Selective Shunt in the Management of Vanrceal Bleeding in the Era of Liver Transplantation
J. MICHAEL HENDERSON, F.R.C.S.,* G. THOMAS GILMORE, M.D.,* MICHAEL A. HOOKS, PHARM.D.,* JOHN R. GALLOWAY, M.D.,* THOMAS F. DODSON, M.D.,* M. MICHELLE HOOD, M.H.A.,t MICHAEL H. KUTNER, PH.D.4t and THOMAS D. BOYER, M.D.§
This study reports the Emory experience with 147 distal splenorenal shunts (DSRS) and 110 orthotopic liver transplants (OLT) between January 1987 and December 1991. The purpose was to clarify which patients with variceal bleeding should be treated by DSRS versus OLT. Distal splenorenal shunts were selected for patients with adequate or good liver function. Orthotopic liver transplant was offered to patients with end-stage liver disease who fulfilled other selection criteria. The DSRS group comprised 71 Child's A, 70 Child's B, and 6 Child's C patients. The mean galactose elimination capacity for all DSRS patients was 330 ± 98 mg/minute, which was significantly (p < 0.01) above the galactose elimination capacity of 237 ± 82 mg/minute in the OLT group. Survival analysis for the DSRS group showed 91% 1-year and 77% 3-year survival, which was better than the 74% 1-year and 60% 3-year survivals in the OLT group. Variceal bleeding as a major component of end-stage disease leading to OLT had significantly (p < 0.05) poorer survival (50%) at 1 year compared with patients without variceal bleeding (80%). Hepatic function was maintained after DSRS, as measured by serum albumin and prothrombin time, but galactose elimination capacity decreased significantly (p < 0.05) to 298 + 97 mg/minute. Quality of life, measured by a self-assessment questionnaire, was not significantly different in the DSRS and OLT groups. Hospital charges were significantly higher for OLT (median, $113,733) compared with DSRS ($32,674). These data support a role for selective shunt in the management of patients with variceal bleeding who require surgery and have good hepatic function. Transplantation should be reserved for patients with end-stage liver disease. A thorough evaluation, including tests of liver function, help in selection of the most appropriate ther-
apeutic approach.
Presented at the I 12th Annual Meeting of the American Surgical Association, April 6-8, 1992, Palm Desert, California. Supported in part by PHS Clinical Research Center grant SMO1 RR00039. Address reprint requests to J. Michael Henderson, F.R.C.S., Department of General Surgery (A 110), The Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195. Accepted for publication on April 10, 1992.
248
From the Departments of Surgery* and Medicine, § Emory University School of Medicine, the Department of Biostatistics,f Emory University School of Public Health, and Emory University Hospital Administration, Emory University, Atlanta, Georgia
IN THE 1990S THERE is a wide choice of therapies for variceal bleeding. The risk ofbleeding can be reduced by pharmacologic therapy.'2 Endoscopic variceal sclerosis is an effective therapy in acute bleeding and reduces the risk of rebleeding.3'4 Decompressive shunts may be total,5 partial,6 or selective,7 may be made by surgeons'-' or by radiologists,8 9 and are effective in preventing recurrent bleeding. Devascularization operations control bleeding in some populations.'" Finally, liver transplantation offers a therapy that not only relieves the portal hypertension, but also treats the underlying liver disease."1"12 All of these therapies may be used in different patients, and the challenge is to select the best therapy for each patient. A full evaluation of patients with variceal hemorrhage includes determination of cause and disease activity, and assessment of the liver's functional capacity. Initial management of varices by sclerotherapy and pharmacologic therapy usually provides the time for this assessment. This information then can form the basis for a decision on the need for shunt or transplant in the 50% of patients who fail medical therapy and require surgical intervention. 1'-15 We review the Emory experience with distal splenorenal shunt (DSRS) and orthotopic liver transplant (OLT) over the past 5 years. Our strategy has been to (1) initially manage patients with variceal bleeding using sclerotherapy, (2) evaluate hepatic function and hemodynamics of all patients with bleeding, (3) use DSRS in good-risk patients and nontransplant candidates who require surgical
VOl. 216.-NO. 3
SELECIIVE SHUNT FOR VARICEAL BLEEDING
therapy for variceal bleeding, and (4) use OLT for management of end-stage liver disease. This study reports on survival, hepatic function, quality of life, and charges of these two surgical treatments performed at a single institution.
Materials and Methods Patient Populations All patients having DSRS and OLT at Emory University Hospital between January 1987 and December 1991 were analyzed. A total of 147 patients underwent DSRS, with follow-up on 143 (97%) of these available for analysis. A total of 110 patients had OLT, with 100% follow-up. The cause of the liver disease for each group is given in Table 1. The mean ± standard deviation age of the DSRS group was 52 ± 16 years, and for the OLT group was 41 ± 12 years. In the DSRS group there were 104 men and 43 women; in the OLT group, 54 men and 56 women. Elective DSRS was performed in 116 patients, and emergent shunt in 31 patients. In the group undergoing OLT, variceal bleeding as a component of their end-stage liver disease was present in 25 (23%) patients. Comparison between these groups must be interpreted in the light oftheir different selection criteria. The purpose of the analysis in this paper is to define which patients are best managed by each operation. Method Patient evaluation was completed before either operation according to a standard protocol. In patients with variceal bleeding, endoscopy'6 and arteriography'7 were performed. These assessed bleeding risk, degree of portal hypertension, and demonstrated vessel patency for surgical options. Hepatic function was assessed in both groups from (1) clinical findings of jaundice, ascites, encephalopathy and nutritional status; (2) standard laboratory tests of bilirubin, albumin, prothrombin time, liver enzymes, and serologic markers; (3) quantitative hepatocyte function by the galactose elimination capacity (GEC)'8; and (4) liver volume by computed tomography scan.'9 ChildTABLE 1. The Cause of Liver Disease in Patients Undergoing DSRS or OLT at Emory 1987-1991
Posthepatitic cirrhosis Alcoholic cirrhosis Primary biliary cirrhosis Sclerosing cholangitis Portal vein thrombosis Others Total
DSRS Patients
OLT Patients
32 62
51 15 12 15
7
3 12 31 147
17 110
249
Pugh score was calculated numerically and patients then classified as A, B, or C.20 Follow-up evaluations were conducted at 6 months, 1 year, and at yearly intervals on either an inpatient or outpatient protocol. These protocols evaluated liver function as outlined above in both groups. Shunt patency was documented by angiography in all patients early after DSRS, and by either angiography or Doppler/ultrasound at late follow-up. Orthotopic liver transplant follow-up included biopsy, vascular, and biliary evaluations as indicated by clinical and laboratory findings. For patients not evaluated in the last 6 months, status was ascertained by phone. Quality of life assessment was assessed by mailing questionnaires to all patients known to be alive in both groups. The patients were asked to respond to the following: (1) a self-assessment score by marking their status on a line 0 to 10, where 0 indicated very poor and 10 indicated very good: (2) whether they had returned to work or were in school; (3) the number and duration of readmissions to a hospital; (4) the number and types of medications currently being taken. Analysis of charges was divided into four phases: (1) the charge of the initial evaluation; (2) hospital charges at the time of the primary surgery; (3) hospital charges for readmissions; and (4) the charge of medication and laboratory tests in the first year after surgery. This analysis of charges did not include professional fees. Items 1 and 4 were estimated for the "typical" uncomplicated patient at these two time intervals. Initial evaluation charges do not include related hospitalization or patient management charges that may have been required concurrent to the evaluation. Outpatient follow-up charges were estimated from a three-medication regimen for DSRS patients and a six-medication regimen for OLT patients. Laboratory charges are estimated using a minimum number of follow-up visits. Items 2 and 3 were calculated from actual hospital charges of 30 DSRS and 22 OLT patients. These patients were systematically sampled by taking every fifth patient chronologically by the date of their primary surgical procedure. The same patient groups were used to generate the charges for hospital readmissions. All hospital charges were evaluated and categorized into (1) diagnostic, which include laboratory, pathology, radiology; (2) pharmacy; and (3) other hospital charges, which include per diem, operating room, and ancillary services. In addition, the charge of organ donor harvest is included in the OLT charge analysis. Data management and analysis. Data were managed using the CLINFO data management system. KaplanMeier survival curves were compared using the generalized Savage test statistic.2' Comparison of means between and within groups was done by unpaired and paired Student's
250
HENDERSON AND OTHERS
t test respectively.22 Data are expressed as mean ± standard deviation. Two sided p-values are reported for all tests of significance. Results
Patient Populations The preoperative status of the DSRS and OLT groups are summarized in Table 2. The average of the standard laboratory values and GEC in the DSRS group are markedly better than the OLT group. This difference was dictated by patient selection criteria, whereby those with poor liver function were infrequently offered DSRS. The DSRS group includes 71 Child's class A, 70 Child's B, and 6 Child's C patients. The OLT group includes 15 Child's B and 95 Child's Class C patients. Figure 1 shows the distribution of galactose elimination capacity in the two groups, which again emphasizes the selection process of better hepatocyte function in the patients managed by DSRS. The following features further characterize the DSRS population. The mean (± standard deviation) number of bleeding episodes was 3.1 + 1.4, with a transfusion requirement before shunt exceeding 10 units of blood in 54%. Sixty-five percent of this group had combined gastric and esophageal varices at endoscopy, with 21% having only esophageal and 14% only gastric varices. Thirty-seven (27%) patients had undergone no prior sclerotherapy for their varices, whereas 64% had undergone chronic sclerotherapy. The 31 patients requiring emergent DSRS were a poorer-risk group than the overall shunt group, with a mean bilirubin of 2.1 ± 1.7 mg/dL, albumin 2.8 ± 0.5 g/ dL, prothrombin time 14.2 ± 1.2 seconds, and GEC 319 + 127 mg/min. In the OLT group the 15 patients with a GEC > 300 mg/min (Figure 1) had a mean bilirubin of 17.6 ± 13 mg/ dL, in contrast to the rest of the OLT patients, who had a mean bilirubin of 7.4 ± 8.9 mg/dL. Most patients with high GEC had primary biliary cirrhosis and sclerosing cholangitis, whereas those with low GECs mainly had chronic active hepatitis with cirrhosis.
Ann. Surg. * September 1992
30 25 20
Number of Patients
DSRS
15
lo~ 5
I
1 50 20c 30 25
OLT
20
Number
of Patients
I 1.
.-
.
6
.
..
!...
'.
400. 450 26--0 3M 3 GALACTOSE ELIMINATION CAPACITY (mg/min). FIG. 1. Profile of galactose elimination capacity for patients managed by distal splenorenal shunt (DSRS) and by orthotopic liver transplant (OLT).
.0X
significantly (p < 0.01) better survival than the patients selected for OLT. Operative mortality rate, defined as death within 30 days of surgery or during the same hospital admission, was 4.8% for DSRS. Five of these seven deaths followed emergency shunt. Six patients were Child's B and one was Child's class C. The operative mortality rate in the OLT group was 14.5%. Nine patients died of multiorgan failure, with sepsis or rejection playing a dominant role: four deaths followed intracranial events, two patients died intraoperatively, and one of graft-versus-host disease. Late mortality, occurring beyond the primary hospital admission, was 13.2% in the DSRS group. This occurred as a result of liver failure in seven patients, was unrelated
p
R
0
p
0.9
DSRS 0.8
0
Survival The overall survival for the two patient populations is given in Figure 2. The patients selected for DSRS have
R T
0.7
l
0.6
N S U
R
TABLE 2. The Preoperative Status of 147 Patients Having DSRS and 110 Patients Having OLT
DSRS
OLT
0.5
OLT
0.4
V
0.3
V
0.2
N G
0.1
p'0.01
0
Bilirubin (mg/dL) Albumin (g/dL) Prothrombin time (sec) GEC (mg/min) Livervolume (mL)
1.4 3.3 13.3 330 1727
± 1.1 ± 0.6 ± 1.0 ± 98 ± 590
9.3 ± 10.0 3.0 ± 0.6 15.8 ± 8.25 237 ± 82 1384 ± 631
0
6
12
18
24
30 36 MONTHS
42
48
54
60
FIG. 2. Kaplan-Meier survival curves for the whole population of DSRS and OLT patients. The survival in the DSRS group is significantly (p < 0.01) better than the survival in the OLT group.
Vol. 216 No. 3
SELECTIVE SHUNT FOR VARICEAL BLEEDING °3
NO VARICEAL BLEED
PRIOR VARICEAL BLEED
p R 0
p 0
R T N S U
R V V
N G
0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1
p'0.05
0
0
6
12
18
24
30 36 MONTHS
42
48
54
60
FIG. 3. Kaplan-Meier survival curves in the OLT group by a positive or negative history of variceal bleeding. Patients with variceal bleeding before OLT had a significantly poorer survival (p < 0.05).
to their liver disease in nine, and from undetermined causes in two patients. In the OLT group, late deaths were primarily related to infection in seven patients, rejection in six patients (two operative mortality rates at retransplantation), two patients with recurrent cholangiocarcinoma, and one patient each from Kaposi's sarcoma, lymphoproliferative disorder, metastatic adenocarcinoma, sudden death of unknown cause, and suicide. Survival analysis for patient subpopulations. In the DSRS group there were no significant differences in survival by urgency of operation, liver function, or age. There were trends to improved survival for patients with nonalcoholic (p = 0.12) compared with alcoholic cirrhosis, and for Child's A (p = 0.06) compared with Child's Class B patients. In the OLT group, there were no significant differences in survival by disease cause or age. Patients with variceal bleeding as a major component in their need for transplantation had a significantly (p < 0.05) poorer survival rate than did patients without variceal bleeding (Fig. 3).
251
DSRS. Early rebleeding within 1 month occurred in two patients in this group: one was controlled by conservative management whereas the other required esophagectomy for a deep sclerotherapy ulcer. Both patients are alive. Shunt thrombosis occurred in four patients (2.8%), with variceal rebleeding in two. Three of these patients were managed by gastric devascularization and splenectomy, whereas the fourth had gastric devascularization alone because she had undergone a splenopneumopexy before her DSRS. All four are alive. Two patients rebled from severe congestive gastropathy confined to the antrum and were managed by antrectomy. Both survived this operation, but have subsequently died. The final two patients bled from gastric varices at 8 months and 21/2 years after surgery. These two patients had patent shunts, with very large gastric collateral varices from the portal vein to the shunt, as previously described.23 They were managed by lesser curve gastric devascularization, and are doing well. Postsurgery Hepatic Function
Table 3 summarizes the changes in standard laboratory tests, liver function measured by GEC, and liver volume in the DSRS and OLT patients with at least 1 year of
follow-up. In the DSRS group, the 63 patients showed no significant change in serum albumin or prothrombin time. Serum bilirubin increased significantly (p < 0.05), and GEC (p < 0.05) and liver volume (p < 0.01) decreased significantly. Table 4 shows the incidence of encephalopathy in these 63 shunt patients before and at late followup. Six patients had encephalopathy before DSRS. At follow-up, 11 (17%) ofthis group ofpatients had mild, easily controlled encephalopathy, whereas more severe encephalopathy requiring hospitalization occurred in four (7%) patients. In the OLT group there were significant (p < 0.001) improvements in bilirubin, albumin, protime, and galactose elimination capacity.
DSRS and Control of Bleeding
Quality of Life Assessment
A total of eight patients had rebleeding secondary to portal hypertension, for a rebleeding rate of 5.6% after
Seventy-two (59%) patients in the DSRS group and 41 (55%) in the OLT group responded to the questionnaire.
TABLE 3. Laboratory Values of 63 Patients Managed by DSRS and 36 Managed by OLT Before and With at Least I Year Follow-up (1-5 Years)
DSRS Pre
Bilirubin (mg/dL) Albumin (g/dL) Prothrombin time (sec) GEC (mg/min) Liver volume (mL) Values are mean ± SD.
1.2 3.3 13.2 325 1733
± 1.0 ± 0.6 ± 1.0 ± 93 ± 546
OLT Post
Pre
Post
2.3 ± 2.1 3.4 ± 0.6 14.1 ± 1.4 298 ± 97 1431 ± 467
8.4 ± 9.0 3.1 ± 0.5 13.1 ± 5.6 247 ± 80 1491 ± 733
0.9 ± 0.4 4.0 ± 0.4 11.9 ± 2.0 420 ± 111 1723 ± 598
HENDERSON AND OTHERS
252
TABLE 4. The Incidence ofEncephalopathy Before and After DSRS in the 63 Patients With at Least I Year of Follow-up
Ann. Surg. * September 1992
TABLE 6. Median Hospital Charges of Surgical Admission for DSRS and OLT
Post-DSRS
DSRS
OLT
None
Mild
Moderate
Total charge* Components Hospital services
$32,674
$113,733
16,910
42 4 2
10 1 0
4
Diagnostic Pharmacy Donor
11,909
40,133 36,447 13,236 15,497
Pre-DSRS None Mild Moderate
0 0
The findings from the questionnaire are summarized in Table 5. There was no significant difference in the self-assessment scores ofthe responding DSRS (7.0 ± 2.6) and OLT (7.4 ± 2.20) patients. The percentage of patients returning to work, or in school, was not significantly different in the two groups. In this sample of patients, the re-admissions to hospital are lower in the DSRS group. The requirement for immunosuppression after liver transplant results in the greater number of medications in the OLT group.
Analysis of Charges Evaluation charges, estimated from the basic tests required in all patients, were similar for DSRS ($2403) and OLT ($2837). This does not include hospitalization and management charges, or additional tests that may be required to assess other organ systems. Hospital charges of surgical admission are summarized in Table 6, and are based on sample sizes of 30 patients in the DSRS group and 22 patients in the OLT group. There is one significant outlier in each group. One DSRS patient had a hospital charge of $135,434 and one OLT patient a charge of > $1,000,000. Excluding these two patients, the range of charges for DSRS was $15,533 to $57,311, and for OLT was $61,639 to $285,897. These charges do not include professional fees. Follow-up charges have been broken down into the charges incurred by hospital readmission based on the same sample of patients used above, and an estimation of charges for outpatient medications and laboratory tests for 1 year after each procedure. TABLE 5. Quality ofLife From Self-Assessment Questionnaire
DSRS
Self-assessment (0-10 score) Working or in school Rehospitalizations 0 wk 1-4 wk >4 wk No. of medications 0 1-4 >5
7.0 ± 2.6 56%
OLT 7.4
±
2.0
58%
59% 31% 10%
36% 42% 22%
22% 64% 14%
0% 17% 83%
2259
* The sum of the median charges for the component services is less than the total charges because of the skew of the data.
Readmission charges. Eight (27%) of the sample of 30 DSRS patients required a total of 10 readmissions for medical management. The average charge incurred for these readmissions was $26,243. Neither of the two DSRS patients who had subsequent liver transplants were selected in this sample for analysis. Twelve (55%) of the 22 patients studied in the OLT sample required a total of 30 readmissions. The average charge of these readmissions was $33,962. One sampled patient in this OLT group has required retransplantation. Outpatient follow-up charges. Patients having DSRS require follow-up care estimated at $147 for medications and $1201 for laboratory tests in the first year. The estimated charges for the first year after liver transplant are $8967 for medications and $4940 for laboratory tests. Discussion The data presented in this paper support a role for DSRS in the management of variceal bleeding in appropriately selected patients. These patients are predominantly Child's class A and B, with stable disease and adequate or good hepatic function. Bleeding control has been good, with low morbidity rate from shunt thrombosis and recurrent bleeding. The 1-, 3-, and 4-year survivals of 91 %, 79%, and 77%, respectively, are in keeping with other series from the literature in which DSRS has been used for Child's A and B patients. Inokuchi and Sugimachi24 reported 3-year survival of 85% in 77 patients, Myburgh showed a 5-year survival of 72% in 127 patients,25 MaffeiFaccioli et al.26 achieved a 3-year survival of 80% and 5year survival of 57% in 70 patients. Paquet and coworkers27 showed a 75% survival at 5 years in 32 selected patients, and Orozco et al.28 had a 69% 5-year survival rate in 107 Child's A patients. The common denominator in these DSRS series has been careful patient selection. Do quantitative liver function tests assist in patient selection? The data in this study suggest that the galactose elimination capacity plays a useful adjunctive, but not a definitive role. Eighty-four per cent of the DSRS group had a GEC > 250 mg/minute, indicating adequate or good hepatocyte mass and function, which has been as-
Vol. 216 -No. 3
SELECTIVE SHUNT FOR VARICEAL BLEEDING
sociated with good survival. Analysis fails to reveal a direct correlation between GEC and survival, however. In contrast to the DSRS group, only 32% of the OLT group had a GEC > 250 mg/minute, and of these patients with good hepatocyte function, 23 had either primary biliary cirrhosis or sclerosing cholangitis. We have previously documented that end-stage cholestatic disease may occur with relatively good GEC.29 Reichen and his co-workers30 have shown that serial measures of GEC in patients with primary biliary cirrhosis provide an independent predictor of death as good as other predictive scores for this disease. The experience from the current study supports the use of quantitative liver function testing in aiding selection of patients for shunt or transplant. In reaching a decision as to which patients with variceal bleeding should be managed by liver transplant, a reliable assessment of expected outcome after OLT is needed. Factors such as the type of disease leading to transplantation, the condition of the patient at the time of transplantation, the age of the patient, and the immunosuppressive regimen all play a role in outcome. In reported series of 100 or more transplants conducted through the 1980s,"131-37 1-year survival rates have ranged from 55% to 85%. In the Liver Transplant Registry Report,38 1- and 2-year survival rates for 1536 patients with postnecrotic cirrhosis who were transplanted under United Network for Organ Sharing (UNOS) regulation were 73% and 67%, respectively. The survival in the present OLT series is similar. Two reports have specifically analyzed outcome after liver transplantation in patients who had variceal bleeding as a component of their end-stage disease. Bismuth reported a 4-year survival of 92% in 39 Child's B patients, and 73% in 29 Child's C patients.39 Iwatsuki reported on 302 Child's C patients with a history of bleeding from esophageal varices before transplant.'2 The 1-, 3-, and 5-year survival rates for this study were 79%, 71%, and 71%, respectively, and were significantly better than their OLT population, who had no prior variceal bleeding. Iwatsuki's data differ from the findings in the current study, which show significantly shorter survival in our transplant population, who had variceal bleeding as a component of their end-stage disease. The reasons for these differences are not apparent. The patients' assessment of their quality of life is remarkably similar in our two groups. Equivalent response rates to the questionnaire should balance any bias in the pattern of response. The rate of return to work or school was almost identical in both groups, but somewhat lower than the 75% reported by Colonna et al.,40 in their study of patients after liver transplant. Most patients who responded in both groups rated their current status as good to excellent, with few limitations imposed by their respective operations. These findings are also in parallel with the data reported from Pittsburgh.4'
253
The charges incurred in treating patients with chronic liver disease are high. The clinical presentations of variceal bleeding, encephalopathy, spontaneous bacterial peritonitis, and liver failure usually require intensive care management and prolonged hospital stays. Unfortunately, just as the financial burden of looking after these complications is high, so too is the charge of treating the underlying problem by liver transplantation. The argument that it is ultimately less expensive to proceed to transplantation when any of these complications develop is not supported by the current study. In the analysis of charges presented in this report, we demonstrate that in patients with cirrhosis and variceal bleeding who have good or adequate liver function, a satisfactory outcome can be achieved by DSRS at a charge significantly less than that required for transplantation. It is of course true that follow-up is relatively short (
J. MICHAEL HENDERSON, F.R.C.S.,* G. THOMAS GILMORE, M.D.,* MICHAEL A. HOOKS, PHARM.D.,* JOHN R. GALLOWAY, M.D.,* THOMAS F. DODSON, M.D.,* M. MICHELLE HOOD, M.H.A.,t MICHAEL H. KUTNER, PH.D.4t and THOMAS D. BOYER, M.D.§
This study reports the Emory experience with 147 distal splenorenal shunts (DSRS) and 110 orthotopic liver transplants (OLT) between January 1987 and December 1991. The purpose was to clarify which patients with variceal bleeding should be treated by DSRS versus OLT. Distal splenorenal shunts were selected for patients with adequate or good liver function. Orthotopic liver transplant was offered to patients with end-stage liver disease who fulfilled other selection criteria. The DSRS group comprised 71 Child's A, 70 Child's B, and 6 Child's C patients. The mean galactose elimination capacity for all DSRS patients was 330 ± 98 mg/minute, which was significantly (p < 0.01) above the galactose elimination capacity of 237 ± 82 mg/minute in the OLT group. Survival analysis for the DSRS group showed 91% 1-year and 77% 3-year survival, which was better than the 74% 1-year and 60% 3-year survivals in the OLT group. Variceal bleeding as a major component of end-stage disease leading to OLT had significantly (p < 0.05) poorer survival (50%) at 1 year compared with patients without variceal bleeding (80%). Hepatic function was maintained after DSRS, as measured by serum albumin and prothrombin time, but galactose elimination capacity decreased significantly (p < 0.05) to 298 + 97 mg/minute. Quality of life, measured by a self-assessment questionnaire, was not significantly different in the DSRS and OLT groups. Hospital charges were significantly higher for OLT (median, $113,733) compared with DSRS ($32,674). These data support a role for selective shunt in the management of patients with variceal bleeding who require surgery and have good hepatic function. Transplantation should be reserved for patients with end-stage liver disease. A thorough evaluation, including tests of liver function, help in selection of the most appropriate ther-
apeutic approach.
Presented at the I 12th Annual Meeting of the American Surgical Association, April 6-8, 1992, Palm Desert, California. Supported in part by PHS Clinical Research Center grant SMO1 RR00039. Address reprint requests to J. Michael Henderson, F.R.C.S., Department of General Surgery (A 110), The Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195. Accepted for publication on April 10, 1992.
248
From the Departments of Surgery* and Medicine, § Emory University School of Medicine, the Department of Biostatistics,f Emory University School of Public Health, and Emory University Hospital Administration, Emory University, Atlanta, Georgia
IN THE 1990S THERE is a wide choice of therapies for variceal bleeding. The risk ofbleeding can be reduced by pharmacologic therapy.'2 Endoscopic variceal sclerosis is an effective therapy in acute bleeding and reduces the risk of rebleeding.3'4 Decompressive shunts may be total,5 partial,6 or selective,7 may be made by surgeons'-' or by radiologists,8 9 and are effective in preventing recurrent bleeding. Devascularization operations control bleeding in some populations.'" Finally, liver transplantation offers a therapy that not only relieves the portal hypertension, but also treats the underlying liver disease."1"12 All of these therapies may be used in different patients, and the challenge is to select the best therapy for each patient. A full evaluation of patients with variceal hemorrhage includes determination of cause and disease activity, and assessment of the liver's functional capacity. Initial management of varices by sclerotherapy and pharmacologic therapy usually provides the time for this assessment. This information then can form the basis for a decision on the need for shunt or transplant in the 50% of patients who fail medical therapy and require surgical intervention. 1'-15 We review the Emory experience with distal splenorenal shunt (DSRS) and orthotopic liver transplant (OLT) over the past 5 years. Our strategy has been to (1) initially manage patients with variceal bleeding using sclerotherapy, (2) evaluate hepatic function and hemodynamics of all patients with bleeding, (3) use DSRS in good-risk patients and nontransplant candidates who require surgical
VOl. 216.-NO. 3
SELECIIVE SHUNT FOR VARICEAL BLEEDING
therapy for variceal bleeding, and (4) use OLT for management of end-stage liver disease. This study reports on survival, hepatic function, quality of life, and charges of these two surgical treatments performed at a single institution.
Materials and Methods Patient Populations All patients having DSRS and OLT at Emory University Hospital between January 1987 and December 1991 were analyzed. A total of 147 patients underwent DSRS, with follow-up on 143 (97%) of these available for analysis. A total of 110 patients had OLT, with 100% follow-up. The cause of the liver disease for each group is given in Table 1. The mean ± standard deviation age of the DSRS group was 52 ± 16 years, and for the OLT group was 41 ± 12 years. In the DSRS group there were 104 men and 43 women; in the OLT group, 54 men and 56 women. Elective DSRS was performed in 116 patients, and emergent shunt in 31 patients. In the group undergoing OLT, variceal bleeding as a component of their end-stage liver disease was present in 25 (23%) patients. Comparison between these groups must be interpreted in the light oftheir different selection criteria. The purpose of the analysis in this paper is to define which patients are best managed by each operation. Method Patient evaluation was completed before either operation according to a standard protocol. In patients with variceal bleeding, endoscopy'6 and arteriography'7 were performed. These assessed bleeding risk, degree of portal hypertension, and demonstrated vessel patency for surgical options. Hepatic function was assessed in both groups from (1) clinical findings of jaundice, ascites, encephalopathy and nutritional status; (2) standard laboratory tests of bilirubin, albumin, prothrombin time, liver enzymes, and serologic markers; (3) quantitative hepatocyte function by the galactose elimination capacity (GEC)'8; and (4) liver volume by computed tomography scan.'9 ChildTABLE 1. The Cause of Liver Disease in Patients Undergoing DSRS or OLT at Emory 1987-1991
Posthepatitic cirrhosis Alcoholic cirrhosis Primary biliary cirrhosis Sclerosing cholangitis Portal vein thrombosis Others Total
DSRS Patients
OLT Patients
32 62
51 15 12 15
7
3 12 31 147
17 110
249
Pugh score was calculated numerically and patients then classified as A, B, or C.20 Follow-up evaluations were conducted at 6 months, 1 year, and at yearly intervals on either an inpatient or outpatient protocol. These protocols evaluated liver function as outlined above in both groups. Shunt patency was documented by angiography in all patients early after DSRS, and by either angiography or Doppler/ultrasound at late follow-up. Orthotopic liver transplant follow-up included biopsy, vascular, and biliary evaluations as indicated by clinical and laboratory findings. For patients not evaluated in the last 6 months, status was ascertained by phone. Quality of life assessment was assessed by mailing questionnaires to all patients known to be alive in both groups. The patients were asked to respond to the following: (1) a self-assessment score by marking their status on a line 0 to 10, where 0 indicated very poor and 10 indicated very good: (2) whether they had returned to work or were in school; (3) the number and duration of readmissions to a hospital; (4) the number and types of medications currently being taken. Analysis of charges was divided into four phases: (1) the charge of the initial evaluation; (2) hospital charges at the time of the primary surgery; (3) hospital charges for readmissions; and (4) the charge of medication and laboratory tests in the first year after surgery. This analysis of charges did not include professional fees. Items 1 and 4 were estimated for the "typical" uncomplicated patient at these two time intervals. Initial evaluation charges do not include related hospitalization or patient management charges that may have been required concurrent to the evaluation. Outpatient follow-up charges were estimated from a three-medication regimen for DSRS patients and a six-medication regimen for OLT patients. Laboratory charges are estimated using a minimum number of follow-up visits. Items 2 and 3 were calculated from actual hospital charges of 30 DSRS and 22 OLT patients. These patients were systematically sampled by taking every fifth patient chronologically by the date of their primary surgical procedure. The same patient groups were used to generate the charges for hospital readmissions. All hospital charges were evaluated and categorized into (1) diagnostic, which include laboratory, pathology, radiology; (2) pharmacy; and (3) other hospital charges, which include per diem, operating room, and ancillary services. In addition, the charge of organ donor harvest is included in the OLT charge analysis. Data management and analysis. Data were managed using the CLINFO data management system. KaplanMeier survival curves were compared using the generalized Savage test statistic.2' Comparison of means between and within groups was done by unpaired and paired Student's
250
HENDERSON AND OTHERS
t test respectively.22 Data are expressed as mean ± standard deviation. Two sided p-values are reported for all tests of significance. Results
Patient Populations The preoperative status of the DSRS and OLT groups are summarized in Table 2. The average of the standard laboratory values and GEC in the DSRS group are markedly better than the OLT group. This difference was dictated by patient selection criteria, whereby those with poor liver function were infrequently offered DSRS. The DSRS group includes 71 Child's class A, 70 Child's B, and 6 Child's C patients. The OLT group includes 15 Child's B and 95 Child's Class C patients. Figure 1 shows the distribution of galactose elimination capacity in the two groups, which again emphasizes the selection process of better hepatocyte function in the patients managed by DSRS. The following features further characterize the DSRS population. The mean (± standard deviation) number of bleeding episodes was 3.1 + 1.4, with a transfusion requirement before shunt exceeding 10 units of blood in 54%. Sixty-five percent of this group had combined gastric and esophageal varices at endoscopy, with 21% having only esophageal and 14% only gastric varices. Thirty-seven (27%) patients had undergone no prior sclerotherapy for their varices, whereas 64% had undergone chronic sclerotherapy. The 31 patients requiring emergent DSRS were a poorer-risk group than the overall shunt group, with a mean bilirubin of 2.1 ± 1.7 mg/dL, albumin 2.8 ± 0.5 g/ dL, prothrombin time 14.2 ± 1.2 seconds, and GEC 319 + 127 mg/min. In the OLT group the 15 patients with a GEC > 300 mg/min (Figure 1) had a mean bilirubin of 17.6 ± 13 mg/ dL, in contrast to the rest of the OLT patients, who had a mean bilirubin of 7.4 ± 8.9 mg/dL. Most patients with high GEC had primary biliary cirrhosis and sclerosing cholangitis, whereas those with low GECs mainly had chronic active hepatitis with cirrhosis.
Ann. Surg. * September 1992
30 25 20
Number of Patients
DSRS
15
lo~ 5
I
1 50 20c 30 25
OLT
20
Number
of Patients
I 1.
.-
.
6
.
..
!...
'.
400. 450 26--0 3M 3 GALACTOSE ELIMINATION CAPACITY (mg/min). FIG. 1. Profile of galactose elimination capacity for patients managed by distal splenorenal shunt (DSRS) and by orthotopic liver transplant (OLT).
.0X
significantly (p < 0.01) better survival than the patients selected for OLT. Operative mortality rate, defined as death within 30 days of surgery or during the same hospital admission, was 4.8% for DSRS. Five of these seven deaths followed emergency shunt. Six patients were Child's B and one was Child's class C. The operative mortality rate in the OLT group was 14.5%. Nine patients died of multiorgan failure, with sepsis or rejection playing a dominant role: four deaths followed intracranial events, two patients died intraoperatively, and one of graft-versus-host disease. Late mortality, occurring beyond the primary hospital admission, was 13.2% in the DSRS group. This occurred as a result of liver failure in seven patients, was unrelated
p
R
0
p
0.9
DSRS 0.8
0
Survival The overall survival for the two patient populations is given in Figure 2. The patients selected for DSRS have
R T
0.7
l
0.6
N S U
R
TABLE 2. The Preoperative Status of 147 Patients Having DSRS and 110 Patients Having OLT
DSRS
OLT
0.5
OLT
0.4
V
0.3
V
0.2
N G
0.1
p'0.01
0
Bilirubin (mg/dL) Albumin (g/dL) Prothrombin time (sec) GEC (mg/min) Livervolume (mL)
1.4 3.3 13.3 330 1727
± 1.1 ± 0.6 ± 1.0 ± 98 ± 590
9.3 ± 10.0 3.0 ± 0.6 15.8 ± 8.25 237 ± 82 1384 ± 631
0
6
12
18
24
30 36 MONTHS
42
48
54
60
FIG. 2. Kaplan-Meier survival curves for the whole population of DSRS and OLT patients. The survival in the DSRS group is significantly (p < 0.01) better than the survival in the OLT group.
Vol. 216 No. 3
SELECTIVE SHUNT FOR VARICEAL BLEEDING °3
NO VARICEAL BLEED
PRIOR VARICEAL BLEED
p R 0
p 0
R T N S U
R V V
N G
0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1
p'0.05
0
0
6
12
18
24
30 36 MONTHS
42
48
54
60
FIG. 3. Kaplan-Meier survival curves in the OLT group by a positive or negative history of variceal bleeding. Patients with variceal bleeding before OLT had a significantly poorer survival (p < 0.05).
to their liver disease in nine, and from undetermined causes in two patients. In the OLT group, late deaths were primarily related to infection in seven patients, rejection in six patients (two operative mortality rates at retransplantation), two patients with recurrent cholangiocarcinoma, and one patient each from Kaposi's sarcoma, lymphoproliferative disorder, metastatic adenocarcinoma, sudden death of unknown cause, and suicide. Survival analysis for patient subpopulations. In the DSRS group there were no significant differences in survival by urgency of operation, liver function, or age. There were trends to improved survival for patients with nonalcoholic (p = 0.12) compared with alcoholic cirrhosis, and for Child's A (p = 0.06) compared with Child's Class B patients. In the OLT group, there were no significant differences in survival by disease cause or age. Patients with variceal bleeding as a major component in their need for transplantation had a significantly (p < 0.05) poorer survival rate than did patients without variceal bleeding (Fig. 3).
251
DSRS. Early rebleeding within 1 month occurred in two patients in this group: one was controlled by conservative management whereas the other required esophagectomy for a deep sclerotherapy ulcer. Both patients are alive. Shunt thrombosis occurred in four patients (2.8%), with variceal rebleeding in two. Three of these patients were managed by gastric devascularization and splenectomy, whereas the fourth had gastric devascularization alone because she had undergone a splenopneumopexy before her DSRS. All four are alive. Two patients rebled from severe congestive gastropathy confined to the antrum and were managed by antrectomy. Both survived this operation, but have subsequently died. The final two patients bled from gastric varices at 8 months and 21/2 years after surgery. These two patients had patent shunts, with very large gastric collateral varices from the portal vein to the shunt, as previously described.23 They were managed by lesser curve gastric devascularization, and are doing well. Postsurgery Hepatic Function
Table 3 summarizes the changes in standard laboratory tests, liver function measured by GEC, and liver volume in the DSRS and OLT patients with at least 1 year of
follow-up. In the DSRS group, the 63 patients showed no significant change in serum albumin or prothrombin time. Serum bilirubin increased significantly (p < 0.05), and GEC (p < 0.05) and liver volume (p < 0.01) decreased significantly. Table 4 shows the incidence of encephalopathy in these 63 shunt patients before and at late followup. Six patients had encephalopathy before DSRS. At follow-up, 11 (17%) ofthis group ofpatients had mild, easily controlled encephalopathy, whereas more severe encephalopathy requiring hospitalization occurred in four (7%) patients. In the OLT group there were significant (p < 0.001) improvements in bilirubin, albumin, protime, and galactose elimination capacity.
DSRS and Control of Bleeding
Quality of Life Assessment
A total of eight patients had rebleeding secondary to portal hypertension, for a rebleeding rate of 5.6% after
Seventy-two (59%) patients in the DSRS group and 41 (55%) in the OLT group responded to the questionnaire.
TABLE 3. Laboratory Values of 63 Patients Managed by DSRS and 36 Managed by OLT Before and With at Least I Year Follow-up (1-5 Years)
DSRS Pre
Bilirubin (mg/dL) Albumin (g/dL) Prothrombin time (sec) GEC (mg/min) Liver volume (mL) Values are mean ± SD.
1.2 3.3 13.2 325 1733
± 1.0 ± 0.6 ± 1.0 ± 93 ± 546
OLT Post
Pre
Post
2.3 ± 2.1 3.4 ± 0.6 14.1 ± 1.4 298 ± 97 1431 ± 467
8.4 ± 9.0 3.1 ± 0.5 13.1 ± 5.6 247 ± 80 1491 ± 733
0.9 ± 0.4 4.0 ± 0.4 11.9 ± 2.0 420 ± 111 1723 ± 598
HENDERSON AND OTHERS
252
TABLE 4. The Incidence ofEncephalopathy Before and After DSRS in the 63 Patients With at Least I Year of Follow-up
Ann. Surg. * September 1992
TABLE 6. Median Hospital Charges of Surgical Admission for DSRS and OLT
Post-DSRS
DSRS
OLT
None
Mild
Moderate
Total charge* Components Hospital services
$32,674
$113,733
16,910
42 4 2
10 1 0
4
Diagnostic Pharmacy Donor
11,909
40,133 36,447 13,236 15,497
Pre-DSRS None Mild Moderate
0 0
The findings from the questionnaire are summarized in Table 5. There was no significant difference in the self-assessment scores ofthe responding DSRS (7.0 ± 2.6) and OLT (7.4 ± 2.20) patients. The percentage of patients returning to work, or in school, was not significantly different in the two groups. In this sample of patients, the re-admissions to hospital are lower in the DSRS group. The requirement for immunosuppression after liver transplant results in the greater number of medications in the OLT group.
Analysis of Charges Evaluation charges, estimated from the basic tests required in all patients, were similar for DSRS ($2403) and OLT ($2837). This does not include hospitalization and management charges, or additional tests that may be required to assess other organ systems. Hospital charges of surgical admission are summarized in Table 6, and are based on sample sizes of 30 patients in the DSRS group and 22 patients in the OLT group. There is one significant outlier in each group. One DSRS patient had a hospital charge of $135,434 and one OLT patient a charge of > $1,000,000. Excluding these two patients, the range of charges for DSRS was $15,533 to $57,311, and for OLT was $61,639 to $285,897. These charges do not include professional fees. Follow-up charges have been broken down into the charges incurred by hospital readmission based on the same sample of patients used above, and an estimation of charges for outpatient medications and laboratory tests for 1 year after each procedure. TABLE 5. Quality ofLife From Self-Assessment Questionnaire
DSRS
Self-assessment (0-10 score) Working or in school Rehospitalizations 0 wk 1-4 wk >4 wk No. of medications 0 1-4 >5
7.0 ± 2.6 56%
OLT 7.4
±
2.0
58%
59% 31% 10%
36% 42% 22%
22% 64% 14%
0% 17% 83%
2259
* The sum of the median charges for the component services is less than the total charges because of the skew of the data.
Readmission charges. Eight (27%) of the sample of 30 DSRS patients required a total of 10 readmissions for medical management. The average charge incurred for these readmissions was $26,243. Neither of the two DSRS patients who had subsequent liver transplants were selected in this sample for analysis. Twelve (55%) of the 22 patients studied in the OLT sample required a total of 30 readmissions. The average charge of these readmissions was $33,962. One sampled patient in this OLT group has required retransplantation. Outpatient follow-up charges. Patients having DSRS require follow-up care estimated at $147 for medications and $1201 for laboratory tests in the first year. The estimated charges for the first year after liver transplant are $8967 for medications and $4940 for laboratory tests. Discussion The data presented in this paper support a role for DSRS in the management of variceal bleeding in appropriately selected patients. These patients are predominantly Child's class A and B, with stable disease and adequate or good hepatic function. Bleeding control has been good, with low morbidity rate from shunt thrombosis and recurrent bleeding. The 1-, 3-, and 4-year survivals of 91 %, 79%, and 77%, respectively, are in keeping with other series from the literature in which DSRS has been used for Child's A and B patients. Inokuchi and Sugimachi24 reported 3-year survival of 85% in 77 patients, Myburgh showed a 5-year survival of 72% in 127 patients,25 MaffeiFaccioli et al.26 achieved a 3-year survival of 80% and 5year survival of 57% in 70 patients. Paquet and coworkers27 showed a 75% survival at 5 years in 32 selected patients, and Orozco et al.28 had a 69% 5-year survival rate in 107 Child's A patients. The common denominator in these DSRS series has been careful patient selection. Do quantitative liver function tests assist in patient selection? The data in this study suggest that the galactose elimination capacity plays a useful adjunctive, but not a definitive role. Eighty-four per cent of the DSRS group had a GEC > 250 mg/minute, indicating adequate or good hepatocyte mass and function, which has been as-
Vol. 216 -No. 3
SELECTIVE SHUNT FOR VARICEAL BLEEDING
sociated with good survival. Analysis fails to reveal a direct correlation between GEC and survival, however. In contrast to the DSRS group, only 32% of the OLT group had a GEC > 250 mg/minute, and of these patients with good hepatocyte function, 23 had either primary biliary cirrhosis or sclerosing cholangitis. We have previously documented that end-stage cholestatic disease may occur with relatively good GEC.29 Reichen and his co-workers30 have shown that serial measures of GEC in patients with primary biliary cirrhosis provide an independent predictor of death as good as other predictive scores for this disease. The experience from the current study supports the use of quantitative liver function testing in aiding selection of patients for shunt or transplant. In reaching a decision as to which patients with variceal bleeding should be managed by liver transplant, a reliable assessment of expected outcome after OLT is needed. Factors such as the type of disease leading to transplantation, the condition of the patient at the time of transplantation, the age of the patient, and the immunosuppressive regimen all play a role in outcome. In reported series of 100 or more transplants conducted through the 1980s,"131-37 1-year survival rates have ranged from 55% to 85%. In the Liver Transplant Registry Report,38 1- and 2-year survival rates for 1536 patients with postnecrotic cirrhosis who were transplanted under United Network for Organ Sharing (UNOS) regulation were 73% and 67%, respectively. The survival in the present OLT series is similar. Two reports have specifically analyzed outcome after liver transplantation in patients who had variceal bleeding as a component of their end-stage disease. Bismuth reported a 4-year survival of 92% in 39 Child's B patients, and 73% in 29 Child's C patients.39 Iwatsuki reported on 302 Child's C patients with a history of bleeding from esophageal varices before transplant.'2 The 1-, 3-, and 5-year survival rates for this study were 79%, 71%, and 71%, respectively, and were significantly better than their OLT population, who had no prior variceal bleeding. Iwatsuki's data differ from the findings in the current study, which show significantly shorter survival in our transplant population, who had variceal bleeding as a component of their end-stage disease. The reasons for these differences are not apparent. The patients' assessment of their quality of life is remarkably similar in our two groups. Equivalent response rates to the questionnaire should balance any bias in the pattern of response. The rate of return to work or school was almost identical in both groups, but somewhat lower than the 75% reported by Colonna et al.,40 in their study of patients after liver transplant. Most patients who responded in both groups rated their current status as good to excellent, with few limitations imposed by their respective operations. These findings are also in parallel with the data reported from Pittsburgh.4'
253
The charges incurred in treating patients with chronic liver disease are high. The clinical presentations of variceal bleeding, encephalopathy, spontaneous bacterial peritonitis, and liver failure usually require intensive care management and prolonged hospital stays. Unfortunately, just as the financial burden of looking after these complications is high, so too is the charge of treating the underlying problem by liver transplantation. The argument that it is ultimately less expensive to proceed to transplantation when any of these complications develop is not supported by the current study. In the analysis of charges presented in this report, we demonstrate that in patients with cirrhosis and variceal bleeding who have good or adequate liver function, a satisfactory outcome can be achieved by DSRS at a charge significantly less than that required for transplantation. It is of course true that follow-up is relatively short (
