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Injection Methods Endoscopic injection of diluted epinephrine into a bleeding peptic ulcer works by volume tamponade and local

vasoconstriction, as blanching and edema of the mucosa are observed. It is an easy technique to learn and diluted epinephrine is non-tissue damaging and therefore safe to use. Diluted epinephrine, however, does not induce vessel thrombosis. Recurrent bleeding after injection with diluted epinephrine alone occurs in 20% to 30% of patients. In theory, the addition of a second agent to cause vessel thrombosis would further reduce the rate of recurrent bleeding. Various sclerosants (e.g., sodium tetradecyl sulfate, polidocanol, absolute alcohol) have been applied to the vessel after initial hemostasis with epinephrine. The addition of a sclerosant has not shown to further reduce rebleeding.129 Sclerosants damage tissue in a dose-dependent manner. Cases of gastric necrosis, some of them fatal, have been reported after sclerosant injection.130 Thrombin and fibrin, derived from both bovine and human sources, have been used as injection agents. A largescale European multicenter trial demonstrated a statistically significant lower rate of recurrent bleeding associated with repeated injections of fibrin sealant (a mixture of fibrin and thrombin) at scheduled daily endoscopic examinations in comparison with a single injection of epinephrine plus polidocanol.131 The close surveillance rather than action of the fibrin sealant per se might have accounted for the difference. A single injection of fibrin sealant was not superior to epinephrine-polidocanol injection. There are also concerns about transmission of viral agents and anaphylaxis with the use of products derived from pooled plasma. Other agents for endoscopic injection therapy are normal saline and hypertonic saline. No single solution is superior to another for hemostasis. Diluted epinephrine is the only remaining agent that is widely used for injection therapy because of its safety, both local and systemic, as well as its low cost and easy availability. Thermal Methods Thermal methods of endoscopic therapy are divided into contact and noncontact methods. Noncontact methods refer to the former use of laser photocoagulation and the current use of argon plasma coagulation. Laser therapy is no longer used because laser units are bulky and difficult to transport. In canine mesenteric artery models, Johnston and colleagues132 compared laser photocoagulation with contact thermal probes in hemostasis. The use of 3.2-mm contact probes consistently sealed arteries up to 2 mm in size. Laser probes were much less effective. The researchers introduced the term coaptive thermocoagulation and emphasized the need for compression of vessel walls. The two walls of an artery are pressed together by firm tamponade. This in itself stops blood flow and reduces the heat-sink effect. Heat energy is then generated, welding the arterial lumen. The commonly used contact thermal probes are the heater probe, which has a polytetrafluoroethylene (Teflon)-coated copper tip with three water ports for targeted irrigation, and bipolar probes. Firm tamponade is the key to successful application of contact probes. At least in animal experiments, thermal methods are superior to injection therapy in achieving hemostasis. Comparative clinical trials of injection and thermal methods did not show any difference in clinical outcomes.

Mechanical Methods Because surgical plication of the bleeding artery is considered the most definitive treatment to achieve hemostasis, mechanical methods such as the endoscopic application of a hemoclip come closer to what would otherwise be done at surgery. The tangential application of hemoclips in treating posterior duodenal bulbar ulcerations or their use with the endoscope in a retroflexed position for treatment of high lesser curvature ulcers can be technically difficult. In a meta-analysis that included 15 randomized studies that compared injection, thermocoagulation, and hemoclipping, successful application of hemoclips was superior to injection alone but comparable to thermocoagulation in producing definitive hemostasis.133 Combination Methods A combination therapy incorporating advantages of injection and thermal methods may represent a better approach than either method alone. Preinjection with diluted epinephrine allows a clear view of the bleeding vessel, making accurate thermocoagulation or application of a second modality possible. The benefit of combination therapy has been confirmed in two meta-analyses.134,135 In the first meta-analysis, the addition of a second modality significantly reduced the rate of recurrent bleeding from 18.4% to 10.6% and that of emergency surgery from 11.3% to 7.6%. The mortality rate decreased significantly from 5.1% to 2.6%. Eleven studies used injected substances such as a sclerosant, tissue adhesive, or thrombin; two added hemoclips; and three evaluated the added use of thermal devices. Findings of the meta-analysis suggest that a second modality should be added after injection of diluted epinephrine to bleeding peptic ulcers. The meta-analysis also confirmed that the rate of significant complications such as perforation and gastric wall necrosis was higher in the combined therapy group (6 of 558 patients) than in the epinephrine-alone group (1 of 560 patients). Furthermore, the improvement in prognosis seems to be more evident in ulcers with active bleeding (Forrest type I ulcers). Despite the large volume of published literature, the best endoscopic therapy for bleeding peptic ulcers remains undefined. It is becoming clear that injection with diluted epinephrine alone is inadequate, especially in ulcers with active bleeding. The most widely adopted method is probably the combination therapy of preinjection with diluted epinephrine followed either by thermocoagulation using a 3.2-mm contact probe or the use of hemoclip. Thermocoagulation or hemoclipping on its own may suffice if the bleeding lesion can be seen clearly for its accurate application. The critical determinant of the efficacy of endoscopic therapy is the size of the eroded artery in the ulcer base. Swain and associates136 studied gastrectomy specimens in patients who required emergency gastrectomy for bleeding gastric ulcers. The researchers suggested that bleeding from arteries larger than 1 mm could not be stopped by existing methods of hemostasis. Most studies on predictors of persistent or recurrent bleeding from ulcers find ulcer size of larger than 2 cm and ulcer location either high on posterior duodenal bulb to be associated with poorer outcomes. These are the classic locations for ulcers that erode into major artery complexes, such as the left gastric artery and the gastroduodenal artery, respectively. Surgery remains

the only definitive method of securing bleeding in these patients.

Antisecretory Therapy
The rationale for antisecretory therapy is based on the fact that both pepsin activity and platelet aggregation are pH dependent. An ulcer stops bleeding when a fibrin or platelet plug blocks the rent in a bleeding artery. When gastric pH exceeds 4, pepsin is inactivated, preventing enzymatic digestion of blood clots. A gastric pH of 6 or greater is critical for clot stability and hemostasis. Labenz and associates137 studied gastric pH in patients with peptic ulcers receiving either a high dose of omeprazole (intravenous bolus 80 mg, followed by 8 mg/hr) or a high-dose ranitidine infusion (intravenous bolus 50 mg, followed by 0.25 mg/kg/hr). The gastric pH was less than 6 just 0.1% of the time in patients with either gastric or duodenal ulcers treated by high-dose omeprazole, much less than with ranitidine (20% in duodenal ulcers and 46% in gastric ulcers). In another study that measured gastric pH over three days, the use of histamine receptor antagonists given either in high-dose intravenous infusion or in bolus form led to progressive loss of antisecretory effect over days two and three because of tolerance. To achieve a gastric pH consistently above 6, a high-dose proton pump infusion is required. The use of H2 receptor antagonists in the management of bleeding peptic ulcers has been evaluated in numerous clinical trials and summarized in meta-analyses. Patients with duodenal ulcer bleeding, who typically have a higher gastric acid output, do not benefit from the use of H2 receptor antagonists. A recent meta-analysis of 30 randomized trials concluded that the use of H2 receptor antagonists would be of benefit only in patients with gastric ulcers (absolute risk reductions of 7.2%, 6.7%, and 3.2% in the rates of recurrent bleeding, surgery, and death, respectively).138 Strong evidence for the use of PPIs in patients with bleeding peptic ulcers comes from a clinical trial reported by Lau and associates,139 in which early endoscopy was used to triage patients with bleeding peptic ulcers; only those at high risk of recurrent bleeding (i.e., those who had actively bleeding ulcers or ulcers with nonbleeding visible vessels) were enrolled. After endoscopic thermocoagulation of the ulcers, patients were randomly assigned to receive a highdose omeprazole infusion or a placebo for 72 hours. The rate of recurrent bleeding in those who received the PPI infusion was 6.7% at day 30, compared with 22.5% in those who received placebo. In addition, the trial showed significant reductions in the need for further intervention, transfusion, and hospitalization as well as a trend in reducing the death rate in patients who received omeprazole. Similar benefits with intravenous esomeprazole given after successful endoscopic therapy in patients at high risk for recurrent ulcer bleeding have recently been reported.140 A Cochrane Systematic Review later concluded that the use of PPI therapy significantly reduces rates of recurrent bleeding and surgery but not mortality.141 In a subgroup analysis including studies that allowed initial endoscopic control, a significant reduction in mortality among Asians was seen in association with the use of a PPI. This supports the use of PPI as an adjunct to endoscopic therapy. The optimal dose to use and the routine of PPI administration

continue to be controversial. The authors advocate the use of early endoscopic triage with a strategy to treat actively bleeding ulcers and ulcers with nonbleeding vessels, followed by adjunctive use of a high-dose intravenous infusion of a PPI. Preemptive use of an intravenous PPI infusion prior to endoscopy was studied in a large-scale randomized study.142 Patients with overt signs of upper GI bleeding were randomized to receive either a high dose PPI infusion or placebo. In the cohort, 60% were found to be bleeding from a peptic ulcer during endoscopy. The study demonstrated that early PPI infusion downstaged bleeding stigmata in ulcers and thereby reduced the need for endoscopic therapy. In the PPI group there were fewer ulcers with active bleeding or with major stigmata observed the next morning during endoscopy. PPI infusion starts ulcer healing, and significantly more clean-based ulcers are seen the next day. The study has cost-saving implications with less endoscopic therapy required with the use of intravenous PPI. In patients awaiting endoscopy it is reasonable to start PPI therapy.

Emergency Surgery
Indications Effective endoscopic intervention and improved pharmacotherapy have greatly reduced the need for emergency ulcer surgery. Not so long ago, surgery was the only reliable means of stopping bleeding. The National United Kingdom Audit performed more than a decade ago revealed an operative rate of 12% among 2071 patients with bleeding peptic ulcers and an associated mortality rate of 24%.143 Endoscopic intervention had not been used in 78% of these patients. In the current literature, surgery is often defined as an outcome in clinical trials of endoscopic therapy. Despite its diminished role in the management of bleeding peptic ulcer, surgery remains important. A common indication for emergency surgery is failure of endoscopic therapy. The usual scenarios are as follows: (1) spurting hemorrhage could not be stopped by endoscopic means; (2) the bleeding point could not be seen because of heavy active bleeding; and (3) recurrent bleeding appeared after initial endoscopic control (although as discussed later it is not entirely clear how many endoscopic attempts should be made before endoscopic therapy is deemed to have failed). Timing The timing of surgery for ulcer bleeding has been a subject of intense debate. In the 1980s, when endoscopic therapy was not available, Morris and colleagues144 published the only prospective randomized study that compared early surgery with delayed surgery, if needed, in 140 patients with bleeding ulcers. In patients younger than 60 years, there was no death in either group, but the more aggressive early surgery policy led to an unacceptably high operation rate (52% compared with only 5% for the delayed surgery group). For those older than 60 years, the operation rate was 62% in the early group and 27% in the delayed group. There were three deaths in 48 patients (6%) in the early surgery group and seven deaths in 52 patients (13%) in the delayed group. On intention-to-treat analysis, the difference did not reach statistical significance. According to treatmentreceived analysis, difference in mortality in patients with gastric ulcers was statistically significant (0 deaths in 19

of the early group vs. 5 in 21 of the delayed group, P 0.01). The trial has been criticized for its small sample size and the use of subgroup analysis. In patients assigned to delayed surgery, ongoing bleeding was allowed before surgical intervention. Nevertheless, the study clearly demon strated that early intervention reduced blood loss in older adult patients and improved outcome. Endoscopic therapy has replaced surgery as the first treatment in bleeding ulcers. After initial endoscopic control, most clinicians would adopt an expectant policy. Most of the affected patients are elderly and have comorbid illnesses. The prospect of long-term cure with a powerful PPI and H. pylori eradication provides incentives for clinicians to adopt a conservative stance. There remains a subgroup of patients predicted to be at risk for recurrent bleeding on the basis of ulcer characteristics at endoscopy. Such characteristics include larger ulcers located at the high lesser curvature and posterior duodenal bulb. The team approach allows experienced gastroenterologists and GI surgeons to confer after initial endoscopic control of bleeding. It is possible that some of these difficult ulcers should be selected for safer early elective surgery. A clinical trial to answer this question is unlikely. Choice of Operation The type of operation to be undertaken at emergency surgery for ulcer bleeding is controversial. Some surgeons maintain that oversewing of ulcers alone combined with acidsuppression therapy is safer than definitive surgery using either gastrectomy or vagotomy. H. pylori eradication and PPIs have provided incentives for surgeons to perform the minimum. Two randomized studies that compared minimal with definitive surgery have been published.145,146 A United Kingdom multicenter study compared minimal surgery (oversewing the vessel or ulcer excision alone plus intravenous H2 receptor antagonist therapy) with a definitive ulcer surgery (vagotomy and pyloroplasty or partial gastrectomy) in patients with bleeding gastric or duodenal ulcerations. Of the 62 patients assigned to conservative treatment, 7 experienced rebleeding, of whom 6 died. Of the 67 patients who received conventional ulcer surgery, 4 had rebleeding and none died; in all rebleeding cases, vagotomy and oversewing of the ulcer had been performed. The overall mortality in this high-risk group of patients was similar in the two groups: 26% after minimal surgery and 19% after conventional surgery. The trial was terminated because of the high rate of fatal rebleeding in the conservative surgery group in comparison with the conventional surgery group.145 In the French Association of Surgical Research trial, patients with duodenal ulcers were randomly assigned to either oversewing plus vagotomy and drainage or partial gastrectomy.146 After oversewing and vagotomy, recurrent postoperative bleeding occurred in 10 of 60 patients (17%), in 6 of whom conversion to a Billroth II gastrectomy was required. Five of these 6 patients experienced duodenal stump dehiscence. In the group of 60 assigned to undergo partial gastrectomy, only 2 patients (3%) had rebleeding, both of whom recovered after conservative treatment. Of the 60 patients assigned to partial gastrectomy, Billroth I reconstruction was performed in 18, Billroth I reconstruction plus vagotomy in 6, Billroth II reconstruction in 20, and Billroth II reconstruction plus vagotomy in 16 patients. No duodenal leak occurred in 24 patients after Billroth I reconstruction.

Among the 36 patients who received Billroth II reconstruction, duodenal stump leaks occurred in 8 (22%). The rate of duodenal stump leak in the overall gastrectomy group was therefore 8 in 60 (13%). When the results were analyzed on an intention-to-treat basis, and data from patients with duodenal leaks after reoperations for rebleeding in the oversewing and vagotomy groups were included, the duodenal leak rates were similar in the two groups (7 of 58 vs. 8 of 60, respectively). The researchers concluded that a more aggressive approach would be warranted in the surgical treatment of duodenal ulcers. The two randomized studies just reviewed emphasize that simple oversewing with or without vagotomy is associated with a higher rate of recurrent bleeding. In patients with recurrent bleeding, the mortality is exceptionally high. Exclusion of an ulcer (see later) or, in the case of gastric ulcers, ulcer excision is important in preventing recurrent bleeding. It is inappropriate, however, to recommend partial gastrectomy in all cases. The decision to perform a gastrectomy has to be balanced against the risk of duodenal stump dehiscence. The choice of resection is determined to a large extent by anatomic and pathologic considerations. The choice of the proper surgical procedure for the individual patient with massive gastric or duodenal ulcer bleeding also rests heavily on the experience and the judgment of the surgeon. Expertise in the surgical management of bleeding ulcers remains an important integral feature of an upper GI bleeding team. Difficult Ulcers Effective endoscopic therapy has selected a group of difficult ulcers for surgery. Anatomic factors that predict failure with endoscopic therapy are size larger than 2 cm and location at the posterior duodenal bulb or lesser curvature of the stomach. An ulcer at the former location often erodes into the gastroduodenal artery complex, and an ulcer at the latter location often erodes into the main left gastric artery or its first-generation branches. The size of the artery well exceeds the limits of endoscopic hemostasis. These ulcers represent challenges to GI surgeons, and expertise is required in dealing with them. At surgery, a bulbar duodenal ulcer can be accessed via a longitudinal pylorotomy extending into the duodenum. Berne and Rosoff147 identified the confluence of several branches of the gastroduodenal artery in the vicinity of a bleeding posterior duodenal ulcer. Ligations above and below the bleeding artery are insufficient to ensure hemostasis. Berne and Rosoff suggested a U stitch in the center after ligations above and below. Many surgeons perform plications at four quadrants, and a few figure-of-eight stitches at varying angles along the course of the artery are often required. The longitudinal pylorotomy is then closed vertically as a Mikulicz-Heineke type of pyloroplasty.147 Whether the procedure should be completed with a truncal vagotomy is unclear, because powerful PPI therapy is now available. Recurrent bleeding occurs in 5% to 17% of cases after a vagotomy and pyloroplasty, often with a fatal outcome. To avoid this complication, many surgeons argue for excluding the duodenal ulcer by closing the duodenal stump distal to the ulcer. Some surgeons advocate end-toend gastroduodenostomy (a Billroth I type reconstruction), in which the gastric remnant is advanced over the ulcer crater and sutured to the normal duodenal mucosa distal to

the ulcer. No attempt is made to dissect the posterior duodenal wall distal to the inferior border of the ulcer. Often the duodenum retracts distally, and the stump can be closed by suturing of the divided anterior duodenal wall onto the distal lip of the ulcer (Nissens method). Other techniques in dealing with a difficult duodenal stump include a side catheter duodenostomy and the technique of Roux-en-Y jejunoduodenal anastomosis. Ulcers located at the incisura angularis and lesser curvature can erode into the left gastric artery or its first branches. In larger chronic ulcers, ulcer resection is often necessary. A high gastric ulcer presents a special problem. Oversewing of the bleeding point through an anterior gastrotomy is a simple option for old and frail patients. For lower-risk patients, a Pauchet operation or a sleeve resection technique can be used. The stomach is transected from the greater curvature side. On the lesser curvature side, a tongue of gastric tissue that is based distally and stretches proximally toward the cardia is excised, usually freehand, to include the ulcer. A Roux-en-Y reconstruction is often required, with a large portion of stomach excised. Closure of duodenal stump is not a concern here because the duodenum is not diseased.

Surgery Versus Endoscopic Retreatment After Recurrent Bleeding

Recurrent ulcer bleeding is a major adverse prognostic factor for morbidity and mortality. Physicians often perform a second endoscopic examination to confirm recurrent bleeding and to re-treat the bleeding ulcer. The avoidance of salvage surgery may be desirable in older adult patients. There is, however, a concern that patients with rebleeding could be worse off after yet another failed endoscopic attempt and episodes of hypotension. The choice between endoscopic re-treatment and surgery for recurrent bleeding after initial endoscopic control was addressed by Lau and colleagues148 in a randomized trial. In a cohort of 1169 patients with bleeding peptic ulcers treated by epinephrine injection followed by thermocoagulation, recurrent bleeding occurred in 8.7%. Ninety-two patients (mean age 65 years, 76% men) were randomly assigned to undergo either endoscopic re-treatment or surgery. Using intention-to-treat analysis, the endoscopic re-treatment and surgery groups did not significantly differ in mortality at 30 days (10% for re-treatment vs. 18% for surgery), duration of hospitalization (median 10 vs. 11 days, respectively), need for intensive care or length of stay in an intensive care unit (5 vs. 10 patients, respectively; median of 59 days for both), or units of blood transfused (median 8 vs. 7 units, respectively). Patients who underwent surgery were significantly more likely to have complications (16 vs. 7, respectively). Endoscopic re-treatment was able to control bleeding in three quarters of the patients. In those for whom endoscopic re-treatment failed, salvage surgery carried substantial mortality. In a regression analysis of a small subgroup of patients, ulcers 2 cm or larger and hypotension at rebleeding were two independent factors predicting failure with endoscopic re-treatment. Findings of this trial suggest that a selective approach can be adopted on the basis of the characteristics of the ulcer.148 Large chronic ulcers should probably be treated with expedited surgery at the time of rebleeding. Early elective surgery may have been more appropriate in these chronic ulcers after initial endoscopic control.

Angiographic embolization of bleeding arteries to peptic ulcer is a nonoperative option. In a nonrandomized comparison to surgery, angiographic embolization carried a similar rate of recurrent bleeding (29% vs. 23%), need for further intervention (16% vs. 31%), and death (26% vs. 21%).149