TECHNOLOGICAL REVIEW. Current diagnosis and treatment of severe obscure GI hemorrhage. Table 1. Cameron ulcers. Dennis M.

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1 TECHNOLOGICAL REVIEW Current diagnosis and treatment of severe obscure GI hemorrhage Dennis M. Jensen, MD Los Angeles, California Patients with GI hemorrhage of uncertain etiology are a diagnostic and therapeutic challenge. Estimates vary in the current prevalence of obscure bleeding among all cases of GI hemorrhage, but this was probably less than 5% before the introduction of capsule endoscopy. 1 When routine endoscopy and colonoscopy are not diagnostic and the patient continues to have recurrent bleeding, further evaluation is warranted. 2,3 Most often the site of hemorrhage is suspected to be the small bowel. 2-4 In the past, the options for diagnosis of potential small-bowel lesions were radiologic (such as routine small-bowel followthrough [SBFT], enteroclysis, abdominal angiogram, or CT), nuclear medicine (technetium-labeled red blood cell [RBC] or a radiolabeled-sulfur colloid), endoscopic (repeat colonoscopy or panendoscopy, push enteroscopy with a colonoscope, or Sonde enteroscopy), or surgical (with or without intraoperative endoscopy). The yields of radiologic studies such as SBFT or enteroclysis for patients with severe obscure hemorrhage without GI obstructive symptoms are extremely low. 1,5,6 Similarly, yields of nuclear scanning (sulfur colloid or RBC) and angiography are low, even with patients who have recurrent melena or hematochezia. 1-7 Although these radiographic studies may have high specificity for a bleeding site localization and potential etiology, the sensitivity is too low to make them useful as a screening test. Yet, in the absence of tests with more sensitivity and specificity, these insensitive tests have been used for many years by clinicians trying to establish a diagnosis in patients with obscure GI hemorrhage. Current affiliations: UCLA School of Medicine, CURE: Digestive Disease Research Center, and the VA Greater Los Angeles Healthcare System, Los Angeles, California. Supported in part by NIH Grant 1K24 DK02650, the CURE CORE NIH Grant DK41301, and General CRC NIH Grant MO1- RR Reprint requests: CURE Digestive Diseases Research Center, Bldg. 115, Rm. 318, VA Greater Los Angeles Healthcare System, Wilshire Blvd., Los Angeles, CA Copyright 2003 by the American Society for Gastrointestinal Endoscopy /2003/$ doi: /mge Table 1. Cameron ulcers Patients present with melena or iron deficiency anemia. Linear ulcerations at the bottom of a large hiatal hernia are best seen in retroflexion. The linear ulcers may heal between GI bleeds. Pathogenesis is mechanical or (ischemic) instead of primarily acid-pepsin. Most cases fail medical therapy with PPIs and iron. Most patients require surgical fundoplication. References 2, 3, 7, 50, 51. PPI, Proton pump inhibitor. Sonde enteroscopy is both sensitive and specific in these patients. 6-8 Although this endoscope is no longer commercially available and was never widely used, Berner et al. 7 reported that visualization of the ileum or beyond was possible in 77% of 545 patients with obscure bleeding (both occult and overt). For EGD, push enteroscopy and Sonde enteroscopy results combined, 58% (322/553) had abnormal examinations with 40% (219/553) beyond the reach of EGD. 7 GI angiomas were diagnosed in 34.5% of the combined enteroscopies (both push and Sonde), small intestinal tumors in 5.6% of patients, and small-bowel ulcers and other lesions in 3%. 7 No bleeding sites were reported in 41.7% of all enteroscopies. The procedure time of Sonde enteroscopy is 6 to 8 hours, and the diagnosis is feasible in ambulatory patients when the Sonde enteroscope is withdrawn from the most distal locale that peristalsis has carried it. Visual diagnosis but not biopsy, treatment, or specific localization is possible. Because of the ability to visualize much of the small bowel, this instrument serves as a benchmark for other, newer techniques for diagnosis in patients with obscure GI bleeding such as capsule endoscopy. For patients with severe obscure GI hemorrhage, the purposes of this report are the following: (1) to define and describe the clinical and laboratory profile of this subgroup of patients, (2) to discuss recent diagnostic approaches, (3) to describe changes in the clinical evaluation with the introduction of capsule endoscopy, and (4) to discuss the limitations of recent reports and what types of future outcome and cost analysis studies are warranted. DEFINITIONS Suspected small-bowel bleeding Suspected small-bowel bleeding is GI hemorrhage thought to be from the small intestine because the clinical and GI evaluations have been negative for an esophageal, gastric, duodenal, or colonic bleeding site. A nasogastric tube and lavage are considered part of the GI evaluation when the patient presents with severe hematochezia or melena in the absence of hematemesis. 3,4 Both EGD and 256 GASTROINTESTINAL ENDOSCOPY VOLUME 58, NO. 2, 2003

2 Current diagnosis and treatment of severe obscure GI hemorrhage D Jensen colonoscopy with intubation of the terminal ileum are requisite before considering a patient as having a potential small-bowel source for bleeding. Obscure GI bleeding Obscure GI bleeding is synonymous in this manuscript with suspected small-bowel bleeding. However, the hemorrhage is yet to be documented as caused by a small-bowel source. Occult bleeding Occult bleeding refers to hemoccult-positive stools with or without iron deficiency anemia. This usually represents slow, chronic GI bleeding that is low volume. This type of bleeding will not be discussed in this manuscript. Overt (severe) bleeding Overt (severe) bleeding is a presentation with evidence of acute GI bleeding such as melena, hematochezia, or hematemesis. This suggests highvolume bleeding and is usually associated with an acute reduction in Hb and with transfusions or volume resuscitation. Overt (severe) bleeding is the focus of this review. Definite versus probable source of hemorrhage versus incidental lesion When lesions can be identified and have active bleeding (at endoscopy, angiography, or surgery) or major stigmata of hemorrhage (non-bleeding visible vessel or adherent clot), they are considered the definitive source of hemorrhage. Lesions without major stigmata of hemorrhage are considered the probable source of hemorrhage when no other lesions are found and there is some clinical evidence of localization such as melena for a foregut lesion or hematochezia for a small bowel or colonic lesion. Incidental lesions are designated when another lesion with stigmata is found during the same examination (such as push enteroscopy, capsule endoscopy, or surgery) or, on subsequent examination, another definite lesion is diagnosed and treatment of that lesion controls the GI bleeding. Active bleeding without identification of any GI lesion may be useful for localization and, potentially, for resection. In this report, this is listed separately as active bleeding, but the reader is reminded that blood in the gut in the absence of a specific lesion may be misleading for localization and resection because of peristalsis or retrograde movement. Patient population included Severe obscure GI hemorrhage that is suspected to be from a small-bowel source usually presents with melena or hematochezia. Hematemesis is rare for small-bowel lesions, unless the patient has a surgical gastrojejunostomy or a fistula between the upper GI (UGI) tract and small bowel. Patients with severe obscure GI hemorrhage often have anemia and signs of hypovolemia, such as tachycardia, orthostatic hypotension, and dizziness. Such patients, who have acute blood loss of high instead of low volume, are the primary focus of this review. EQUIPMENT AND TECHNIQUES FOR SMALL-BOWEL ENDOSCOPY Colonoscopes Patients with severe obscure GI bleeding require retrograde ileoscopy at colonoscopy to exclude a terminal ileal source of hemorrhage such as Crohn s disease (with ulcerations) or a tumor. 4,9 Before the development of push enteroscopes, sterilized, peroral colonoscopes were used for many years to examine the distal duodenum and proximal jejunum. 10,11 Some endoscopists prefer pediatric colonoscopes for push enteroscopy because of the small diameter (usually less than mm). The introduction of smaller diameter (11-12 mm) standard videocolonoscopes (with 3.8-mm suction channels) has facilitated enteroscopy of the foregut, and most investigators report examination of 50 to 75 cm of the jejunum. 10,11 Colonoscopes are often useful for diagnosis and treatment of foregut lesions in severe obscure hemorrhage when other push enteroscopes are not available. Push enteroscopes Push videoenteroscopes vary in length from 220 to 250 cm and are marketed by Pentax and Olympus. Overtubes are available for these. The techniques for passage of the push enteroscopes are to use conscious sedation and to pass the instrument, similar to an endoscope, into the distal duodenum. Continuous axial pressure (usually moderate) is used to pass the instrument into the jejunum as long as the lumen is visualized. When looping or paradoxical movement is noted, withdrawal of the enteroscope to reduce loops (usually in the stomach) is recommended. Changing of the patient s position by rotating the patient onto his or her back and applying pressure on the greater curvature of the stomach (left upper quadrant or left epigastrium) and duodenum (right epigastrium or right upper quadrant) may also facilitate passage of the enteroscope. Suctioning also may be helpful. Some endoscopists advocate passage of a probe or biopsy forceps to help stiffen and advance the instrument. 10 Fluoroscopy with or without an overtube may also facilitate passage of the enteroscope further into the jejunum. The disadvantages of the overtube are the inconvenience and the potential for compli- VOLUME 58, NO. 2, 2003 GASTROINTESTINAL ENDOSCOPY 257

3 D Jensen Current diagnosis and treatment of severe obscure GI hemorrhage cations, including damage to the duodenal papilla or bowel by trapping these between the overtube and endoscope with subsequent shearing or stripping. 12 Although some investigators report deeper passage into the jejunum with use of an overtube compared with no overtube, these techniques have not been shown to impact favorably on diagnostic sensitivity. 13 Fluroscopy should be considered with overtube use to minimize complications. Sonde enteroscopes Sonde enteroscopy affords good visualization of the small intestine. 6-8 However, the disadvantages, such as long procedure time, need for peristalsis, fluoroscopy to determine insertion depth of localization of lesions, inconvenience to patients, and inability to obtain a biopsy specimen or treat through the endoscope, outweigh the advantages. Now other options are available, including longer push enteroscopes and capsule endoscopy. Intraoperative enteroscopy Before the development of capsule endoscopy, for patients who were operative candidates and had severe recurrent obscure bleeding, laparotomy with intraoperative enteroscopy was strongly considered early in their course When a focal lesion instead of diffuse disease is suspected, such a combined approach affords high diagnostic and therapeutic yields A 220-cm-long push enteroscope is passed orally, after the surgeon completes the exploration and has dissected out any adhesions to free up the small bowel. With assistance by the surgeon, the entire small bowel can be accordioned or pleated over the enteroscope The small intestine is inspected on initial entry in 10- to 20-cm segments. Transillumination of the bowel is recommended to detect any potential bleeding sites. Muscosal trauma and contact bleeding will often result upon manipulation of the bowel over the endoscope, and these artifacts are often confused with definitive bleeding sites if the bowel is primarily examined upon withdrawal. Lesions should be marked with a suture by the surgeon for later resection. Occasionally, active bleeding or a column of blood is detected at laparotomy. The proximal margin should be marked. Intraluminally, the mucosa can be washed, blood can be suctioned with the enteroscope, and lesions may be localized, diagnosed, and/or coagulated. Examination can be problematic in patients with extensive adhesions or prior radiation therapy. Capsule endoscopy Capsule endoscopy allows for a new era in the study of potential small-bowel disorders, including GI bleeding Capsule endoscopy has received U.S. Food and Drug Administration approval, and a procedure code has been assigned by the Center for Medicare and Medicaid Services, allowing payment when the procedure is performed in both hospital and non-hospital settings. With the latter, practice expenses related to the disposable capsule and necessary computer hardware and software have been incorporated into the payment. There are major advantages of capsule endoscopy. It can be performed without sedation or complete fasting in an outpatient setting. Good to excellent images may be obtained for over 8 hours Capsule endoscopy is producing new information about the anatomy, pathology, and motility of the small intestine The examination is well tolerated in adults and large children without gut strictures, hypomotility, or obstruction. Unlike small-bowel radiographs, there is no radiation exposure; repeat examinations are feasible and well tolerated. The images can be seen even when fluid is in the lumen or the capsule lens is close to the gut wall. Absolute contraindications to the procedure include the presence of a known stricture that might result in failure of the capsule to pass. In addition, presence of a pacemaker is also a contraindication because of regulatory issues (associate editor s personal communication with Given Imaging). Although much more convenient for the patient and physician than Sonde enteroscopy, capsule endoscopy shares many characteristics with it. The procedures both depend on peristalsis and have the potential of viewing much of the small bowel in patients with normal motility and without strictures. Visual diagnosis is possible but not biopsy, labeling, or treatment. Localization may be problematic. Capsule endoscopy has supplanted Sonde enteroscopy, primarily because of its convenience and initial diagnostic yields The reader is also referred to a recent ASGE status evaluation report by the Technology Assessment Committee, 30 ASGE Standards of Practice Report, 31 and two other reviews on enteroscopy, which include lists of recent abstracts on capsule endoscopy LOCALIZATION AND THERAPY OF SEVERE OBSCURE GI HEMORRHAGE Approximately 50% of patients initially thought to have severe obscure GI hemorrhage are identified to have lesions within reach of EGD The high rate of missed lesions has many practical implications on studies that assess the role of new technology in the evaluation of these patients. Therefore, the yield of different diagnostic modalities will be further discussed by site of abnormality. 258 GASTROINTESTINAL ENDOSCOPY VOLUME 58, NO. 2, 2003

4 Current diagnosis and treatment of severe obscure GI hemorrhage D Jensen Table 2. Gastric antral vascular ectasia Antral stripes of red, raised mucosa radiating from pylorus Superficial vascular ectasia on histopathology Clinical setting of slow GIB in the elderly Patients may present with melena or iron deficiency anemia Different than portal hypertensive gastropathy Most cases amenable to endoscopic palliation References 2, 3, 7, 50, 52. GIB, Gastrointestinal bleeding. Subgroup 1. Bleeding sites within reach of EGD Example Case 1. A 68-year-old woman was referred for recurrent melena, anemia requiring transfusions, and a history of GERD managed with a proton pump inhibitor (PPI). Before the referral, the evaluation included two endoscopies showing a large hiatal hernia, two colonoscopies revealing diverticulosis, a negative small-bowel series, and a negative technetium-labeled RBC scan. At our referral center, Cameron ulcers were diagnosed in the base of a large hiatal hernia on push enteroscopy, but no other lesions were found. This patient failed PPI therapy and later required surgery (Nissen fundoplication) to control severe bleeding (Table 1). 2,3,7,50,51 Example Case 2. An 87-year-old woman was self-referred for another opinion about severe obscure GI bleeding. She had been transfused 54 units of RBCs over 27 months for severe recurrent melena and anemia. The history included two nondiagnostic panendoscopies, two colonoscopies, and a delayed RBC scan (24 hrs) reported as positive in the right colon. Despite a right hemicolectomy, melena recurred, and the patient received more RBC transfusions. Push enteroscopy demonstrated a gastric antral vascular ectasia (GAVE), or watermelon stomach, and was otherwise negative for bleeding sites (Fig. 1, Table 2). This patient was treated with endoscopic coagulation in serial treatment sessions until obliteration of the watermelon lesions. She has not had melena or transfusions in 3 years of followup. 2,3,7,50,52 Results of push enteroscopy within reach of an endoscope. The results of push enteroscopy will be discussed as diagnostic yield, types of diagnosis, hemostasis rates, and recommendations for a change in overall management or outcome. For patients with severe obscure GI bleeding, diagnostic yields of push enteroscopy are reported of 30% to 76%, for definitive or probable causes of hemorrhage The CURE Hemostasis Group reported results for 206 consecutive patients with severe obscure GI bleeding referred to a tertiary medical center, with a diagnostic yield of bleeding sites in the foregut of 76%, by push enteroscopy. 50 Refer to Figure 2, which presents the localization and subgroups of diag- Figure 1. Gastric antral vascular ectasia with red folds radiating back from pyloris. This patient was successfully treated with endoscopic hemostasis. See Table 3. noses. Many of these definitive diagnoses were either found in the esophagus, stomach, or duodenal bulb (Subgroup 1). In this cohort of referred patients, almost half the diagnoses made (77/155) were in this subgroup, within reach of a panendoscope. The most common lesions were angiomas, ulcers, Cameron ulcers, GAVE or watermelon stomach, and varices (gastric or esophageal). Comments and discussion on Subgroup 1 lesions. This 50% rate is similar to other large cohort studies for the proportion of missed UGI lesions within reach of standard panendoscopes-egd Although the yield of push enteroscopy has varied significantly in different studies, the clinically important lesions found by push enteroscopy are amenable to coagulation and biopsy or Indiaink labeling. 53 The high rate of missed lesions emphasizes the importance of referral of such patients for re-examination to qualified experts. The potential reasons for a lack of a diagnosis in the esophagus, stomach, or duodenum by EGD include hypovolemia and under-perfusion or filling of lesions (e.g., varices, angiomas, or GAVE), lack of familiarity with the clinical entity or endoscopic appearance (Cameron ulcers, gastric varices, or GAVE), failure to recognize an obvious lesion as a bleeding source (ulcer, angiomas, gastric polyp), or failure to find a small but significant lesion (Dieulafoy s lesion, isolated angioma, or ulcer). This high proportion (about 50% of diagnosed lesions) is clinically significant and suggests that all patients with severe obscure GI bleeding would benefit significantly from re-examination by experienced endoscopists with either a panendoscope or an enteroscope. 50 It also suggests that there is substantial need for improvement in the training of VOLUME 58, NO. 2, 2003 GASTROINTESTINAL ENDOSCOPY 259

5 D Jensen Current diagnosis and treatment of severe obscure GI hemorrhage Figure 2. Results of push enteroscopy for severe obscure hemorrhage from CURE Hemostasis study. A cohort of 206 consecutive patients were studied before the availability of capsule endoscopy. new endoscopists and retraining of other endoscopists (who are outside training programs) in the diagnosis and treatment of such lesions. It needs to be emphasized that the current capsule endoscope will not be the method of choice for diagnosis of esophageal, stomach, or duodenal bulbar lesions. Simultaneous diagnosis and treatment are feasible with push enteroscopy. Biopsies are possible, and gut motility is not a limitation of push enteroscopy for these organs. In contrast, capsule endoscopy is limited by all these factors. Subgroup 2. Post-bulbar duodenal lesions Example Case 3. A 46-year-old man had recurrent melena and a history of peptic ulcers, treated with ranitidine daily to prevent ulcer recurrence. He had a negative panendoscopy, colonoscopy, smallbowel series, and angiogram before referral. An ulcerated duodenal cancer was diagnosed in the third portion of the duodenum by push enteroscopy. This patient had endoscopic hemostasis, biopsies, and, later, surgery. Results and comments on push enteroscopy and/or duodenoscopy for post-bulbar lesions. In the CURE Hemostasis Group s report, 18% of patients had a diagnosis of post-bulbar duodenal lesions. 50 Refer to Figure 2. These diagnoses were made either by push enteroscopy and/or duodenoscopy. The most common lesions were angiomas, but others included polyps, cancer, ulcers, or a diverticulum with a stigmata of hemorrhage (non-bleeding visible vessel). All patients in this subgroup had definite lesions (with major stigmata) and were treated endoscopically with polypectomy or hemostasis. This localization in the post-bulbar duodenum compares with yields of 10% to 20% for other large cohort series of severe obscure bleeding investigated by push enteroscopy The potential reasons for a referring endoscopist not to diagnose the lesion in this site are similar to those in Subgroup 1. In addition, they may not have used colonoscopes 10,11 or duodenoscopes 2 to examine patients under elective conditions. Subgroup 3. Jejunal lesions and severe obscure GI bleeding Example Case 4. A 74-year-old Hispanic woman with a history of 5 hospitalizations and 14 units of RBC transfused was referred because of obscure severe GI bleeding suspected to be from the small bowel. She had a history of moderate chronic renal insufficiency, mild chronic obstructive pulmonary disease, atrial fibrillation, congestive heart failure, diabetes mellitus, hypertension, and osteoarthritis. Between hospitalizations, she was prescribed erythropoietin (Epogen; Amgen Inc., Thousand Oaks, Calif.) and iron but did not take aspirin or nonsteroidal anti-inflammatory drugs (NSAID). Previous GI evaluations were negative, including 3 panendoscopies, 3 colonoscopies, 4 RBC scans, and an SBFT. On push enteroscopy at our referral center, multiple jejunal angiomas were diagnosed and treated with endoscopic thermal coagulation. She did not require further transfusions over the last 24 months and has continued to take iron and erythropoietin, with maintenance of a stable Hb. Results and comments about push enteroscopy for jejunal lesions. In the CURE Hemostasis Group s study, about 20% of patients referred for severe obscure bleeding had jejunal sources of hemorrhage diagnosed by push enteroscopy. 50 The most prevalent lesions were jejunal angiomas. Other common causes were anastomotic ulcers, cancers, polyps, and other ulcers (NSAID or ideopathic). All the patients in this group were considered to have definitive or presumptive diagnoses for the bleeding site. Evidence was either stigmata of recent hemor- 260 GASTROINTESTINAL ENDOSCOPY VOLUME 58, NO. 2, 2003

6 Current diagnosis and treatment of severe obscure GI hemorrhage D Jensen rhage on the lesions (clot, oozing, or visible vessel); fresh blood in the jejunum near the lesion, without other lesions; or multiple large angiomas that bled with target irrigation. Target irrigation, suctioning, changing of position and re-examination facilitated the endoscopic diagnosis and treatment. 50 In other large push enteroscopy series, diagnostic yields of jejunal lesions vary from 15% to 25% Because this yield is clinically significant and relatively high and the endoscopist can direct diagnosis, biopsy, labeling (with India ink), and treatment, push enteroscopy by an experienced and careful endoscopist ought to be considered before other testing. 14,15,40-50 Examination as far as 100 cm beyond the ligament of Treitz is possible with current push enteroscopes that are 220 to 250 cm long. 14,15,40-50 In patients with recurrent melena of uncertain etiology, this is a particularly important region to examine and treat The ability to combine diagnosis and treatment, as well as determine localization and label the lesions, is important. Such capabilities are not possible with any other current method except laparotomy and intraoperative enteroscopy. 14,15 Although celiac disease may be a cause of iron deficiency anemia, 1 it is not the cause of severe occult bleeding in the absence of ulcerations or neoplasia. Subgroup 4. Ileal lesions and severe obscure GI bleeding Example Case 5. A 43-year-old woman was referred for another opinion for recurrent, severe melena. She had no major comorbidity and was not ingesting aspirin, NSAIDs, gingko, or anticoagulants. She had had one hospitalization per year for each of the last 4 years because of melena and hypovolemia. She was transfused 2 to 4 units of packed RBCs (PRBC) each admission for resuscitation. The evaluations at other institutions were negative for a source of hemorrhage, including 4 panendoscopies, 3 colonoscopies, 2 RBC scans, 2 Meckel s scans, 1 SBFT, and 1 enteroclysis. She had severe obscure GI bleeding, suspected to be from a Meckel s diverticulum. She previously refused surgery, and a Meckel s diverticulum was never diagnosed before surgery. During the last hospitalization for severe hematochezia, an abdominal angiogram and push enteroscopy with a 220-cm instrument were also negative. She presented with a Hb of 5.0 g/dl (normal: g/dl) and required transfusion of 5 units of PRBCs. A laparotomy and intraoperative enteroscopy were recommended and the former was later performed. At laparotomy, the diagnosis was Meckel s diverticulum, which was resected (Table 3). An intraoperative enteroscopy was not required. Subsequently, the patient has had a normal Hb, and Table 3. Meckel s diverticulum as a cause of severe obscure hemorrhage in adults Most common SI embryonic abnormality (the omental vitelline duct), found in 2%-5% of autopsies. Accounts for 1%-2% of SI lesions causing severe GIB. Unlike children, Meckel s scans in adults are usually negative. Suspect in patients 50 years old with painless recurrent obscure GIB and no major comorbidity. Usually not visualized by enteroclysis, RBC scan, or capsule endoscopy. Usually requires surgery for diagnosis and treatment. References 16, 17, 26. SI, Small intestine; GIB, gastrointestinal bleeding; RBC, red blood cell. there has been no recurrence of bleeding in 5 years of follow-up. Results and comments on laparotomy and intraoperative enteroscopy. The diagnostic yields reported for laparotomy vary considerably for patients with severe obscure GI bleeding. Because enteroscopy has been used in conjunction with surgery, yields are reported to be 60% to 100% and depend upon patient selection, including severity and acuity of the GI bleeding, the completeness of the prior GI evaluation, the expertise of the team (both the endoscopist and surgeon), the definition of diagnosis, and whether intraoperative enteroscopy was performed One would expect the diagnostic yield to be higher if investigators report both nonbleeding lesions that may be incidental and not the bleeding site (such as diverticulosis, erosions, or small angiomas), as well as definitive bleeding sites (lesions with stigmata of hemorrhage) and probable bleeding sites (with blood in the bowel segment of the lesion without other lesions found). The highest diagnostic yield for patients with severe obscure GI bleeding was reported by Szold et al. 14 in 71 patients. They used a stepwise approach to diagnose the bleeding site before, during, and after surgery, which included Sonde enteroscopy, 6-8 laparotomy and intraoperative push enteroscopy, or RBC scintigraphy, when diagnoses were not evident at surgery. 14 In this retrospective series, the most common diagnoses were angiomas (40%), malignant neoplasms (27%), benign small-bowel tumors (11%), Crohn s disease (6%), GAVE (4%), Meckel s diverticulum (4%), small intestine varices (3%), and other small intestine lesions (10%). Fifty-six patients (78.9%, most with focal lesions) had no further bleeding after diagnosis and surgical treatment. 14 In contrast, 9 patients with multiple small-bowel angiomas (12.7% of all patients) had recurrent bleeding. Six patients died of recurrent bleeding, and 6 patients died of metastatic cancer. VOLUME 58, NO. 2, 2003 GASTROINTESTINAL ENDOSCOPY 261

7 D Jensen Current diagnosis and treatment of severe obscure GI hemorrhage Until the introduction of capsule endoscopy, the combined reference standards for diagnosis and treatment were endoscopy, push enteroscopy, and Sonde enteroscopy. If these were negative, then laparotomy and intraoperative enteroscopy were added as the reference standard in patients with severe obscure bleeding. 5-8,16-25,40-50 Intraoperative scintigraphy 14 and methylene blue injection before surgery 54 were also combined in some series. Because patients with multiple or diffuse lesions such as angiomas repeatedly bled 12.7% of the time in follow-up, 14 diagnoses by push enteroscopy or capsule enteroscopy is warranted in all such patients before surgery. In the future, the role of laparotomy and intraoperative endoscopy for diagnosis alone should be reduced with capsule endoscopy. Unless the plan at laparotomy is treatment by resection, oversewing, or coagulation, capsule or push enteroscopy should be able to diagnose most patients with diffuse disease and obviate the need for laparotomy. An aggressive approach to diagnosis and surgical treatment has been recommended by some investigators for patients with jejunal or ileal angiomas and severe small-bowel bleeding when they fail to respond to endoscopic coagulation and medical treatment RESULTS OF CAPSULE ENDOSCOPY FOR DIAGNOSIS OF SEVERE OBSCURE GI BLEEDING In the last 2 years, there has been a change in the diagnostic approach to severe obscure GI bleeding with the introduction of capsule endoscopy by Given Imaging With the introduction of the M2A capsule (Given Imaging, Inc., Norcross, Ga.), many clinical studies have been presented in GI meetings, but most are still in abstract form and await peer review and publication. The purpose of this section is to describe recent results and the potential impact of capsule endoscopy on the diagnosis in patients who have severe obscure GI bleeding, based primarily upon peer-reviewed reports. A comprehensive review of capsule endoscopy is not intended. Among the initial peer-reviewed papers published, capsule endoscopy was compared with push enteroscopy or small-bowel series 38 for initial diagnostic yield for patients with either occult or overt obscure GI hemorrhage. No uniform standard terminology was used for definitive bleeding sites, presumptive diagnoses, incidental findings, or red blood only. For example, Lewis and Swain 35 reported a yield of capsule endoscopy of 55% (11/20). However, only fresh blood (without a lesion identified) was reported in 4 patients (20%) and angiomas (without stigmata) in 5 patients (25%). Other diagnoses were an ileal ulcer in one patient and a tumor in another. 35 Therefore, another interpretation for the yield of capsule endoscopy for the presumptive diagnosis of a lesion as a bleeding site was 35% (7/20). In this report, push enteroscopy revealed angiomas in 6 patients, and these were coagulated during the procedure in all patients. For these same 6 patients, capsule endoscopy identified fresh blood only in one patient and non-bleeding angiomas in the 5 others. In two patients, Cameron ulcers and large hiatal hernias were diagnosed as the cause of obscure hemorrhage by push enteroscopy, but, because the capsule was not used to evaluate the stomach, these patients were excluded from analysis. It was the authors conclusion that the diagnostic yield was higher with capsule than push enteroscopy. However, the examinations appear to be complementary. Furthermore, push enteroscopy, in addition to identifying stomach sites, could be used for hemostasis. A substantial proportion of patients within this study fall into Subgroup 1 (bleeding sites within reach of EGD), Subgroup 2 (post-bulbar duodenal), and Subgroup 3 (jejunal lesions) amenable to simultaneous endoscopic diagnosis and treatment via push enteroscopy. 35 Washing away blood to identify and diagnose underlying lesions is a major advantage of push enteroscopy, even though visualization of only part of the small bowel is possible. In contrast, the capsule has the major advantage of being able to examine significantly more small bowel beyond the reach of current push enteroscopes. Ell et al. 36 reported a comparison of capsule endoscopy with push enteroscopy in patients with chronic GI bleeding. Although 65 patients were referred for the study, 33 were excluded, including 6 who had a GI diagnosis by repeat conventional GI tests. For the 32 patients included in this study, a complete diagnostic evaluation (enteroclysis, angiography, tagged RBC scan), as well as push enteroscopy and capsule endoscopy were performed. The definitive diagnostic yields were the following: conventional procedure 16% (5/32), push enteroscopy 28% (9/32), and capsule endoscopy 66% (21/32). Definitive diagnoses included angiomas 53% (17/32), malignancy 6.3% (2/32), and inflammatory disease 6.3% (2/32). Questionable bleeding sources were reported in an additional 9% of push enteroscopy and 22% capsule endoscopy patients. Neither the push nor capsule endoscopy procedures were associated with complications. This study included a highly selected group of patients with either occult or overt GI blood loss. The admixture and selection probably explains the high prevalence of GI angiomas and the low rates of malignancy and inflammatory disease. The high rate of definite diagnosis was not confirmed by other GI tests or follow-up. In this report, there was no 262 GASTROINTESTINAL ENDOSCOPY VOLUME 58, NO. 2, 2003

8 Current diagnosis and treatment of severe obscure GI hemorrhage D Jensen discussion of whether outcomes or management were changed by capsule results of either definitive or questionable findings. Scapa et al. 37 reported an initial experience with capsule endoscopy in another heterogeneous group of patients with iron deficiency anemia, suspected Crohn s disease, lymphectasia, or celiac disease. For the patients with iron deficiency anemia and either overt or occult GI bleeding, the mean Hb was 9.2 gm%. They reported the diagnostic yield as 75% (15/20). However, 3 patients in this subgroup had blood clots only and no lesion diagnosis. Therefore, the actual definitive diagnostic yield for GI lesions was 60% in this study. No outcome data were reported on the subgroup of patients with iron deficiency anemia. 37 Costamagna et al. 38 also reported a study of another heterogeneous group of 20 patients with suspected small-bowel disease in whom they compared diagnostic yields of small-bowel series and capsule endoscopy. Patients included had obscure bleeding, small-bowel polyps, and suspected Crohn s recurrence. The barium studies were diagnostic in 20% of the patients. In contrast, capsule endoscopy was considered diagnostic in 45%, suspicious in 4%, and failed (no diagnosis) in 15%. For the subgroup of 13 patients with obscure bleeding, the diagnostic yield was 30.8% (4/13) definitive, 53.8% suspicious, and 15.4% negative. Findings were reported as suspicious when capsule findings failed to explain completely the signs and symptoms, and further investigation was necessary to evaluate the patient or findings. 38 The CURE Hemostasis Research Group and collaborators reported on a large multicenter study for patients with severe obscure GI hemorrhage suspected to be from the small bowel. 39 All patients in this study had recurrent melena or hematochezia and required transfusions. 39 For 6 U.S. study sites, 52 patients were included, who had negative standard evaluations, including 378 prior GI procedures or surgeries for severe recurrent GI bleeding. The definite diagnostic yield of capsule endoscopy was 40.0% (21/52). Red blood only was seen in 11.5% (6/52), a false positive diagnosis (later another lesion was found as the bleeding site) was reported in 3.8% (2/52), and no diagnosis was found in 44.5% (23/52). There were no complications and the capsule examinations were well tolerated. However, management was not changed or definitive in most patients. 39 Other procedures were recommended in 63.5% of patients. Laparotomy with intraoperative enteroscopy was specifically recommended in 32.7% of patients, either because of lack of diagnosis, severity of recurrent bleeding, or a possible localized lesion. Specific localization within the small bowel was often found to be imprecise with capsule endoscopy, as determined by laparotomy and intraoperative enteroscopy in those patients later operated upon. 15 Incidental diagnosis (such as small angiomas, small-bowel diverticulosis, or erosions) were common, reported in 26.8% of capsule endoscopies in this study. In all those patients with an incidental diagnosis on capsule endoscopy, the patients rebled and another definitive diagnosis was later made by push enteroscopy, surgery, intraoperative enteroscopy, or another procedure. ALGORITHM FOR CURRENT DIAGNOSIS AND TREATMENT OF SEVERE OBSCURE GI HEMORRHAGE The definition of severe obscure GI hemorrhage requires that prior EGD and colonoscopy with terminal ileum intubation were non-diagnostic. When initially evaluating these patients, the first triage is to decide whether there is a history of hematochezia (in a patient with intact ileocecal valve) or melena. Refer to Figure 3. The hematochezia patients will benefit from colonic purge and urgent colonoscopy with intubation of the terminal ileum. 4,61 For patients with angiomas or other lesions with stigmata (such as diverticulosis, ulcers, or solitary rectal ulcers), treatment with thermal or combination therapies (epinephrine plus thermal, mechanical clipping, or banding) are recommended For colonic polyps, colitis, internal hemorrhoids, ulcerations or focal lesions, biopsies, polypectomy, or specific therapies are recommended. 9,64 Patients with severe or recurrent hematochezia without a diagnosis by urgent colonoscopy should be evaluated by push enteroscopy, 3,4 similar to patients with recurrent melena. For patients with severe or recurrent melena of obscure etiology or hematochezia (without a diagnosis by urgent colonoscopy), push enteroscopy with a 220- to 250-cm enteroscope is highly recommended This affords careful examination of the foregut, with the potential of endoscopic diagnosis, biopsy, tattooing, and hemostasis. 2,3,40-50 If this examination does not yield a definitive diagnosis, capsule endoscopy is recommended. If the capsule endoscopy yields a definitive diagnosis, then medical, endoscopic, or surgical therapy can be initiated The subsequent treatment will depend upon whether the lesion is single or multiple and whether the patient is a candidate for surgery and intraoperative enteroscopy. 3,15-25,39 For patients with recurrent melena, and negative push enteroscopy and capsule enteroscopy in a referral center, repeat colonoscopy with retrograde ileoscopy is recommended. 9 Rarely ambulatory, elderly patients with delayed colonic emptying will have a right colonic or terminal ileal lesion that causes melena instead of hematochezia. Lesions such as ulcers or angiomas also can be detected and treated via colonoscopy. 9,62 VOLUME 58, NO. 2, 2003 GASTROINTESTINAL ENDOSCOPY 263

9 D Jensen Current diagnosis and treatment of severe obscure GI hemorrhage Figure 3. Algorithm for diagnosis and treatment of severe obscure GI bleeding. For patients who have recurrent melena, RBC scanning with early scans (at 1-4 hours) compared with baseline scans may be helpful for a probable localization. 3,50 Because of the problems of localization and the lack of a specific etiologic diagnosis with RBC scans, abdominal angiography ought to be considered to verify location and presumptive diagnosis in all patients with positive RBC scans, especially before laparotomy and resection. Finally, for patients who have a reasonable operative risk and have recurrent melena but nondiagnostic push enteroscopy, capsule endoscopy, colonoscopy and retrograde ileoscopy, RBC scan, abdominal angiography, laparotomy and, if negative, intraoperative enteroscopy ought to be highly considered. Such an approach is expected to be diagnostic in 60% to 100% of cases Laparotomy and intraoperative enteroscopy is particularly recommended in patients younger than 50 years, because of the higher frequency of small-bowel tumors 6,7 and also Meckel s diverticulum CAPSULE ENDOSCOPY: FUTURE STUDIES IN PATIENTS WITH SEVERE OBSCURE GI BLEEDING The 4 major problems related to diagnosis and treatment of patients with severe obscure bleeding with capsule endoscopy are the following: (1) determining what constitutes a definitive diagnosis versus a presumptive diagnosis or incidental finding; (2) localization of lesions within the small bowel; (3) limited evidence that capsule endoscopy changes outcomes or reduces costs compared with other approaches, such as push enteroscopy and, if negative, laparotomy and intraoperative enteroscopy; and (4) inability to control capsule movements or to mark, sample, or treat lesions. In regard to a reference standard for diagnosis, either endoscopic procedures (push enteroscopy or retrograde ileoscopy via colonoscopy) or laparotomy with intraoperative enteroscopy can serve to combine diagnosis, biopsy, and/or treatment (coagulation, polypectomy, or resection). For focal lesions this collection of tests can be considered the reference standard because the definitive diagnostic yield is 92% to 100%, and 70% to 80% of all patients who undergo these combined procedures have been reported not to have recurrent bleeding or require further GI procedures when the diagnosis is combined with therapy. 7,14,15 In these series, recurrent bleeding has been attributed to diffuse lesions (such as angiomas) where surgery or endoscopy therapies are considered palliative. Whether capsule endoscopy will obviate the need for further therapeutic or diagnostic procedures in patients with diffuse or multiple lesions has not been reported. Nevertheless, there has been a substantial increase in both incidental diagnoses and multiple diagnoses by capsule endoscopy, as high as 40% in one series 38 and somewhat less (22%-27%) in other reports. 36,39 Standard terminology and further studies to define a reference standard for diagnosis and treatment outcomes with capsule endoscopy will be necessary and are recommended. The specificity and sensitivity of capsule endoscopy for severe obscure bleeding have not yet been defined. Specific localization of lesions by capsule endoscopy within the small intestine has been reported as a problem relative to surgery or other procedures. 38,39,50 Improvements in software have been introduced (Given Imaging), but evidence about their impact and accuracy relative to surgery and intraoperative enteroscopy have not yet been published in peer-reviewed reports. Real-time imaging 264 GASTROINTESTINAL ENDOSCOPY VOLUME 58, NO. 2, 2003

10 Current diagnosis and treatment of severe obscure GI hemorrhage D Jensen or other innovations in capsule control may be necessary to improve localization in the small bowel. This is particularly important when laparotomy and resections are contemplated. The inability to control the capsule, to mark the bowel, to sample or biopsy the mucosa, to wash or treat lesions are limitations of the current capsule endoscope. However, future improvements in technology and newer generations of capsule endoscopes are anticipated. These may require real-time imaging but are likely to combine diagnosis with treatment. Beyond the multiple initial abstracts and few peerreviewed papers about diagnostic yields, good tolerance, and safety of capsule endoscopy, there are few reports or any quantitation about changes in patient outcomes, costs, or management with capsule endoscopy. These types of studies and results are warranted and anticipated because investigators, health care planners, and GI societies are particularly interested in them. 30,31,38,39 Unbiased, objective studies to evaluate such outcomes will be important in allocating current and future health care resources. Until the practical issues about capsule endoscopy are resolved and evidence-based studies documenting improvement in outcomes with capsule endoscopy relative to current diagnoses and treatment are reported, a stepwise approach to the patient with severe obscure GI hemorrhage is recommended. ACKNOWLEDGMENTS The author thanks the members of the CURE Hemostasis Team for their contributions and support: Thomas O. G. Kovacs, MD, Gustavo A. Machicado, MD, Rome Jutabha, MD, Ian Gralnek, MD, MSHS, and Gareth Dulai, MD, MSHS. 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