- Email: [email protected]
Endoscopic treatment of bleeding gastric varices by N-butyl-2-cyanoacrylate (Histoacryl) injection: long-term efficacy and safety
Endoscopic treatment of bleeding gastric varices by N-butyl-2-cyanoacrylate (Histoacryl) injection: long-term efficacy and safety Yi-Hsiu Huang, MD, Hong-Zen Yeh, MD, Gran-Hum Chen, MD, Chi-Sen Chang, MD, Chun-Ying Wu, MD, MPH, Sek-Kwong Poon, MD, Han-Chung Lien, MD, Sheng-Shun Yang, MD Taichung and Taipei, Taiwan
Background: The long-term efficacy and safety of the endoscopic injection of N-butyl-2-cyanoacrylate (Histoacryl) were evaluated to define its role as the initial treatment for bleeding gastric varices. Methods: Ninety patients with bleeding gastric varices underwent endoscopic injections of Histoacryl for hemostasis within a 6-year period. Histoacryl was injected intravariceally as a 1:1 mixture with Lipiodol. Among the 90 patients, 5 had active bleeding and 85 had recent bleeding. Most of the varices were large (F2 or F3, 85 cases). The most common locations were the fundus and the posterior wall of the proximal body (94.4%). After Histoacryl injection, patients were followed endoscopically with retreatment as necessary. Results: The rate of hemostasis at 1 week was 94.4%. Recurrent bleeding occurred in 23.3% of the patients from 3 days to 16 months after the initial injection. Recurrent bleeding was stopped with reinjections of Histoacryl in 16.7% of the patients. The rate of definitive hemostasis was 93.3% (84 of 90). The treatment failure–related mortality rate was 2.2% (2 of 90). To date, 35 patients have died, mostly as a result of malignancy or liver failure, and 55 are still alive. The determining factor for long-term survival was the underlying disease leading to portal hypertension. There were few long-term complications except for Histoacryl cast extrusion–related mucosal defects. Conclusions: Endoscopic injection of Histoacryl is highly effective for the treatment of bleeding gastric varices, with rare complications both acutely and long term. This treatment modality is appropriate as the first choice for bleeding gastric varices. (Gastrointest Endosc 2000;52:160-7.)
Bleeding from gastric varices, although not as common as bleeding from esophageal varices, is usually more severe.1,2 Nonendoscopic techniques, such as surgical procedures3,4 or transjugular intrahepatic portosystemic shunt (TIPS),5,6 provide effective hemostasis but are not ideal first–choice therapies because of their technical requirements or invasiveness. Endoscopic techniques have become the first choice for treatment for bleeding esophagogastric varices. Various endoscopic modalities7-10 have also been applied to obtain hemostasis with bleeding gastric varices. To date, there is no consensus on the ideal treatment modality for bleeding gastric varices. Endoscopic tissue adhesive injection was first applied in Received June 15, 1999. For revision September 9, 1999. Accepted December 9, 1999. From the Division of Gastroenterology, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, and National Yang-Ming University, Taipei, Taiwan. Reprint requests: Hong-Zen Yeh, MD, Division of Gastroenterology, Department of Internal Medicine, Taichung Veterans General Hospital, No. 160, Sec. 3, Chung-Kang Rd., Taichung 40705, Taiwan, Republic of China. Copyright © 2000 by the American Society for Gastrointestinal Endoscopy 0016-5107/2000/$12.00 + 0 37/1/104976 doi:10.1067/mge.2000.104976 160
GASTROINTESTINAL ENDOSCOPY
the treatment of bleeding gastric varices by Gotlib and Zimmermann11 and Ramond et al.12 in 1984 and 1986, respectively. In 1986, Soehendra et al.13 also reported a large series with this endoscopic treatment. Since then, this procedure has been accepted and approved in many countries other than the United States as an effective, nonsurgical method for achieving hemostasis in patients with bleeding gastric varices.14-16 However, controversies concerning its long-term efficacy and safety still exist. The rate of recurrent bleeding17,18 and episodic complications such as systemic embolization have been the main issues.19-21 Technical aspects, including the risk of injector clogging, damage to the endoscope, and the difficulty in preparation of the N-butyl-2-cyanoacrylate solution, have been mentioned in other reports.7,15 The aim of this study, therefore, was to evaluate the long-term results of N-butyl-2-cyanoacrylate injection for bleeding gastric varices and to clarify its role as the therapy of choice among endoscopic modalities. PATIENTS AND METHODS Patients From November 1992 to October 1998, 893 patients were seen at our hospital because of esophagogastric VOLUME 52, NO. 2, 2000
Long-term efficacy and safety of Histoacryl injection for gastric varices
variceal bleeding. Among them, 90 patients, including 70 men and 20 women, with proven gastric variceal bleeding underwent endoscopic injection of N-butyl-2-cyanoacrylate for the purpose of hemostasis or prevention of recurrent bleeding. Four patients with respiratory distress or cyanosis were excluded from treatment. Among these 90 patients, 5 had active bleeding (spurting or oozing) and 85 had recent bleeding (90% within 24 hours). Recent bleeding was defined as fibrin clots on varices (80% of cases) or blood in the stomach with no other bleeding source (20% of cases). Liver function was classified according to the method of Child-Pugh22 (Table 1). The most common cause of gastric varices was viral hepatitis–related cirrhosis (74.5%) (Table 1). The form and location of the gastric varices were classified according to the system proposed by Hashizume et al.23; form was classified into 3 types: tortuous (F1), nodular (F2), and tumorous (F3); and location was 5 areas: anterior (La), posterior (Lp), lesser (Ll) and greater curvature (Lg) of the cardia, and the fundic area (Lf). Most of the gastric varices were large (Table 1). Associated esophageal varices were usually small or absent. The most common locations of these gastric varices were the fundus (Lf) and the most proximal body on the posterior wall (Lp) (94.4%) (Table 1). Methods Injections were performed by using a commercial flexible sclerotherapy injector, with a 6 mm 21–gauge needle. A standard forward-viewing videoendoscope was used in most cases. N-butyl-2-cyanoacrylate (Histoacryl; B. Braun, Melsungen, Germany), the main injection component, was mixed with Lipiodol (Laboratoire Guerbet, Aulnay-SousBois France) in a 1:1 ratio and injected as a bolus of 1 to 2 mL according to variceal size. The actual volume of the injection was based on the variceal appearance (F2 ≅ 1 mL, F3 ≅ 2 mL). The injection was stopped when the varices became engorged. Lipiodol was used to flush the injection needle before and after the injection. The tip of the endoscope and the accessory channel were treated with silicone oil to prevent endoscopic damage. The intravariceal injection was made near, but not on, the bleeding point and was given in 1 or 2 squirts. If unobliterated varices (soft sensation on palpation with a blunt probe) were found contiguous to an injected varix, however, another injection was made during endoscopic follow-up. We did not intend to inject varices at a distance from the one that was bleeding. An x-ray film was taken after each session to check the contour of the Histoacryl cast. If the cast shape was similar to that of the vascular channel, the intraluminal injection was considered accurate. If a poorly defined cast shape was noted, the intravariceal injection was presumed to have been inaccurate. Reinjection was performed during the same session for persistent bleeding or inadequate obliteration (about 20% of the time) or during a follow-up session for poor variceal obliteration (about 80% of the time). A chest x-ray was also taken to ascertain whether any embolic material had migrated into the chest. Patients underwent endoscopic follow-up in the second week, fourth week, second month, fourth month, and seventh month after injection and then every half year. VOLUME 52, NO. 2, 2000
Y-H Huang, H-Z Yeh, G-H Chen, et al.
Figure 1. Kaplan-Meier analysis of cumulative rebleedingfree time. One-week hemostasis was defined as an absence of clinically detectable bleeding within 1 week after the first injection of Histoacryl for acute bleeding. Recurrent bleeding was defined as any bleeding arising from the injected varices, or varices contiguous to or in proximity to the injected varix, after a period of 24 or more hours of stable vital signs and hemoglobin/hematocrit levels after an episode of acute bleeding. Primary success was defined as an absence of recurrent bleeding after the first Histoacryl injection and during the entire follow-up period. Secondary success was defined as an absence of recurrent bleeding after the reinjection of Histoacryl for recurrent bleeding. Definitive hemostasis included both primary and secondary success. Treatment failure was defined as failure to obtain definitive hemostasis. The risk factors for recurrent bleeding, including Child-Pugh class, portal vein thrombosis, and variceal size, were analyzed by Spearman’s correlation and the chi-square test. Cumulative survival and time free from recurrent bleeding curves were both described with Kaplan-Meier plots. A log rank test was used for the comparison of survival between each curve. A p value < 0.05 was considered to be significant. The study was approved by the ethics committee of our hospital. Written consent was obtained from each patient or a relative.
RESULTS The median duration of follow-up in this study was 13 ± 2.02 months (range 1 day to 67 months). Among the 90 patients, there was no instance of immediate postinjection hemostatic failure. Eightyfive patients were free from significant bleeding within 1 week after Histoacryl injection. Five patients had recurrent bleeding during the first week. Among them, 1 patient bled at 3 days and 4 within 1 week. One died of recurrent bleeding. The other 4 stopped bleeding but 2 died of sepsis or liver failure. Thus, the rate of one-week hemostasis was GASTROINTESTINAL ENDOSCOPY
161
Y-H Huang, H-Z Yeh, G-H Chen, et al.
Long-term efficacy and safety of Histoacryl injection for gastric varices
Table 1. Clinical characteristics of patients with gastric varices No. of patients Mean age (yr) Range (yr) Men:women Etiology of gastric varices Cirrhosis Viral hepatitis (B & C) Alcoholism Secondary biliary cirrhosis Klatskin tumor Idiopathic Bleeding status Active bleeding Recent bleeding Child-Pugh classification (A/B/C) Form of gastric varices F1/F2/F3 Location of gastric varices Lp+Lf Lg+La Associated esophageal varices Non/F1/F2/F3 Association with Hepatocellular carcinoma Portal vein thrombosis
No.
%
90 58 ± 12 34-80 70:20
78:22
88 67 19 2 1 1
97.8 74.5 21.1 2.2 1.1 1.1
5 85 33/43/14
5.6 94.4 36/48/16
5/53/32
6/59/35
85 5
94.4 5.6
28/46/12/4
31/51/13/5
24 17
26.7 18.9
94.4% (Table 2). Sixty-nine (76.6%) of the 90 patients remained free from further bleeding (primary success) during the entire course of follow-up. Episodes of recurrent bleeding were noted in 21 patients (23.3%) (Table 2) from 3 days to 16 months after the initial injection, but most occurred within the first 6 months (Fig. 1). The incidence of recurrent bleeding was relatively high (44%) during the first year of therapy and was less than 20% in following years. Recurrence of bleeding subsided after repeat injection of Histoacryl in 15 of these 21 cases. The rate of secondary success was 16.7%. Thus, the rate of definitive hemostasis, including primary successes and secondary successes, was 93.3%. The average number of sessions required to achieve definitive hemostasis for each patient with recurrent bleeding was 1.3 ± 0.7. Three patients underwent devascularization surgery and one underwent a TIPS procedure because of failure to obtain definitive hemostasis. Two patients died of massive recurrent bleeding. Thus, the treatment failure rate was 6.7% (6 of 90), and the treatment failure–related mortality rate was 2.2% (2 of 90). The rates of recurrent bleeding for F1 (0 of 5) plus F2 (10 of 53), and of F3 (11 of 32) varices were 17.2% and 34.4%, respectively (p < 0.05). The rates of recurrent bleeding were 15.1% (5 of 33) for patients with Child-Pugh class A liver disease, 25.6% (11 of 162
GASTROINTESTINAL ENDOSCOPY
Table 2. Results of Histoacryl injection One-week hemostasis Definitive hemostasis Primary success Secondary success Sessions needed (mean) Recurrent bleeding Treatment failure Surgery Mortality TIPS Cast extrusion Time of extrusion Obliteration
n = 90
%
85 84 69 15 1.3 ± 0.7 21 6 3 2 1 24 6 ± 4 mo 22 (n = 61)*
94.4 93.3 76.6 16.7 23.3 6.7 3.4 2.2 1.1
36.1
*Cases that can be well evaluated.
43) for patients with class B, and 35.7% (5 of 14) for patients with class C (p > 0.05). Also, the rate of recurrent bleeding was 23.3% (17 of 73) for patients without portal vein thrombosis and 23.5% (4 of 17) for patients with portal vein thrombosis (p > 0.05). Most patients did not have prominent symptoms during or after the injection. Some reported mild, transient upper abdominal discomfort (less than 30%). However, it was difficult to attribute this to the Histoacryl injection. One patient experienced significant epigastric pain that persisted for more than 2 weeks, requiring the administration of analgesics. Two patients experienced cough instantly on injection but then became symptom free afterward. Radiopaque material in the pulmonary hilar area was noted in these 2 patients, and Lipiodol migration was considered because we did not evacuate the Lipiodol from the injector before injection. No migration of radiopaque material away from the variceal location was found on x-ray film except in these 2 cases. There were no signs of distant embolization. One patient received a Histoacryl injection because of recurrent gastric variceal bleeding but died of shock shortly after the injection. An autopsy was performed, and a cirrhotic liver and cardiomegaly due to idiopathic pulmonary hypertension were found. Postinjection ulcers on the obliterated varices were noted in more than 90% of the patients during the entire course of the study. Cast extrusion was expected in the patients who developed ulcers on the injected varices, but this could not always be observed during follow-up because the radiopaque casts noted on the x-ray films almost all disappeared within 1 year after injection. To date, 35 patients have died. Malignancy, liver failure and sepsis were the most common causes. Fifty-five patients are still alive. The overall cumulative survival rate at the sixth year was 43%. There VOLUME 52, NO. 2, 2000
Long-term efficacy and safety of Histoacryl injection for gastric varices
Y-H Huang, H-Z Yeh, G-H Chen, et al.
were no significant complications noted in these patients except for injection-related mucosal defects. Patients with well-compensated liver disease who were free from advanced malignancy achieved longterm survival. Patients with decompensating liver disease or advanced malignancy usually died within 1 to 2 years (Fig. 2). The differences in each survival curve among the 3 Child-Pugh classes were all significant (p = 0.0146 for A and B, p < 0.0001 for B and C, A and C). The differences between the survival curves of patients with and without malignancy and between those with and without portal vein thrombosis were all significant (p < 0.001). DISCUSSION Before the widespread use of cyanoacrylate, various types of sclerosant had been used for endoscopic injection of gastric varices.1,24 We have noted significant complications, similar to those in other reports,25-28 when using sclerotherapy with conventional sclerosants in the management of bleeding gastric varices. Inefficient hemostasis tends to exacerbate the decompensation of liver function and fails to stop the progression of life-threatening events. So, effective hemostasis is crucial when considering a modality for treating bleeding gastric varices. Although Sarin29 has reported satisfactory results by using sclerotherapy with absolute alcohol in treating gastric varices, these were mainly gastroesophageal varices, so-called GOV1. These seem not to be the same as varices in our cases, in that most of the gastric varices in our study were located on the posterior wall of the fundus and there usually were no significant esophageal varices. Satisfactory outcomes with Histoacryl injection have been confirmed in many series. Billi et al.30 reported a 24-month follow-up of 50 patients who had undergone cyanoacrylate injections for gastric varices, with rates of 92% for acute hemostasis and 94.5% for variceal eradication. Fuster et al.31 also reported excellent results by using this technique in pediatric patients. Although the potential risks of Histoacryl injection have been a major concern, this procedure is still our first choice for treatment of bleeding gastric varices because of its satisfactory hemostatic effect. In this study the rate of acute hemostasis was comparable to or better than that in most series of patients treated with a tissue adhesive; these rates have usually been above 90% to 95%.11,30,32,33 We used the term one-week hemostasis to describe the acute hemostatic effect because most patients presented with recent bleeding. Life-threatening bleeding was usually stopped promptly. Stable patients with good liver function (40%) could even be discharged from hospital in 2 to 3 days. For patients VOLUME 52, NO. 2, 2000
A
B Figure 2. Kaplan-Meier analysis of cumulative survival after Histoacryl injection. A, Solid line, the total number of patients; dotted line, patients according to Child-Pugh grade. B, Solid line, presence or absence of malignancy; dotted line, presence or absence of portal vein (PV ) thrombosis.
(10%) referred from other hospitals, usually with a blood-free stomach, Histoacryl injection was even performed on an outpatient basis. Most patients in this study did not have really active bleeding (spurting or oozing) during the endoscopic procedure. This may be due to the infusion of vasoactive agents (vasopressin or somatostatin) given to many patients (70% to 80%) in the emergency department before endoscopic injection of Histoacryl. Although the acute hemostatic effect was excellent, recurrent bleeding still occurred in a significant proportion of the patients. Most episodes occurred within 6 months after Histoacryl injection. Some Histoacryl casts remained in the variceal channel for longer than 1 year with only minimal ulceration. As assessed endoscopically, these varices were still obliterated. However, once cast extrusion occurs, bleeding may reoccur. This may explain why some episodes of recurrent bleeding were delayed and not GASTROINTESTINAL ENDOSCOPY
163
Y-H Huang, H-Z Yeh, G-H Chen, et al.
easy to prevent. However, most recurrent bleeding was not serious and could be controlled with repeated Histoacryl injections if the variceal channel still existed. Conservative treatment with ulcer healing agents usually achieved hemostasis if no prominent variceal channel was observed around the cast extrusion ulcer. For those few patients who respond poorly to reinjection, surgical or TIPS procedures are still needed. However, no patient was referred for surgery during the last 4 years of this study. Incomplete obliteration and portal vein thrombosis have been cited most often as causes of recurrent bleeding in previous studies.13,34 In this study there was no significant association between recurrent bleeding and Child-Pugh class or portal vein thrombosis. It might be argued that the patients with short survival would have less recurrent bleeding because nearly half of the episodes (11 of 23) occurred at longer than 1 month after injection. We also compared the rates of recurrent bleeding for patients who died within 1 month and those who survived more than 1 month. There were still no significant differences between these two factors and recurrent bleeding. There was a weak association between recurrent bleeding and the size of the gastric varices (Spearman’s correlation coefficient = 0.21, p < 0.05). The relationships between variceal size and recurrence of bleeding are complicated. Although Histoacryl is considered to be best suited for larger varices because of ease of intravariceal injection,13 it is more difficult to assess the precise volume needed for variceal obliteration. Because the occurrence of extravariceal embolization may be related to excess Histoacryl,13,34 the dosage used for injection was usually determined in a conservative manner that tended to result in incomplete variceal obstruction. Inaccurate intravariceal injection may also occur when difficult endoscopic conditions result in extravasation of Histoacryl (either paravariceal or through leakage). With accurate intravariceal injection, the Histoacryl cast will fill out the variceal channel appropriately and not just compress it. Injection is more likely to be intravariceal if there is less active bleeding and a clear visual field. The adequacy of variceal obliteration can be judged from the shape of the HistoacrylLipiodol cast on a radiograph (Fig. 3) or simply by endoscopic palpation with a blunt probe. Whether the use of EUS35,36 would improve the evaluation of variceal channel filling beyond radiography requires further study. We proposed to inject only the bleeding varix and those varices in close proximity to the bleeding point. Under these conditions, more than 75% of the patients had no further bleeding after a single ses164
GASTROINTESTINAL ENDOSCOPY
Long-term efficacy and safety of Histoacryl injection for gastric varices
sion of treatment. In other studies25,37,38 sclerosants other than a tissue adhesive were used for hemostasis, and usually several sessions were required to achieve definitive hemostasis. Thus, the use of Histoacryl can save substantial time and effort in obtaining definitive hemostasis. It is difficult to accurately estimate eradication time because Histoacryl casts usually remain within varices for varying amounts of time. Most varices after injection were firm to palpation. As time passed, Histoacryl cast extrusion ulcers were noted several weeks to months after injection. The Histoacryl casts ultimately sloughed in most cases, but a few just shrank in size without development of ulceration. In patients surviving long term, mucosal converging folds were observed after 1 year of follow-up. Histoacryl injection did little to prolong the survival of patients with terminal liver disease or advanced malignancy, which is similar to results after treatment of esophageal variceal bleeding.39-41 However, bleeding episodes were usually terminated promptly, and thus Histoacryl injection may reduce the cost of care for patients with bleeding gastric varices. For those with compensated liver disease, Histoacryl injection usually resulted in long-term hemostasis. No significant adverse sequelae could be attributed to Histoacryl injection in these patients. With respect to an ideal therapy, the incidence of severe complications may be of greater concern than success rate. The occurrence of systemic embolization with Histoacryl injections has been reported.19,21,42 Risk factors include a large volume injection13,34 and the existence, albeit rare, of shunts between the portal system and the pulmonary vein.21 There were no proven cases of distant embolization in this study. This might be due to the limited but appropriate volumes injected and the avoidance of the procedure in cyanotic patients. The speed of injection has also been mentioned as a risk factor.34 Rapid injection may cause increased intravariceal pressure and induce migration of the Histoacryl before full polymerization. With an equal amount of Lipiodol in mixture, the injection speed was usually limited. Two patients in our study developed acute cough during the injection. Lipiodol retention was noted in the pulmonary hilar region on chest x-ray film. However, no further complication was noted during later follow-up. These 2 patients underwent Histoacryl injection during the early part of this study, and Lipiodol was not evacuated from the injection needle before the Histoacryl injection. These conditions did not occur after modification of the preparation for injection (to evacuate the Lipiodol from the injector before injection). However, potential risks still exist. Thus, detailed VOLUME 52, NO. 2, 2000
Long-term efficacy and safety of Histoacryl injection for gastric varices
Y-H Huang, H-Z Yeh, G-H Chen, et al.
A
B
C
D
Figure 3. Plain x-rays of abdomen after Histoacryl. A and B, satisfactory obliteration of gastric varices; C and D, unsatisfactory obliteration.
communication with patients and their families to obtain informed consent is essential. The technical aspects of the preparation of the Histoacryl and the related risks of equipment damage are also of concern.7,8,15 In our experience, preparation of the Histoacryl solution and related procedures require no more time than for preparation of other sclerosing agents. To date, we have not encountered damage to an endoscope as a result of treatment of VOLUME 52, NO. 2, 2000
gastric varices. We experienced clogging of the accessory channel only once, when attempting to inject Histoacryl into a profusely bleeding esophageal varix; the endoscope was completely repaired. There were only 5 episodes (less than 5%) of needle clogging that occurred before or during the injection of Histoacryl in this study. Because our injectors were not disposable, we planned to reuse them after cleaning and sterilization. Thus, it was necessary to discard the injector GASTROINTESTINAL ENDOSCOPY
165
Y-H Huang, H-Z Yeh, G-H Chen, et al.
after 5 to 8 injection procedures. No injury to medical personnel occurred during any procedure. However, precautionary measures, such as protection around the connection site of the injector and the wearing of a transparent head mask, should always be taken to prevent a spill of the Histoacryl solution that might result in harm to medical personnel. In conclusion, the endoscopic injection of Histoacryl for bleeding gastric varices required relatively few treatment sessions and a low injection volume and was a relatively fast procedure to perform. It was highly effective for hemostasis of bleeding gastric varices, with rare complications both acutely and long term. Therefore, with proper handling, it is appropriate to adopt endoscopic Histoacryl injection as the first choice of therapy for bleeding gastric varices. REFERENCES 1. Sarin SK, Lahoti D. Management of gastric varices. Baillieres Clin Gastroenterol 1992;6:527-48. 2. Millar AJ, Brown RA, Hill ID, Rode H, Cywes S. The fundal pile: bleeding gastric varices. J Pediatr Surg 1991;26:707-9. 3. Sanyal AJ, Purdum PP III, Luketic VA, Shiffman ML. Bleeding gastroesophageal varices. Semin Liver Dis 1993; 13:328-42. 4. Bornman PC, Krige JEJ, Terblanche J. Management of oesophageal varices. Lancet 1994;343:1079-84. 5. Skeens J, Semba C, Dake M. Transjugular intrahepatic portosystemic shunts. Annu Rev Med 1995;46:95-102. 6. Sanyal AJ, Freedman AM, Luketic VA, Purdum PP, Shiffman ML, Tisnado J, et al. Transjugular intrahepatic portosystemic shunts for patients with active variceal hemorrhage unresponsive to sclerotherapy. Gastroenterology 1996;111:138-46. 7. Jutabha R, Jensen DM, Egan J, Machicado GA, Hirabayashi K. Randomized, prospective study of cyanoacrylate injection, sclerotherapy, or rubber band ligation for endoscopic hemostasis of bleeding canine gastric varices. Gastrointest Endosc 1995;41:201-5. 8. Chang KY, Wu CS, Chen PC. Endoscopic treatment of bleeding fundic varices with 50% glucose injection. Endoscopy 1996;28:398. 9. Chun HJ, Hyun JH. A new method of endoscopic variceal ligation-injection sclerotherapy (EVLIS) for gastric varices. Korean J Intern Med 1995;10:108-19. 10. Yoshida T, Hayashi N, Suzumi N, Miyazaki S, Terai S, Itoh T, et al. Endoscopic ligation of gastric varices using a detachable snare. Endoscopy 1994;26:502-5. 11. Gotlib JP, Zimmermann P. Une nouvelle technique de traitement endoscopique des varices oesophagiennes: l’obliteration. Endosc Dig 1984;7:10-2. 12. Ramond MJ, Valla D, Gotlib JP, Rueff B, Benhamou JP. Obturation endoscopique des varices oeso-gastriques par le Bucrylate, 1: Etude clinique de 49 malades. Gastroenterol Clin Biol 1986;10:575-9. 13. Soehendra N, Grimm H, Nam VC, Berger B. N-butyl-2-cyanoacrylate: a supplement to endoscopic sclerotherapy. Endoscopy 1987;19:221-4. 14. Feretis C, Tabakopoulos D, Benakis P, Xenofontos M, Golematis B. Endoscopic hemostasis of esophageal and gastric variceal bleeding with Histoacryl. Endoscopy 1990;22: 282-4. 166
GASTROINTESTINAL ENDOSCOPY
Long-term efficacy and safety of Histoacryl injection for gastric varices
15. Ramond MJ, Valla D, Mosnier JF, Degott C, Bernuau J, Rueff B, et al. Successful endoscopic obturation of gastric varices with butyl cyanoacrylate. Hepatology 1989;10:488-93. 16. D’Imperio N, Piemontese A, Baroncini D, Billi P, Borioni D, Dal Monte PP, et al. Evaluation of undiluted N-butyl-2-cyanoacrylate in the endoscopic treatment of upper gastrointestinal tract varices. Endoscopy 1996;28:239-43. 17. Oho K, Iwao T, Sumino M, Toyonaga A, Tanikawa K. Ethanolamine oleate versus butyl cyanoacrylate for bleeding gastric varices: a nonrandomized study. Endoscopy 1995;27: 349-54. 18. Kim HG, Han KH, Lee CY, Chon CY, Moon YM, Kang JK, et al. Outcome of endoscopic injection therapy of Histoacryl in bleeding gastric varices [abstract]. Gastroenterology 1998; 114:A1273. 19. Naga M, Foda A. An unusual complication of Histoacryl injection. Endoscopy 1997;29:140. 20. Shim CS, Cho YD, Kim JO, Bong HK, Kim YS, Lee JS, et al. A case of portal and splenic vein thrombosis after Histoacryl injection therapy in gastric varices. Endoscopy 1996;28: 461. 21. See A, Florent C, Lamy P, Levy VG, Bouvry M. Cerebrovascular accidents after endoscopic obturation of esophageal varices with isobutyl 2 cyanoacrylate in 2 patients. Gastroenterol Clin Biol 1986;10:604-7. 22. Pugh RNN, Murray Lyon IM, Dawson JL, Pietronic MC, Williams R. Transection of esophagus for bleeding esophageal varices. Br J Surg 1973;60:646-9. 23. Hashizume M, Kitano S, Yamaga H, Koyanagi N, Sugimachi K. Endoscopic classification of gastric varices. Gastrointest Endosc 1990;36:276-80. 24. Cheng LF, Li L, Wang HZ. Sclerotherapy of gastric varices. Chung Hua Nei Ko Tsa Chih 1992;31:87-9, 126. 25. Trudeau W, Prindiville T. Endoscopic injection sclerosis in bleeding gastric varices. Gastrointest Endosc 1986;32:264-8. 26. Bretagne JF, Dudicort JC, Morisot D, Thevenet P, Raoul JL, Gastard J. Is endoscopic variceal sclerotherapy effective for the treatment of gastric varices? [abstract]. Dig Dis Sci 1986;31:WS31. 27. Ng EK, Chung SC, Leong HT, Li AK. Perforation after endoscopic injection sclerotherapy for bleeding gastric varices. Surg Endosc 1994;8:1221-2. 28. Goff JS. Endoscopic sclerotherapy for esophageal and gastric varices: safety and efficacy. Endoscopy 1994;26:483-5. 29. Sarin SK. Long-term follow-up of gastric variceal sclerotherapy: an eleven–year experience. Gastrointest Endosc 1997;46: 8-14. 30. Billi P, Milandri GL, Borioni D, Fabbri C, Baroncini D, Cennamo V, et al. Endoscopic treatment of gastric varices with N-butyl-2-cyanoacrylate: a long term follow up [abstract]. Gastrointest Endosc 1998;47:AB26. 31. Fuster S, Costaguta A, Tabacco O. Sclerotherapy of bleeding gastric varices with cyanoacrylate in children [abstract]. Gastroenterology 1998;114:A1244. 32. Krajina A, Hlava A, Vacek Z, Podrabsky P, Steinhart L. Cyanoacrylates: an ideal agent for intravascular embolotherapy? Sb Ved Pr Lek Fak Karlovy Univerzity Hradci Kralove 1991;34:403-14. 33. Mostafa I, Omar MM, Nouh A. Endoscopic control of gastric variceal bleeding with butyl cyanoacrylate in patients with schistosomiasis. J Egypt Soc Parasitol 1997;27:405-10. 34. Cheng PN, Sheu BS, Chen CY, Chang TT, Lin XZ. Splenic infarction after Histoacryl injection for bleeding gastric varices. Gastrointest Endosc 1998;48:426-7. 35. Fischer G, Sackmann M. Value of endoscopic color Doppler ultrasound in the diagnosis of gastric varices and follow-up of VOLUME 52, NO. 2, 2000
Long-term efficacy and safety of Histoacryl injection for gastric varices
36.
37.
38.
39.
therapeutic cyanoacrylate obliteration. Z Gastroenterol 1995; 33:727-8. Iwase H, Suga S, Morise K, Kuroiwa A, Yamaguchi T, Horiuchi Y. Color Doppler endoscopic ultrasonography for the evaluation of gastric varices and endoscopic obliteration with cyanoacrylate glue. Gastrointest Endosc 1995;41:150-4. Sarin SK, Sachdev G, Nanda R, Misra SP, Broor SL. Endoscopic sclerotherapy in the treatment of gastric varices. Br J Surg 1988;75:747-50. Chang KY, Wu CS, Chen PC. Prospective, randomized trial of hypertonic glucose water and sodium tetradecyl sulfate for gastric variceal bleeding in patients with advanced liver cirrhosis. Endoscopy 1996;28:481-6. Ng WD, Chan YT, Ho WW, Kong CK. Injection sclereotherapy
Y-H Huang, H-Z Yeh, G-H Chen, et al.
for bleeding esophageal varices in cirrhotic patients with hepatocellular carcimoma. Gastrointest Endosc 1989;35:69-70. 40. Lo GH, Lin CY, Lai KH, Malik U, Ng WW, Lee FY, et al. Endoscopic injection sclerotherapy versus conservative treatment for patients with unresectable hepatocellular carcinoma and bleeding esophageal varices. Gastrointest Endosc 1991;37:161-4. 41. Sung JJ, Yeo W, Suen R, Lee YT, Chung SC, Chan FK, et al. Injection sclerotherapy for variceal bleeding in patients with hepatocellular carcinoma: cyanoacrylate versus sodium tetradecyl sulphate. Gastrointest Endosc 1998;47:235-9. 42. Benedetti G. Endoscopic treatment of bleeding duodenal varices by bycrylate injection. Endoscopy 1993;25:432-3.
Bound volumes available to subscribers Bound volumes of Gastrointestinal Endoscopy are available for the 2000 issues from the Publisher at a cost of $95.00 ($111.00 international, $118.77 Canada) for Vol. 51 (January-June) and Vol. 52 (July-December). Shipping charges are included. Each bound volume contains a subject and author index and all advertising is removed. Copies are shipped within 60 days after publication of the last issue of the volume. The binding is durable buckram with the journal name, volume number, and year stamped in gold on the spine. Payment must accompany all orders. Contact Mosby, Subscription Customer Service, 6277 Sea Harbor Dr., Orlando, FL 32887; phone 800-654-2452 or 407-345-4000; fax 407-363-9661.
VOLUME 52, NO. 2, 2000
GASTROINTESTINAL ENDOSCOPY
167
Background: The long-term efficacy and safety of the endoscopic injection of N-butyl-2-cyanoacrylate (Histoacryl) were evaluated to define its role as the initial treatment for bleeding gastric varices. Methods: Ninety patients with bleeding gastric varices underwent endoscopic injections of Histoacryl for hemostasis within a 6-year period. Histoacryl was injected intravariceally as a 1:1 mixture with Lipiodol. Among the 90 patients, 5 had active bleeding and 85 had recent bleeding. Most of the varices were large (F2 or F3, 85 cases). The most common locations were the fundus and the posterior wall of the proximal body (94.4%). After Histoacryl injection, patients were followed endoscopically with retreatment as necessary. Results: The rate of hemostasis at 1 week was 94.4%. Recurrent bleeding occurred in 23.3% of the patients from 3 days to 16 months after the initial injection. Recurrent bleeding was stopped with reinjections of Histoacryl in 16.7% of the patients. The rate of definitive hemostasis was 93.3% (84 of 90). The treatment failure–related mortality rate was 2.2% (2 of 90). To date, 35 patients have died, mostly as a result of malignancy or liver failure, and 55 are still alive. The determining factor for long-term survival was the underlying disease leading to portal hypertension. There were few long-term complications except for Histoacryl cast extrusion–related mucosal defects. Conclusions: Endoscopic injection of Histoacryl is highly effective for the treatment of bleeding gastric varices, with rare complications both acutely and long term. This treatment modality is appropriate as the first choice for bleeding gastric varices. (Gastrointest Endosc 2000;52:160-7.)
Bleeding from gastric varices, although not as common as bleeding from esophageal varices, is usually more severe.1,2 Nonendoscopic techniques, such as surgical procedures3,4 or transjugular intrahepatic portosystemic shunt (TIPS),5,6 provide effective hemostasis but are not ideal first–choice therapies because of their technical requirements or invasiveness. Endoscopic techniques have become the first choice for treatment for bleeding esophagogastric varices. Various endoscopic modalities7-10 have also been applied to obtain hemostasis with bleeding gastric varices. To date, there is no consensus on the ideal treatment modality for bleeding gastric varices. Endoscopic tissue adhesive injection was first applied in Received June 15, 1999. For revision September 9, 1999. Accepted December 9, 1999. From the Division of Gastroenterology, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, and National Yang-Ming University, Taipei, Taiwan. Reprint requests: Hong-Zen Yeh, MD, Division of Gastroenterology, Department of Internal Medicine, Taichung Veterans General Hospital, No. 160, Sec. 3, Chung-Kang Rd., Taichung 40705, Taiwan, Republic of China. Copyright © 2000 by the American Society for Gastrointestinal Endoscopy 0016-5107/2000/$12.00 + 0 37/1/104976 doi:10.1067/mge.2000.104976 160
GASTROINTESTINAL ENDOSCOPY
the treatment of bleeding gastric varices by Gotlib and Zimmermann11 and Ramond et al.12 in 1984 and 1986, respectively. In 1986, Soehendra et al.13 also reported a large series with this endoscopic treatment. Since then, this procedure has been accepted and approved in many countries other than the United States as an effective, nonsurgical method for achieving hemostasis in patients with bleeding gastric varices.14-16 However, controversies concerning its long-term efficacy and safety still exist. The rate of recurrent bleeding17,18 and episodic complications such as systemic embolization have been the main issues.19-21 Technical aspects, including the risk of injector clogging, damage to the endoscope, and the difficulty in preparation of the N-butyl-2-cyanoacrylate solution, have been mentioned in other reports.7,15 The aim of this study, therefore, was to evaluate the long-term results of N-butyl-2-cyanoacrylate injection for bleeding gastric varices and to clarify its role as the therapy of choice among endoscopic modalities. PATIENTS AND METHODS Patients From November 1992 to October 1998, 893 patients were seen at our hospital because of esophagogastric VOLUME 52, NO. 2, 2000
Long-term efficacy and safety of Histoacryl injection for gastric varices
variceal bleeding. Among them, 90 patients, including 70 men and 20 women, with proven gastric variceal bleeding underwent endoscopic injection of N-butyl-2-cyanoacrylate for the purpose of hemostasis or prevention of recurrent bleeding. Four patients with respiratory distress or cyanosis were excluded from treatment. Among these 90 patients, 5 had active bleeding (spurting or oozing) and 85 had recent bleeding (90% within 24 hours). Recent bleeding was defined as fibrin clots on varices (80% of cases) or blood in the stomach with no other bleeding source (20% of cases). Liver function was classified according to the method of Child-Pugh22 (Table 1). The most common cause of gastric varices was viral hepatitis–related cirrhosis (74.5%) (Table 1). The form and location of the gastric varices were classified according to the system proposed by Hashizume et al.23; form was classified into 3 types: tortuous (F1), nodular (F2), and tumorous (F3); and location was 5 areas: anterior (La), posterior (Lp), lesser (Ll) and greater curvature (Lg) of the cardia, and the fundic area (Lf). Most of the gastric varices were large (Table 1). Associated esophageal varices were usually small or absent. The most common locations of these gastric varices were the fundus (Lf) and the most proximal body on the posterior wall (Lp) (94.4%) (Table 1). Methods Injections were performed by using a commercial flexible sclerotherapy injector, with a 6 mm 21–gauge needle. A standard forward-viewing videoendoscope was used in most cases. N-butyl-2-cyanoacrylate (Histoacryl; B. Braun, Melsungen, Germany), the main injection component, was mixed with Lipiodol (Laboratoire Guerbet, Aulnay-SousBois France) in a 1:1 ratio and injected as a bolus of 1 to 2 mL according to variceal size. The actual volume of the injection was based on the variceal appearance (F2 ≅ 1 mL, F3 ≅ 2 mL). The injection was stopped when the varices became engorged. Lipiodol was used to flush the injection needle before and after the injection. The tip of the endoscope and the accessory channel were treated with silicone oil to prevent endoscopic damage. The intravariceal injection was made near, but not on, the bleeding point and was given in 1 or 2 squirts. If unobliterated varices (soft sensation on palpation with a blunt probe) were found contiguous to an injected varix, however, another injection was made during endoscopic follow-up. We did not intend to inject varices at a distance from the one that was bleeding. An x-ray film was taken after each session to check the contour of the Histoacryl cast. If the cast shape was similar to that of the vascular channel, the intraluminal injection was considered accurate. If a poorly defined cast shape was noted, the intravariceal injection was presumed to have been inaccurate. Reinjection was performed during the same session for persistent bleeding or inadequate obliteration (about 20% of the time) or during a follow-up session for poor variceal obliteration (about 80% of the time). A chest x-ray was also taken to ascertain whether any embolic material had migrated into the chest. Patients underwent endoscopic follow-up in the second week, fourth week, second month, fourth month, and seventh month after injection and then every half year. VOLUME 52, NO. 2, 2000
Y-H Huang, H-Z Yeh, G-H Chen, et al.
Figure 1. Kaplan-Meier analysis of cumulative rebleedingfree time. One-week hemostasis was defined as an absence of clinically detectable bleeding within 1 week after the first injection of Histoacryl for acute bleeding. Recurrent bleeding was defined as any bleeding arising from the injected varices, or varices contiguous to or in proximity to the injected varix, after a period of 24 or more hours of stable vital signs and hemoglobin/hematocrit levels after an episode of acute bleeding. Primary success was defined as an absence of recurrent bleeding after the first Histoacryl injection and during the entire follow-up period. Secondary success was defined as an absence of recurrent bleeding after the reinjection of Histoacryl for recurrent bleeding. Definitive hemostasis included both primary and secondary success. Treatment failure was defined as failure to obtain definitive hemostasis. The risk factors for recurrent bleeding, including Child-Pugh class, portal vein thrombosis, and variceal size, were analyzed by Spearman’s correlation and the chi-square test. Cumulative survival and time free from recurrent bleeding curves were both described with Kaplan-Meier plots. A log rank test was used for the comparison of survival between each curve. A p value < 0.05 was considered to be significant. The study was approved by the ethics committee of our hospital. Written consent was obtained from each patient or a relative.
RESULTS The median duration of follow-up in this study was 13 ± 2.02 months (range 1 day to 67 months). Among the 90 patients, there was no instance of immediate postinjection hemostatic failure. Eightyfive patients were free from significant bleeding within 1 week after Histoacryl injection. Five patients had recurrent bleeding during the first week. Among them, 1 patient bled at 3 days and 4 within 1 week. One died of recurrent bleeding. The other 4 stopped bleeding but 2 died of sepsis or liver failure. Thus, the rate of one-week hemostasis was GASTROINTESTINAL ENDOSCOPY
161
Y-H Huang, H-Z Yeh, G-H Chen, et al.
Long-term efficacy and safety of Histoacryl injection for gastric varices
Table 1. Clinical characteristics of patients with gastric varices No. of patients Mean age (yr) Range (yr) Men:women Etiology of gastric varices Cirrhosis Viral hepatitis (B & C) Alcoholism Secondary biliary cirrhosis Klatskin tumor Idiopathic Bleeding status Active bleeding Recent bleeding Child-Pugh classification (A/B/C) Form of gastric varices F1/F2/F3 Location of gastric varices Lp+Lf Lg+La Associated esophageal varices Non/F1/F2/F3 Association with Hepatocellular carcinoma Portal vein thrombosis
No.
%
90 58 ± 12 34-80 70:20
78:22
88 67 19 2 1 1
97.8 74.5 21.1 2.2 1.1 1.1
5 85 33/43/14
5.6 94.4 36/48/16
5/53/32
6/59/35
85 5
94.4 5.6
28/46/12/4
31/51/13/5
24 17
26.7 18.9
94.4% (Table 2). Sixty-nine (76.6%) of the 90 patients remained free from further bleeding (primary success) during the entire course of follow-up. Episodes of recurrent bleeding were noted in 21 patients (23.3%) (Table 2) from 3 days to 16 months after the initial injection, but most occurred within the first 6 months (Fig. 1). The incidence of recurrent bleeding was relatively high (44%) during the first year of therapy and was less than 20% in following years. Recurrence of bleeding subsided after repeat injection of Histoacryl in 15 of these 21 cases. The rate of secondary success was 16.7%. Thus, the rate of definitive hemostasis, including primary successes and secondary successes, was 93.3%. The average number of sessions required to achieve definitive hemostasis for each patient with recurrent bleeding was 1.3 ± 0.7. Three patients underwent devascularization surgery and one underwent a TIPS procedure because of failure to obtain definitive hemostasis. Two patients died of massive recurrent bleeding. Thus, the treatment failure rate was 6.7% (6 of 90), and the treatment failure–related mortality rate was 2.2% (2 of 90). The rates of recurrent bleeding for F1 (0 of 5) plus F2 (10 of 53), and of F3 (11 of 32) varices were 17.2% and 34.4%, respectively (p < 0.05). The rates of recurrent bleeding were 15.1% (5 of 33) for patients with Child-Pugh class A liver disease, 25.6% (11 of 162
GASTROINTESTINAL ENDOSCOPY
Table 2. Results of Histoacryl injection One-week hemostasis Definitive hemostasis Primary success Secondary success Sessions needed (mean) Recurrent bleeding Treatment failure Surgery Mortality TIPS Cast extrusion Time of extrusion Obliteration
n = 90
%
85 84 69 15 1.3 ± 0.7 21 6 3 2 1 24 6 ± 4 mo 22 (n = 61)*
94.4 93.3 76.6 16.7 23.3 6.7 3.4 2.2 1.1
36.1
*Cases that can be well evaluated.
43) for patients with class B, and 35.7% (5 of 14) for patients with class C (p > 0.05). Also, the rate of recurrent bleeding was 23.3% (17 of 73) for patients without portal vein thrombosis and 23.5% (4 of 17) for patients with portal vein thrombosis (p > 0.05). Most patients did not have prominent symptoms during or after the injection. Some reported mild, transient upper abdominal discomfort (less than 30%). However, it was difficult to attribute this to the Histoacryl injection. One patient experienced significant epigastric pain that persisted for more than 2 weeks, requiring the administration of analgesics. Two patients experienced cough instantly on injection but then became symptom free afterward. Radiopaque material in the pulmonary hilar area was noted in these 2 patients, and Lipiodol migration was considered because we did not evacuate the Lipiodol from the injector before injection. No migration of radiopaque material away from the variceal location was found on x-ray film except in these 2 cases. There were no signs of distant embolization. One patient received a Histoacryl injection because of recurrent gastric variceal bleeding but died of shock shortly after the injection. An autopsy was performed, and a cirrhotic liver and cardiomegaly due to idiopathic pulmonary hypertension were found. Postinjection ulcers on the obliterated varices were noted in more than 90% of the patients during the entire course of the study. Cast extrusion was expected in the patients who developed ulcers on the injected varices, but this could not always be observed during follow-up because the radiopaque casts noted on the x-ray films almost all disappeared within 1 year after injection. To date, 35 patients have died. Malignancy, liver failure and sepsis were the most common causes. Fifty-five patients are still alive. The overall cumulative survival rate at the sixth year was 43%. There VOLUME 52, NO. 2, 2000
Long-term efficacy and safety of Histoacryl injection for gastric varices
Y-H Huang, H-Z Yeh, G-H Chen, et al.
were no significant complications noted in these patients except for injection-related mucosal defects. Patients with well-compensated liver disease who were free from advanced malignancy achieved longterm survival. Patients with decompensating liver disease or advanced malignancy usually died within 1 to 2 years (Fig. 2). The differences in each survival curve among the 3 Child-Pugh classes were all significant (p = 0.0146 for A and B, p < 0.0001 for B and C, A and C). The differences between the survival curves of patients with and without malignancy and between those with and without portal vein thrombosis were all significant (p < 0.001). DISCUSSION Before the widespread use of cyanoacrylate, various types of sclerosant had been used for endoscopic injection of gastric varices.1,24 We have noted significant complications, similar to those in other reports,25-28 when using sclerotherapy with conventional sclerosants in the management of bleeding gastric varices. Inefficient hemostasis tends to exacerbate the decompensation of liver function and fails to stop the progression of life-threatening events. So, effective hemostasis is crucial when considering a modality for treating bleeding gastric varices. Although Sarin29 has reported satisfactory results by using sclerotherapy with absolute alcohol in treating gastric varices, these were mainly gastroesophageal varices, so-called GOV1. These seem not to be the same as varices in our cases, in that most of the gastric varices in our study were located on the posterior wall of the fundus and there usually were no significant esophageal varices. Satisfactory outcomes with Histoacryl injection have been confirmed in many series. Billi et al.30 reported a 24-month follow-up of 50 patients who had undergone cyanoacrylate injections for gastric varices, with rates of 92% for acute hemostasis and 94.5% for variceal eradication. Fuster et al.31 also reported excellent results by using this technique in pediatric patients. Although the potential risks of Histoacryl injection have been a major concern, this procedure is still our first choice for treatment of bleeding gastric varices because of its satisfactory hemostatic effect. In this study the rate of acute hemostasis was comparable to or better than that in most series of patients treated with a tissue adhesive; these rates have usually been above 90% to 95%.11,30,32,33 We used the term one-week hemostasis to describe the acute hemostatic effect because most patients presented with recent bleeding. Life-threatening bleeding was usually stopped promptly. Stable patients with good liver function (40%) could even be discharged from hospital in 2 to 3 days. For patients VOLUME 52, NO. 2, 2000
A
B Figure 2. Kaplan-Meier analysis of cumulative survival after Histoacryl injection. A, Solid line, the total number of patients; dotted line, patients according to Child-Pugh grade. B, Solid line, presence or absence of malignancy; dotted line, presence or absence of portal vein (PV ) thrombosis.
(10%) referred from other hospitals, usually with a blood-free stomach, Histoacryl injection was even performed on an outpatient basis. Most patients in this study did not have really active bleeding (spurting or oozing) during the endoscopic procedure. This may be due to the infusion of vasoactive agents (vasopressin or somatostatin) given to many patients (70% to 80%) in the emergency department before endoscopic injection of Histoacryl. Although the acute hemostatic effect was excellent, recurrent bleeding still occurred in a significant proportion of the patients. Most episodes occurred within 6 months after Histoacryl injection. Some Histoacryl casts remained in the variceal channel for longer than 1 year with only minimal ulceration. As assessed endoscopically, these varices were still obliterated. However, once cast extrusion occurs, bleeding may reoccur. This may explain why some episodes of recurrent bleeding were delayed and not GASTROINTESTINAL ENDOSCOPY
163
Y-H Huang, H-Z Yeh, G-H Chen, et al.
easy to prevent. However, most recurrent bleeding was not serious and could be controlled with repeated Histoacryl injections if the variceal channel still existed. Conservative treatment with ulcer healing agents usually achieved hemostasis if no prominent variceal channel was observed around the cast extrusion ulcer. For those few patients who respond poorly to reinjection, surgical or TIPS procedures are still needed. However, no patient was referred for surgery during the last 4 years of this study. Incomplete obliteration and portal vein thrombosis have been cited most often as causes of recurrent bleeding in previous studies.13,34 In this study there was no significant association between recurrent bleeding and Child-Pugh class or portal vein thrombosis. It might be argued that the patients with short survival would have less recurrent bleeding because nearly half of the episodes (11 of 23) occurred at longer than 1 month after injection. We also compared the rates of recurrent bleeding for patients who died within 1 month and those who survived more than 1 month. There were still no significant differences between these two factors and recurrent bleeding. There was a weak association between recurrent bleeding and the size of the gastric varices (Spearman’s correlation coefficient = 0.21, p < 0.05). The relationships between variceal size and recurrence of bleeding are complicated. Although Histoacryl is considered to be best suited for larger varices because of ease of intravariceal injection,13 it is more difficult to assess the precise volume needed for variceal obliteration. Because the occurrence of extravariceal embolization may be related to excess Histoacryl,13,34 the dosage used for injection was usually determined in a conservative manner that tended to result in incomplete variceal obstruction. Inaccurate intravariceal injection may also occur when difficult endoscopic conditions result in extravasation of Histoacryl (either paravariceal or through leakage). With accurate intravariceal injection, the Histoacryl cast will fill out the variceal channel appropriately and not just compress it. Injection is more likely to be intravariceal if there is less active bleeding and a clear visual field. The adequacy of variceal obliteration can be judged from the shape of the HistoacrylLipiodol cast on a radiograph (Fig. 3) or simply by endoscopic palpation with a blunt probe. Whether the use of EUS35,36 would improve the evaluation of variceal channel filling beyond radiography requires further study. We proposed to inject only the bleeding varix and those varices in close proximity to the bleeding point. Under these conditions, more than 75% of the patients had no further bleeding after a single ses164
GASTROINTESTINAL ENDOSCOPY
Long-term efficacy and safety of Histoacryl injection for gastric varices
sion of treatment. In other studies25,37,38 sclerosants other than a tissue adhesive were used for hemostasis, and usually several sessions were required to achieve definitive hemostasis. Thus, the use of Histoacryl can save substantial time and effort in obtaining definitive hemostasis. It is difficult to accurately estimate eradication time because Histoacryl casts usually remain within varices for varying amounts of time. Most varices after injection were firm to palpation. As time passed, Histoacryl cast extrusion ulcers were noted several weeks to months after injection. The Histoacryl casts ultimately sloughed in most cases, but a few just shrank in size without development of ulceration. In patients surviving long term, mucosal converging folds were observed after 1 year of follow-up. Histoacryl injection did little to prolong the survival of patients with terminal liver disease or advanced malignancy, which is similar to results after treatment of esophageal variceal bleeding.39-41 However, bleeding episodes were usually terminated promptly, and thus Histoacryl injection may reduce the cost of care for patients with bleeding gastric varices. For those with compensated liver disease, Histoacryl injection usually resulted in long-term hemostasis. No significant adverse sequelae could be attributed to Histoacryl injection in these patients. With respect to an ideal therapy, the incidence of severe complications may be of greater concern than success rate. The occurrence of systemic embolization with Histoacryl injections has been reported.19,21,42 Risk factors include a large volume injection13,34 and the existence, albeit rare, of shunts between the portal system and the pulmonary vein.21 There were no proven cases of distant embolization in this study. This might be due to the limited but appropriate volumes injected and the avoidance of the procedure in cyanotic patients. The speed of injection has also been mentioned as a risk factor.34 Rapid injection may cause increased intravariceal pressure and induce migration of the Histoacryl before full polymerization. With an equal amount of Lipiodol in mixture, the injection speed was usually limited. Two patients in our study developed acute cough during the injection. Lipiodol retention was noted in the pulmonary hilar region on chest x-ray film. However, no further complication was noted during later follow-up. These 2 patients underwent Histoacryl injection during the early part of this study, and Lipiodol was not evacuated from the injection needle before the Histoacryl injection. These conditions did not occur after modification of the preparation for injection (to evacuate the Lipiodol from the injector before injection). However, potential risks still exist. Thus, detailed VOLUME 52, NO. 2, 2000
Long-term efficacy and safety of Histoacryl injection for gastric varices
Y-H Huang, H-Z Yeh, G-H Chen, et al.
A
B
C
D
Figure 3. Plain x-rays of abdomen after Histoacryl. A and B, satisfactory obliteration of gastric varices; C and D, unsatisfactory obliteration.
communication with patients and their families to obtain informed consent is essential. The technical aspects of the preparation of the Histoacryl and the related risks of equipment damage are also of concern.7,8,15 In our experience, preparation of the Histoacryl solution and related procedures require no more time than for preparation of other sclerosing agents. To date, we have not encountered damage to an endoscope as a result of treatment of VOLUME 52, NO. 2, 2000
gastric varices. We experienced clogging of the accessory channel only once, when attempting to inject Histoacryl into a profusely bleeding esophageal varix; the endoscope was completely repaired. There were only 5 episodes (less than 5%) of needle clogging that occurred before or during the injection of Histoacryl in this study. Because our injectors were not disposable, we planned to reuse them after cleaning and sterilization. Thus, it was necessary to discard the injector GASTROINTESTINAL ENDOSCOPY
165
Y-H Huang, H-Z Yeh, G-H Chen, et al.
after 5 to 8 injection procedures. No injury to medical personnel occurred during any procedure. However, precautionary measures, such as protection around the connection site of the injector and the wearing of a transparent head mask, should always be taken to prevent a spill of the Histoacryl solution that might result in harm to medical personnel. In conclusion, the endoscopic injection of Histoacryl for bleeding gastric varices required relatively few treatment sessions and a low injection volume and was a relatively fast procedure to perform. It was highly effective for hemostasis of bleeding gastric varices, with rare complications both acutely and long term. Therefore, with proper handling, it is appropriate to adopt endoscopic Histoacryl injection as the first choice of therapy for bleeding gastric varices. REFERENCES 1. Sarin SK, Lahoti D. Management of gastric varices. Baillieres Clin Gastroenterol 1992;6:527-48. 2. Millar AJ, Brown RA, Hill ID, Rode H, Cywes S. The fundal pile: bleeding gastric varices. J Pediatr Surg 1991;26:707-9. 3. Sanyal AJ, Purdum PP III, Luketic VA, Shiffman ML. Bleeding gastroesophageal varices. Semin Liver Dis 1993; 13:328-42. 4. Bornman PC, Krige JEJ, Terblanche J. Management of oesophageal varices. Lancet 1994;343:1079-84. 5. Skeens J, Semba C, Dake M. Transjugular intrahepatic portosystemic shunts. Annu Rev Med 1995;46:95-102. 6. Sanyal AJ, Freedman AM, Luketic VA, Purdum PP, Shiffman ML, Tisnado J, et al. Transjugular intrahepatic portosystemic shunts for patients with active variceal hemorrhage unresponsive to sclerotherapy. Gastroenterology 1996;111:138-46. 7. Jutabha R, Jensen DM, Egan J, Machicado GA, Hirabayashi K. Randomized, prospective study of cyanoacrylate injection, sclerotherapy, or rubber band ligation for endoscopic hemostasis of bleeding canine gastric varices. Gastrointest Endosc 1995;41:201-5. 8. Chang KY, Wu CS, Chen PC. Endoscopic treatment of bleeding fundic varices with 50% glucose injection. Endoscopy 1996;28:398. 9. Chun HJ, Hyun JH. A new method of endoscopic variceal ligation-injection sclerotherapy (EVLIS) for gastric varices. Korean J Intern Med 1995;10:108-19. 10. Yoshida T, Hayashi N, Suzumi N, Miyazaki S, Terai S, Itoh T, et al. Endoscopic ligation of gastric varices using a detachable snare. Endoscopy 1994;26:502-5. 11. Gotlib JP, Zimmermann P. Une nouvelle technique de traitement endoscopique des varices oesophagiennes: l’obliteration. Endosc Dig 1984;7:10-2. 12. Ramond MJ, Valla D, Gotlib JP, Rueff B, Benhamou JP. Obturation endoscopique des varices oeso-gastriques par le Bucrylate, 1: Etude clinique de 49 malades. Gastroenterol Clin Biol 1986;10:575-9. 13. Soehendra N, Grimm H, Nam VC, Berger B. N-butyl-2-cyanoacrylate: a supplement to endoscopic sclerotherapy. Endoscopy 1987;19:221-4. 14. Feretis C, Tabakopoulos D, Benakis P, Xenofontos M, Golematis B. Endoscopic hemostasis of esophageal and gastric variceal bleeding with Histoacryl. Endoscopy 1990;22: 282-4. 166
GASTROINTESTINAL ENDOSCOPY
Long-term efficacy and safety of Histoacryl injection for gastric varices
15. Ramond MJ, Valla D, Mosnier JF, Degott C, Bernuau J, Rueff B, et al. Successful endoscopic obturation of gastric varices with butyl cyanoacrylate. Hepatology 1989;10:488-93. 16. D’Imperio N, Piemontese A, Baroncini D, Billi P, Borioni D, Dal Monte PP, et al. Evaluation of undiluted N-butyl-2-cyanoacrylate in the endoscopic treatment of upper gastrointestinal tract varices. Endoscopy 1996;28:239-43. 17. Oho K, Iwao T, Sumino M, Toyonaga A, Tanikawa K. Ethanolamine oleate versus butyl cyanoacrylate for bleeding gastric varices: a nonrandomized study. Endoscopy 1995;27: 349-54. 18. Kim HG, Han KH, Lee CY, Chon CY, Moon YM, Kang JK, et al. Outcome of endoscopic injection therapy of Histoacryl in bleeding gastric varices [abstract]. Gastroenterology 1998; 114:A1273. 19. Naga M, Foda A. An unusual complication of Histoacryl injection. Endoscopy 1997;29:140. 20. Shim CS, Cho YD, Kim JO, Bong HK, Kim YS, Lee JS, et al. A case of portal and splenic vein thrombosis after Histoacryl injection therapy in gastric varices. Endoscopy 1996;28: 461. 21. See A, Florent C, Lamy P, Levy VG, Bouvry M. Cerebrovascular accidents after endoscopic obturation of esophageal varices with isobutyl 2 cyanoacrylate in 2 patients. Gastroenterol Clin Biol 1986;10:604-7. 22. Pugh RNN, Murray Lyon IM, Dawson JL, Pietronic MC, Williams R. Transection of esophagus for bleeding esophageal varices. Br J Surg 1973;60:646-9. 23. Hashizume M, Kitano S, Yamaga H, Koyanagi N, Sugimachi K. Endoscopic classification of gastric varices. Gastrointest Endosc 1990;36:276-80. 24. Cheng LF, Li L, Wang HZ. Sclerotherapy of gastric varices. Chung Hua Nei Ko Tsa Chih 1992;31:87-9, 126. 25. Trudeau W, Prindiville T. Endoscopic injection sclerosis in bleeding gastric varices. Gastrointest Endosc 1986;32:264-8. 26. Bretagne JF, Dudicort JC, Morisot D, Thevenet P, Raoul JL, Gastard J. Is endoscopic variceal sclerotherapy effective for the treatment of gastric varices? [abstract]. Dig Dis Sci 1986;31:WS31. 27. Ng EK, Chung SC, Leong HT, Li AK. Perforation after endoscopic injection sclerotherapy for bleeding gastric varices. Surg Endosc 1994;8:1221-2. 28. Goff JS. Endoscopic sclerotherapy for esophageal and gastric varices: safety and efficacy. Endoscopy 1994;26:483-5. 29. Sarin SK. Long-term follow-up of gastric variceal sclerotherapy: an eleven–year experience. Gastrointest Endosc 1997;46: 8-14. 30. Billi P, Milandri GL, Borioni D, Fabbri C, Baroncini D, Cennamo V, et al. Endoscopic treatment of gastric varices with N-butyl-2-cyanoacrylate: a long term follow up [abstract]. Gastrointest Endosc 1998;47:AB26. 31. Fuster S, Costaguta A, Tabacco O. Sclerotherapy of bleeding gastric varices with cyanoacrylate in children [abstract]. Gastroenterology 1998;114:A1244. 32. Krajina A, Hlava A, Vacek Z, Podrabsky P, Steinhart L. Cyanoacrylates: an ideal agent for intravascular embolotherapy? Sb Ved Pr Lek Fak Karlovy Univerzity Hradci Kralove 1991;34:403-14. 33. Mostafa I, Omar MM, Nouh A. Endoscopic control of gastric variceal bleeding with butyl cyanoacrylate in patients with schistosomiasis. J Egypt Soc Parasitol 1997;27:405-10. 34. Cheng PN, Sheu BS, Chen CY, Chang TT, Lin XZ. Splenic infarction after Histoacryl injection for bleeding gastric varices. Gastrointest Endosc 1998;48:426-7. 35. Fischer G, Sackmann M. Value of endoscopic color Doppler ultrasound in the diagnosis of gastric varices and follow-up of VOLUME 52, NO. 2, 2000
Long-term efficacy and safety of Histoacryl injection for gastric varices
36.
37.
38.
39.
therapeutic cyanoacrylate obliteration. Z Gastroenterol 1995; 33:727-8. Iwase H, Suga S, Morise K, Kuroiwa A, Yamaguchi T, Horiuchi Y. Color Doppler endoscopic ultrasonography for the evaluation of gastric varices and endoscopic obliteration with cyanoacrylate glue. Gastrointest Endosc 1995;41:150-4. Sarin SK, Sachdev G, Nanda R, Misra SP, Broor SL. Endoscopic sclerotherapy in the treatment of gastric varices. Br J Surg 1988;75:747-50. Chang KY, Wu CS, Chen PC. Prospective, randomized trial of hypertonic glucose water and sodium tetradecyl sulfate for gastric variceal bleeding in patients with advanced liver cirrhosis. Endoscopy 1996;28:481-6. Ng WD, Chan YT, Ho WW, Kong CK. Injection sclereotherapy
Y-H Huang, H-Z Yeh, G-H Chen, et al.
for bleeding esophageal varices in cirrhotic patients with hepatocellular carcimoma. Gastrointest Endosc 1989;35:69-70. 40. Lo GH, Lin CY, Lai KH, Malik U, Ng WW, Lee FY, et al. Endoscopic injection sclerotherapy versus conservative treatment for patients with unresectable hepatocellular carcinoma and bleeding esophageal varices. Gastrointest Endosc 1991;37:161-4. 41. Sung JJ, Yeo W, Suen R, Lee YT, Chung SC, Chan FK, et al. Injection sclerotherapy for variceal bleeding in patients with hepatocellular carcinoma: cyanoacrylate versus sodium tetradecyl sulphate. Gastrointest Endosc 1998;47:235-9. 42. Benedetti G. Endoscopic treatment of bleeding duodenal varices by bycrylate injection. Endoscopy 1993;25:432-3.
Bound volumes available to subscribers Bound volumes of Gastrointestinal Endoscopy are available for the 2000 issues from the Publisher at a cost of $95.00 ($111.00 international, $118.77 Canada) for Vol. 51 (January-June) and Vol. 52 (July-December). Shipping charges are included. Each bound volume contains a subject and author index and all advertising is removed. Copies are shipped within 60 days after publication of the last issue of the volume. The binding is durable buckram with the journal name, volume number, and year stamped in gold on the spine. Payment must accompany all orders. Contact Mosby, Subscription Customer Service, 6277 Sea Harbor Dr., Orlando, FL 32887; phone 800-654-2452 or 407-345-4000; fax 407-363-9661.
VOLUME 52, NO. 2, 2000
GASTROINTESTINAL ENDOSCOPY
167