0016-5107/90/3602-0127$02.00
GASTROINTESTINAL ENDOSCOPY Copyright © 1990 by the American Society for Gastrointestinal Endoscopy
A comparative evaluation of sclerosants for esophageal varices: a prospective randomized controlled study R. Kochhar, MO, OM, M. K. Goenka, MO, OM S. Mehta, MO, S. K. Mehta, MO Chandigarh. India
The aim of this prospective randomized controlled study was to find a safe and effective sclerosing solution for endoscopic injection sclerotherapy in the treatment of esophageal variceal bleeding. Ninety consecutive patients with portal hypertension and variceal bleeding were randomized to receive sclerotherapy with 5% ethanolamine oleate, 3% sodium tetradecyl sulfate, or absolute alcohol at an interval of 3 weeks. Sixty-four patients who received more than three sessions were analyzed. All three agents were found to have similar success and complication rates (p > 0.05). However, absolute alcohol required fewer sessions (p < 0.01) and lesser amounts (p < 0.01) to produce successful variceal sclerosis and had the added advantage of low cost and easy availability. (Gastrointest Endosc 1990;36:127-130)
Although the role of endoscopic injection sclerotherapy (EIS) in the treatment of esophageal varices is now well established, there is no agreement regarding the choice of sclerosant, dose, and frequency of injection. Different sclerosants are preferentially used in different countries, for example, ethanolamine oleate in the United Kingdom and South Africa,1·2 polidocanol in Germany,3,4 sodium morrhuate and sodium tetradecyl sulfate in the United States,5,6 and alcohol in India. 7 ,s There are only a few studies comparing the efficacy of different sclerosants in human beings.s- 13 On the basis of available literature, there is little to help choose between the different sclerosants. Availability and cost may be important considerations, especially in the developing world. We evaluated three different sclerosants in patients with portal hypertension due to diverse etiology who had bled from esophageal varices. MATERIALS AND METHODS
Ninety consecutive patients with portal hypertension presenting with a history of upper gastrointestinal bleeding between January 1985 and December 1987 were entered into the trial. Non-variceal causes of bleeding were excluded in Received March 3. 1989. For revision April 20, 1989. Accepted August 23,1989. From the Department of Gastroenterology. Postgraduate Institute of Medical Education and Research. Chandigarh, India. Reprint requests: R. Kochhar, MD, Department of Gastroenterology, Postgraduate Institute of Medical Education and Research, Chandigarh, 160012, India. VOLUME 36. NO.2, 1990
all of the patients by endoscopy. After obtaining informed consent, the patients were randomized to undergo EIS at a 3-week interval with 5% ethanolamine oleate (ETH), 3% sodium tetradecyl sulfate (STD), or absolute alcohol (AA). Eleven patients, all cirrhotics including 4 patients from the AA group, 4 from the ETH, and 3 from the STD group died due to hepatic encephalopathy (7 patients) or gastrointestinal bleeding (4 patients) during hospitalization, and 15 patients (4 from the AA, 5 from the ETH, and 6 from the STD group) did not comply with the EIS schedule and dropped out after one to three injections. The remaining 64 subjects form the basis of this study. All of the patients had undergone liver function tests, viral marker studies, abdominal ultrasonography, splenoportovenography, and/or liver biopsy to diagnose the etiology of portal hypertension. Esophageal varices were graded from 1 to 4 using Conn's criteria. 14 Severity of the underlying liver disease was graded at the time of presentation according to Child's classification. IS Endoscopic sclerotherapy was performed using a straight viewing flexible fiberoptic endoscope (Olympus GIF-Q) and a standard injector needle (Olympus NM-3K) after premedication with intravenous pentazocine and hyoscine N-butyl bromide. Diazepam was given intravenously to children and apprehensive patients. The injections were given intravariceally by the free hand technique and 1.0 to 2.0 ml of the sclerosant were injected in each varix close to the gastroesophageal junction in a circumferential manner. One to three injections, spaced 2 cm apart, were given in each varix, to a total up to 15 ml of sclerosant in each sitting. Sclerotherapy was repeated at a 3-week interval, and at each session evaluation of variceal grading was done and the presence of ulceration and/or stricture was noted. Injection 127
into a varix having ulceration was deferred until the next session. A significant stricture was defined as the inability to negotiate it with a GIF-Q endoscope (outer diameter 11 mm). At every session, the variceal score was recorded in each patient. It was calculated by adding the grades of all of the varices noted just above the gastroesophageal junction. Thus, a patient with three varices of grade 2 was given a variceal score of 6. For the purpose of analysis, we considered successful sclerotherapy as complete obliteration of all of the varices or at least 50% downgrading of the variceal score. Comparison among the three different sclerosants was then made considering the success rate as well as the number of sessions and the volume of sclerosant required for successful EIS. The data were analyzed using the x 2 test and Student's t test. RESULTS
The patients in each of the three groups were comparable with respect to age, sex, etiology of portal hypertension, Child's grading, and the initial variceal score (Table 1). It required a greater force to inject ethanolamine oleate and blanching was more pronounced after injection with alcohol. Table 2 shows the results of EIS with three different sclerosants. The success rate (obliteration or ;:a, 50% downgrading of variceal score) of EIS was similar with the three agents, being 82.6% with AA, 86.4% with ETH, and 73.7% with STD (p > 0.05). However, the number of EIS sessions required for successful EIS was lower in patients receiving alcohol when compared with the other two groups (p < 0.01). The mean total volume of sclerosant required for successful EIS was also lower in the alcohol-treated group as compared with the ETH- and STD-treated groups (p < 0.01). There was no difference in the number of sessions and the volume of sclerosant required for successful EIS between the patients given ETH or STD (p > 0.005). With all three agents, there was a progressively decreasing
amount of sclerosant required in consecutive EIS sessions. Complications
Ulcerations and stricture formation (as seen at endoscopy at 3 weeks after the last injection) as well as interval rebleeding occurred at the same rate with the three agents (Table 2). In all patients, rebleeding occurred between the first and fourth sessions of EIS and was successfully controlled with balioon tamponade. Stricture formation was seen in 11 of the 13 patients who had ulceration at 3 weeks after the last EIS session. All of the strictures were successfully dilated by metal or balloon dilators with an average of 3.21 sessions. Detailed results on stricture dilation are included in a separate report. No patient in any of the groups had esophageal perforation, mediastinitis, or empyema thoracis. Follow-up
Thirty patients were followed up after eradication of varices for a mean (±SD) period of 8.5 (±3.8) months with endoscopy at 3-month intervals) (Table 3). The rate of reappearance of varices was 36.4% for AA and ETH and 25.0% for STD, p being >0.05 for any of the two agents. Two patients in the AA-treated group and one each in the ETH- and STD-treated groups had rebleeding during the follow-up. DISCUSSION
The variables which can possibly influence the efficacy and complications of EIS include the nature, concentration, and amount of the sclerosant used as well the site (intravariceal or paravariceal) and frequency of injections. Comparison of different studies shows that intravariceal EIS is as effective as paravariceal EIS. 16- 18 Controlled trials have also shown
Table 1. Clinical characteristics of the patients in three groups
Age" (mean ± SD)b Sex (M/F)b Child's classification b A
B C Etiologyb Cirrhosis
Non-cirrhotic portal fibrosis Extrahepatic obstruction Initial variceal score" (mean ±
AA (N = 23)
(N = 22)
ETH
34.8 ± 15.3 16/7
32.2 ± 16.7 16/6
35.2 ± 15.5 14/5
16 (69.6)< 5 (21.7) 2 (8.7)
15 (68.2) 5 (22.7) 2 (9.1)
13 (68.4) 4 (21.0) 2 (10.5)
11 (47.8) (ALD-7, HBV-3, OTH-l)d 5 (21.7) 7 (30.4) 11.3 ± 3.9
11 (50.0) (ALD-8, HBV-2, OTH-l)d 4 (18.2) 7 (31.8) 13.4 ± 4.6
10 (52.6) (ALD-7, HBV-2, OTH-1)d 4 (21.0) 5 (26.3) 11.8 ± 2.9
STD = 19)
(N
SD)b
• Student's t test, All others x2 test. b Not significant (p > 0.05) for any two groups when compared with each other. C Percentages in parentheses. d ALD, Alcoholic liver disease; HBV, hepatitis B liver disease; OTH, others.
128
GASTROINTESTINAL ENDOSCOPY
Table 2. Results of EIS with different sclerosants
AA
ETH (N = 22) (C:11, NC:11)
STD (N = 19) (C:10, NC:9)
19 (82.6)' 9 (81.8) 10 (83.3) 13 (56.5) 6 (26.1) 4.8 ± 1.7a
19 (86.4) 10 (90.9) 9 (81.8) 13 (59.1) 6 (27.3) 10.1 ± 4.6b
14 (73.7) 7 (70.0) 7 (77.8) 10 (52.6) 4 (21.0) 9.2 ± 3.4c
36.8 ± 16.7d
97.8 ± 31.Oe
79.3 ± 27.5f
8.7 ± 2.5 7.2 ± 2.5 5.0 ± 1.2
14.2 ± 5.0 12.0 ± 3.8 10.0 ± 1.0
10.4 ± 3.7 8.0 ± 1.6 7.4 ± 0.4
5 (21.7) 4 (17.4) 4 (17.4)
4 (18.2) 4 (18.2) 5 (22.7)
4 (21.0) 3 (15.8) 3 (15.8)
(N = 23) (C:11, NC:12)" Successful EIS b Cirrhotics b Non-cirrhotics b Complete obliteration b ~50% downgradingb No. of sessions/patient for successful EIS (mean ± SD)d Volume of sclerosant/patient for successful EIS (m!) (mean ± SD)d Mean volume (ml) (mean ± SD) First session Third session Fifth session Major complications Ulcer b Stricture b Rebleeding b
• C. cirrhotics; NC. non-cirrhotics. b p > 0.05 for any of two groups when compared with one another. Numbers in parentheses are percentages. 2 d Student's t test, all others x test. Differences: abo ac, de. df, p < 0.01; be, ef. p > 0.05.
C
Table 3. Follow-up of 30 patients with complete eradication of varices
AA (N
Reappearance" of varices Variceal bleeding" during followup (no. of patients)
= 11)
4 (36.4)b
ETH = 11)
STD
(N
(N = 8)
4 (36.4)
2 (25.0)
2
"Not significant (p > 0.05) for any of the two groups when compared with one another using x 2 test. b Percentages in parentheses.
that weekly EIS is as successful as three weekly EIS,19 although esophageal ulceration may make injections risky with the weekly EIS schedule. Going by the literature available on the use of single sclerosants, it is difficult to choose between the different agents. There are only a few controlled studies comparing the efficacy of different sclerosants in human beings8-13 and the data from experimental studies on animal models of portal hypertension are also scanty.20,21 Our results show that all three sclerosants achieved comparable success rates. The success rate was 82.6% with alcohol, 86.4% with ETH, and 73.7% with STD (p > 0.05 for any of the two agents). In studies on individual sclerosing agents, the success rates with alcohol have varied between 72 and 80%,22,23 with STD between 28 and 62%,24,25 and with ETH between 95 and 100%.2,26 Of the various comparative trials with different sclerosants in humans, four 8 ,ll-13 have comVOLUME 36, NO.2, 1990
pared the efficacy of alcohol with that of another sclerosant. Although two groups12,13 concluded that the use of absolute alcohol was associated with a significantly higher complication rate as compared with ethoxysclerol, another 11 felt that ethanolamine oleate was better than 50% alcohol. Sarin et al. 8 , on the other hand, while comparing AA with ETH found the former to be a superior agent. In a series of reports, these studies have shown the efficacy and safety of AA. 8,18,19,22,27 Our observations that AA is as effective and safe as ETH and STD would support the contention of Sarin et al.8,18,19 that the easy availability and the low cost of AA may make it the sclerosant of choice. However, the poor results of others ll -13 with AA have led to skepticism about the safety of this agent. 28 It has been suggested that 50% alcohol may be less damaging than absolute alcohol. 28 In the only comparative evaluation of 50% alcohol versus absolute alcohol, however, the latter was found to be a more effective sclerosant. 27 The reasons for widely variable results with the use of AA are difficult to pinpoint. Etiology of portal hypertension may· have some bearing on the results. A majority of patients included in trials by Sarin et al. were not cirrhotic while most of the patients in a study from Italy13 were alcoholic cirrhotics. Other variables like the speed of injection may be very difficult to monitor. 28 In order to avoid local complications, one may need to try different permutations of sclerosants and techniques. 28 There are only a few studies available in the literature which have commented on the volume of sclerosant required for successful EIS with different scle129
rosants. Kitano et al. 9 observed no difference between 5% ethanolamine oleate and 2% STD, while Sarin et
al. 8 needed a significantly lower amount of alcohol as compared with ETH. We observed that the volume of the sclerosant required was significantly lower (p < 0.01) when AA was used as compared with ETH and STD, but between the latter two there was no difference (p > 0.05). Similarly, the number of EIS sessions required was also less for alcohol than with ETH or STD (p < 0.01), but was similar for ETH and STD. From this data and the observation of Sarin et al.,8 it seems that AA has a better sclerosing effect than ETH and STD. Support for this contention also comes from experimental work where Silpa et al. 20 in a canine model of portal hypertension found 95% alcohol to be the most thrombogenic agent followed by 1.5% STD andETH. Data on comparative complication rates with different sclerosants are also scanty. Kitano et al. 9 found a higher ulceration rate with STD than with ETH while Sarin et al. 8 did not find any difference when AA and ETH were compared. Although some studies have reported higher complication rates with alcohol when compared with ETH l l and polidocanol,12.13 we observed similar rates of ulceration, stricture formation, and rebleeding with the three agents used by us. Serious pulmonary complications like adult respiratory distress syndrome were not observed by us in any patient. We found that AA, 5% ETH, and 3% STD were equally effective in achieving variceal sclerosis and had similar complication rates. However, the number of sessions of EIS and the volume of sclerosant required were significantly less with AA than with 5% ETH and 3% STD. Since alcohol is much cheaper than the other sclerosants and is readily available in the developing world, its use can make EIS cheaper. Moreover, since the number of EIS sessions required with AA is less than with others, successful sclerotherapy can be achieved in a shorter time when this agent is used. ACKNOWLEDGMENT
The authors are grateful to Mr. T. N. Sharma for his help in statistical analyses.
REFERENCES 1. Westaby D, Williams R. Elective sclerotherapy-technique and results. Endoscopy 1986;18 (suppl):28-31. 2. Terblanche J, Bornman PC, Kahn D, et al. Failure of repeated injection sclerotherapy to improve long-term survival after oesophageal variceal bleeding. A five year prospective controlled clinical trial. Lancet 1983;2:1328-32. 3. Witzel L, Wolbergs S, Merki H. Prophylactic endoscopic sclerotherapy of oesophageal varices: a prospective controlled study. Lancet 1985;1:773-5. 4. Soehendra N, de Heer K, Kempeneers I, Frommelt L. Morphological alterations of the oesophagus after endoscopic sclerotherapy of varices. Endoscopy 1983;15:291-6. 130
5. Cello JP, Grendell JH, Crass RA, Trunkey DD, Cobb EE, Heilbron DC. Endoscopic sclerotherapy versus portacaval shunt in patients with severe cirrhosis and variceal hemorrhage. N Engl J Med 1984;311:1589-94. 6. Fleischer D. Endoscopic therapy of upper gastrointestinal bleeding in humans. Gastroenterology 1986;90:212-34. 7. Chawla YK, Dilawari JB, Kaur U. Variceal sclerotherapy in cirrhosis. Indian J GastroenteroI1988;7:215-7. 8. Sarin SK, Misra SP, Sachdev GK, Thorat V, Dalal L, Broor SL. Ethanolamine oleate versus absolute alcohol as a variceal sclerosant: a prospective randomized controlled trial. Am J Gastroenterol 1988;83:526-30. 9. Kitano S, Iso Y, Yamaga H, Hashizume M, Higashi H, Sugimachi K. Trial of sclerosing agents in patients with oesophageal varices. Br J Surg 1988;75:751-3. 10. Kitano S, Iso Y, Koyanagi N, Higashi H, Sugimachi K. Ethanolamine oleate is superior to polidocanol (aethoxysklerol) for endoscopic injection sclerotherapy of esophageal varices: a prospective randomized trial. Hepatogastroenterology 1987;34:1923. 11. Vij JC, Kumar N, Kumar A, Anand BS, Broor SL. A comparative study of 50% alcohol and ethanolamine oleate for oesophageal sclerotherapy. Indian J Gastroenterol 1988;7:211-3. 12. Atmakuri SP, Bhargava DK, Sharma MP. Endoscopic sclerotherapy for esophageal varices: a prospective, randomised trial of absolute alcohol versus polidocanol. Indian J Gastroenterol 1988;7:87-9. 13. Paoluzi P, Pietroiusti A, Ferrari S, Cappa M, Pagnanelli A. Absolute alcohol in esophageal vein sclerosis. Gastrointest Endose 1988;34:400-2. 14. Conn HO. Ammonia tolerance in the diagnosis of oesophageal varices. A comparison of endoscopic, radiological and biochemical techniques. J Lab Clin Med 1967;70:442-51. 15. Pugh RNH, Murray Lyon 1M, Dawson JL, Pietroni MC, Williams R. Transection of the oesophagus for bleeding oesophageal varices. Br J Surg 1973;60:646-9. 16. Paquet KJ. Prophylactic endoscopic sclerosing treatment of the esophageal wall in varices-a prospective controlled randomized trial. Endoscopy 1982;14:4-5. 17. Terblanche J, Northover JM, Bornman P, et al. A prospective evaluation of injection sclerotherapy in the treatment of acute bleeding from esophageal varices. Surgery 1979; 85:239-45. 18. Sarin SK, Nanda R, Sachdev G, Chari S, Anand BS, Broor SL. Intravariceal versus paravariceal sclerotherapy: a prospective, controlled randomized trial. Gut 1987;28:657-62. 19. Sarin SK, Sachdev G, Nanda R, Batra SK, Anand BS. Comparison of the two time schedules for endoscopic sclerotherapy-a prospective randomized controlled study. Gut 1986;27:710-3. 20. Silpa ML, Jensen DM, Machicado GA, Tapia JI, Beilin DB. Efficacy and safety of agents for variceal sclerotherapy [Abstract). Gastrointest Endosc 1982;28:152-3. 21. Blenkinsopp WK. Comparison of tetradecyl sulfate with other sclerosants in rats. Br J Exp PathoI1968;49:197-9. 22. Sarin SK, Sachdev G, Nanda R. Follow up of the patients after variceal eradication. A comparison of patients with cirrhosis, non-cirrhotic portal fibrosis and extrahepatic obstruction. Ann Surg 1986;204:78-82. 23. Sarin SK, Sachdeva GK, Nanda R, Vij JC, Anand BS. Endoscopic sclerotherapy using absolute alcohol. Gut 1985;26:120-4. 24. Korula J, Balart LA, Radvan G, et al. A prospective, randomized controlled trial of chronic esophageal variceal sclerotherapy. Hepatology 1985;5:584-9. 25. Sarles HE, Sanowski RA, Talbert G. Course and complications of endoscopic variceal sclerotherapy: a prospective study of 50 patients. Am J Gastroenterol 1985;80:595-9. 26. Westaby D, Melia WM, MacDougall BRD, Hegarty JE, Williams R. Injection sclerotherapy for oesophageal varices: a prospective randomized trial of different treatment schedules. Gut 1984;25:129-32. 27. Sarin SK, Nanda R, Sachdev G. Relative efficacy and safety of absolute alcohol ancl 50% alcohol as variceal sclerosants. Gastrointest Enclose 1987;33:362-5. 28. Schuman BM. Alcohol for variceal injection-pure but not so simple. Gastrointest Enclose 1988;34:434-6.
GASTROINTESTINAL ENDOSCOPY
GASTROINTESTINAL ENDOSCOPY Copyright © 1990 by the American Society for Gastrointestinal Endoscopy
A comparative evaluation of sclerosants for esophageal varices: a prospective randomized controlled study R. Kochhar, MO, OM, M. K. Goenka, MO, OM S. Mehta, MO, S. K. Mehta, MO Chandigarh. India
The aim of this prospective randomized controlled study was to find a safe and effective sclerosing solution for endoscopic injection sclerotherapy in the treatment of esophageal variceal bleeding. Ninety consecutive patients with portal hypertension and variceal bleeding were randomized to receive sclerotherapy with 5% ethanolamine oleate, 3% sodium tetradecyl sulfate, or absolute alcohol at an interval of 3 weeks. Sixty-four patients who received more than three sessions were analyzed. All three agents were found to have similar success and complication rates (p > 0.05). However, absolute alcohol required fewer sessions (p < 0.01) and lesser amounts (p < 0.01) to produce successful variceal sclerosis and had the added advantage of low cost and easy availability. (Gastrointest Endosc 1990;36:127-130)
Although the role of endoscopic injection sclerotherapy (EIS) in the treatment of esophageal varices is now well established, there is no agreement regarding the choice of sclerosant, dose, and frequency of injection. Different sclerosants are preferentially used in different countries, for example, ethanolamine oleate in the United Kingdom and South Africa,1·2 polidocanol in Germany,3,4 sodium morrhuate and sodium tetradecyl sulfate in the United States,5,6 and alcohol in India. 7 ,s There are only a few studies comparing the efficacy of different sclerosants in human beings.s- 13 On the basis of available literature, there is little to help choose between the different sclerosants. Availability and cost may be important considerations, especially in the developing world. We evaluated three different sclerosants in patients with portal hypertension due to diverse etiology who had bled from esophageal varices. MATERIALS AND METHODS
Ninety consecutive patients with portal hypertension presenting with a history of upper gastrointestinal bleeding between January 1985 and December 1987 were entered into the trial. Non-variceal causes of bleeding were excluded in Received March 3. 1989. For revision April 20, 1989. Accepted August 23,1989. From the Department of Gastroenterology. Postgraduate Institute of Medical Education and Research. Chandigarh, India. Reprint requests: R. Kochhar, MD, Department of Gastroenterology, Postgraduate Institute of Medical Education and Research, Chandigarh, 160012, India. VOLUME 36. NO.2, 1990
all of the patients by endoscopy. After obtaining informed consent, the patients were randomized to undergo EIS at a 3-week interval with 5% ethanolamine oleate (ETH), 3% sodium tetradecyl sulfate (STD), or absolute alcohol (AA). Eleven patients, all cirrhotics including 4 patients from the AA group, 4 from the ETH, and 3 from the STD group died due to hepatic encephalopathy (7 patients) or gastrointestinal bleeding (4 patients) during hospitalization, and 15 patients (4 from the AA, 5 from the ETH, and 6 from the STD group) did not comply with the EIS schedule and dropped out after one to three injections. The remaining 64 subjects form the basis of this study. All of the patients had undergone liver function tests, viral marker studies, abdominal ultrasonography, splenoportovenography, and/or liver biopsy to diagnose the etiology of portal hypertension. Esophageal varices were graded from 1 to 4 using Conn's criteria. 14 Severity of the underlying liver disease was graded at the time of presentation according to Child's classification. IS Endoscopic sclerotherapy was performed using a straight viewing flexible fiberoptic endoscope (Olympus GIF-Q) and a standard injector needle (Olympus NM-3K) after premedication with intravenous pentazocine and hyoscine N-butyl bromide. Diazepam was given intravenously to children and apprehensive patients. The injections were given intravariceally by the free hand technique and 1.0 to 2.0 ml of the sclerosant were injected in each varix close to the gastroesophageal junction in a circumferential manner. One to three injections, spaced 2 cm apart, were given in each varix, to a total up to 15 ml of sclerosant in each sitting. Sclerotherapy was repeated at a 3-week interval, and at each session evaluation of variceal grading was done and the presence of ulceration and/or stricture was noted. Injection 127
into a varix having ulceration was deferred until the next session. A significant stricture was defined as the inability to negotiate it with a GIF-Q endoscope (outer diameter 11 mm). At every session, the variceal score was recorded in each patient. It was calculated by adding the grades of all of the varices noted just above the gastroesophageal junction. Thus, a patient with three varices of grade 2 was given a variceal score of 6. For the purpose of analysis, we considered successful sclerotherapy as complete obliteration of all of the varices or at least 50% downgrading of the variceal score. Comparison among the three different sclerosants was then made considering the success rate as well as the number of sessions and the volume of sclerosant required for successful EIS. The data were analyzed using the x 2 test and Student's t test. RESULTS
The patients in each of the three groups were comparable with respect to age, sex, etiology of portal hypertension, Child's grading, and the initial variceal score (Table 1). It required a greater force to inject ethanolamine oleate and blanching was more pronounced after injection with alcohol. Table 2 shows the results of EIS with three different sclerosants. The success rate (obliteration or ;:a, 50% downgrading of variceal score) of EIS was similar with the three agents, being 82.6% with AA, 86.4% with ETH, and 73.7% with STD (p > 0.05). However, the number of EIS sessions required for successful EIS was lower in patients receiving alcohol when compared with the other two groups (p < 0.01). The mean total volume of sclerosant required for successful EIS was also lower in the alcohol-treated group as compared with the ETH- and STD-treated groups (p < 0.01). There was no difference in the number of sessions and the volume of sclerosant required for successful EIS between the patients given ETH or STD (p > 0.005). With all three agents, there was a progressively decreasing
amount of sclerosant required in consecutive EIS sessions. Complications
Ulcerations and stricture formation (as seen at endoscopy at 3 weeks after the last injection) as well as interval rebleeding occurred at the same rate with the three agents (Table 2). In all patients, rebleeding occurred between the first and fourth sessions of EIS and was successfully controlled with balioon tamponade. Stricture formation was seen in 11 of the 13 patients who had ulceration at 3 weeks after the last EIS session. All of the strictures were successfully dilated by metal or balloon dilators with an average of 3.21 sessions. Detailed results on stricture dilation are included in a separate report. No patient in any of the groups had esophageal perforation, mediastinitis, or empyema thoracis. Follow-up
Thirty patients were followed up after eradication of varices for a mean (±SD) period of 8.5 (±3.8) months with endoscopy at 3-month intervals) (Table 3). The rate of reappearance of varices was 36.4% for AA and ETH and 25.0% for STD, p being >0.05 for any of the two agents. Two patients in the AA-treated group and one each in the ETH- and STD-treated groups had rebleeding during the follow-up. DISCUSSION
The variables which can possibly influence the efficacy and complications of EIS include the nature, concentration, and amount of the sclerosant used as well the site (intravariceal or paravariceal) and frequency of injections. Comparison of different studies shows that intravariceal EIS is as effective as paravariceal EIS. 16- 18 Controlled trials have also shown
Table 1. Clinical characteristics of the patients in three groups
Age" (mean ± SD)b Sex (M/F)b Child's classification b A
B C Etiologyb Cirrhosis
Non-cirrhotic portal fibrosis Extrahepatic obstruction Initial variceal score" (mean ±
AA (N = 23)
(N = 22)
ETH
34.8 ± 15.3 16/7
32.2 ± 16.7 16/6
35.2 ± 15.5 14/5
16 (69.6)< 5 (21.7) 2 (8.7)
15 (68.2) 5 (22.7) 2 (9.1)
13 (68.4) 4 (21.0) 2 (10.5)
11 (47.8) (ALD-7, HBV-3, OTH-l)d 5 (21.7) 7 (30.4) 11.3 ± 3.9
11 (50.0) (ALD-8, HBV-2, OTH-l)d 4 (18.2) 7 (31.8) 13.4 ± 4.6
10 (52.6) (ALD-7, HBV-2, OTH-1)d 4 (21.0) 5 (26.3) 11.8 ± 2.9
STD = 19)
(N
SD)b
• Student's t test, All others x2 test. b Not significant (p > 0.05) for any two groups when compared with each other. C Percentages in parentheses. d ALD, Alcoholic liver disease; HBV, hepatitis B liver disease; OTH, others.
128
GASTROINTESTINAL ENDOSCOPY
Table 2. Results of EIS with different sclerosants
AA
ETH (N = 22) (C:11, NC:11)
STD (N = 19) (C:10, NC:9)
19 (82.6)' 9 (81.8) 10 (83.3) 13 (56.5) 6 (26.1) 4.8 ± 1.7a
19 (86.4) 10 (90.9) 9 (81.8) 13 (59.1) 6 (27.3) 10.1 ± 4.6b
14 (73.7) 7 (70.0) 7 (77.8) 10 (52.6) 4 (21.0) 9.2 ± 3.4c
36.8 ± 16.7d
97.8 ± 31.Oe
79.3 ± 27.5f
8.7 ± 2.5 7.2 ± 2.5 5.0 ± 1.2
14.2 ± 5.0 12.0 ± 3.8 10.0 ± 1.0
10.4 ± 3.7 8.0 ± 1.6 7.4 ± 0.4
5 (21.7) 4 (17.4) 4 (17.4)
4 (18.2) 4 (18.2) 5 (22.7)
4 (21.0) 3 (15.8) 3 (15.8)
(N = 23) (C:11, NC:12)" Successful EIS b Cirrhotics b Non-cirrhotics b Complete obliteration b ~50% downgradingb No. of sessions/patient for successful EIS (mean ± SD)d Volume of sclerosant/patient for successful EIS (m!) (mean ± SD)d Mean volume (ml) (mean ± SD) First session Third session Fifth session Major complications Ulcer b Stricture b Rebleeding b
• C. cirrhotics; NC. non-cirrhotics. b p > 0.05 for any of two groups when compared with one another. Numbers in parentheses are percentages. 2 d Student's t test, all others x test. Differences: abo ac, de. df, p < 0.01; be, ef. p > 0.05.
C
Table 3. Follow-up of 30 patients with complete eradication of varices
AA (N
Reappearance" of varices Variceal bleeding" during followup (no. of patients)
= 11)
4 (36.4)b
ETH = 11)
STD
(N
(N = 8)
4 (36.4)
2 (25.0)
2
"Not significant (p > 0.05) for any of the two groups when compared with one another using x 2 test. b Percentages in parentheses.
that weekly EIS is as successful as three weekly EIS,19 although esophageal ulceration may make injections risky with the weekly EIS schedule. Going by the literature available on the use of single sclerosants, it is difficult to choose between the different agents. There are only a few controlled studies comparing the efficacy of different sclerosants in human beings8-13 and the data from experimental studies on animal models of portal hypertension are also scanty.20,21 Our results show that all three sclerosants achieved comparable success rates. The success rate was 82.6% with alcohol, 86.4% with ETH, and 73.7% with STD (p > 0.05 for any of the two agents). In studies on individual sclerosing agents, the success rates with alcohol have varied between 72 and 80%,22,23 with STD between 28 and 62%,24,25 and with ETH between 95 and 100%.2,26 Of the various comparative trials with different sclerosants in humans, four 8 ,ll-13 have comVOLUME 36, NO.2, 1990
pared the efficacy of alcohol with that of another sclerosant. Although two groups12,13 concluded that the use of absolute alcohol was associated with a significantly higher complication rate as compared with ethoxysclerol, another 11 felt that ethanolamine oleate was better than 50% alcohol. Sarin et al. 8 , on the other hand, while comparing AA with ETH found the former to be a superior agent. In a series of reports, these studies have shown the efficacy and safety of AA. 8,18,19,22,27 Our observations that AA is as effective and safe as ETH and STD would support the contention of Sarin et al.8,18,19 that the easy availability and the low cost of AA may make it the sclerosant of choice. However, the poor results of others ll -13 with AA have led to skepticism about the safety of this agent. 28 It has been suggested that 50% alcohol may be less damaging than absolute alcohol. 28 In the only comparative evaluation of 50% alcohol versus absolute alcohol, however, the latter was found to be a more effective sclerosant. 27 The reasons for widely variable results with the use of AA are difficult to pinpoint. Etiology of portal hypertension may· have some bearing on the results. A majority of patients included in trials by Sarin et al. were not cirrhotic while most of the patients in a study from Italy13 were alcoholic cirrhotics. Other variables like the speed of injection may be very difficult to monitor. 28 In order to avoid local complications, one may need to try different permutations of sclerosants and techniques. 28 There are only a few studies available in the literature which have commented on the volume of sclerosant required for successful EIS with different scle129
rosants. Kitano et al. 9 observed no difference between 5% ethanolamine oleate and 2% STD, while Sarin et
al. 8 needed a significantly lower amount of alcohol as compared with ETH. We observed that the volume of the sclerosant required was significantly lower (p < 0.01) when AA was used as compared with ETH and STD, but between the latter two there was no difference (p > 0.05). Similarly, the number of EIS sessions required was also less for alcohol than with ETH or STD (p < 0.01), but was similar for ETH and STD. From this data and the observation of Sarin et al.,8 it seems that AA has a better sclerosing effect than ETH and STD. Support for this contention also comes from experimental work where Silpa et al. 20 in a canine model of portal hypertension found 95% alcohol to be the most thrombogenic agent followed by 1.5% STD andETH. Data on comparative complication rates with different sclerosants are also scanty. Kitano et al. 9 found a higher ulceration rate with STD than with ETH while Sarin et al. 8 did not find any difference when AA and ETH were compared. Although some studies have reported higher complication rates with alcohol when compared with ETH l l and polidocanol,12.13 we observed similar rates of ulceration, stricture formation, and rebleeding with the three agents used by us. Serious pulmonary complications like adult respiratory distress syndrome were not observed by us in any patient. We found that AA, 5% ETH, and 3% STD were equally effective in achieving variceal sclerosis and had similar complication rates. However, the number of sessions of EIS and the volume of sclerosant required were significantly less with AA than with 5% ETH and 3% STD. Since alcohol is much cheaper than the other sclerosants and is readily available in the developing world, its use can make EIS cheaper. Moreover, since the number of EIS sessions required with AA is less than with others, successful sclerotherapy can be achieved in a shorter time when this agent is used. ACKNOWLEDGMENT
The authors are grateful to Mr. T. N. Sharma for his help in statistical analyses.
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GASTROINTESTINAL ENDOSCOPY
