In this study, our results demonstrate that ECIT can effectively stop active bleeding and preventing rebleeding for refractory high-risk peptic ulcer bleeding by conventional endoscopic therapy. To our knowledge, this is the first study to evaluate the outcomes of refractory high-risk peptic ulcer bleeding by ECIT.
Peptic ulcer bleeding remains the most common cause of upper gastrointestinal bleeding and main cause of peptic ulcer patient death. Endoscopic hemostatic treatment is currently recommended as its primary treatment 10,11,17. Conventional endoscopic therapy has been proven to be effective for most bleeding peptic ulcer patients. However, successful application of mechanical and thermal device may be difficult for ulcers in difficult-to-access anatomical locations. Clips are also difficult to apply in large ulcers with hard fibrotic bases 18,19. There is therefore a need to explore endoscopic hemostatic modality to improve outcomes of these refractory high-risk bleeding peptic ulcers.
Cyanoacrylate is a liquid substance which polymerizes and hardens rapidly when in contact with blood and produces a solid mass. Because the solid mass can induce vascular obliteration or strongly compress bleeding vessels, endoscopic intravascular or perivascular cyanoacrylate injection is widely used to treat esophageal and gastric varices, which can effectively stop and prevent variceal bleeding 20,21. Cyanoacrylate is also often used to occlude the major feeding artery to ulcers as embolic agent to treat bleeding peptic ulcers on doing angiographic intervention therapy 22. We think that cyanoacrylate can occlude vessel to ulcer to treat bleeding peptic ulcers on angiographic intervention therapy, we also can occlude feeding vessel to bleeding ulcer with cyanoacrylate through endoscopic intravascular injection. In addition, even if it is failure to do endoscopic intravascular injection, perivascular cyanoacrylate injection-producing solid mass is non-absorbable and has a longer compressing effect on bleeding vessel in comparison to epinephrine injection. We have done endoscopic gastric and esophageal intravariceal cyanoacrylate injection for many years23, and endoscopic injection was easily carried out, even at difficult anatomic locations. Therefore, we attempted to treat refractory high-risk bleeding peptic ulcer by conventional endoscopic therapy through using ECIT.
Our study showed that intravascular cyanoacrylate injection success rate achieved 62.18% in 119 patients accepting ECIT and perivascular injection was performed only in 45 patients (37.82%). Immediate hemostatic rate for active bleeding achieved 90.91%. Overall rebleeding rate was 12.07% and successful hemostasis rates achieved 87.93%. Rebleeding rate in intravascular injection patients was 2.70%, which was markedly lower than that in perivascular injection (28.57%). This demonstrates that ECIT, especial intravascular cyanoacrylate injection, can effectively stop active bleeding and prevent rebleeding for refractory high-risk peptic ulcer bleeding by conventional endoscopic therapy.
We further evaluated intravascular injection success in Forrest classification and ulcer location. We found that intravascular injection success was not associated with Forrest classification, but with ulcer location. There was markedly higher intravascular injection success rate in ulcers at the gastric angulus and body in comparison to ulcers at other locations, whereas there was lower intravascular injection success rate in ulcers at the pylorus and junction of duodenal bulb and descending part. It is likely to be due to the endoscopic operation is easily performed in the gastric angulus and body.
The literature regarding the efficacy of ECIT for bleeding peptic ulcers is scant. In a previous randomized trial, Lee and colleagues reported that initial hemostasis rate of ECIT for bleeding peptic ulcers achieved 95.2% (60/63) and rebleeding rate was 11.67% (7/60) 15. However, not all patients in their study were high-risk peptic ulcer bleeding. In another retrospective study, Repici and colleagues performed endoscopic cyanoacrylate plus epinephrine injection in the base of ulcer, close to vessel or bleeding point for 18 peptic ulcer bleeding patients with failure in conventional endoscopic therapy 14. 17 patients obtained successful hemostasis without occurring rebleeding and no complications related to cyanoacrylate injection occurred, which demonstrated that ECIT is safe and effective in treating peptic ulcer bleeding. It is pity that there were only small patients in the study. Previous some case reports showed that endoscopic cyanoacrylate injection for bleeding gastric and duodenal ulcers resulted in the complications of duodenal ulcer perforation and abdominal arterial embolization.24–26 In our 119 patients, 10 intravascular cyanoacrylate injection (13.51%, 10/74) and 1 perivascular cyanoacrylate injection patients (2.22%, 1/45) occurred abdominal pain. The abdominal pains in all patients were relived at 1 to 4 days by PPI and symptomatic treatment, and endoscopy for these patients showed no significant delay in ulcer healing. No other complication occurred. We think that newly-produced cyanoacrylate has strong polymerization and can harden rapidly at 2 to 3 seconds after injection. A low dose of cyanoacrylate (0.25-0.5 ml) injected into gastric or duodenal mucosal artery is almost impossible to induce abdominal artery embolization or ectopic embolization. Therefore, ECIT with a low dose is safe, without severe complications.
In this study, the 30-day all-cause mortality was 8.40% (10/119), which was lower than the predicted rate as per Rockall score. Most of deaths died of the progression of cormordities after rebleeding, which further demonstrates that rebleeding is still an important predictor of increased mortality 27,28, and achieving primary hemostasis and preventing rebleeding are very important for reducing mortality.
We further analyzed effects of Forrest classification, Rockall and Blatch scoring on rebleeding and all-cause mortality. Our patients were at high risk, with high baseline median Rockall score (6, IQR 5-8) and Blatchford score (12, IQR 10-14). The data showed that Forrest Ia had a higher rebleeding in comparison to other types, but there was no significant difference in all-cause mortality between Forrest classifications. Both high Rockall score and Blatchford score increased the risks of rebleeding and all-cause mortality, indicating that Rockall scoring and Blockford scoring can serve as predictor of rebleeding and mortality for high-risk peptic ulcer bleeding.
Endoscopic treatment remains the primary therapy for high-risk peptic ulcer bleeding, because angiographic or surgical intervention is associated with considerable high complications.29 In order to further improve the clinical outcomes of patients with high-risk peptic ulcer bleeding, some new endoscopic hemostatic modalities, including over-the-scope clips (OTSC) and hemospray, have been developed. A recently published study showed that in Hemospray-treated 202 patients with peptic ulcer bleeding, immediate hemostasis rate was 88% (178/202), 17% (26/154) experienced rebleeding, and overall all-cause mortality was 34% (59/175) within 30 days 30. A previous study showed that successful hemostasis rate of OTSC treatment was 77.8% in refractory peptic ulcer bleeding with big size 31. The recent study for patients with recurrent bleeding of peptic ulcers showed that the rebleeding rate of OTSC treatment was 15.15% (5/33) and all-cause mortality was 12.12% (4/33) 32. In our study, rebleeding rate was 12.07% (14/116) and all-cause mortality was 8.40% (10/119). Despite having a high-risk population, this study was able to show superior clinical outcomes over the reported efficacy of Hemospray and OTSC for peptic ulcer bleeding. Moreover, endoscopic intravacular cyanoacrylate injection had a more superior efficacy, with 2.7% rebleeding rate and 1.35% all-cause mortality. We think that OTSC is still difficult to ulcers at some difficult anatomic locations, and also expensive for the developing countries. ECIT is easily performed even at difficult anatomic locations. Moreover, endoscopic intravascular cyanoacrylate injection is simple and safe in contrast to angiographic cyanoacrylate embolization. Therefore, it is worth to be recommended for the management of refractory high-risk peptic ulcer bleeding by conventional endoscopic therapy.
Limitation of our study is the lack of control group and randomization. In addition, cyanoacrylate injection was administered at the discretion of the endoscopist at the time of endoscopy, which can lead to selection bias. However, considering the limited data available evaluating the efficacy of ECIT as an initial therapy for refractory high-risk peptic ulcer bleeding by conventional endoscopic therapy, we think that our findings are novel and this study remains to be valuable for real-world data. Our study support that ECIT can be used as first-line therapy for refractory high-risk peptic ulcer bleeding by conventional endoscopic therapy. However, controlled randomized clinical trials are required to validate the real clinical impact of using endoscopic cyanoacrylate injection as first-line therapy in the management of refractory high-risk peptic ulcer bleeding.