lost portal flow immediately after surgery and were not further evaluated. Although portal perfusion was well maintained at all study intervals in sclerotherapy patients, only 50% of distal splenorenal shunt patients had continuing portal flow to the liver at 1 year and at 3 to 6 years after surgery (Table IV). CSP was also significantly lower in the shunt group at 1 year. Total EHBF was similar in both groups at aU study intervals. Eneephalopathy: The total incidence of clinically detectable encephalopathy was similar after shunt and sclerotherapy (Table V). Spontaneous episodes of encephalopathy tended to be more common in shunt patients, whereas encephalopathy that was induced by gastrointestinal bleeding occurred in the sclerotherapy group only. No patient in either group had severe, disabling encephalopathy. Subclinical encephalopathy, defined as at least one abnormal NCT at any time after the initiation of therapy, developed in significantly more shunt patients. More shunt patients than sclerotherapy patients had abnormal EEGs and NCTs on the preoperative evaluation, making them potentially more prone to abnormal tests postoperatively. COMMENTS Five randomized, controlled trials have compared elective shunt surgery with long-term endoscopic sclerotherapy for the prevention of recurrent variceal hemorrhage in patients with cirrhosis [1-5]. Four of these investigations, including the present one, have either exclusive-
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ly or predominantly utilized the selective distal splenorenal shunt in the surgical arm of the trial [1-4]. A common finding of all of these studies is the clear superiority of surgical portal decompression over long-term endoscopic variceal sclerosis for prevention of recurrent bleeding. The percentage of patients who experienced rebleeding ranged from 3% to 17% for the shunt groups and from 35% to 60% for those randomized to sclerotherapy. These relatively high rebleeding rates for patients receiving long-term sclerotherapy are consistent with the extensive experience reported in the literature for this treatment option [12]. The unique finding of the present study, which differs from our earlier preliminary report [1] and from the other published trials [2-5], is that survival was significantly prolonged in patients who underwent shunt placement. The survival advantage of the shunt patients was due to an excess of bleeding deaths in the sclerotherapy group. The numbers of patients who died of hepatic failure and of miscellaneous causes in the two treatment groups were nearly identical. Three controlled trials, all with follow-up of 2 years or less, have found no difference in survival between shunt and sclerotherapy groups [3-5]. The Atlanta investigation reported longer survival for sclerotherapy patients, a third of whom underwent surgical portal decompression when they could no longer be successfully managed by sclerotherapy [2]. This latter trial and our own contain several similarities and some important differences. Both investigations were nearly identical in design, were conducted in the United States, and had the longest available follow-up of the surviving patients. The Atlanta patients were followed for a median of 5 years, during which 59% of sclerotherapy patients had rebleeding. Thirty-five percent of sclerotherapy patients eventually experienced a failure of this treatment as defined by death secondary to hemorrhage or the necessity of undergoing a rescue operation to definitively control rebleeding. The mean patient follow-up in the present report exceeds 7 years, and the rebleeding and failure of therapy rates in the sclerotherapy group are 60% and 43%, respectively. The major difference in these two trials, which is most likely responsible for the conflicting survival results, is that nearly all patients who had failure of sclerotherapy (92%) in the Atlanta trial underwent successful salvage by shunt surgery, whereas nearly two thirds of our patients who had sclerotherapy failure bled to death before an operation could be performed. The percentage of patients who eventually had a failure of endoscopic sclerotherapy in the other trials with shorter lengths of follow-up were 5% [4], 20% [3], and 23% [5], respectively; salvage therapy was successful in fewer than half of these patients. Why was the salvage rate of sclerotherapy failure so much higher in the Atlanta investigation? Is a salvage rate of 92% for patients who continue to bleed despite repeated attempts at sclerotherapy a realistic goal for most institutions who treat patients with portal hypertension? Characteristics of the Atlanta patient population that might contribute to the good sclerotherapy results include residence within the Atlanta metropolitan area,
allowing rapid referral for surgery when recurrent hemorrhage developed, and a relatively high percentage (40%) of patients with nonalcoholic cirrhosis, increasing the likelihood of compliance with any treatment regimen [2]. In contrast, many of our patients were referred from small communities in the intermountain West and Great Plains, over half were derived from the Veterans Administration system, and most (87%) were alcoholic. Five of the eight sclerotherapy patients who bled to death lived in non-urban areas, and one Omaha patient refused further treatment when bleeding recurred. Based on the results of this trial, we have concluded that an elective portal-systemic shunt is a safer and more effective option than long-term sclerotherapy for patients with variceal bleeding who do not have tertiary medical care readily available to them. Patients who experience bleeding from gastric varices, which are generally ineffectively treated by sclerotherapy, and those who are unlikely to be compliant with respect to a long-term sclerotherapy schedule are also probably better served by a shunt placement. When patients have a failure of sclerotherapy, they often bleed from the stomach rather than the esophagus. As a result, nonoperative treatment options are limited, necessitating urgent or emergent surgical intervention in most cases. Many patients who bleed from varices in the United States are alcoholics, and the number of surgeons experienced in emergency shunt surgery is limited. Therefore, surgical rescue of less than 50% of sclerotherapy failures as was achieved in our trial is probably more realistic for most hospitals than the remarkable 92% salvage rate achieved by the Atlanta surgeons. Ideally, sclerotherapy failure would be predictable so that elective shunt surgery rather than long-term variceal sclerosis could be chosen for such patients. In the present study, one index of hepatic function (total serum bilirubin level) and one coagulation parameter (partial thromboplastin time) significantly differentiated sclerotherapy patients who had rebleeding episodes from those who did not, but the overlap between the groups was extensive, and no variable reliably predicted those patients in whom this therapeutic approach would ultimately fail. Both Child's class and GEC tended to be lower in patients in the Atlanta investigation who had unsuccessful sclerotherapy [2]. Other authors have also reported less success with endoscopic sclerotherapy in patients with limited functional hepatic reserve [13,14]. However, surgical morbidity and mortality rates are also higher in such patients. Hepatic transplantation, which was not widely available when our study and the Atlanta trial were initiated, is probably the best treatment option for many patients with variceal bleeding with advanced hepatic functional decompensation. The most frequently stated objections to shunt surgery as compared with long-term sclerotherapy are an increased early mortality rate, a higher likelihood of encephalopathy, and greater expense. In the five controlled trials of shunt versus sclerotherapy, early mortality (within 30 days) was similar in both groups [1-5]. Encephalopathy was more common after portacaval shunt in one
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trial, but severe psychoneurologic dysfunction was infrequent in both arms of that investigation [5]. A significantly higher incidence of encephalopathy after the distal splenorenal shunt was observed in another study, but the retroperitoneal surgical approach used precluded ligation of the coronary vein and other collaterals, possibly leading to a more rapid attrition of hepatic portal perfusion than usually occurs after selective variceal decompression [3]. Although long-term sclerotherapy was more effective than the distal splenorenal shunt in preserving portal flow to the liver in our study as well as in the Atlanta investigation [2], over 50% of shunt patients maintained portal perfusion into the later postoperative interval. Clinical encephalopathy was no more common in the shunt groups than in the sclerotherapy arms of these two trials. The fairly high incidence of spontaneous encephalopathy in both groups of our trial (shunt: 23%, sclerotherapy: 13%) is most likely due to the length of followup. A higher percentage of our shunt patients developed subclinical encephalopathy as manifested by an abnormal score on a psychometric test. A greater number of shunt patients had abnormal EEGs and psychometric tests on the preoperative evaluation, although the difference was not statistically significant. In none of the trials in which it has been calculated has the total cost of treatment been greater after a shunt than after long-term sclerotherapy [1,5,15]. It has become increasingly apparent that no single therapy is ideal for all cirrhotic patients who experience variceal hemorrhage. In fact, in many cases, a sequence of treatments, e.g., sclerotherapy to shunt to transplant, may provide the best results [16]. In order to accrue sufficient numbers of patients, most controlled trials considering this problem have included patients with a variety of liver diseases and a wide spectrum of socioeconomic circumstances. In general, two therapeutic approaches have been compared. The present investigation is no exception. For the heterogenous population of patients included, selective variceal decompression was superior to long-term sclerotherapy with regard to both control of bleeding and long-term survival. However, two thirds of bleeding deaths in the sclerotherapy group were in either rural and/or noncompliant patients. As other investigators have reported, these two treatment modalities may be more equivalent when the study population consists of compliant urban patients, especially those with good hepatic function [2-5]. In such patients, a reasonable initial approach is sclerotherapy. When it is apparent that sclerotherapy is failing because of the frequency or severity of recurrent hemorrhage, those patients with good hepatic reserve should undergo prompt shunt surgery, whereas transplantation should be considered in patients with advanced liver dysfunction who are otherwise acceptable candidates. REFERENCES 1. Rikkers LF, Burnett DA, Volentine GD, Buchi KN, Cormier RA. Shunt surgery versus endoscopic sclerotherapy for long-term treatment of varieeal bleeding: early results of a randomized trial. Ann Surg 1987; 206: 261-71. 32
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2. Henderson JM, Kutner MH, Millikan WJ Jr, et al. Endoscopic variceal sclerosiscompared with distal splenorenal shunt to prevent recurrent variceal bleeding in cirrhosis: a prospective, randomized trial. Ann Intern Med 1990; 112: 262-9. 3. Teres J, Bordas JM, Bravo D, et al. Sclerotherapy vs. distal splenorenal shunt in the elective treatment of variceal hemorrhage: a randomized controlled trial. Hepatology 1987; 7: 430-6. 4. Spina GP, Santambrogio R, Opocher E, et al. Distal splenorenal shunt versus endoscopicsclerotherapy in the prevention of variceal rebleeding. Ann Surg 1990; 211: 178-86. 5. Planas R, Boix J, Broggi M, et al. Portacaval shunt versus endoscopic sclerotherapy in the electivetreatment of variceal hemorrhage. Gastroenterology 1991; 100: 1078-86. 6. Efron B. Biostatistics casebook. Miller RG, editor. New York: John Wiley and Sons, Inc., 1980: 19-30. 7. Campbell DP, Parker DE, Anagnostopoulos CE. Survival prediction in portacaval shunts: a computerized statistical analysis. Am J Surg 1973; 126: 748-51. 8. Tygstrup N. The galactose elimination capacity in control subjects and in patients with cirrhosis of the liver. Acta Med Scand 1964; 175: 281-9. 9. Moody FG, Rikkers LF, Aldrete JS. Estimation of the functional reserve of human liver. Ann Surg 1974; 180: 592-8. 10. Conn HO. Trailmaking and number connection tests in the assessment of mental state in portal-systemic encephalopathy. Am J Dig Dis 1977; 22: 541-50. 11. Henderson JM, Millikan WJ Jr, Wright L, et al. Quantitative estimation of metabolic and hemodynamic function: the effects of shunt surgery. Surg Gastroenterol 1982; 1: 77-85. 12. Burroughs AK, McCormick PA. Prevention of variceal rebleeding. Gastroenterol Clin North Am 1992; 21: 119-47. 13. Sauerbruch T, Weinziere M, Ansari H, et al. Injection sclerotherapy of oesophageal variceal hemorrhage: a prospective longterm follow-up study. Endoscopy 1987; 19: 181-6. 14. Van Hottegem P, Van BesienK, Broeckaert L, et al. Endoscopic sclerotherapy of esophageal varices. J Clin Gastroenterol 1988; 10: 368-73. 15. Cello JP, Grendell JH, Crass RA, Weber TE, Trunkey DD. Endoscopic sclerotherapy versus portacaval shunt in patients with severe cirrhosis and acute variceal hemorrhage: long-term followup. N Engl J Med 1987; 316: 11-5. 16. Rikkers LF. Definitivetherapy for variceal bleeding:a personal view. Am J Surg 1990; 160: 80-5.
DISCUSSION J. Henderson (Cleveland, OH): In our study, as you have pointed out, we had different results. After a followup of 9 years, our data remain the same as previously published. After 9 years, the survival rate in our randomized sclerotherapy group, one third of whom have required surgical rescue, is 50%, and in our shunt group, the survival rate is 30%. The survival curves remain parallel at 9 years, with a survival advantage to patients randomized to sclerotherapy. Our study was initiated 10 years ago. We concluded that sclerotherapy is a good management option for patients with acute variceal bleeding. How should we proceed with patients whose bleeding has stabilized? You conducted quantitative tests. Should these tests play a role in the selection of patients who are to undergo shunt surgery? How many patients would you now treat with transplantation rather than shunt surgery? There are other therapies on the horizon. We're going
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to hear a lot more about intrahepatic portal systemic shunts (TIPS) in the next few years. Is there a role for this procedure? Which patients are now considered for shunt surgery? I think sclerotherapy should be used to stabilize patients initially, giving us time to fully evaluate them and to prepare a treatment strategy in the event of rebleeding or when their varices appear to be high risk. Layton F. Rikkers: We have also performed quantitative tests of liver function. One of the few predictors of long-term survival in the shunt group was the galactose elimination capacity. Although we are not presently measuring this parameter in all patients with bleeding varices, I believe that we should do so. Those patients with low results should probably undergo transplantation. Currently, our major selection criterion is Child's classification. Patients who are Child's class A or B and have no other symptoms of liver disease other than variceal hemorrhage undergo either initial long-term sclerotherapy or shunt surgery. Patients who are Child's class C or who have significant symptoms of liver disease, such as fatigue, bone pain, or ascites, should undergo initial transplantation. At our institution, only patients who have access to tertiary medical and surgical care undergo longterm sclerotherapy. Those patients who live in remote geographic areas generally undergo an initial shunt operation if they are not considered to be immediate transplant candidates. Although I believe that TIPS will be an excellent bridge to transplantation for those patients who have a failure of acute sclerotherapy, we have no experience with the TIPS procedure. Whether this new shunt will be effective in the long-term remains to be proven. The effects of this procedure on hepatic portal perfusion and late shunt patency have not yet been determined. I. J. S a d e h (Irvine, CA): The rebleeding rate of 63% after long-term sclerotherapy seems to indicate that this modality has provided little, if any, protection from variceal hemorrhage, at least in the group of patients that you studied. We should remember that your patient population consisted mostly of alcoholics. As we and others have demonstrated, alcohol is extremely damaging to the portal hypertensive gastric mucosa. Moreover, D'Amico recently demonstrated that sclerotherapy increases the incidence and severity of congestive gastropathy. Was gastropathy a cause of rebleeding in your patients?
L a y t o n F. Rikkers: Sixty percent, not 63%, of our sclerotherapy patients experienced rebleeding during the follow-up period. The percentage of patients who had rebleeding during long-term sclerotherapy ranges from 40% to 60% in the literature. Since we had so few patients with nonalcoholic liver disease in our trial, I cannot determine whether sclerotherapy failure is more frequent in alcoholic patients than in those with nonalcoholic diseases. Approximately two thirds of our patients with sclerotherapy failure had bleeding of the stomach, either from gastric varices or portal hypertensive gastropathy. K. J. Paquet: (Bad Kissingen, Germany): Your conclusions have changed since your original publication in which you concluded that the two modalities are equal. Should patients classified as Child's C be included in this trial? Thirty-three percent of your patients were Child's C, and no modality seems to prolong survival in these patients. Are you able to perform a distal splenorenal shunt in a high percentage of patients with alcoholic disease, especially in those who have pancreatitis? In our trial, we were not able to perform distal splenorenal shunt in 20% of our patients and performed a narrow lumen mesocaval interposition shunt. After long-term follow-up, there was no difference in encephalopathy or shunt patency between these two shunts. Layton F. Rikkers: Patients with Child's C liver disease tend to do poorly with all palliative therapies. We prefer to perform transplantation in such patients whenever possible. Unfortunately, many Child's C patients are not candidates for transplantation because they are unreformed alcoholics or for other reasons. Although there is no good solution for these individuals, we initially treat them with long-term sclerotherapy and then perform the appropriate shunt procedure if the patient is still salvageable, when and if sclerotherapy fails to control their bleeding. If they have intractable ascites at that time, we perform some type of side-to-side shunt. Otherwise, we would prefer a distal splenorenal shunt. In contrast to your experience, we have seldom been prevented from doing a distal splenorenal shunt in an alcoholic cirrhotic patient because of prior pancreatitis. For unknown reasons, liver disease and chronic pancreatitis seldom coexist in alcoholic patients.
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