Nonvariceal upper gastrointestinal bleeding

Gastroenterol Clin N Am 32 (2003) 1053–1078

Nonvariceal upper gastrointestinal bleeding Christopher S. Huang, MDa, David R. Lichtenstein, MDa,b,* a

Section of Gastroenterology, Boston Medical Center, 88 East Newton Street, D-408, Boston, MA 02118, USA b Department of Medicine, Boston University School of Medicine, 88 East Newton Street, D-408, Boston, MA 02118, USA

Upper gastrointestinal (UGI) bleeding remains a common and major medical problem, resulting in significant morbidity and mortality. An estimated 300,000 to 350,000 hospital admissions for UGI bleeding occur annually in the United States, with an overall mortality rate of approximately 7% to 10% [1,2]. Despite advancements in intensive medical and surgical care, pharmacologic therapy, and endoscopic technology, this mortality rate has remained essentially unchanged for the past half century [3–5]. This observation likely reflects the increasing age and comorbidities of this patient population, factors which are known adversely to affect prognosis in UGI bleeding [3,6]. As such, optimal management of these patients requires a coordinated, multidisciplinary approach among primary care physicians, gastroenterologists, intensivists, surgeons, and interventional radiologists. Overall, peptic ulcer disease remains the most common etiology of UGI bleeding. Variceal hemorrhage is a distinct clinical entity and is not reviewed here. This article covers the diagnosis and management of acute nonvariceal UGI bleeding. Etiologies of nonvariceal UGI bleeding The major etiologies of acute nonvariceal UGI bleeding are listed in Table 1. Peptic ulcer disease accounts for most cases, followed by less common causes including mucosal erosive disease; Mallory-Weiss tears; gastric antral vascular ectasia (watermelon stomach); angiomas; tumors; and Dieulafoy’s lesions. Rare causes, such as hemobilia, aortoenteric fistula, and vasculitis, must be considered in the appropriate clinical situation. * Corresponding author. Section of Gastroenterology, Boston Medical Center, 88 East Newton Street, D-408, Boston, MA 02118. E-mail address: [email protected] (D.R. Lichtenstein). 0889-8553/03/$ - see front matter Ó 2003 Elsevier Inc. All rights reserved. doi:10.1016/S0889-8553(03)00092-X

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Table 1 Etiology of non-variceal UGI bleeding Symptom

Frequency (%)

Peptic ulcers Erosions Mallory-Weiss tear Watermelon stomach Carcinomas Angiomata Dieulafoy’s lesion Hemobilia Aorto-enteric fistula Other

50 25–30 8 3–5 1–5 1–2 1–2 \1 \1 6–10

Adapted from Gupta PK, Fleischer DE. Nonvariceal upper gastrointestinal bleeding. Med Clin North Am 1993;77:973–92.

Acute hemorrhage from peptic ulcer disease (gastric or duodenal ulcer) accounts for approximately 50% of cases of UGI bleeding, resulting in 150,000 hospital admissions annually in the United States [7,8]. This number has remained relatively unchanged over the past 20 to 30 years, whereas hospitalization and surgery for uncomplicated ulcers have decreased [7]. The main risk factors for the development of peptic ulcers are Helicobacter pylori infection and use of nonsteroidal anti-inflammatory drugs (NSAIDs). Whereas both have been shown to be independent risk factors for ulcer development, their interaction in relation to ulcer bleeding is controversial, and studies have reported conflicting results [9–15]. The use of NSAIDs has been shown to be associated with an increased risk of ulcer bleeding in several studies [7,16]; this risk increases with the use of conventional NSAIDs (versus selective cyclooxygenase-2 inhibitors), comorbid conditions, concomitant use of steroids and anticoagulants, age, and prior history of gastrointestinal ulcers or complications [17,18]. A recent meta-analysis found that both H pylori infection and NSAID use independently and significantly increased the risk of ulcer bleeding; moreover, when both risk factors were present, their effect on the risk of ulcer bleeding was synergistic [19].

Clinical presentation Acute blood loss from the UGI tract is manifested in three ways: (1) hematemesis, (2) melena, and (3) hematochezia, with the former two being most common. Hematemesis is the vomiting of blood, which can be either fresh, bright red, or ‘‘coffee-ground’’ in appearance. Melena is black, tarry, and characteristically foul-smelling stool, which results from the degradation of blood during its passage through the GI tract. Melena can result from as little as 50 to 100 mL of blood in the stomach, but is more consistently produced with 1 unit of blood [20,21]. Hematochezia (maroon or bright red blood per rectum) can be a presenting symptom in nearly

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15% of cases of UGI bleeding [22]. When arising from the UGI tract, hematochezia indicates more severe bleeding (at least 1000 mL of blood) [20], and is associated with a worse prognosis [3,22,23].

Initial evaluation and prognostication Pre-endoscopic risk assessment During the initial evaluation of a patient with acute UGI bleeding, a focused history and physical examination is required to determine the severity of bleeding, and triage the patient appropriately. Clinical factors that are associated with poor outcome (Box 1) include hemodynamic instability on presentation; advanced age (>60 years); presence of comorbid conditions; onset of bleeding in hospital; hematochezia; red blood in the nasogastric lavage; and continued or recurrent bleeding [3,6,23–25]. Several clinical scoring systems have been developed for determining the prognosis of UGI bleeding, such as the Rockall scoring system [6], the Baylor Bleeding Score [26], and the Cedars-Sinai Medical Center predictive index [27]. A common feature of most of these systems is the pivotal role of endoscopy in determining patient prognosis. Blatchford et al [28] devised a risk score to quantify patient risk of requiring intervention based on admission hemoglobin, blood urea, pulse, systolic blood pressure, presentation with syncope or melena, and evidence of hepatic disease or cardiac failure. Whereas this system is appealing in its sole reliance on clinical and laboratory variables, external validation is required before widespread implementation can be recommended. Value of nasogastric aspiration and lavage Nasogastric aspiration and lavage have traditionally been standard procedures in the diagnosis and management of UGI bleeding. Iced saline

Box 1. Adverse clinical prognostic factors for UGI bleeding Age greater than 60 years Presence of comorbid medical conditions Onset of bleeding in hospital Hemodynamic instability on presentation Severe hemorrhage Red nasogastric aspirate History of hematochezia or hematemesis Multiple transfusions (> 5) Need for emergency surgical intervention Continued or recurrent bleeding

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gastric lavage, once considered essential for controlling UGI bleeding, has been shown to be ineffective in achieving hemostasis and is no longer recommended [29–32]. Nasogastric aspiration, however, may provide useful prognostic information. In the American Society for Gastrointestinal Endoscopy (ASGE) survey on UGI bleeding, a clear gastric aspirate on presentation was associated with a 6% mortality rate, compared with 18% when the aspirate revealed red blood, and nearly 30% when the aspirate and stool both contained red blood [3]. Placement of a nasogastric tube may also help localize the site of hemorrhage when the patient presents with melena or hematochezia without hematemesis. The presence of blood or ‘‘coffee grounds’’ confirms a UGI source, whereas a clear aspirate reduces the likelihood, but does not exclude the possibility of a UGI source. Approximately 15% to 20% of patients with endoscopically documented UGI bleeding have a clear gastric aspirate [3,33,34]. In a study by Cuellar et al [33], the sensitivity and specificity of physician assessment of nasogastric aspirate appearance for the presence of active UGI bleeding were low (79% and 55%, respectively). The same was true for assessing the presence of bile (sensitivity 48%, specificity 74%). The authors concluded that the visual appearance of a nasogastric aspirate was neither accurate in assessing activity or location of bleeding, nor useful for determining the presence or absence of bile [33]. The authors do not recommend routine nasogastric aspirates in patients suspected to have acute UGI bleeding, particularly if endoscopy is planned within the next several hours.

Diagnosis It is now widely accepted that upper endoscopy is the best test for determining the location and nature of the bleeding lesion, and should be performed in virtually all patients presenting with UGI bleeding. Endoscopy also provides critical prognostic information regarding the risk of further bleeding based on the presence or absence of stigmata of recent hemorrhage (SRH). Moreover, therapeutic interventions can be performed during the initial endoscopy. The question is not if, but rather when, endoscopy should be performed. Timing of endoscopy The goal of endoscopy is to stop active hemorrhage and to reduce the risk of continued or recurrent bleeding. Although the optimal timing of endoscopy has not been clearly established, early endoscopy has been advocated by most gastroenterologists to achieve prompt diagnosis, provide risk stratification, and perform therapeutic hemostasis in high-risk patients. Low-risk patients may also benefit from early endoscopy by safely avoiding unnecessary hospitalization [35]. This issue is controversial, however, because opponents of early endoscopy contend that there is little evidence

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to support the claim that endoscopy has any beneficial effect on mortality, regardless of timing [36–38]; however, most of these studies were performed before the development of therapeutic endoscopy. There is a paucity of high-quality studies that specifically examine the impact of early endoscopy; moreover, the definition of ‘‘early’’ varies from study to study, making it difficult to establish clear guidelines. Nonetheless, the data that are currently available from observational and controlled trials suggest the following: (1) early endoscopy and prompt discharge of low-risk patients is safe and effective [39]; (2) early endoscopy in high-risk patients may result in decreased transfusion requirement [40], rate of rebleeding, or surgery [41]; and (3) early endoscopy significantly reduces hospital length of stay for all risk groups with nonvariceal UGI bleeding without evidence of cost shifting to the outpatient setting [38–40,42]. The authors recommend that endoscopy be performed urgently in all high-risk patients, and within 12 to 24 hours of presentation in all others with acute, self-limited episodes of UGI bleeding. SRH The SRH are endoscopically identified features that provide information on the risk of rebleeding and subsequent outcome, and help to determine which patients should receive endoscopic therapy. The SRH have been classified as follows, in order of decreasing risk of rebleeding: (1) active bleeding (spurting or oozing); (2) nonbleeding visible vessel; (3) adherent clot; (4) flat pigmented spot; and (5) clean base. Table 2 summarizes the risk of rebleeding based on SRH, based on data from the Center for Ulcer Research and Education (CURE) group and other investigators [7,43,44]. Clean-based ulcers (Fig. 1), found in 20% to 50% of cases, reliably predict a benign course with a negligible risk for rebleeding, emergency surgery, or mortality [7]. Rebleeding in these patients in all likelihood represents an overlooked translucent visible vessel or a missed second bleeding source. Ulcers with flat pigmented spots (Fig. 2) or adherent clots (Fig. 3) account for approximately 30% of ulcers found at endoscopy, and are termed ‘‘minor’’ SRH. Patients with these ulcers are at somewhat increased risk for Table 2 Risk of ulcer rebleeding based on endoscopic appearance SRH

Rebleeding rate (%)

Active bleeding Nonbleeding visible vessel Adherent clot Flat spot Clean base

55–90 40–50 10–33 7–10 3–5

Data from Laine L, Peterson W. Bleeding peptic ulcer. N Engl J Med 1994;331:717–27, and Savides TJ, Jensen DM. Therapeutic endoscopy for nonvariceal gastrointestinal bleeding. Gastroenterol Clin North Am 2000;29:465–87.

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Fig. 1. Clean-based ulcer. (See also Color Plate 4.)

rebleeding, surgery, and mortality [44–48] and may warrant a longer period of hospitalization, although usually not in an ICU. The optimal approach to ulcers with adherent clots has not yet been clearly defined, as discussed in greater detail later. Finally, the major SRH of actively bleeding ulcers and nonbleeding visible vessels are at greatest risk for rebleeding and mortality, and warrant endoscopic therapy. An actively bleeding ulcer is identified in approximately 5% to 25% of patients at the time of endoscopy, and is associated with continued or recurrent bleeding in over half of all cases [7]. It is important to distinguish spurting hemorrhage from oozing hemorrhage, because the former is associated with a significantly higher risk of recurrent bleeding. The term ‘‘nonbleeding visible vessel’’ is used to describe a 2- to 3-mm protuberance in the base of an ulcer (Fig. 4). The protruding structure is usually not the vessel itself, but rather an adherent sentinel clot plugging the eroded artery [49]. The color of the protuberance may be predictive

Fig. 2. Ulcer containing a flat spot. (See also Color Plate 5.)

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Fig. 3. Ulcer with an adherent clot. (See also Color Plate 6.)

of rebleeding, with nonpigmented lesions (white-pale) having a higher risk of rebleeding (71%) than red or purple lesions (38%) [50]. One important caveat regarding identification of SRH is that interobserver agreement is only fair overall, and actually poor for identifying nonbleeding visible vessels, flat pigmented spots, and clean-based ulcers [51]. Risk stratification and individual patient management should not be based solely on the visualized SRH, but must also take into account clinical variables of prognostic significance (eg, the presence of hemodynamic instability). Improving visualization Inability to adequately visualize the entire stomach because of uncleared blood or clots reduces the diagnostic and therapeutic yield of endoscopy, and may be associated with substantial morbidity and mortality [52,53]. Various modalities have been proposed to minimize this problem, including

Fig. 4. Ulcer with a nonbleeding visible vessel. (See also Color Plate 7.)

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patient repositioning; vigorous gastric lavage and suction with a largechannel endoscope [54]; endoscopic hydrogen peroxide spraying [55]; and the use of prokinetic agents, such as metoclopramide or erythromycin [56,57]. The efficacy of erythromycin was recently demonstrated in two randomized, controlled trials comparing erythromycin with no treatment or placebo. Both studies showed that a single infusion of erythromycin (3 mg/kg given intravenously 20 or 60 to 120 minutes before endoscopy) significantly improved the quality of the endoscopic examination, resulting in a reduction of the need for second-look endoscopy [56,57]. Whether or not this translates into improvement of other outcomes, such as reduced rebleeding rates, transfusion requirements, length of hospital stay, and mortality, remains to be seen. Patient triage and disposition Based on the natural history of SRH, a treatment and hospitalization algorithm can be devised that incorporates clinical factors and endoscopic findings (Fig. 5). Patients can be classified as high- or low-risk for rebleeding and adverse outcome based on clinical factors, such as hemodynamic status and comorbid conditions (see Box 1). High-risk patients should be admitted to an ICU, whereas low-risk patients can undergo triage in the emergency room with diagnostic endoscopy, or be admitted to the general hospital ward before undergoing endoscopy. Further decisions regarding therapy, refeeding, and length of hospitalization can be guided by endoscopic findings and result of endoscopic therapy. Patients with clean-based ulcers or MalloryWeiss tears without SRH combined with low risk clinical criteria (eg, age \ 60 years, stable vital signs, and absence of serious comorbid conditions) can be refed immediately and safely discharged after volume resuscitation and stabilization [44,58,59]. Selected patients with flat pigmented spots may also be considered for early discharge and outpatient management [60], although a 3-day hospital stay has been recommended for most patients [7,58]. Patients with active bleeding or nonbleeding visible vessels should be treated endoscopically and observed in an ICU for 24 hours, and then transferred to the ward if there are no signs of rebleeding. Most patients with an uncomplicated hospital course can be discharged safely after a total of 3 to 4 days, because most rebleeding occurs within the first 72 hours [58]. Endoscopic therapy Indications According to the National Institutes of Health Consensus Conference report in 1989, endoscopic therapy should be reserved for patients at high risk for persistent or recurrent bleeding and death. This group includes those with clinical evidence of a large initial blood loss and the presence of major endoscopic SRH (active bleeding or nonbleeding visible vessel). The report

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Fig. 5. Treatment algorithm for acute peptic ulcer hemorrhage. EGD, esophagogastroduodenoscopy; ER, emergency room; ICU, intensive care unit; SRH, stigmata of recent hemorrhage.

also concluded that minor SRH (nonbleeding clot, flat pigmented spots) and clean-based ulcers were not indications for endoscopic treatment [61,62]. Although most individual trials of endoscopic therapy have not documented a significant reduction in mortality, two meta-analyses have shown a significant reduction in rates of continued or recurrent bleeding, emergency surgery, and mortality in patients receiving endoscopic therapy compared with those who did not [63,64]. Subgroup analysis indicated that these benefits were only seen in patients with major SRH (active bleeding or nonbleeding visible vessels). Endoscopic therapy did not significantly improve outcomes in patients with the minor SRH of adherent clots or flat, pigmented spots. Adherent clot Optimal management of ulcers with adherent clot is controversial. The 1989 National Institutes of Health Consensus Conference recommended

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against the removal of the clot and suggested only gentle washing [61]. This has since been challenged by recent studies advocating for aggressive treatment of adherent clots by removing the clot and treating the underlying lesion [65–67]. The rationale for this approach is based on the belief that the stigmata underlying the clot are a major determinant of the patient’s risk of rebleeding. Accordingly, the rebleeding rates on medical therapy range from approximately 50% for a nonbleeding visible vessel, to 10% for a flat pigmented spot, to less than 5% for a clean-based ulcer [67]. Two randomized, controlled trials designed to evaluate endoscopic therapy for adherent clots were recently published. Bleau et al [66] randomized 56 patients with adherent clots and no active bleeding to receive endoscopic therapy or medical therapy alone. Endoscopic therapy consisted of injection of the clot base with 1:10,000 epinephrine in four quadrants, followed by vigorous attempts to remove the clot by various means, including suction, snare removal, and manipulation with biopsy forceps or the tip of the endoscope. The underlying lesions were then treated with heater probe coagulation. Patients who received endoscopic therapy had a significantly lower rebleeding rate compared with those receiving medical therapy alone (4.8% versus 34.3%, respectively). Jensen et al [67] also used an aggressive technique in clot removal, with epinephrine injection followed by cold guillotining with a polyp snare to shave the clot down to 3 to 4 mm above the ulcer base. The residual clot or the underlying stigmata were then treated with coaptive coagulation to achieve flattening of the lesion, white coagulum, and complete hemostasis. This technique resulted in significantly lower rates of rebleeding and need for further endoscopic treatment (0% for both) as compared with medically treated patients (35% and 24%, respectively). There were no statistically significant differences in transfusion requirements, duration of hospital stay, need for surgery, or mortality. Although these results seem promising, small sample size and unequal distribution of confounding factors (eg, age and hospitalization status of patient at onset of bleeding) were limitations of the latter study. Because endoscopic therapy is not without risk, it is prudent to perform aggressive clot removal and subsequent treatment in selected patients with adherent clots and independent predictors of rebleeding, such as comorbid illness, shock, or low initial hemoglobin (\ 10 g/dL) [45].

Endoscopic hemostasis modalities The effectiveness of endoscopic treatment in UGI bleeding is firmly established, and numerous trials have demonstrated the benefit of endoscopic intervention when compared with medical treatment alone [63]. Endoscopic treatment modalities (Box 2) can be broadly categorized into three groups: (1) injection, (2) thermal, and (3) mechanical. It is not clear whether any single modality consistently renders the best results;

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Box 2. Endoscopic hemostasis modalities Injection Epinephrine Ethanol Ethanolamine Polidocanol Thrombin Fibrin Cyanoacrylate glue Thermal Monopolar electrocoagulation Bipolar or multipolar electrocoagulation Laser: argon or neodymium:yttrium–aluminum–garnet Argon plasma coagulation Heater probe Microwave Mechanical Hemoclips Band ligation Sewing Endoloop

however, it is generally believed that injection and thermal modalities are equally effective [68–70]. A meta-analysis of 12 randomized controlled trials including 1813 patients randomized to injection therapy or thermal methods found no significant difference in continued or recurrent bleeding or need for surgery [71]. Recently, combinations of endoscopic therapies have become more commonly used, although the data to support this practice as the standard of care are still preliminary. This section reviews the major endoscopic treatment modalities, with particular focus on recently published comparative trials of endoscopic intervention. Injection therapy A variety of agents have been used in injection therapy, including diluted epinephrine; hypertonic saline; absolute ethanol; sclerosants (polidocanol or sodium tetradecyl sulfate); distilled water; thrombin; and fibrin sealant. Injected agents are proposed to act by varying mechanisms, including local tamponade (all solutions); vasoconstriction (eg, epinephrine); tissue fixation (eg, ethanol); and spasm of the bowel wall and artery (eg, polidocanol). A primary role for local tamponade has been suggested by animal and clinical studies, which demonstrated that injected saline or distilled water had hemostatic effects comparable with those of ethanol or epinephrine [72–74].

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A recent randomized trial of normal saline injection versus bipolar electrocoagulation for high-risk bleeding ulcers, however, reported a high rate of further bleeding with saline injection (30% versus 12%, respectively) [75]. It is not clear whether any single injection agent or combination of agents is superior to the others. Since the landmark study by Chung et al [76] in which 1:10,000 epinephrine was shown to be superior to medical therapy, this injection agent has probably become the most frequently used in clinical practice. Because epinephrine injection does not induce vessel thrombosis, there is a hypothetical advantage to adding a sclerosing agent, such as polidocanol or ethanol. Clinical trials, however, have not definitively demonstrated a benefit to this combination strategy [77–81]. Likewise, randomized trials comparing the use of thrombin or fibrin sealant with other injection modalities have yielded conflicting results [82–86]. In a study by Kubba et al [85], the combination of epinephrine plus thrombin injection significantly reduced the rates of rebleeding (4.3% versus 20%) and mortality (0% versus 10%) compared with epinephrine alone. More recently, Lin et al [82] reported significantly lower rebleeding rates with fibrin sealant injection compared with epinephrine alone (15% versus 56%), but no statistical difference in transfusion requirement, need for surgery, length of hospital stay, or mortality. Overall, however, the available data do not convincingly show the superiority of either thrombin or fibrin injection over epinephrine or sclerosing agents. Because submucosal injections of epinephrine do not damage tissue or have appreciable systemic effects, large volumes can be used with a low risk of complication [87]. Although plasma epinephrine levels have been shown to rise four to five times above baseline immediately after injection [88], cardiovascular complications are uncommon. Furthermore, injection of a large volume (>13 mL) of epinephrine was recently shown to be superior to lower volumes when used as monotherapy to achieve sustained hemostasis [89]. It is the authors’ practice to use 1:10,000 epinephrine injections delivered in 1-mL aliquots into and adjacent to the bleeding point, up to a total of 20 to 25 mL, until hemostasis is achieved. Thermal therapy Thermal therapy can be delivered by coaptive techniques (eg, bipolar electrocoagulation, heater probe) or noncoaptive techniques (eg, argon plasma coagulation, laser). In coaptive coagulation a probe is used physically to compress and tamponade the vessel, followed by thermal sealing of the vessel. In controlled laboratory experiments, arteries as large as 2.5 mm in diameter can be coagulated with a heater probe using this technique [90]. Bipolar or multipolar electrocoagulation probes and heater probes are the most widely used devices for delivering thermal therapy. The advantages of these devices are their excellent efficacy, safety, portability,

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and the ability to combine irrigation, tamponade, and coagulation. Table 3 outlines the guidelines proposed by the CURE Hemostasis Research Group, based on laboratory and randomized endoscopic studies. In general, for high-risk bleeding ulcers, the preferred technique includes the use of a large probe (3.2 mm) [91] placed with maximal pressure directly on or adjacent to the bleeding point. With bipolar electrocoagulation probes, a relatively low power setting of 15 to 20 W applied for prolonged time periods (10 to 14 seconds) is recommended to achieve the greatest depth of coagulation [92,93]. With heater probes, coagulation should be delivered in a succession of four pulses of 25 to 30 J before changing the position of the probe [90,94]. For either modality, there is no defined limit on the number of pulses that can be safely delivered. As shown in Table 3, the recommended techniques for thermal treatment of Mallory-Weiss tears, Dieulafoy’s lesions, and angiomas differ from those for bleeding ulcers. Noncoaptive techniques, including laser photocoagulation and argon plasma coagulation, are less commonly used thermal modalities of acute hemostasis. The use of lasers has been limited by lack of portability, expense, technical expertise required, need for special electrical outlets and eye protection, and the risk of perforation caused by transmural injury. The argon plasma coagulator is a relatively new device that offers controlled noncontact electrocoagulation by means of a high-frequency energy delivered to tissue through ionized argon gas. One advantage of the argon plasma coagulator over coaptive techniques is the ability to bend the electrical current toward adjacent tissue, thereby enabling the endoscopist to work in poorly accessible areas where direct application of a probe may be difficult or impossible. In one small, randomized trial, the argon plasma coagulator was as effective as heater probe for the treatment of high-risk bleeding ulcers, and was associated with significantly shorter mean time to hemostasis [95]. The argon plasma coagulation has also been shown to be safe and efficacious in the treatment of nonulcer causes of UGI bleeding, such as gastric antral vascular ectasia (watermelon stomach) [96,97]. Comparative studies of the various thermal modalities have not clearly demonstrated superiority of one technique over the others in terms of efficacy and safety [98–101]. In a randomized comparative study of neodymium:yttrium-aluminum-garnet laser, heater probe, and bipolar electrocoagulation in patients with actively bleeding ulcers, there were no significant differences among the three groups in rebleeding rate, length of hospital stay, or need for surgery [100]. Randomized controlled trials conducted by the CURE Hemostasis Research Group have suggested trends toward lower rates of rebleeding and emergency surgery with heater probe therapy compared with multipolar electrocoagulation or bipolar electrocoagulation, but statistical significance was not achieved [94,101]. The choice of thermal modality can be guided by the individual endoscopist’s preference and experience, taking into account the nature and location of the bleeding lesion, and issues of cost, portability, and ease of use.

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Peptic ulcer

Bipolar electrocoagulation Probe size Pressure Power setting Pulse duration/ tamponade station End point Heater probe Probe size Pressure Power setting # pulses/tamponade station End point

Mallory-Weiss tear

Active bleeding

Nonbleeding visible vessel

Active bleeding or visible vessel

Large Very firm 15–20 W 10 s

Large Very firm 15–20 W 10 s

Bleeding stops

Dieulafoy’s lesion

Angioma

Active bleeding

Nonbleeding visible vessel

Active bleeding

Nonbleeding

Large/small Moderate 15–20 W 4s

Large Firm 15–20 W 10 s

Large Firm 15–20 W 10 s

Large vs. small Moderate 10–15 W 2s

Large vs. small Light 10–15 W 2s

Visible vessel flattened

Bleeding stops

Bleeding stops

Visible vessel flattened

Bleeding stops

Visible vessel flattened

Large Very firm 30 J 4

Large Very firm 30 J 4

Large/small Moderate 20 J 3

Large Firm 30 J 4

Large Firm 30 J 4

Large vs. small Moderate 10–15 J 2–3

Large vs. small Light 10–15 J 2

Bleeding stops

Visible vessel flattened

Bleeding stops

Bleeding stops

Visible vessel flattened

Bleeding stops

Lesion white

Adapted from Savides TJ, Jensen DM. Therapeutic endoscopy for nonvariceal gastrointestinal bleeding. Gastroenterol Clin North Am 2000;29:465–87; with permission.

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Table 3 Recommended technical parameters for bipolar electrocoagulation and heater probe treatment (Center for Ulcer Research and Education Hemostasis Research Group)

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Mechanical therapy Among the various options for mechanical therapy, hemoclips have been the most extensively studied in UGI bleeding. Recent trials comparing hemoclipping, injection therapy alone, and the combination of injection plus hemoclipping have yielded conflicting results. In one such trial involving 124 patients with high-risk bleeding ulcer bleeding, Chung et al [102] randomized patients to receive hemoclips, hypertonic saline–epinephrine injection, or combination therapy. Initial hemostasis rates were above 95% for all three groups. The rate of recurrent bleeding was slightly higher in the hypertonic saline-epinephrine group (14.6% for hypertonic saline-epinephrine versus 2.4% for hemoclip, 9.5% for combination therapy), but the difference was not statistically significant. In a subsequent trial of similar design, Gevers et al [103] randomized 105 patients to receive hemoclips alone, injection therapy with epinephrine and polidocanol, or combination therapy. Comparison among the three groups showed no statistical difference in the rates of initial failure or early recurrence of bleeding (37% for hemoclips, 15% for injection, 25% for combination). The overall failure rate, however, was significantly different among the three groups, with the highest rate occurring in the hemoclip group (34%) versus the injection and combination therapy groups (6% and 25%, respectively). The authors concluded that endoscopic hemoclip therapy was significantly less effective than injection therapy for high-risk ulcers, citing unsuccessful hemoclip placement as the main reason for the failure of this modality. Prospective, randomized trials comparing hemoclips with thermal therapy for high-risk ulcers have also reported conflicting results. In a study by Cipolletta et al [104], hemoclip therapy was associated with significantly lower rebleeding rate compared with heater probe therapy (1.8% versus 21%, respectively). Length of hospital stay and transfusion requirements were also significantly lower in the hemoclip group. Somewhat contradictory results were found in a randomized study by Lin et al [105] in which rates of initial and ultimate hemostasis were significantly higher in the heater probe group, and rebleeding rates were no different between the two groups (8.8% for hemoclips versus 5% for heater probe, P = NS). Several factors may limit the efficacy of hemoclip therapy in bleeding ulcers, including ulcer location along the proximal lesser curvature of the stomach or posterior wall of the duodenal bulb [105]. A firm, scarred ulcer base may also prohibit adequate mechanical compression of the underlying vessel by the hemoclips that are currently available. Other types of bleeding lesions, such as Mallory-Weiss tears and Dieulafoy’s lesions, may be more consistently amenable to hemoclipping [106,107]. Firm conclusions cannot be drawn regarding the relative efficacy of hemoclips compared with the more traditional modalities of endoscopic hemostasis. There is accumulating evidence through several case series supporting the safety and efficacy of endoscopic band ligation for nonvariceal, nonulcer

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lesions including Mallory-Weiss tears, Dieulafoy’s lesions, and angiodysplasia [107–110]. Greater experience in prospective trials is required before this technique becomes widely practiced for these indications. Combination therapy Although combinations of different treatment modalities are commonly used, the data to support this practice are scarce. Studies evaluating the combination of different injection agents, and combination of injection therapy with hemoclips, were discussed previously. The combination of injection and contact thermal modalities has become widely practiced and is considered by many to be the standard of care, despite the relative paucity of supporting data. Two prospective, randomized trials have been published in recent years comparing epinephrine injection alone with the combination of epinephrine injection and contact thermal therapy (with either heater probe or bipolar electrocoagulation). In a study by Chung et al [111], patients with actively bleeding ulcers were randomized to receive epinephrine injection therapy alone or the combination of epinephrine injection plus heater probe treatment. Their results demonstrated no statistical differences between the two groups in rates of rebleeding, need for surgery, transfusion requirements, length of hospital stay, or mortality. In the subgroup of patients with spurting hemorrhage (as opposed to those with nonpulsatile oozing), combination therapy was associated with a statistically significant reduction in the need for surgery (6.5% versus 29.6%) and length of hospital stay (4 days versus 6 days). In a subsequent study including 96 patients with active bleeding or nonbleeding visible vessels, Lin et al [68] compared epinephrine injection alone, bipolar electrocoagulation alone, and combined treatment using the injection gold probe (Microvasive/Boston Scientific, Natick, Massachusetts). Rebleeding rates were significantly lower in the combination group (6.7%) than in the bipolar electrocoagulation (30%) and injection therapy (35.5%) groups. Combination therapy was also associated with reduced treatment failure rates and transfusion requirements. Endoscopic failures Despite successful initial endoscopic hemostasis, approximately 15% to 20% of patients rebleed, typically within the first 72 hours. The main clinical and endoscopic factors associated with failure of endoscopic therapy include (1) active, spurting hemorrhage; (2) ulcer size greater than 2 cm; (3) shock; and (4) low hemoglobin level (\ 10 g/dL). Other factors, such as ulcer location on the lesser curvature of the stomach or posterior duodenal bulb, may also increase the likelihood of rebleeding following initial endoscopic hemostasis [112–116]. Endoscopic Doppler ultrasound has been shown in small studies to be useful in predicting the risk of

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rebleeding after initial endoscopic hemostasis [117]. Ulcers that remain persistently Doppler positive immediately after endoscopic therapy have a significantly higher rate of rebleeding than those in which the Doppler signal is abolished. Although it was once thought that surgery was mandatory in all patients who rebled after initial endoscopic control, endoscopic retreatment is now recommended for most patients. A prospective, randomized study comparing endoscopic retreatment with surgery found that repeat endoscopy was associated with fewer complications than surgery, without increasing the risk of death [118]. Mortality rates were high when salvage surgery was required for a second rebleeding episode; accurate identification of those patients at highest risk for endoscopic treatment failure is critical, and early surgical consultation is mandatory. Interventional radiology provides a nonoperative modality to control bleeding when therapeutic endoscopy is unsuccessful, thereby avoiding the high morbidity and mortality of emergency surgery. Therapeutic angiography is most strongly indicated in frail or severely ill patients who are poor surgical candidates, and in treatment of certain uncommon causes of UGI bleeding, such as hemobilia and ruptured pseudoaneurysms complicating pancreatitis. Therapeutic options include selective intra-arterial vasopressin infusion or embolotherapy with microcoils, gelatin sponge pledgets, or polyvinyl alcohol particles. Embolotherapy is becoming increasingly popular, and has been shown to be safe and effective in UGI bleeding from numerous causes, including peptic ulcers, stress ulcers, and Mallory-Weiss tears [119]. Arterial embolization is generally safe in the UGI tract because of its rich arterial collateral supply. Patients with severe vascular disease, or who have undergone prior visceral surgery, however, may be at increased risk for gastric or duodenal ischemia after embolotherapy. Second-look endoscopy There is currently no consensus regarding the optimal strategy to minimize recurrent peptic ulcer hemorrhage once endoscopic hemostasis is achieved. The role of routine second-look endoscopy remains controversial, because randomized controlled trials have reported conflicting results [83,120–122]. Most endoscopists adopt an expectant management strategy and perform repeat endoscopy only when rebleeding becomes clinically evident. A recent meta-analysis demonstrated that routine second-look endoscopy with retreatment significantly reduced the risk of recurrent ulcer bleeding compared with patients undergoing expectant management (absolute risk reduction 6.2%, P \ 0.01) [123]. Selective second-look endoscopy only in patients at high risk for rebleeding (based, for example, on the Baylor Bleeding Score) may prove to be the optimal approach in terms of patient outcomes and cost-effectiveness [122,124].

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Medical therapy Recurrent bleeding occurs in approximately 15% to 20% of patients, contributing significantly to the morbidity and mortality in these patients. Gastric acidity may play an important role in the pathogenesis of recurrent bleeding. In vitro studies have shown that high gastric pH can facilitate platelet aggregation and stabilize clot by inhibiting pepsinogen activation [125,126]. Reduction in gastric acidity should theoretically prevent recurrent bleeding. The evidence for the effectiveness of H2RAs in bleeding peptic ulcers is conflicting. A meta-analysis of 27 randomized trials found that H2RAs modestly reduced the rate of continued bleeding, the need for surgery, and the risk of death, but these benefits seemed to be confined to patients with gastric ulcers [127]. A subsequent multicenter trial of 1005 patients comparing famotidine infusion with placebo found no difference in rebleeding rates between the two groups (24% versus 26%, respectively) [128]. More recently, trials have investigated the efficacy of proton pump inhibitors in the treatment of acute UGI bleeding. An earlier study comparing intravenous omeprazole with placebo showed no difference in rebleeding rates between the two groups [129]. This study, however, included all patients with acute UGI bleeding, regardless of the cause of bleeding or risk factors for rebleeding; any possible benefit of treatment with omeprazole could have been diluted by the inclusion of a large number of low-risk patients. The first randomized study to demonstrate a significant benefit of proton pump inhibition in acute UGI bleeding was reported by Khuroo et al [130] in 1997. They showed that treatment with high-dose oral omeprazole (40 mg twice a day) was associated with significant reduction in rates of rebleeding and need for surgery as compared with placebo (9% versus 35%, and 7% versus 24%, respectively). Subgroup analysis revealed that this benefit was limited to patients with nonbleeding visible vessels or adherent clots. Of note, initial endoscopic therapy was not performed in this study. A subsequent study from the same institution confirmed that adding oral omeprazole to endoscopic injection sclerotherapy significantly reduced rebleeding rates (7% versus 21%); length of hospital stay (4.6 days versus 6 days); and need for blood transfusion (35% versus 73%) compared with endoscopic therapy alone [131]. Randomized trials have also demonstrated significant reduction in rebleeding rates with intravenous omeprazole following endoscopic therapy (with heater probe, multipolar electrocoagulation, or combination of epinephrine injection and heater probe) when compared with placebo (6.7% versus 22.5%) [132] or cimetidine (4% versus 24%) [133]. Treatment with intravenous omeprazole was not associated with statistically significant reductions in mortality or need for surgery. Studies have reported the possible benefit of somatostatin and octreotide in the treatment of nonvariceal UGI bleeding (in particular, peptic ulcer

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bleeding). Although the evidence is conflicting, somatostatin may be associated with improved rates of hemostasis and reduced rates of rebleeding and transfusion requirements when compared with placebo and H2RAs [134], and perhaps proton pump inhibitors [135]. This suggestion is supported by a meta-analysis of 14 trials totaling 1829 patients, which indicated that somatostatin reduced the relative risk (RR) of persistent or recurrent bleeding (RR 0.53; 95% CI, 0.43 to 0.63) compared with controls. Subgroup analysis revealed that the effectiveness of somatostatin was limited to peptic ulcer bleeding (RR 0.48; 95% CI, 0.39 to 0.59) [136]. The available data regarding the benefit of pharmacologic therapy in acute UGI bleeding in North American patients are inconclusive. Nevertheless, the authors recommend treatment with a proton pump inhibitor (preferably intravenous while the patient is fasting) for at least 3 to 5 days as an adjunct to endoscopic therapy, or when endoscopy is unsuccessful, contraindicated, or unavailable. Summary Nonvariceal UGI bleeding is one of the most common emergencies that gastroenterologists encounter, and continues to be a significant cause of morbidity and mortality. The keys to management are rapid resuscitation and stabilization; appropriate triage based on pre-endoscopic risk factors; early endoscopy to achieve prompt diagnosis and implement hemostatic therapy to high-risk lesions; and aggressive antisecretory therapy (in the case of peptic ulcer bleeding) to reduce the risk of continued or recurrent bleeding. References [1] Eisen GC, Dominitz J, Faigel D, Goldstein J, Kalloo A, Petersen B, et al. An annotated algorithmic approach to upper gastrointestinal bleeding. Gastrointest Endosc 2001; 53:853–8. [2] Yavorski R, Wong R, Maydonovitch C, Battin L, Furnia A, Amundson D. Analysis of 3,294 cases of upper gastrointestinal bleeding in military medical facilities. Am J Gastroenterol 1995;90:568–73. [3] Silverstein FE, Gilbert DA, Tedesco FJ, Buenger NK, Persing J. The national ASGE survey on upper gastrointestinal bleeding. II. Clinical prognostic factors. Gastrointest Endosc 1981;27:80–93. [4] Schiller KF, Truelove SC, Williams DG. Haematemesis and melaena, with special reference to factors influencing the outcome. BMJ 1970;2:7–14. [5] Allan R, Dykes P. A study of the factors influencing mortality rates from gastrointestinal haemorrhage. Q J Med 1976;45:533–50. [6] Rockall TA, Logan RF, Devlin HB, Northfield TC. Risk assessment after acute upper gastrointestinal haemorrhage. Gut 1996;38:316–21. [7] Laine L, Peterson WL. Bleeding peptic ulcer. N Engl J Med 1994;331:717–27. [8] Kurata JH, Corboy ED. Current peptic ulcer time trends: an epidemiological profile. J Clin Gastroenterol 1988;10:259–68.

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[9] Aalykke C, Lauritsen JM, Hallas J, Reinholdt S, Krogfelt K, Lauritsen K. Helicobacter pylori and risk of ulcer bleeding among users of nonsteroidal anti-inflammatory drugs: a case-control study. Gastroenterology 1999;116:1305–9. [10] Hawkey CJ. Risk of ulcer bleeding in patients infected with Helicobacter pylori taking non-steroidal anti-inflammatory drugs. Gut 2000;46:310–1. [11] Pilotto A, Leandro G, Di Mario F, Franceschi M, Bozzola L, Valerio G. Role of Helicobacter pylori infection on upper gastrointestinal bleeding in the elderly: a casecontrol study. Dig Dis Sci 1997;42:586–91. [12] Pilotto A, Franceschi M, Leandro G, Di Mario F, Valerio G. The effect of Helicobacter pylori infection on NSAID-related gastroduodenal damage in the elderly. Eur J Gastroenterol Hepatol 1997;9:951–6. [13] Stack WA, Atherton JC, Hawkey GM, Logan RF, Hawkey CJ. Interactions between Helicobacter pylori and other risk factors for peptic ulcer bleeding. Aliment Pharmacol Ther 2002;16:497–506. [14] Jensen D, You S, Pelayo E, Jensen M. The prevalence of Helicobacter pylori and NSAID use in patients with severe UGI hemorrhage and their potential role in recurrence of ulcer bleeding. Gastroenterology 1992;102:A90. [15] Hosking S, Yung M, Chung S, Li A. Differing prevalence of helicobacter in bleeding and nonbleeding ulcers. Gastroenterology 1992;102:A85. [16] Gabriel SE, Jaakkimainen L, Bombardier C. Risk for serious gastrointestinal complications related to use of nonsteroidal anti-inflammatory drugs: a meta-analysis. Ann Intern Med 1991;115:787–96. [17] Godil A, DeGuzman L, Schilling RC III, Khan SA, Chen YK. Recent nonsteroidal antiinflammatory drug use increases the risk of early recurrence of bleeding in patients presenting with bleeding ulcer. Gastrointest Endosc 2000;51:146–51. [18] Laine L. Approaches to nonsteroidal anti-inflammatory drug use in the high-risk patient. Gastroenterology 2001;120:594–606. [19] Huang JQ, Sridhar S, Hunt RH. Role of Helicobacter pylori infection and non-steroidal anti- inflammatory drugs in peptic-ulcer disease: a meta-analysis. Lancet 2002;359:14–22. [20] Schiff L, Stevens R, Shapiro N, Goodman S. Observations on the oral administration of citrated blood in man. II: The effect on the stools. Am J Med Sci 1942;203:409–12. [21] Daniel W, Egan S. The quantity of blood required to produce a tarry stool. JAMA 1939;15:131–4. [22] Wilcox CM, Alexander LN, Cotsonis G. A prospective characterization of upper gastrointestinal hemorrhage presenting with hematochezia. Am J Gastroenterol 1997; 92:231–5. [23] Provenzale D, Sandler RS, Wood DR, Levinson SL, Frakes JT, Sartor RB, et al. Development of a scoring system to predict mortality from upper gastrointestinal bleeding. Am J Med Sci 1987;294:26–32. [24] Hussain H, Lapin S, Cappell MS. Clinical scoring systems for determining the prognosis of gastrointestinal bleeding. Gastroenterol Clin North Am 2000;29:445–64. [25] Corley D, Stefan A, Wolf M, Cook E, Lee T. Early indicators of prognosis in upper gastrointestinal hemorrhage. Am J Gastroenterol 1998;93:336–40. [26] Saeed Z, Ramirez F, Hepps K, Cole R, Graham D. Prospective validation of the Baylor bleeding score for predicting the likelihood of rebleeding after endoscopic hemostasis of peptic ulcers. Gastrointest Endosc 1995;41:561–5. [27] Hay J, Lyubashevsky E, Elashoff J, Maldonado L, Weingarten S, Ellrodt A. Upper gastrointestinal hemorrhage clinical guideline: determining the optimal hospital length of stay. Am J Med 1996;100:313–22. [28] Blatchford O, Murray W, Blatchford M. A risk score to predict need for treatment for upper gastrointestinal haemorrhage. Lancet 2000;356:1318–21. [29] Gilbert DA, Saunders D, Peoples J, Sillery J, Gulaseik C. Failure of iced saline lavage to suppress hemorrhage from experimental bleeding ulcers. Gastroenterology 1979;76:1138.

C.S. Huang, D.R. Lichtenstein / Gastroenterol Clin N Am 32 (2003) 1053–1078

1073

[30] Gilbert DA, Saunders D. Iced saline lavage does not slow bleeding from experimental canine gastric ulcers. Dig Dis Sci 1981;26:1065–8. [31] Ponsky J, Hoffman M, Swayngim D. Saline irrigation in gastric hemorrhage: the effect of temperature. J Surg Res 1980;28:204–5. [32] Andrus C, Ponsky J. The effects of irrigant temperature in upper gastrointestinal hemorrhage: a requiem for iced saline lavage. Am J Gastroenterol 1987;82:1062–4. [33] Cuellar R, Gavaler J, Alexander J, Brouillette D, Chien M-C, Yoo Y-K, et al. Gastrointestinal tract hemorrhage: the value of a nasogastric aspirate. Arch Intern Med 1990;150:1381–4. [34] Silverstein FE, Gilbert DA, Tedesco FJ, Buenger NK, Persing J. The national ASGE survey on upper gastrointestinal bleeding. I. Study design and baseline data. Gastrointest Endosc 1981;27:73–9. [35] Rockall TA, Logan RF, Devlin HB, Northfield TC. Selection of patients for early discharge or outpatient care after acute upper gastrointestinal haemorrhage. National Audit of Acute Upper Gastrointestinal Haemorrhage. Lancet 1996;347:1138–40. [36] Peterson W, Barnett C, Smith H, Allen M, Corbett D. Routine early endoscopy in uppergastrointestinal-tract bleeding: a randomized, controlled trial. N Engl J Med 1981; 304:925–9. [37] Graham D. Limited value of early endoscopy in the management of acute upper gastrointestinal bleeding: a prospective controlled trial. Am J Surg 1980;140:284–90. [38] Spiegel B, Vakil N, Ofman J. Endoscopy for acute nonvariceal upper gastrointestinal tract hemorrhage: is sooner better? A systematic review. Arch Intern Med 2001;161: 1393–404. [39] Lee JG, Turnipseed S, Romano PS, Vigil H, Azari R, Melnikoff N, et al. Endoscopybased triage significantly reduces hospitalization rates and costs of treating upper GI bleeding: a randomized controlled trial. Gastrointest Endosc 1999;50:755–61. [40] Lin HJ, Wang K, Perng CL, Chua RT, Lee FY, Lee CH, et al. Early or delayed endoscopy for patients with peptic ulcer bleeding: a prospective randomized study. J Clin Gastroenterol 1996;22:267–71. [41] Cooper GS, Chak A, Way LE, Hammar PJ, Harper DL, Rosenthal GE. Early endoscopy in upper gastrointestinal hemorrhage: associations with recurrent bleeding, surgery, and length of hospital stay. Gastrointest Endosc 1999;49:145–52. [42] Hay JA, Maldonado L, Weingarten SR, Ellrodt AG. Prospective evaluation of a clinical guideline recommending hospital length of stay in upper gastrointestinal tract hemorrhage. JAMA 1997;278:2151–6. [43] Savides TJ, Jensen DM. Therapeutic endoscopy for nonvariceal gastrointestinal bleeding. Gastroenterol Clin North Am 2000;29:465–87. [44] Laine L, Cohen H, Brodhead J, Cantor D, Garcia F, Mosquera M. Prospective evaluation of immediate versus delayed refeeding and prognostic value of endoscopy in patients with upper gastrointestinal hemorrhage. Gastroenterology 1992;102:314–6. [45] Lin HJ, Wang K, Perng CL, Lee FY, Lee CH, Lee SD. Natural history of bleeding peptic ulcers with a tightly adherent blood clot: a prospective observation. Gastrointest Endosc 1996;43:470–3. [46] Wara P. Endoscopic prediction of major rebleeding: a prospective study of stigmata of hemorrhage in bleeding ulcer. Gastroenterology 1985;88:1209–14. [47] Chang-Chien CS, Wu CS, Chen PC, Lin DY, Chu CM, Fang KM, et al. Different implications of stigmata of recent hemorrhage in gastric and duodenal ulcers. Dig Dis Sci 1988;33:400–4. [48] Matthewson K, Swain CP, Bland M, Kirkham JS, Bown SG, Northfield TC. Randomized comparison of Nd:YAG laser, heater probe, and no endoscopic therapy for bleeding peptic ulcers. Gastroenterology 1990;98:1239–44. [49] Swain CP, Storey DW, Bown SG, Heath J, Mills TN, Salmon PR, et al. Nature of the bleeding vessel in recurrently bleeding gastric ulcers. Gastroenterology 1986;90:595–608.

1074

C.S. Huang, D.R. Lichtenstein / Gastroenterol Clin N Am 32 (2003) 1053–1078

[50] Freeman ML, Cass OW, Peine CJ, Onstad GR. The non-bleeding visible vessel versus the sentinel clot: natural history and risk of rebleeding. Gastrointest Endosc 1993;39: 359–66. [51] Lau JY, Sung JJ, Chan AC, Lai GW, Lau JT, Ng EK, et al. Stigmata of hemorrhage in bleeding peptic ulcers: an interobserver agreement study among international experts. Gastrointest Endosc 1997;46:33–6. [52] Stollman NH, Putcha RV, Neustater BR, Tagle M, Raskin JB, Rogers AI. The uncleared fundal pool in acute upper gastrointestinal bleeding: implications and outcomes. Gastrointest Endosc 1997;46:324–7. [53] Cheng CL, Lee CS, Liu NJ, Chen PC, Chiu CT, Wu CS. Overlooked lesions at emergency endoscopy for acute nonvariceal upper gastrointestinal bleeding. Endoscopy 2002;34: 527–30. [54] Hintze RE, Binmoeller KF, Adler A, Veltzke W, Thonke F, Soehendra N. Improved endoscopic management of severe upper gastrointestinal hemorrhage using a new widechannel endoscope. Endoscopy 1994;26:613–6. [55] Wu DC, Lu CY, Lu CH, Su YC, Perng DS, Wang WM, et al. Endoscopic hydrogen peroxide spray may facilitate localization of the bleeding site in acute upper gastrointestinal bleeding. Endoscopy 1999;31:237–41. [56] Coffin B, Pocard M, Panis Y, Riche F, Laine MJ, Bitoun A, et al. Erythromycin improves the quality of EGD in patients with acute upper GI bleeding: a randomized controlled study. Gastrointest Endosc 2002;56:174–9. [57] Frossard JL, Spahr L, Queneau PE, Giostra E, Burckhardt B, Ory G, et al. Erythromycin intravenous bolus infusion in acute upper gastrointestinal bleeding: a randomized, controlled, double-blind trial. Gastroenterology 2002;123:17–23. [58] Hsu PI, Lai KH, Lin XZ, Yang YF, Lin M, Shin JS, et al. When to discharge patients with bleeding peptic ulcers: a prospective study of residual risk of rebleeding. Gastrointest Endosc 1996;44:382–7. [59] Lai KC, Hui WM, Wong BC, Ching CK, Lam SK. A retrospective and prospective study on the safety of discharging selected patients with duodenal ulcer bleeding on the same day as endoscopy. Gastrointest Endosc 1997;45:26–30. [60] Cebollero-Santamaria F, Smith J, Gioe S, Van Frank T, Mc Call R, Airhart J, et al. Selective outpatient management of upper gastrointestinal bleeding in the elderly. Am J Gastroenterol 1999;94:1242–7. [61] Consensus conference. Therapeutic endoscopy and bleeding ulcers. JAMA 1989;262: 1369–72. [62] Consensus statement on therapeutic endoscopy and bleeding ulcers. Consensus Development Panel. Gastrointest Endosc 1990;36:S62–5. [63] Cook DJ, Guyatt GH, Salena BJ, Laine LA. Endoscopic therapy for acute nonvariceal upper gastrointestinal hemorrhage: a meta-analysis. Gastroenterology 1992; 102:139–48. [64] Sacks HS, Chalmers TC, Blum AL, Berrier J, Pagano D. Endoscopic hemostasis: an effective therapy for bleeding peptic ulcers. JAMA 1990;264:494–9. [65] Laine L, Stein C, Sharma V. A prospective outcome study of patients with clot in an ulcer and the effect of irrigation. Gastrointest Endosc 1996;43:107–10. [66] Bleau BL, Gostout CJ, Sherman KE, Shaw MJ, Harford WV, Keate RF, et al. Recurrent bleeding from peptic ulcer associated with adherent clot: a randomized study comparing endoscopic treatment with medical therapy. Gastrointest Endosc 2002;56:1–6. [67] Jensen DM, Kovacs TO, Jutabha R, Machicado GA, Gralnek IM, Savides TJ, et al. Randomized trial of medical or endoscopic therapy to prevent recurrent ulcer hemorrhage in patients with adherent clots. Gastroenterology 2002;123:407–13. [68] Lin HJ, Tseng GY, Perng CL, Lee FY, Chang FY, Lee SD. Comparison of adrenaline injection and bipolar electrocoagulation for the arrest of peptic ulcer bleeding. Gut 1999;44:715–9.

C.S. Huang, D.R. Lichtenstein / Gastroenterol Clin N Am 32 (2003) 1053–1078

1075

[69] Chung SC, Leung JW, Sung JY, Lo KK, Li AK. Injection or heat probe for bleeding ulcer. Gastroenterology 1991;100:33–7. [70] Llach J, Bordas JM, Salmeron JM, Panes J, Garcia-Pagan JC, Feu F, et al. A prospective randomized trial of heater probe thermocoagulation versus injection therapy in peptic ulcer hemorrhage. Gastrointest Endosc 1996;43:117–20. [71] Naveau S, Borotto E, Giraud J. Meta-analysis of endoscopic injection therapy versus thermal methods in peptic ulcer haemorrhage. Gastroenterology 1996;110:A207. [72] Lai KH, Peng SN, Guo WS, Lee FY, Chang FY, Malik U, et al. Endoscopic injection for the treatment of bleeding ulcers: local tamponade or drug effect? Endoscopy 1994;26: 338–41. [73] Lin HJ, Perng CL, Lee FY, Chan CY, Huang ZC, Lee SD, et al. Endoscopic injection for the arrest of peptic ulcer hemorrhage: final results of a prospective, randomized comparative trial. Gastrointest Endosc 1993;39:15–9. [74] Pinkas H, McAllister E, Norman J, Robinson B, Brady PG, Dawson PJ. Prolonged evaluation of epinephrine and normal saline solution injections in an acute ulcer model with a single bleeding artery. Gastrointest Endosc 1995;42:51–5. [75] Laine L, Estrada R. Randomized trial of normal saline solution injection versus bipolar electrocoagulation for treatment of patients with high-risk bleeding ulcers: is local tamponade enough? Gastrointest Endosc 2002;55:6–10. [76] Chung SC, Leung JW, Steele RJ, Crofts TJ, Li AK. Endoscopic injection of adrenaline for actively bleeding ulcers: a randomised trial. BMJ 1988;296:1631–3. [77] Villanueva C, Balanzo J, Espinos JC, Fabrega E, Sainz S, Gonzalez D, et al. Endoscopic injection therapy of bleeding ulcer: a prospective and randomized comparison of adrenaline alone or with polidocanol. J Clin Gastroenterol 1993;17:195–200. [78] Lin HJ, Perng CL, Lee SD. Is sclerosant injection mandatory after an epinephrine injection for arrest of peptic ulcer haemorrhage? A prospective, randomised, comparative study. Gut 1993;34:1182–5. [79] Choudari CP, Palmer KR. Endoscopic injection therapy for bleeding peptic ulcer: a comparison of adrenaline alone with adrenaline plus ethanolamine oleate. Gut 1994; 35:608–10. [80] Chung SC, Leong HT, Chan AC, Lau JY, Yung MY, Leung JW, et al. Epinephrine or epinephrine plus alcohol for injection of bleeding ulcers: a prospective randomized trial. Gastrointest Endosc 1996;43:591–5. [81] Chung SC, Leung JW, Leong HT, Lo KK, Li AK. Adding a sclerosant to endoscopic epinephrine injection in actively bleeding ulcers: a randomized trial. Gastrointest Endosc 1993;39:611–5. [82] Lin HJ, Hsieh YH, Tseng GY, Perng CL, Chang FY, Lee SD. Endoscopic injection with fibrin sealant versus epinephrine for arrest of peptic ulcer bleeding: a randomized, comparative trial. J Clin Gastroenterol 2002;35:218–21. [83] Rutgeerts P, Rauws E, Wara P, Swain P, Hoos A, Solleder E, et al. Randomised trial of single and repeated fibrin glue compared with injection of polidocanol in treatment of bleeding peptic ulcer. Lancet 1997;350:692–6. [84] Song SY, Chung JB, Moon YM, Kang JK, Park IS. Comparison of the hemostatic effect of endoscopic injection with fibrin glue and hypertonic saline-epinephrine for peptic ulcer bleeding: a prospective randomized trial. Endoscopy 1997;29:827–33. [85] Kubba AK, Murphy W, Palmer KR. Endoscopic injection for bleeding peptic ulcer: a comparison of adrenaline alone with adrenaline plus human thrombin. Gastroenterology 1996;111:623–8. [86] Balanzo J, Villanueva C, Sainz S, Espinos JC, Mendez C, Guarner C, et al. Injection therapy of bleeding peptic ulcer: a prospective, randomized trial using epinephrine and thrombin. Endoscopy 1990;22:157–9. [87] Rutgeerts P, Geboes K, Vantrappen G. Experimental studies of injection therapy for severe nonvariceal bleeding in dogs. Gastroenterology 1989;97:610–21.

1076

C.S. Huang, D.R. Lichtenstein / Gastroenterol Clin N Am 32 (2003) 1053–1078

[88] Sung JY, Chung SC, Low JM, Cocks R, Ip SM, Tan P, et al. Systemic absorption of epinephrine after endoscopic submucosal injection in patients with bleeding peptic ulcers. Gastrointest Endosc 1993;39:20–2. [89] Lin HJ, Hsieh YH, Tseng GY, Perng CL, Chang FY, Lee SD. A prospective, randomized trial of large- versus small-volume endoscopic injection of epinephrine for peptic ulcer bleeding. Gastrointest Endosc 2002;55:615–9. [90] Johnston JH, Jensen DM, Auth D. Experimental comparison of endoscopic yttriumaluminum-garnet laser, electrosurgery, and heater probe for canine gut arterial coagulation: importance of compression and avoidance of erosion. Gastroenterology 1987;92:1101–8. [91] Morris DL, Brearley S, Thompson H, Keighley MR. A comparison of the efficacy and depth of gastric wall injury with 3.2- and 2.3-mm bipolar probes in canine arterial hemorrhage. Gastrointest Endosc 1985;31:361–3. [92] Laine L. Determination of the optimal technique for bipolar electrocoagulation treatment: an experimental evaluation of the BICAP and Gold probes. Gastroenterology 1991;100:107–12. [93] Swain CP, Mills TN, Shemesh E, Dark JM, Lewin MR, Clifton JS, et al. Which electrode? A comparison of four endoscopic methods of electrocoagulation in experimental bleeding ulcers. Gut 1984;25:1424–31. [94] Jensen DM. Heat probe for hemostasis of bleeding peptic ulcers: technique and results of randomized controlled trials. Gastrointest Endosc 1990;36:S42–9. [95] Cipolletta L, Bianco MA, Rotondano G, Piscopo R, Prisco A, Garofano ML. Prospective comparison of argon plasma coagulator and heater probe in the endoscopic treatment of major peptic ulcer bleeding. Gastrointest Endosc 1998;48:191–5. [96] Chang YT, Wang HP, Huang SP, Lee YC, Chang MC, Wu MS, et al. Clinical application of argon plasma coagulation in endoscopic hemostasis for non-ulcer nonvariceal gastrointestinal bleeding: a pilot study in Taiwan. Hepatogastroenterology 2002; 49:441–3. [97] Yusoff I, Brennan F, Ormonde D, Laurence B. Argon plasma coagulation for treatment of watermelon stomach. Endoscopy 2002;34:407–10. [98] Rollhauser C, Fleischer DE. Current status of endoscopic therapy for ulcer bleeding. Baillieres Best Pract Res Clin Gastroenterol 2000;14:391–410. [99] Lin HJ, Wang K, Perng CL, Lee CH, Lee SD. Heater probe thermocoagulation and multipolar electrocoagulation for arrest of peptic ulcer bleeding: a prospective, randomized comparative trial. J Clin Gastroenterol 1995;21:99–102. [100] Hui WM, Ng MM, Lok AS, Lai CL, Lau YN, Lam SK. A randomized comparative study of laser photocoagulation, heater probe, and bipolar electrocoagulation in the treatment of actively bleeding ulcers. Gastrointest Endosc 1991;37:299–304. [101] Gralnek IM, Jensen DM, Gornbein J, Kovacs TO, Jutabha R, Freeman ML, et al. Clinical and economic outcomes of individuals with severe peptic ulcer hemorrhage and nonbleeding visible vessel: an analysis of two prospective clinical trials. Am J Gastroenterol 1998;93:2047–56. [102] Chung IK, Ham JS, Kim HS, Park SH, Lee MH, Kim SJ. Comparison of the hemostatic efficacy of the endoscopic hemoclip method with hypertonic saline-epinephrine injection and a combination of the two for the management of bleeding peptic ulcers. Gastrointest Endosc 1999;49:13–8. [103] Gevers AM, De Goede E, Simoens M, Hiele M, Rutgeerts P. A randomized trial comparing injection therapy with hemoclip and with injection combined with hemoclip for bleeding ulcers. Gastrointest Endosc 2002;55:466–9. [104] Cipolletta L, Bianco MA, Marmo R, Rotondano G, Piscopo R, Vingiani AM, et al. Endoclips versus heater probe in preventing early recurrent bleeding from peptic ulcer: a prospective and randomized trial. Gastrointest Endosc 2001;53:147–51.

C.S. Huang, D.R. Lichtenstein / Gastroenterol Clin N Am 32 (2003) 1053–1078

1077

[105] Lin HJ, Hsieh YH, Tseng GY, Perng CL, Chang FY, Lee SD. A prospective, randomized trial of endoscopic hemoclip versus heater probe thermocoagulation for peptic ulcer bleeding. Am J Gastroenterol 2002;97:2250–4. [106] Huang SP, Wang HP, Lee YC, Lin CC, Yang CS, Wu MS, et al. Endoscopic hemoclip placement and epinephrine injection for Mallory-Weiss syndrome with active bleeding. Gastrointest Endosc 2002;55:842–6. [107] Chung IK, Kim EJ, Lee MS, Kim HS, Park SH, Lee MH, et al. Bleeding Dieulafoy’s lesions and the choice of endoscopic method: comparing the hemostatic efficacy of mechanical and injection methods. Gastrointest Endosc 2000;52:721–4. [108] Abi-Hanna D, Williams SJ, Gillespie PE, Bourke MJ. Endoscopic band ligation for nonvariceal non-ulcer gastrointestinal hemorrhage. Gastrointest Endosc 1998;48:510–4. [109] Ertekin C, Taviloglu K, Barbaros U, Guloglu R, Dolay K. Endoscopic band ligation: alternative treatment method in nonvariceal upper gastrointestinal hemorrhage. J Laparoendosc Adv Surg Tech A 2002;12:41–5. [110] Matsui S, Kamisako T, Kudo M, Inoue R. Endoscopic band ligation for control of nonvariceal upper GI hemorrhage: comparison with bipolar electrocoagulation. Gastrointest Endosc 2002;55:214–8. [111] Chung SS, Lau JY, Sung JJ, Chan AC, Lai CW, Ng EK, et al. Randomised comparison between adrenaline injection alone and adrenaline injection plus heat probe treatment for actively bleeding ulcers. BMJ 1997;314:1307–11. [112] Wong SK, Yu LM, Lau JY, Lam YH, Chan AC, Ng EK, et al. Prediction of therapeutic failure after adrenaline injection plus heater probe treatment in patients with bleeding peptic ulcer. Gut 2002;50:322–5. [113] Chung IK, Kim EJ, Lee MS, Kim HS, Park SH, Lee MH, et al. Endoscopic factors predisposing to rebleeding following endoscopic hemostasis in bleeding peptic ulcers. Endoscopy 2001;33:969–75. [114] Brullet E, Campo R, Calvet X, Coroleu D, Rivero E, Simo Deu J. Factors related to the failure of endoscopic injection therapy for bleeding gastric ulcer. Gut 1996;39:155–8. [115] Brullet E, Calvet X, Campo R, Rue M, Catot L, Donoso L. Factors predicting failure of endoscopic injection therapy in bleeding duodenal ulcer. Gastrointest Endosc 1996; 43:111–6. [116] Choudari CP, Rajgopal C, Elton RA, Palmer KR. Failures of endoscopic therapy for bleeding peptic ulcer: an analysis of risk factors. Am J Gastroenterol 1994;89: 1968–72. [117] Wong RC, Chak A, Kobayashi K, Isenberg GA, Cooper GS, Carr-Locke DL, et al. Role of Doppler US in acute peptic ulcer hemorrhage: can it predict failure of endoscopic therapy? Gastrointest Endosc 2000;52:315–21. [118] Lau JY, Sung JJ, Lam YH, Chan AC, Ng EK, Lee DW, et al. Endoscopic retreatment compared with surgery in patients with recurrent bleeding after initial endoscopic control of bleeding ulcers. N Engl J Med 1999;340:751–6. [119] Lefkovitz Z, Cappell MS, Kaplan M, Mitty H, Gerard P. Radiology in the diagnosis and therapy of gastrointestinal bleeding. Gastroenterol Clin North Am 2000;29:489–512. [120] Messmann H, Schaller P, Andus T, Lock G, Vogt W, Gross V, et al. Effect of programmed endoscopic follow-up examinations on the rebleeding rate of gastric or duodenal peptic ulcers treated by injection therapy: a prospective, randomized controlled trial. Endoscopy 1998;30:583–9. [121] Villanueva C, Balanzo J, Torras X, Soriano G, Sainz S, Vilardell F. Value of second-look endoscopy after injection therapy for bleeding peptic ulcer: a prospective and randomized trial. Gastrointest Endosc 1994;40:34–9. [122] Saeed ZA, Cole RA, Ramirez FC, Schneider FE, Hepps KS, Graham DY. Endoscopic retreatment after successful initial hemostasis prevents ulcer rebleeding: a prospective randomized trial. Endoscopy 1996;28:288–94.

1078

C.S. Huang, D.R. Lichtenstein / Gastroenterol Clin N Am 32 (2003) 1053–1078

[123] Marmo R, Rotondano G, Bianco MA, Piscopo R, Prisco A, Cipolletta L. Outcome of endoscopic treatment for peptic ulcer bleeding: Is a second look necessary? A metaanalysis. Gastrointest Endosc 2003;57:62–7. [124] Spiegel BM, Ofman JJ, Woods K, Vakil NB. Minimizing recurrent peptic ulcer hemorrhage after endoscopic hemostasis: the cost-effectiveness of competing strategies. Am J Gastroenterol 2003;98:86–97. [125] Barkham P, Tocantins L. Action of human gastric juice on human blood clot. J Appl Physiol 1953;6:1–7. [126] Green FW Jr, Kaplan MM, Curtis LE, Levine PH. Effect of acid and pepsin on blood coagulation and platelet aggregation: a possible contributor prolonged gastroduodenal mucosal hemorrhage. Gastroenterology 1978;74:38–43. [127] Collins R, Langman M. Treatment with histamine H2 antagonists in acute upper gastrointestinal hemorrhage: implications of randomized trials. N Engl J Med 1985; 313:660–6. [128] Walt RP, Cottrell J, Mann SG, Freemantle NP, Langman MJ. Continuous intravenous famotidine for haemorrhage from peptic ulcer. Lancet 1992;340:1058–62. [129] Daneshmend TK, Hawkey CJ, Langman MJ, Logan RF, Long RG, Walt RP. Omeprazole versus placebo for acute upper gastrointestinal bleeding: randomised double blind controlled trial. BMJ 1992;304:143–7. [130] Khuroo MS, Yattoo GN, Javid G, Khan BA, Shah AA, Gulzar GM, et al. A comparison of omeprazole and placebo for bleeding peptic ulcer. N Engl J Med 1997;336:1054–8. [131] Javid G, Masoodi I, Zargar SA, Khan BA, Yatoo GN, Shah AH, et al. Omeprazole as adjuvant therapy to endoscopic combination injection sclerotherapy for treating bleeding peptic ulcer. Am J Med 2001;111:280–4. [132] Lin HJ, Lo WC, Lee FY, Perng CL, Tseng GY. A prospective randomized comparative trial showing that omeprazole prevents rebleeding in patients with bleeding peptic ulcer after successful endoscopic therapy. Arch Intern Med 1998;158:54–8. [133] Lau JY, Sung JJ, Lee KK, Yung MY, Wong SK, Wu JC, et al. Effect of intravenous omeprazole on recurrent bleeding after endoscopic treatment of bleeding peptic ulcers. N Engl J Med 2000;343:310–6. [134] Tulassay Z, Gupta R, Papp J, Bodnar A. Somatostatin versus cimetidine in the treatment of actively bleeding duodenal ulcer: a prospective, randomized, controlled trial. Am J Gastroenterol 1989;84:6–9. [135] Coraggio F, Rotondano G, Marmo R, Balzanelli MG, Catalano A, Clemente F, et al. Somatostatin in the prevention of recurrent bleeding after endoscopic haemostasis of peptic ulcer haemorrhage: a preliminary report. Eur J Gastroenterol Hepatol 1998;10: 673–6. [136] Imperiale TF, Birgisson S. Somatostatin or octreotide compared with H2 antagonists and placebo in the management of acute nonvariceal upper gastrointestinal hemorrhage: a meta-analysis. Ann Intern Med 1997;127:1062–71.