Esophagus �

Hepato-Gastroenterology 2011; 58:1-6© H.G.E. Update Medical Publishing S.A., Athens-Stuttgart

A Randomized-Controlled Trial of Endoscopic Treatment of Acute Esophageal Variceal H­emorrhage: N-Butyl-2-Cyanoacrylate

I­njection vs. Variceal LigationNeven LJubičić, Alen Bišćanin, Marko Nikolić, Vladimir Supanc, Davor Hrabar,

Tajana Pavić and Marko BobanInterventional Gastroenterology Unit, Division of Gastroenterology, Department of Internal Medicine,

Medical and Dental School University of Zagreb, «Sestre milosrdnice» Clinical Hospital, Zagreb, CroatiaCorresponding Author: Prof. Neven LJubičić, MD, PhD, FACG, Department of Internal Medicine,

«Sestre milosrdnice» Clinical Hospital, Zagreb 10000, Vinogradska 29, CroatiaTel: +0038513768286, Fax: +0038513768286, E-mail: ljubicic@kbsm.hr

KEY WORDS: Esophageal varices; Hemorrhage; Cyanoacrylate; Variceal ligation

Background/Aims: This prospective rand-omized trial compares the efficacy of N-butyl-2-cyanoacrylate injection and variceal ligation in emergency endoscopic treatment of acute esopha-geal variceal hemorrhage in patients with portal hypertension and chronic liver disease.Methodology: Between January 2004 to Decem-ber 2008 43 patients with endoscopy-proven acute esophageal variceal hemorrhage were randomly assigned to one of the two treatment groups: en-doscopic injection with N-butyl-2-cyanacrylate (n=22) and endoscopic variceal ligation (n=21). Vital signs, the amount of blood transfusion and infection status were recorded before and after endoscopic treatment. Within two weeks after ini-tial endoscopic treatment, prophylactic variceal ligation was performed until the varices were

eradicated.Results: Success in arresting acute bleeding was no different in either group. The re-bleeding rate was higher in the cyanoacrylate group than the ligation group (13.6% vs. 4.7%), with no statis-tical difference (p=0.60692). The mean amount of blood transfused was similar in both groups. Ten (45.5%) patients in the cyanoacrylate group and 7 (33%) in the ligation group died during an observational period of 14.1±13.9 months and 21.0±17.2 months, respectively (p=0.3272).Conclusions: The efficacy of endoscopic injection therapy with N-butyl-2-cyanoacrylate to control acute esophageal variceal hemorrhage showed no difference to endoscopic variceal ligation nor did the esophageal variceal re-bleeding rate and mortality rate.

ABSTRACT

INTRODUCTION

Esophageal varices secondary to portal hyper-tension are a common complication and bleeding from esophageal varices is a lethal complication. Despite significant improvements over the past two decades, acute esophageal variceal hemorrhage is still the most serious complication of portal hyper-tension and chronic liver disease (1). According to the recent meta-analyses, endoscopic esophageal variceal ligation was demonstrated to be more ef-fective and safer than injection sclerotherapy and particularly because of reduced complication rates, it seems to be the endoscopic treatment of choice for esophageal varices (2-4).

N-butyl-2-cyanoacrylate was studied in the treatment of acute esophageal variceal hemorrhage in a few randomized control trials. When compared to various sclerosants, cyanoacrylate showed equal efficacy and in one study an absolute reduction in the intrahospital mortality rate of 39% was demon-strated (5-7). The addition of cyanoacrylate to scle-

rosants, particularly in larger esophageal varices may also promote hemostasis, minimize re-bleeding and improve survival (8-10). Obviously, the thera-peutic position and role of cyanoacrylate in acute esophageal variceal hemorrhage is still unclear.

At the time of planning of this trial, there were no published randomized control trials conducted to compare endoscopic injection of N-butyl-2-cy-anoacrylate with endoscopic variceal ligation in the treatment of acute esophageal variceal hemor-rhage. Therefore, we designed a prospective rand-omized trial to compare the efficacy of N-butyl-2-cyanoacrylate injection and variceal ligation in the emergency endoscopic treatment of acute esopha-geal variceal hemorrhage in patients with portal hypertension and chronic liver disease.

METHODOLOGY

PatientsFrom January 2004 to December 2008, all pa-

tients with proven liver cirrhosis who had been

� Hepato-Gastroenterology 58 (�0��) N LJubicčicč, A Bišcčanin, M Nikoličc, et al.

admitted to our hospital with acute gastrointes-tinal bleeding or who were already hospitalized and who developed acute gastrointestinal bleed-ing, received emergency endoscopy. Only patients with endoscopy-proven acute esophageal variceal hemorrhage were candidates for inclusion in the study. Acute esophageal variceal hemorrhage was diagnosed using the following criteria: (I) clinical signs of hematemesis and/or melena, (II) endo-scopic signs of an active spurting or oozing from es-ophageal varices, (III) adherent blood clots, white nipple signs or erosions of the esophageal varices, or (IV) the presence of esophageal varices with a red-color sign and absence of other bleeding sourc-es. Cases with concomitant large esophageal and gastric varices without stigmata of recent bleeding were not included in this study. Patients were not included in the trial if they had (I) previous en-doscopic or surgical treatment for bleeding varices including TIPSS and/or (II) a terminal illness of any major organ system, such as heart failure, uremia or malignancy including hepatocellular carcinoma.

TABLE 1 Clinical Characteristics of Patients with Esophageal Variceal Hemorrhage

Cyanoacrylate (n=22)

Ligation (n=21) p-value

Age (yrs)mean±SD 57±11.9 59±9.3 NSrange (37–80) (42–77)

Sex (M/F) 16/6 15/6 NSChild Pugh classification (n)

A/B/C 4/9/9 8/9/4 NSAscites (n (%)) 7 (31.8) 9 (42.9) NSShock (n (%)) 13 (50.1) 3 (14.3) 0.00647Albumin (g/L)

mean±SD 23.2±11.3 30.8±12.9 NSrange (18.0–39.0) (27.0–39.9)

Bilirubin (μmol/L)mean±SD 66.5±51.6 52.3±81.8 NSrange (11.4–231.0) (13.2–398)

Prothrombin time (%)mean±SD 51.9±15.3 57.1±17.1 NSrange (23.0–83.0) (22.0–97.0)

Hemoglobin (g/L)mean±SD 88.6±27.4 92.0±29.2 NSrange (48–148) (40–151)

Hematocritmean±SD 25.9±7.4 27.8±8.8 NSrange (15–43) (12–44)

Platelet (x109/L)mean±SD 126.8±96.3 102.8±60.9 NSrange (46–449) (29–258)

Creatinine (μmol/L)mean±SD 91.5±34.6 90.0±28.4 NSrange (58–121) (57–128)

Endoscopic presentation (n (%))Spurting or oozing 20 (90.9) 11 (52.4) 0.01331Associated gastric varices 4 (18.2) 5 (23.8) NS

FI­GURE 1 The Cumulative Survival after N-butyl-2-Cyanoacrylate Injection and Variceal Ligation in Patients with Esophageal Variceal Hemorrhage (p=0.3272, log-rank test)

3Hepato-Gastroenterology 58 (�0��)Cyanoacrylate vs. Ligation for Esophageal Variceal Hemorrhage

The severity of liver failure was assessed in ac-cordance with the Child-Pugh classification (11).

The study was approved by the Ethics Commit-tee of the “Sestre milosrdnice” Clinical Hospital in 2003. Informed consent from the patients or their families was obtained.

Treatment MethodsPatients who fulfilled the inclusion criteria were

randomly assigned to one of the two treatment groups using consecutively numbered envelopes that contained the treatment assignment: patients undergoing endoscopic injection with N-butyl-2-cy-anacrylate-the cyanoacrylate group and patients undergoing endoscopic variceal ligation – the liga-tion group. Emergent endoscopy and endoscopic treatment was performed within six hours of hem-orrhage by well-experienced endoscopist with the same level of experience.

N-butyl-2-cyanoacrylate (Histoacryl®, Braun, Germany) injection was performed using Olympus video-endoscopes (Olympus Optical Co. Ltd, Tokyo, Japan) and a 23-gauge disposable injection needle. N-butyl-2-cyanoacrylate was injected intravariceal-ly by free hand as a bolus contained 0.5mL cyanoacr-ylate and 0.8mL lipiodol (Lipiodol®, Guerbet Lab, France). No more than two boluses were performed in each session. Ligation was performed using the same Olympus video-endoscopes and Saeed Four or Six Shooter Multi-Band Ligator® (Wilson-Cook, USA) or Quick-Loop For Variceal Ligation® (Olym-pus, Japan). No more than seven ligatures were ap-plied in each session. The bleeding site was always ligated first and then the surrounding prominent varices were ligated as possible.

For all patients included in the study blood volume resuscitation was undertaken prior or im-mediately after emergency endoscopy to maintain hemodynamic stability and a blood transfusion was given if a hemoglobin level was below 80g/L. The transfusion of fresh frozen plasma and platelets was considered in patients with significant coagu-lopathy and/or thrombocytopenia.

Immediately after the endoscopic treatment, a proton pump inhibitor (pantoprazole 40mg t.i.d. or esomeprazole 40mg t.i.d.) was administered intra-venously for at least 24 hours followed by a same oral proton pump inhibitor once daily for at least four weeks. Vasoactive drug (octreotide, bolus of 100μg i.v. followed by continuous infusion of 50μg/h for at least 48 hours) as well as antibiotic prophy-laxis was used immediately after emergency endos-copy was performed.

Clinical Assessment and Follow-upVital signs, the amount of blood transfusion and

infection status were recorded before and after en-doscopic treatment. Complications related to endo-scopic therapy were well documented.

In all patients, follow-up endoscopy was per-formed 24 hours after initial endoscopic treatment. If re-bleeding occurred, the same endoscopic thera-peutic modality was used for its control.

The outcomes assessed in this study were con-trol of active bleeding, re-bleeding and mortality. Patients were followed-up until death or at least 4 months after the last patient was included in the study.

Within two weeks after initial endoscopic treat-ment, prophylactic variceal ligation was started

TABLE 2 Hemostatic Outcomes Following N-butyl-2-Cyanoacrylate Injection or Variceal Ligation in Patients with Esophageal Variceal Hemorrhage

Cyanoacrylate (n=22)

Ligation (n=21) p-value

Control of active bleeding (n (%)) 22 (100) 21 (100) NS

Patients with recurrent bleeding (n (%)) 3 (13.6) 1 (4.7) NS

Blood transfusion (n (%)) 16 (72.7) 14 (66.7) NSBlood transfusion (mL)

mean±SD 1248.7±831 1023.6±559 NSrange (560–3600) (400–1950)

Plasma transfusion (n (%)) 14 (63.6) 11 (52.4) NSPlasma transfusion (mL)

mean±SD 950.7±523.1 947.2±307.9 NSrange (280–1820) (520–1430)

In-hospital mortality (n (%)) 6 (27.3) 2 (9.5%) NS

Hospital stay (days)mean±SD 6.8±4.6 9.0±5.7 NSrange (1–19) (3–24)

NS, not significant.

� Hepato-Gastroenterology 58 (�0��) N LJubicčicč, A Bišcčanin, M Nikoličc, et al.

in all patients by using Saeed Four or Six Shooter Multi-Band Ligator® (Wilson-Cook, USA) on regu-lar intervals of four to five weeks until the varices were eradicated. Eradication was defined as non-visualization of patent esophageal varices.

Statistical AnalysisEach continuous variable between the two

treatment groups was expressed as mean±SD and/or a median, and analyzed with the non-parametric test (Mann Whitney U test). Categorical data were examined using the chi-square test with Yates’ cor-rection and differences in proportions were comput-ed assuming a normal distribution. Kaplan-Meier analysis was used to examine the time to death, and the log-rank test was used to compare differ-ences between the groups. Univariate analysis was performed to assess the potential risk factors for mortality with ninety-five percent confidence inter-vals (CI). A p values of less than 0.05 was consid-ered to indicate statistical significance.

RESULTS

Study PopulationThe baseline characteristics of the two study

groups of patients are shown in Table 1. The most common cause of esophageal varices was alcohol-related liver cirrhosis (37 out of 43 patients, 86%). Both groups of patients had similar demographic data, hepatic functional reserve according to the Child-Pugh classification and period of follow-up. Among 22 patients from the cyanoacrylate group, 90.9% had active (spurting or oozing) hemorrhage, whereas among 21 patients treated with ligation, 52.4% had active bleeding (p=0.01331). Hypovo-lemic shock was observed in 13 out of 22 patients (50.1%) endoscopically treated with cyanoacrylate, and in 3 out of 21 patients (14.3%) treated with variceal ligation (p=0.00647) (Table 1).

Hemostatic OutcomesThe median number of band or mini-loops per

session in acute treatment of esophageal variceal hemorrhage were 5.6±0.8 (median 6, range 4-6) and 2.8±2.7 (median 1, range 1-7), respectively. The me-dian number of boluses used per session in the pa-tient group treated with cyanoacrylate was one.

Success in arresting acute bleeding was not different in the cyanoacrylate and ligation groups (Table 2). The re-bleeding rate was higher in the

cyanoacrylate group than those undergoing ligation (13.6% vs. 4.7%) although the difference did not reach statistical difference (p=0.60692). The seve-rity of esophageal variceal bleeding, as indicated by the mean amount of blood transfused, was similar in both groups (cyanoacrylate, 1249±832mL vs. li-gation, 1024±559mL, p=0.44097) (Table 2).

Univariate analysis showed that the risk of int-rahospital mortality was significantly linked to the presence of hypovolemic shock, advanced liver fail-ure and baseline values of mean arterial pressure (Table 3).

Complete eradication of esophageal varices fol-lowing multiple ligation sessions was achieved in 15 out of 16 patients (93.8%) initially treated with cyanoacrylate and in 17 out of 19 patients (89.5%) initially treated with variceal ligation.

ComplicationsThere were no differences in complications be-

tween the cyanoacrylate and ligation groups (Table 4). Most of the complications were infections.

Mortality and SurvivalTen (45.5%) patients in the cyanoacrylate group

and 7 (33%) patients in the ligation group died dur-ing an observational period of 14.1±13.9 months and 21.0±17.2 months, respectively. This did not reach statistical significance when Kaplan-Meier life-time analysis was performed (Log-rank test, p=0.3272) (Figure 1).

Univariate analysis showed that the cumulative mortality was significantly linked to the initial lev-els of prothrombin time (relative hazard 0.406; 95% CI 0.21-0.78; p=0.0099), hematocrit levels (relative hazard 0.623; 95% CI 0.40-0.98; p=0.0450), and de-gree of liver failure (relative hazard 0.834; 95% CI 0.72-0.97; p=0.0266) (Table 3).

DISCUSSIONAcute esophageal variceal hemorrhage is a med-

ical emergency with a high mortality and morbid-ity. Current treatment strategies have significantly improved the outcome of acute esophageal variceal hemorrhage. However, it is still associated with a mortality of at least 20% at six weeks, and the management of patients with bleeding esophageal varices remains a challenging field (12, 13). In a meta-analysis, variceal ligation was found to be su-perior to endoscopic sclerotherapy when hemostasis for active bleeding, variceal obliteration, recurrent

TABLE 3 Univariate Analysis of Potential Risk Factors for Mortality in Patients with Esophageal Variceal Hemorrhage

In-hospital mortality Cumulative mortalityR.h. 95% OR p-value R.h. 95% OR p-value

Child Pugh C 5.625 1.04–30.30 0.0447 0.623 0.40–0.98 0.0450Shock 7.500 1.22–46.01 0.0303 3.054 0.81–11.51 0.0969Prothrombin time 2.356 1.16–4.79 0.0227 0.406 0.21–0.78 0.0099Mean arterial pressure 0.810 0.67–0.98 0.0335 0.834 0.72–0.97 0.0266Rh: relative hazard. OR: Odds ratio.

5Hepato-Gastroenterology 58 (�0��)Cyanoacrylate vs. Ligation for Esophageal Variceal Hemorrhage

hemorrhage, mortality and complications were as-sessed (2). Furthermore, a recent randomized con-trolled trial has shown that adding somatostatin to emergency endoscopic variceal ligation significantly improves the efficacy and safety achieved with the addition of somatostatin infusion to endoscopic scle-rotherapy (14). This strongly supports the combi-nation of vasoactive drugs and emergency variceal ligation as first-line therapy for acute esophageal variceal bleeding (15).

Endoscopic injection of N-butyl-2-cyanoacrylate for esophageal varices hemorrhage was first re-ported in 1986 (16). Due to its excellent efficacy, cy-anoacrylate is considered the optimal initial therapy for gastric variceal hemorrhage by many clinicians worldwide despite some controversies concerning its safety and long-term results (17, 18). However, the role of cyanoacrylate in acute esophageal variceal hemorrhage is still unclear. When compared with the various sclerosants, cyanoacrylate is very ef-fective and stops the hemorrhage almost immedi-ately, which is extremely important particularly in cirrhotic patients with advanced liver failure and massive spurting or bleeding (19, 20). Namely, it has been claimed that emergency variceal ligation may be difficult to perform due to factors such as a reduced field of view because of the attachment of the banding or loop device, which may fill with blood during active hemorrhage, hampering the ap-propriate placement of bands or loops (21). There-fore, it is possible to assume that particularly in pa-tients with spurting esophageal variceal bleeding cyanoacrylate injection will be a “rescue” therapy for immediate hemorrhage control. In our study, immediate hemostasis was obtained in 100% of the patients in both treatment groups despite the fact that among there were significantly more patients treated with cyanoacrylate injection than with ac-tive (spurting or oozing) bleeding from esophageal varices. The success rate in controlling even active bleeding was 100% for both treatment modalities and was comparable or even higher to that of previ-ous trials (5-7). The difference in the success rates of bleeding control between studies may be attrib-utable at least to a different technical application.

Recurrent bleeding during hospital stay was slightly more common in the cyanoacrylate group than in the ligation group. Several authors have re-ported relatively high early re-bleeding rates of up to 28% following cyanoacrylate injection (5-7). Rela-tively low rate of early re-bleeding rate observed in our patients treated with N-butyl-2-cyanoacrylate injection may be attributable to vasoactive drug (octreotide) administered in all patients following endoscopic hemostasis (14, 15).

Two trials, published only in abstract form, have compared cyanoacrylate injection with variceal ligation in the treatment of acute es-

ophageal variceal hemorrhage (22, 23). Duvall et al. (22) found similar rates of bleeding control in the cyanoacrylate group and in the ligation group. The second study reported difficulty with variceal eradication in the cyanoacrylate group (23). It should be emphasized that in those trials cyanoacrylate injection was used for acute bleed-ing and for secondary prophylaxis as well, prima-rily because of high rates (up to 40%) of late re-current esophageal variceal bleeding episodes that have been observed following cyanoacrylate injec-tion therapy (24). Since there are several case re-ports of embolization of cyanoacrylate to the lung, spleen and brain (25-27), cyanoacrylate adhesive should be regarded as an embolic agent and should not be used in the prevention of re-bleeding from esophageal varices. Our data strongly suggest that the late recurrent bleeding from the esophageal varices following cyanoacrylate injection should be avoided if the prophylactic variceal ligation is to be performed within two weeks after the initial hemostasis with cyanoacrylate.

Complications were unusual in both groups of patients. A bacterial infection often coexists with acute variceal hemorrhage and has been document-ed in 35% to 60% of patients (28). The relatively low rate of infections observed among our patients could be attributed to the prophylactic antibiotic therapy.

Although the esophageal variceal re-bleeding rate was higher in patients treated with cyanoacr-ylate injection, the re-bleeding events were control-led with the same method, and most patients sur-vived the bleeding episode. Therefore, the increased re-bleeding rate did not reflect on survival at all. Ac-tually, most patients died of hepatic failure regard-less of whether they were treated with cyanoacr-ylate or ligation. Not surprisingly, an advanced degree of liver failure and presence of hypovolemic shock were the most critical determinants of both intra-hospital and cumulative mortality. Although the proportion of patients with hypovolemic shock was much higher in a group of patients treated with cyanoacrylate, the intra-hospital as well as cumula-tive long-term mortality was not different between two groups of patients.

In conclusion, the efficacy of endoscopic injec-tion therapy with N-butyl-2-cyanoacrylate to con-trol acute esophageal variceal hemorrhage was not different to endoscopic variceal ligation. Esophageal variceal re-bleeding rate as well as the mortality rate are both similar for patients treated with N-butyl-2-cyanoacrylate injection and patients treated with variceal ligation. Therefore, N-butyl-2-cy-anoacrylate injection seems to be an effective and safe endoscopic therapy particularly in patients with active, spurting or oozing bleeding in whom esopha-geal variceal ligation is not technically feasible.

� Hepato-Gastroenterology 58 (�0��) N LJubicčicč, A Bišcčanin, M Nikoličc, et al.

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