A Randomized, Controlled Trial of the Distal Splenorenal Shunt LAYTON F. RIKKERS, M.D., * DANIEL RUDMAN, M.D., JOHN T. GALAMBOS, M.D., J. TIMOTHY FULENWIDER, M.D., WILLIAM J. MILLIKAN, M.D., MICHAEL KUTNER, PH.D., ROBERT B. SMITH, III, M.D., ATEF A. SALAMN, M.D., PETER J. JONES, JR., M.D., W. DEAN WARREN, M.D.
In 1971 a prospective, randomized trial was initiated to determine efficacy of the distal splenorenal shunt in the management of cirrhotic patients who had previously bled from esophageal varices. When entry into the trial was terminated in 1976, 26 patients had received the distal splenorenal shunt (selective) and 29 had undergone a nonselective shunting procedure (18 interposition mesorenal, six interposition mesocaval, and five other nonselective shunts). Three operative deaths occurred in each group. Early postoperative angiography revealed preservation of hepatic portal perfusion in 14 of 16 selective patients (88%), but in only one of 20 nonselective patients (5%; p < .001). Quantitative measures of hepatic function (maximal rate of urea synthesis or MRUS and Child's score) were similar to preoperative values in the selective group but were significantly decreased in nonselective patients on the first postoperative evaluation (p < .001 for MRUS; p < .05 for Child's score). Eighty-seven per cent of selective and 81% of nonselective patients have now been followed for three to six years since surgery. Late postoperative evaluation of 29 survivors (12 selective, 17 nonselective) still shows an advantage to the selective group with respect to MRUS, Child's score, and incidence of hepatopetal portal blood flow, but differences are no longer statistically significant. However, if the seven patients with portal flow (five selective; two nonselective) are compared to the 20 with absent portal flow (seven selective; 13 nonselective), the former group has significantly higher values for MRUS (p < .05) and Child's score (p < .025). No patient with continuing portal perfusion has developed encephalopathy as compared to a 45% incidence of this complication in individuals without portal flow (p < .05). No significant differences between selective and nonselective groups have appeared with respect to total cumulative mortality (ten selective; 38%; eight nonselective, 28%), shunt occlusion (two selective, 10%; five nonselective, 18%), or recurrent variceal hemorrhage (one selective, 4%; two nonselective, 8%). Overall, significantly fewer selective patients have developed postoperative encephalopathy (three selective, 12%; 15 nonselective, 52%; p < .001). Therefore, we conclude that the
From the Department of Surgery and Clinical Research Facility, Emory University, Atlanta, Georgia distal splenorenal shunt, especially when its objective of maintaining hepatic portal perfusion is achieved, results in significantly less morbidity than nonselective shunting procedures.
T HE ROLE OF PORTASYSTEMIC SHUNTS in the manage-
Presented at the Annual Meeting of the American Surgical Association April 26-28, 1978, Dallas, Texas. *Current Address: Department of Surgery, University of Utah Medical Center, Salt Lake City, Utah 84132. Supported by USPHS Grant Numbers AM15736 and RR00039. Reprint requests: W. Dean Warren, M.D., Department of Surgery, Emory University Hospital, 1364 Clifton Road, N.E., Atlanta, Georgia 30322.
ment of cirrhotic patients who have hemorrhaged from esophageal varices remains controversial. Four prospective, randomized trials have been conducted to determine the effects of totally diverting shunts (endto-side and side-to-side portocaval shunts) on liver function and survival.7'94'6 Although three of the studies7.9"14 show prolongation of survival in shunted patients when compared to medically treated controls, in no instance is the difference statistically significant. While medically managed patients have a high fatality secondary to recurrent variceal hemorrhage, surgically treated patients have an accelerated rate of death from hepatic failure. In addition, some of these studies,7'9"6 as well as others,'0 indicate that quality of life following a portocaval shunt is impaired because of an increased incidence and severity of portasystemic encephalopathy. A probable explanation for these adverse effects of shunting procedures is their elimination of hepatic portal perfusion. Several experimental studies8" " have suggested that splanchnic perfusion of the liver is essential for optimal hepatic function. Portal blood appears to contain hepatotrophic factors which maintain hepatocyte integrity and capacity for regeneration.4"8 Another detrimental effect of total portal diversion is shunting of intestinally absorbed nitrogenous substances, normally extracted by the liver, into the systemic circulation. It has been hypothesized that some of these compounds may be cerebral toxins and play a role in the pathogenesis of encephalopathy.17 To avoid these potential complications of portal deprivation, the distal splenorenal or selective shunt
0003-4932/78/0900/0271 $01.15 C) J. B. Lippincott Company
RIKKERS AND OTHERS
was developed in the late 1960's.22 The objectives of this operation are selective decompression of esophageal varices through the gastrosplenic component of the splanchnic circulation and maintenance of superior mesenteric venous perfusion of the liver. Initial experience with this operation indicated that it did indeed attain these objectives in most patients with prevention of further variceal hemorrhage and a minimal incidence of postoperative encephalopathy.21 Therefore, in 1971 a prospective trial, randomly allocating cirrhotic patients who had bled from varices to either the distal splenorenal shunt (selective) or to one of a variety of nonselective shunting procedures, was begun at Emory University Affiliated Hospitals. Early results from this trial have already been published.5 The present report provides a later follow-up with surviving patients now at an average of four years since surgery. Since entry into the trial was terminated in early 1976, all patients have been followed for a minimum of two years.
To be considered for randomization each patient had to meet the following requirements: 1) Biopsy-docu-
mented cirrhosis. 2) At least one episode of upper gastrointestinal hemorrhage (requiring a minimum three unit transfusion) caused by portal hypertension and not by other upper gastrointestinal lesions (documented by barium studies + endoscopy). 3) No significant ascites at the time of surgery. 4) No appreciable hepatocellular necrosis or inflammation on current liver biopsy. 5) No anatomic abnormality, e.g. absence of the spleen, which would make it impossible to construct a distal splenorenal shunt. 6) Proof of hepatopetal portal blood flow (opacification of intrahepatic branches of portal vein during venous phase of superior mesenteric or celiac axis angiography). Patients were randomized to either selective (distal splenorenal) or nonselective shunt from treatment assignments contained within sealed envelopes prepared by the Department of Biometry before the beginning of the study. Twenty-seven and 28 patients were randomized for the selective and nonselective
shunts, respectively. Three patients received an operation different from the one determined by the randomization process. One patient, who had been randomized to nonselective shunt, insisted on receiving the selective shunt because he personally believed it to be a superior method of treatment. In two patients the selective shunt was abandoned intraoperatively because of technical difficulties; nonselective shunts were constructed in these individuals. Accordingly, 26 selective and 29 nonselective shunts were actually performed. Mortality and encephalopathy results are presented both by randomization status (with the three protocol violations deleted) and by the type of shunt actually constructed. All other results are tabulated as to type of shunt performed. The majority of nonselective shunts were constructed with interposition Dacron® grafts. Eighteen grafts were interposed between superior mesenteric and left renal veins (mesorenal); six grafts were interposed between superior mesenteric vein and inferior vena cava (mesocaval). Side-to-side splenorenal (2), end-to-side renosplenic (1), splenocaval (1), and end-to-side portocaval (1), made up the remaining nonselective shunts. Technical and anatomic considerations at the time of surgery generally determined which variety of nonselective shunt was chosen. The distal splenorenal shunt operation consisted of anastomosis of distal splenic vein to left renal vein, ligation or suture closure of proximal splenic vein, and interruption of left gastric, right gastroepiploic, and umbilical veins. The operative technique has been presented in detail previously.21 The two patient groups were similar with respect to age, sex, and etiology of cirrhosis (Table 1). Patients were treated at one of three hospitals within the Emory University Affiliated Hospitals system: Emory University Hospital (private), Grady Memorial Hospital (general hospital for the underprivileged of the Metropolitan Atlanta area), and the Atlanta Veterans Administration Hospital. A greater proportion of nonselective shunt patients were private, but this difference was not statistically significant (Table 1). All episodes of preoperative encephalopathy were induced by gastrointestinal hemorrhage and cleared when the bleeding was controlled. No patient had spontaneous
TABLE 1. Historical Status at Randomization
Selective Nonselective p Values
AVAHW and GMH§ Patients
49 51 NS
16 (62%) 19 (66%) NS
18 (69%) 22 (76%) NS
4 (15%) 9 (31%) NS
14 (54%) 20 (69%) NS
12 (46%) 9 (31%) NS
* All episodes of preoperative encephalopathy were induced by gastrointestinal Veterans Administration Hospital. § Grady Memorial Hospital.
hemorrhage. t Emory University Hospital. t Atlanta
Ann. Surg. e September 1978
SPLENORENAL SHUNT TRIAL
encephalopathy. Although preoperative encephalopathy was more common in the nonselective group, frequencies were not significantly different between groups (Table 1). Preoperative and Postoperative Evaluation
Whenever possible patient evaluations
out under controlled conditions (40 gm protein diet; two week in-patient visit) at the Emory University
Clinical Research Facility (CRF). All 55 patients were evaluated preoperatively (73% in CRF); 39 of 49 survivors were studied in the early postoperative period (within six months of surgery; 95% in CRF); 40 patients were evaluated in the late postoperative interval (85% in CRF). All individuals not evaluated as in-patients were either seen as out-patients or interviewed by telephone. No patient was lost to follow-up. During the course of the trial the data base applied to these patients progressively expanded so that all tests were not performed at each visit. A complete evaluation consisted of the following. 1) History and physical examination. During the interview particular attention was directed to episodes of encephalopathy, recurrent gastrointestinal bleeding and, during the last 18 months of the study, a quantitative estimate of alcohol consumption was recorded. Alcohol intake was considered heavy if it chronically exceeded 100 g per day or consisted of spree drinking of more than 160 g per day. Subtle neurological and mental status changes were noted on physical examination. 2)Routine laboratory tests. Hematocrit, white blood cell count (WBC), platelet count, prothrombin time, serum albumin, total bilirubin, alkaline phosphatase, serum glutamic oxalacetic transaminase (SGOT), and blood urea nitrogen (BUN) were generally determined at each evaluation. 3) Tests of niitrogen metabolism. Fasting plasma ammonia (NH3) and tolerance to an oral dose of ammonium chloride were determined in the Clinical Research Laboratory under carefully controlled conditions. The methodology utilized in determination of plasma ammonia and ammonia tolerance has been reported previously.6 4) Quantitative tests of liver function. A modified Child's Classification was used to grade severity of liver disease.2 Two biochemical indices (serum albumin and total bilirubin) and three clinical measures (nutrition, ascites, and encephalopathy) were given values of 1 (best) to 3 (worst) and totalled for each individual score (range 5-15). Therefore, high scores are indicative of poor liver function. At the beginning of the trial, maximal rate of urea synthesis (MRUS) was measured
during an oral challenge of nitrogen in the form of casein.15 After July, 1974, MRUS was determined during an intravenous infusion of amino acids.15 Since the IV method results in values approximately 15 percent higher than the oral method, the different techniques are not compared in this report. Two additional quantitative tests were introduced into the data base in July, 1976. Galactose elimination capacity (GEC) was calculated from serial peripheral venous blood samples after a bolus intravenous injection of galactose, 500 mg per kg ideal body weight, as described by Tygstrup.'9 Clearance of an oral dose of antipyrine, 15 mg per kg ideal body weight, was measured from sequential venous plasma samples carried out to 96 hours.' 5) Assessment of cerebral function. An episode of clinical encephalopathy was defined as an incident of mental confusion clearly related by the patient or a family member, or detection of disorientation and/or asterixis by a physician. Specifically excluded were mental confusion or coma appearing just prior to death from hepatic failure and encephalopathy induced by gastrointestinal hemorrhage, electrolyte imbalance, or drugs. Electroencephalograms (EEG) were graded by the Parsons-Smith classification12 with 0 and A considered normal and B through E considered abnormal. Beginning in July, 1976, psychometric testing was conducted to detect more subtle neuropsychologic deficits. The Reitan trail making test,'3 which requires the subject to connect alternating numbers and letters spatially arranged on a sheet of paper, and the cancelling A's test, which requires the subject to cancel out words containing A's from a long list of words, were utilized. 6) Visceral angiography. The status of hepatic portal perfusion was qualitatively assessed by visceral angiography. Preoperative studies also provided essential information about anatomy of the splanchnic circulation and position of the left renal vein, while postoperative angiography also determined patency status of the portasystemic shunt. If the venous phase of the superior mesenteric or splenic arterial injection opacified the intrahepatic portal branches, the patient was considered to have hepatopetal portal flow. Visualization of the main portal vein only or total lack of opacification indicated hepatofugal portal flow. Patent mesocaval and mesorenal shunts could be identified on the venous phase of the superior mesenteric arterial injection, while patent distal splenorenal shunts were visualized following splenic arterial
injection. Statistics All data were entered into the Emory University main computer. Appropriate statistical analysis, in-
Ann. Surg. a September 1978
RIKKERS AND OTHERS TABLE 2. Preoperative Comparison of Groups
Nonselective (29) p Value
Albumin (gm/100 ml) 3.7 ± .7 (26) 3.7 Total bilirubin (mg/100 ml) 1.5 ± 1.3 (26) 1.5 Hematocrit (%) 36 ± 6 (26) 35 Prothrombin* time (sec) 1.6 ± 1.4 (24) 1.8 MRUS (IV)t (mg N/h/kg BW.75) 47.5 ± 8.5 (8) 48.0 MRUS (PO)t (mg N/h/kg BW.75) 46.4 ± 9.9 (8) 42.4 Child's score 6.7 ± 1.6 (26) 7.1
± .7 (29) ± 4 (29)
± 1.0 (28)
± 6.6 (7)
± 10.6 (15) ± 1.6 (29)
All values are mean + standard deviation. Number in parentheses indicates number of patients studied. * Seconds beyond control time. t Maximal rate of urea synthesis determined by intravenous method. : Maximal rate of urea synthesis determined by oral method.
cluding Chi square analysis and unpaired and paired t tests, was performed utilizing the Statistical Package for the Social Sciences (SPSS). Results Preoperative Comparison of Selective and Nonselective Groups Table 2 reveals the comparability of selective and nonselective groups prior to shunt surgery. The two groups did not differ significantly with regard to albumin, bilirubin, hematocrit, prothrombin time, or MRUS. Although not presented in tabular form, mean values for WBC, platelet count, alkaline phosphatase, SGOT, and BUN were also not significantly different between the two groups.
Length of Follow-up All survivors have been followed for a minimum of two years since surgery: Fourteen of 16 selective pa-
tients (87%) and 17 of 21 nonselective patients (81%) at least three years postoperative. Fifty and 13% of selective patients and 43 and 19% of nonselective patients have been followed for four and five years are
respectively. Mortality (Tables 3 and 4) Hospital mortality was defined as death occurring during the same hospitalization as the shunt surgery. Three patients in each group died in this early postoperative period within a range of 20 to 41 days. Progressive hepatic failure caused death in five patients, and the sixth individual died from sepsis secondary to infected ascites. Four of the five patients who succumbed in hepatic coma had relatively poor preoperative liver function manifested by Child's scores ranging from nine to eleven. Seven selective and five nonselective patients have expired in the late postoperative period (three months to four years after surgery). Four of the five nonselective patients died within 16 months of surgery, whereas all of the selective late fatalities survived for at least 16 months. This difference in length of survival between the seven selective (mean = 26.7 months) and five nonselective fatalities (mean= 12.8 months) is statistically significant (p .05). Three nonselective and four selective late deaths were secondary to hepatic failure. Chronic, heavy alcohol consumption contributed to the progression of liver disease in three selective, but in none of the nonselective fatalities. As of December, 1977, a total of ten selective and eight nonselective patients had died (Table 4). Figure 1 graphically depicts survival versus time after surgery for both selective and nonselective groups. At no point are the two curves significantly different. When protocol violations are deleted, there is one less nonselective fatality, but the difference remains insignificant (Table 4).