Adrenaline plus cyanoacrylate injection for treatment of bleeding peptic ulcers after failure of conventional endoscopic haemostasis

IGEG~IUEENGOSCOPY

DIGEST LIVER OIS 2002;34:349-55

renaline plus cyanoacrylate injection for treatment eeding peptic ulcers after failure of conventional doscopic haemostasi A. A. C. S. C. S. A. P W. M. G.

Repici Ferrari De Angelis Caronna Barletti Paganin Musso Carucci Debernardi-Venon Rizzetto Saracco

Background. Endoscopic therapy is a safe and effective method for treating non-variceal upper gastrointestinal bleeding. However: failure of therapy, in terms of continuing bleeding or rebleeding, is seen in up to 20%. Cyanoact-y/ate is a tissue glue used for variceal bleeding that has occasionally been reported as an alternative haemostatic technique in non-variceal haemorrhage. Aim. To retrospectively describe personal experience using cyanoacrylate injection in the management of bleeding ulcers after failure of firstline endoscopic modalities. Patients and methods. Between January 1995 and March 7998, 18 [I2 M/6 F; mean age 68. I years] out of 176 patients, referred to our Unit for non-variceal upper gastrointestinal bleeding, were treated with intralesional injection of adrenaline plus undiluted cyanoacrylate. Persistent bleeding after endoscopic haemostasis or early rebleeding were the indications for cyanoacrylate treatment. Results. Definitive haemostasis was achieved in 17 out of 18 patients treated with cyanoacrylate. One patient needed surgery No early or late rebleeding occurred during the follow-up. No complications or instrument lesions related to cyanoacrylate were recorded. Conclusions. In our retrospective series, cyanoacrylate plus adrenaline injection was found to be a potentially safe and effective alternative to endoscopic haemostasis when conventional treatment modalities fail in controlling bleeding from gastroduodenal ulcers.

Digest

Liver

Key words:

Department of Gastroenterology, Endoscopy Unit, “Molinette” Hospital, Turin, &a/y.

Addma fer cemepdence Dr. A. Repici, Dipartimento di Gestroenterologie, Unitii Endoscopica, / Ospedeie “Molinette”, torso Bramante 88, 10126 Turin, &a/y. Fax: +39-01 I-679477. E-mail: endoe/eit@hotmail. corn Submitted March I, 2001. Accepted after revision October 29, 2001.

of

Dis 2002;34:349-55 bleeding

ulcer;

cyanoacrylate;

endoscopic

haemostasis

Endoscopy is the primary diagnostic and therapeutic tool used for evaluation and treatment of upper gastrointestinal bleeding (UGIB) patients. The majority of patients presenting with acute non-variceal UGIB are found to bleed from peptic ulcers. Several endoscopic methods of haemostasis have been proven to be effective with similar rates of efficacy in terms of stopping bleeding, rebleeding rates, blood transfusions, need for surgery and mortality 1-S.Nevertheless, failure of endoscopic haemostasis is reported in 3-5% of treated patients and early rebleeding still occurs in about 20%, despite successful initial haemostasis 6. New and alternative endoscopic haemostatic modalities (haemoclips ‘, sewing machine *, ligating devices y, argon plasma coagulation lo, injection of cyanoacrylate ‘I, fibrin sealant I?, thrombin 13, gelatine 14) have recently been introduced to improve initial success rates and reduce rebleeding. N-butyl-2-cyanoacrylate (Histoacryl, Braun Melsungen, Germany) is a tissue adhesive mainly used to obliterate large oesophago-gastric varices I5 16.

349

Adrenaline plus cyanoacrylate

injection for treatment

of UGIG

Occasionally, it has been reported to be effective in treating non-variceal UGIB l7 19. The aim of this study was to retrospectively review our experience in the use of cyanoacrylate injection for treatment of bleeding ulcers as “rescue therapy” after failure of our conventional endoscopic haemostasis.

Patients and methods Between January 1995 and March 1998, 176 out of 43 1 patients, referred to our Unit for non-variceal gastrointestinal bleeding (NVUGB), were treated by endoscopy. Following initial resuscitation, all patients underwent emergency endoscopy within two hours of hospital admission or bleeding was clinically evident in hospitalised patients. Endoscopy was carried out using a large channel fiberoptic or video endoscope (Olympus GIF 1T 10 and GIF lT140). Our conventional endoscopic therapy for bleeding ulcers consisted of injecting 1: 10000 diluted epinephrine for Forrest (F) Ia and Ib lesions and epinephrine plus low volume (1%) polidocanol (0.5-l ml) for FIIa lesions. All the procedures were carried out by the same group of experienced endoscopists, each of whom had performed more than 200 examinations for upper GI bleeding. As far as concerns these 176 patients, initial haemostasis was not achieved in 10 patients and early rebleeding occurred in 15 (total number of failures of conventional endoscopic haemostasis: 25/176 patients (14.3%). Seven of the patients in the group in which endoscopic therapy failed underwent surgery because of torrential bleeding precluding any further endoscopic attempt. Eighteen out of the 25 patients (12 male/6

We

went n. 1 2 3 4 5 6 7 8

I. Data on patients who underwent cyanoacrylate injection during first emergency andoscopy after failure of conventional haemostasis. seG/w fpnJ M/42 F/71 F/83 M/21 MIS7 fvv62 M/69 F/SO

coidlw& NSAlDs intake none Renal cancer Polytrauma Gastric cancer NSAlDs intake None Diabetes

S: stomach; D: duadenum; E: epinephrine.

350

female, mean age 68.1 years, range 21-88) were treated with endoscopic injection of adrenaline plus the tissue glue cyanoacrylate. Of these 18, 7 bled while hospitalised. The decision to again treat this group of patients by endoscopy was made because of the high surgical risk (due to advanced age or severe comorbidities) in 16 patients and refusal of operation in 2 (patients nos. 1 and 7). For all patients, endoscopic and clinical data were collected by reviewing endoscopy records and hospital charts. Data regarding location and size of ulcers and type of bleeding or stigmata according to the classification of Forrest ‘O of this subgroup of patients are given in Tables I and II. Patients who underwent cyanoacrylate injection may be divided into two different groups. In group one, comprising eight patients (5 FIa, 3 Fib), cyanoacrylate was used during the first emergency endoscopy after initial failure to control active bleeding (defined as persistence of active bleeding despite the fact that conventional endoscopic treatment had been correctly attempted) with conventional first-line modalities. In group two (ten patients), cyanoacrylate injection was performed 24-48 hours after successful conventional endoscopic treatment due to rebleeding. Rebleeding was clinically suspected in cases of recurrence of blood in emesis or nasogastric aspirate, recurrence of melena coupled with haemodynamic instability (systolic blood pressure less than 100 mm Hg or postural hypotension associated with a pulse rate higher than 100 beats/min), drop in haemoglobin level, after stabilisation, of more than 2 g/d1 in 24 hours or need of four or more blood units over a 24-hour period. Cyanoacrylate was used undiluted and delivered in a single 0.5 ml injection by a 23 G (Variject Microvasive, Natick, USA) standard sclerosis needle.

~~ S body D D D S fundus S antrum s pylorus D

FomGt 15 10 IO 10 30 15 5 10

la la lb la

la lb lb la

* tfv!iLt E E E E E E E E

~~~ Yes Nalsurg Yes Yes Yes Yes Yes Yes

No

8

No No No No No No

9 22 4 18 13 15

A. Repici et al.

area of active bleeding and all around it, at the dose of about lo-15 ml. Haemorrhage due to ulcer stopped immediately in 7 out of 8 patients using intralesional injection of cyanoacrylate. In one patient (n. 2), with an FIa bleeding ulcer located in the posterior duodenal bulb, oozing persisted around the glue plug. A progressive decrease in haemoglobin level, during the next twelve hours, induced us to choose surgical treatment. Surgical resection was successfully carried out without any complication. Because of persistent haemodynamic instability, patient n. 8, one hour after cyanoacrylate injection, underwent selective arteriography in order to attempt embolization of the bleeding vessel. Arteriography demonstrated absence of active bleeding and the complete occlusion of a branch of the gastroduodenal artery (Fig. 1) that was thought to be the vessel responsible for the bleeding episodes. The patient was discharged one week later without further episodes of digestive haemorrhage. In the second group of treated patients, rebleeding occurred within 48 hours of successful primary haemostasis. At the second emergency endoscopy, 2 patients had a FIa lesion, 4 a Fib and 4 a FIIa (Table II). All patients in this group were considered poor candidates for surgical management, on account of advanced age or the presence of severe comorbidities (Table 11). Cyanoacrylate was delivered as previously described in a single 0.5 ml injection following the injection of 1: 10000 solution of epinephrine in 0.5-l ml aliquots, in the four quadrants around the bleeding point or the visible vessel. Active bleeding stopped in all six patients with FIa and Fib lesions.

The site of injection was the bleeding point in the case of FIa or Fib ulcers and the visible vessel for FIIa lesions. The needle channel was flushed with distilled water before glue injection. Two ml of distilled water ensured an adequate intratissutal delivery of the substance and clearing of the needle channel immediately after glue injection. Lipiodol, to mix the glue or to rinse the needle, was not used in any of these cases. All patients were admitted to the same intensive care gastrointestinal unit. Vital sign parameters were monitored and iv infusion of ranitidine (50 mg every 6 hours) or omeprazole (40 mg every 12 hours) was started soon after the endoscopic procedures. Gastric contents were monitored by hourly nasogastric aspiration. In the case of rebleeding, a second emergency endoscopy was promptly carried out in order to attempt endoscopic retreatment.

Results Group 1, in the present series, comprises 8 patients with active bleeding (5 FIa and 3 Fib) ulcers, located in the gastric body (l), fundus (l), antrum (l), pylorus (1) and in the duodenal bulb (4). Two of these patients (nos. 1 and 6) had a history of non-steroidal anti-inflammatory drugs (NSAIDs) intake, one had an inoperable renal adenocarcinona with multiple metastases (n. 3), one had a large neoplastic bleeding ulcer of the fundus and hepatic metastases (n. 5). Cyanoacrylate injection was carried out after failure of primary endoscopic haemostasis using diluted epinephrine in the

Table II. Data on patients who underwent cyanoacrylate injection for rebleeding. Patient n.

SdA@e tyrd

Comorbiiity

sief bleedin@

Ulcer size tmml

Forrest

Firat treatment

9

Mf72

f-leart failure

S antrum

IO

Ila

E+P

la

Yes

No

24

IO

F/49

Ovarian cancer

0

IO

la

E

Ila

Yes

No

4

M/58 MA38 lw59

OLT None Liver cirrhosis

S angulus S body S entrum

2: IO

lb la Ila

E E+P

Ha lb Ila

Yes Yes Yes

No No No

9

1: 13

1:

14

M/77

lschaemic Eo;; disease

0

5

Ila

E+P

Ila

Yes

No

4

15 16

MB2 F/57

Liver cirrhosis

0 S antrum

1:

lb Ile

E EiP

lb la

Yes Yes

No No

3 13

17

WE7

Renal failure

0

15

lb

E

lb

Yes

No

5

18

F/83

None

0

10

Ila

E+P

lb

Yes

No

15

OLT:

orthotopic liver transplantation;

S: stomach;

0: duodenum;

E: epinephrine;

Robleding

Haemoetasis with cyanee

Roblooh~ aftercgmma

Follow-up (mantbsl

P polidocanol.

351

Adrenaline plus cyanoaqlate

injection for treatment

of UGIB

Fig. 1. Arteriography showing absence of active bleeding and obliteration of a gastroduodenal artery branch.

No rebleeding occurred in the two groups, either during the early or the late follow-up (mean 13 months, range 9-24). Four weeks later, all patients underwent upper endoscopy which demonstrated partial (7 patients) or complete (9 patients) healing of the ulcer lesions. In patient n. 5, an increase in size of the neoplastic mass of the fundus, without further bleeding, was documented. No local or systemic complications and no endoscopic instrument lesions were recorded, in our series.

Discussion Despite improvements in endoscopic methods of haemostasis, bleeding peptic ulcer remains a lifethreatening emergency with a mortality rate of around l(yg I 2 21 22 The initial rates of success of endoscopic haemostasis are as high as 90% of treated patients in most published studies I-621. Various endoscopic thermal methods of haemostasis and injection therapy have been evaluated in clinical trials over the past 20 years but no studies have demonstrated significant differences between the treatment modalities ’ 2 2223. Injection therapy with epinephrine alone or in combination with sclerotherapy, bipolar electrocoagulation and heater probe treatment are the most commonly used haemostatic techniques and compare favourably to each other, in terms of safety and efficacy.

352

Several trials have examined the usefulness of adding a sclerotherapy (3% sodium tetatradecyl sulfate 14, 5% ethanolamine 25, polidocanol 26, alcohol 27) after epinephrine injection: none of which demonstrated differences between the two treatments. As for the use of a thermal device after injection therapy, in a large prospective randomized trials, Chung et al. 28had compared epinephrine alone with epinephrine injection followed by heater probe thermocoagulation. No differences were shown in outcome in the two groups, as measured by rebleeding, need for surgery, need for transfusion, hospital stay, and mortality or healing at 4 weeks. Only in the subgroup of patients with Fl A ulcers, did the dual treatment result in a better outcome than adrenaline alone, in terms of need for surgery and length of hospital stay. Failure to control the acute bleeding or rebleeding occurs in at least 20% of treated patients 23-3’).Unfortunately, morbidity and mortality in patients with further bleeding are higher than when bleeding ceases, with mortality in up to 35% of cases 30m12. Which approach is the best in the management of patients with persistent bleeding or severe recurrent bleeding remains controversial Zx. Endoscopic retreatment or emergency surgery are the two potential options. Endoscopic retreatment could offer a further opportunity to control bleeding with a relatively less invasive approach, especially in elderly patients and those at high surgical risk. Choice of treatment usually depends upon local availability and expertise, i.e., access to a specific treatment modality. The present study is a retrospective review of our experience with adrenaline plus cyanoacrylate injection in the treatment of a small number of patients with bleeding gastroduodenal ulcers in whom we failed to obtain permanent haemostasis. Cyanoacrylate is a watery substance that polymerises and hardens within lo-20 seconds of contact with blood. It is mainly used in Europe for treating oesophagogastric varices Is but it has been occasionally reported to be useful in the management of non-variceal bleeding. In a randomised study by Choudari and Palmer, the tissue glue did not show any significant advantage compared to diluted adrenaline “. Kok et al. reported on 5 patients with acute upper gastrointestinal bleeding in whom conventional endoscopic therapy had failed ‘I. In all patients, bleeding was stopped and the authors recommended cyanoacrylate injection as the last endoscopic resort before surgery. Lee et al. compared the efficacy of N-butyl-2-cyanoacrylate and hypertonic saline-epinephrine (HSE) in the endoscopic treatment of major peptic ulcer haemorrhage. There were no statistically significant differences in haemostatic results, except for decreasing

---

--.-.-_-

the rebleeding rate in the patients with active arterial bleeding 13.Although no complications followed HSE therapy, arterial embolisation with infarction occurred in 2 patients in the cyanoacrylate group, of whom one died. In our series, 17 out of 18 patients (94%) were successfully treated with cyanoacrylate haemostasis both for persisting or relapsing haemorrhage. In one patient with FIa of the posterior bulb, satisfactory haemostasis was not achieved and surgical treatment was carried out. Probably, the ulcer position contributed to the unsuccessful endoscopic approach. Absence of complications in our small series reflects the low rate of complications reported in the recent Literature using cyanoacrylate for varices I5 I6 and confirms the data of Choudari and Palmer who reported no serious complications in 32 cases of ulcer bleeding injected with diluted cyanoacrylate (mixed with iodised oil) 17. It was, indeed, with great caution that we decided to use a well known ulcerogenic agent as cyanoacrylate after a first treatment with polidocanol but no adverse effects after the combined therapy were observed. Furthermore, no significant delay in ulcer healing, potentially related to glue injection was documented in follow-up endoscopic examinations. The small volume of glue (0.5 ml) injected in the ulcers could have contributed to reduced risk of tissue damage. In addition, in our opinion, the use of undiluted glue could greatly contribute to reducing the potential for glue embolisation. The polymerisation time of cyanoacrylate is increased by mixing the glue with lipiodol and this can, theoretically, increase the risk of distant embolisation as previously described both for variceal and non-variceal bleeding I5 33. Our choice to use the glue as rescue therapy in patients with “difficult bleeding” was related to multiple factors. The first is the great confidence we have developed using glue injection since 1993 in a large number of patients with bleeding oesophagogastric varices (unpublished data). In addition, the characteristics of the substance, that rapidly hardens when in contact with blood and produces a solid mass strongly compressing the bleeding vessel, were deemed a potential solution to obtain a more definitive haemostasis after failure of other conventional techniques. Finally, we, as many Units in Italy, do not have great experience with thermal haemostasis of bleeding ulcers. At the time we began to use the glue for the ulcers, the optimum strategy for the management of patients with persistent or recurrent bleeding was not yet known. Even now, it is not clearly understood whether repeat endoscopy or referral for surgery carries a better overall risk-benefit in the event of rebleeding 11.

A. Repici et al.

In a single-centre, large, prospective randomised trial Lau et al. compared endoscopic retreatment (adrenaline injection plus heater probe) with surgery in patients with recurrent bleeding after endoscopic treatment 3s. The main conclusion of this study is that in patients with recurrent bleeding, endoscopic retreatment reduces the need for surgery and is associated with fewer complications than surgery. Unfortunately, there are no published series comparing different methods of endoscopic haemostasis in the treatment of patients with failure of primary haemostasis. Retreatment with a thermal device such as the heater probe or with a sclerotherapy agent appears to increase the risk of complications. Fibrin glue injection and haemoclipping are two haemostatic modalities which do not induce mucosal damage. Therefore they could, potentially, be indicated when first endoscopic treatment fails to control bleeding. Despite the results of the European trial published by Rutgeerts et al. “, the experience with fibrin glue is still limited, and the use of fibrin was uncommon in Italy for the treatment of bleeding ulcers. The injection of the two-component glue requires (other than an appropriate needle) a specific expertise such as for haemoclips placement. This expertise was not available, in our Unit, at the time we treated the patients with the cyanoacrylate, while the glue injection was a well-established, easy-to-perform technique for all the endoscopists and nurses working in our team. Furthermore, the fibrin glue needs to be stored between -4°C and -2°C. The process of warming glue components, in order to obtain the optimal temperature (37°C) for injection, is time-consuming and can preclude the use of the glue in an emergency situation where a rapid and effective method of haemostasis is required. Due to the retrospective nature, the small number of patients and the absence of randomisation, in our study, no definitive conclusions could be drawn concerning the use of the cyanoacrylate in the treatment of severe ulcer bleeding. The findings in our series probably indicate that when a low dose of cyanoacrylate is injected in the base of the ulcer, close to the vessel or the bleeding point, it is possible to induce a mechanical obliteration or destruction of the bleeding vessels leading to more definitive haemostasis. This correlates with the favourable results obtained in our patients injecting cyanoacrylate as rescue therapy after failure of conventional modalities of endoscopic haemostasis. Unfortunately, the lack of a comparison group does not allow us to compare the efficacy of glue injection

353

Adrenaline plus cyanoacrylate

injection far treatment

of UGIG

with other haemostatic modalities in patients with bleeding not responding to conventional treatment. Despite the absence of complications, in our series, the potential for tissue damage 37, glue embolisation and perforation, justifies our caution in recommending cyanoacrylate injection as index therapy in difficult bleeding ulcers. In conclusion, even if the role of the cyanoacrylate in the field of endoscopic haemostasis remains to be delined, our results support the hypothesis that it could be used as a last resort in selected cases of severe ulcer bleeding in which a more aggressive endoscopic therapy is required due to the failure of other conventional haemostatic modalities.

versus polidocanol 1994;26:528-30.

F: Forrest; HSE: hypertonic saline-epinephrine: NSAID: non-steroidal anti-inflammatory drug; NVUGB: non-variceal upper gastrointestinal bleeding; UGIB: upper gastrointestinal bleeding.

‘A Mizuno Y, Kato for gastrointestinal apy. Endoscopy ” Binmoeller bleeding

2 Sacks HS, Chalmers TC, Blum AL, Berrier J, Pagan0 scopic hemostasis: an effective therapy for bleeding cers. J Am Med Ass 1990;264:494-9. 3 Jensen DM. Heater probe for endoscopic bleeding peptic ulcers. Gastrointest Endosc 1991;1:319-39.

D. Endopeptic ul-

hemostasis

Clin

of

N Am

4 Rutgeerts P, Vantrappen G, Broeckaert L, Coremans G, Janssens J, Hiele M. Comparison of endoscopic polidocanol injection and YAG laser therapy for bleeding peptic ulcer. Lancet 1989;1:1164-6. 5 Matthewson K, Swain CP, Bland M, Kirkham JS, Bown SG, Northfield TC. Randomized comparison of Nd: YAG laser, heater probe and nonendoscopic therapy for bleeding peptic ulcers. Gastroenterology 1990;98:1239-44. 6 Laine L, Peterson WL. Bleeding peptic ulcer. N Engl J Med 1994;331:717-27. ’ Shimizu T, Akamatsu T, Hasebe 0. Experience of endoscopic hemostatic therapy using clipping apparatus. Endosc Forum Dig Dis 1993;9:300-4. * Escourrou J, Delvaux M, Buscail L, Darmana R, Frexinos J, Morucci JP, et al. First clinical evaluation and experimental study of a new mechanical suture device for endoscopic hemostasis. Gastrointest Endosc 1990;36:494-7. 9 Matsui S, Inoue I, Takahei K. Endoscopic band ligation for hemostasis of non-variceal upper gastrointestinal bleeding. Endoscopy 1996;28:S67. lo Grund KE, Storek D, Farin ulation (APC). First clinical End Surg 1994;2:42-6.

G. Endoscopic experiences

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354

argon plasma coagin flexible endoscopy.

hemostasis last resort injection

of upper gasbefore surgery. of fibrin

glue

Endoscopy

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D,

” Choudari CP, Palmer adrenaline or tissue 1994;108:A72.

of

KR. Bleeding peptic adhesive (Histoacryl).

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KB,

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3RDWORLD

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CONGRESS

September

OF DIGESTOLOGY

23-25,2002

The Third World Chinese Congress of Digestology (WCDD) will be co-sponsored by the World Journal of Gastroenterology (English), World Chinese Journal of Digestology, and Diagnosis and Treatment of Digestive Diseases, September 23-25, 2002 in China. Contact: Lian-Sheng Ma President of WCCD PO. Box 2345, Beijing 100230, China Fax: +89-65891893 l

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