Small Bowel Bleeding Aug2015

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nature publishing group 1

2015 by the American College of Gastroenterology The American Journal of GASTROENTEROLOGY

PRACTICE GUIDELINES

Bleeding rom the small intestine remains a relatively uncom-mon event, accounting or ~510% o all patients presentingwith gastrointestinal (GI) bleeding ( 1,2). Known previously asobscure GI hemorrhage (OGIB), we propose in this guidelinethat the ormer term re erred to as OGIB be reclassi ed as smallbowel bleeding. Te reason or this change in terminology isowing to the act that the cause o bleeding can now be detectedin the majority o patients given advances in small bowel imag-ing with video capsule endoscopy (VCE), deep enteroscopy, andradiographic imaging. Te term OGIB would then be reserved

or patients in whom a source o bleeding cannot be identi edanywhere in the GI tract and may represent a source o bleedingoutside o the small bowel.

Te purpose o this guideline will be to review the de nition,epidemiology, causes o small bowel bleeding, and therapeu-

tic options. Te guideline will provide a review o diagnosticmodalities or patients with small bowel hemorrhage includingVCE, endoscopic evaluation with push and/or deep enteroscopy,and radiographic modalities including cross-sectional imaging(computed tomography (C ) and magnetic resonance (MR))enterography, angiography, and scintigraphy. Approaches to treat-ment will be reviewed as endoscopic, medical, and surgical options.

As part o this guideline preparation, a literature search wasconducted using Ovid MEDLINE rom 1946 to present, EMBASE1988 to present, and SCOPUS rom 1980 to present using majorsearch terms and subheadings including obscure or occult,gastrointestinal hemorrhage, iron-de ciency anemia, cap-sule endoscopy, enteroscopy angiography, computed tomo-graphic enterography, magnetic resonance enterography,tagged red blood cell, angioectasia, Meckels diverticulum,

ACG Clinical Guideline: Diagnosis and Management of

Small Bowel Bleeding Lauren B. Gerson , MD, MSc, FACG1 , Jeff L. Fidler, MD2 , David R. Cave, MD, PhD, FACG 3 and Jonathan A. Leighton , MD, FACG4

Bleeding from the small intestine remains a relatively uncommon event, accounting for ~510% of all patientspresenting with gastrointestinal (GI) bleeding. Given advances in small bowel imaging with video capsuleendoscopy (VCE), deep enteroscopy, and radiographic imaging, the cause of bleeding in the small bowel cannow be identied in most patients. The term small bowel bleeding is therefore proposed as a replacement forthe previous classication of obscure GI bleeding (OGIB). We recommend that the term OGIB should be reservedfor patients in whom a source of bleeding cannot be identied anywhere in the GI tract. A source of small bowelbleeding should be considered in patients with GI bleeding after performance of a normal upper and lowerendoscopic examination. Second-look examinations using upper endoscopy, push enteroscopy, and/or colonoscopycan be performed if indicated before small bowel evaluation. VCE should be considered a rst-line procedurefor small bowel investigation. Any method of deep enteroscopy can be used when endoscopic evaluation andtherapy are required. VCE should be performed before deep enteroscopy if there is no contraindication. Computedtomographic enterography should be performed in patients with suspected obstruction before VCE or after negativeVCE examinations. When there is acute overt hemorrhage in the unstable patient, angiography should be performedemergently. In patients with occult hemorrhage or stable patients with active overt bleeding, multiphasic computedtomography should be performed after VCE or CTE to identify the source of bleeding and to guide further management.If a source of bleeding is identied in the small bowel that is associated with signicant ongoing anemia and/oractive bleeding, the patient should be managed with endoscopic therapy. Conservative management is recommendedfor patients without a source found after small bowel investigation, whereas repeat diagnostic investigations arerecommended for patients with initial negative small bowel evaluations and ongoing overt or occult bleeding.

Am J Gastroenterol 2015; 110:12651287; doi:10.1038/ajg.2015.246; published online 25 August 2015

1 Division of Gastroenterology, California Pacic Medical Center and Department of Medicine, University of California School of Medicine , San Francisco ,California , USA ; 2 Division of Radiology, Mayo Clinic School of Medicine , Rochester , Minnesota , USA ; 3 Division of Gastroenterology, University of MassachusettsMedical Center , Worcester , Massachusetts , USA ; 4 Division of Gastroenterology, Mayo Clinic School of Medicine , Scottsdale , Arizona , USA . Correspondence:Lauren B. Gerson, MD, MSc, Director of Clinical Research, GI Fellowship Program, Division of Gastroenterology, California Pacic Medical Center , 2340 ClayStreet, 6th Floor , San Francisco , California 94115 , USA . E-mail: [email protected] 7 January 2015 ; accepted 21 June 2015

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Table 1 . Recommendation statements

Diagnosis of small bowel bleeding

1. Second-look upper endoscopy should be considered in cases of recurrent hematemesis, melena, or a previously incomplete exam (strong recommenda-tion, low level of evidence).

2. Second-look colonoscopy should be considered in the setting of recurrent hematochezia or if a lower source is suspected (conditional recommendation,

very low level of evidence).3. If the second-look examinations are normal, the next step should be a small bowel evaluation (strong recommendation, moderate level of evidence).

4. Push enteroscopy can be performed as a second-look examination in the evaluation of suspected small bowel bleeding (conditional recommendation,moderate level of evidence).

5. Video capsule endoscopy (VCE) should be considered as a rst-line procedure for SB evaluation after upper and lower GI sources have been excluded,including second-look endoscopy when indicated (strong recommendation, moderate level of evidence).

6. Owing to the lower detection rate of lesions in the duodenum and proximal jejunum with VCE, push enteroscopy should be performed if proximal lesionsare suspected (strong recommendation, very low level of evidence).

7. Total deep enteroscopy should be attempted if there is a strong suspicion of a small bowel lesion based on clinical presentation (strong recommendation,moderate level of evidence).

8. Any method of deep enteroscopy can be used when endoscopic evaluation and therapy is required based on similar diagnostic yields (strong recommen-dation, high level of evidence).

9. Intraoperative enteroscopy is a highly sensitive but invasive diagnostic and effective therapeutic procedure. Its usage should be limited to scenarios whereenteroscopy cannot be performed, such as patients with prior surgeries and intestinal adhesions (strong recommendation, low level of evidence).

10. VCE should be performed before deep enteroscopy to increase diagnostic yield. Initial deep enteroscopy can be considered in cases of massive hemor-rhage or when VCE is contraindicated (strong recommendation, high level of evidence).

Usage of radiographic examinations

11. Barium studies should not be performed in the evaluation of small bowel bleeding (strong recommendation, high level of evidence).

12. Computed tomographic enterography (CTE) should be performed in patients with suspected small bowel bleeding and negative capsule endoscopybecause of higher sensitivity for the detection of mural-based small bowel masses, superior capability to locate small bowel masses, and ability to guidesubsequent deep enteroscopy (strong recommendation, low level of evidence).

13. CT is preferred over magnetic resonance (MR) imaging for the evaluation of suspected small bowel bleeding. MR can be considered in patients withcontraindications for CT or to avoid radiation exposure in younger patients (conditional recommendation, very low level of evidence).

14. CTE could be considered before VCE in the setting of established inammatory bowel disease, prior radiation therapy, previously small bowel surgery,and/or suspected small bowel stenosis (strong recommendation, very low level of evidence).

15. In patients with suspected small bowel bleeding and negative VCE examination, CTE should be performed if there is high clinical suspicion for a smallbowel source despite performance of a prior standard CT of the abdomen (conditional recommendation, very low level of evidence).

16. In acute overt massive GI bleeding, conventional angiography should be performed emergently for hemodynamically unstable patients (strongrecommendation, low level of evidence).

17. In hemodynamically stable patients with evidence of active bleeding, multiphasic CT (CTA) can be performed to identify the site of bleeding and guidefurther management (strong recommendation, low level of evidence).

18. In patients with acute overt GI bleeding and slower rates of bleeding (0.10.2 ml/min), or uncertainty if actively bleeding, tagged red blood cell scintig-raphy should be performed if deep enteroscopy or VCE are not performed to guide timing of angiography (strong recommendation, moderate level ofevidence).

19. In brisk active overt bleeding, CT angiography (CTA) is preferred over CTE (conditional recommendation, very low level of evidence).

20. Conventional angiography should not be performed as a diagnostic test in patients without overt bleeding (conditional recommendation, very low level ofevidence).

21. Provocative angiography can be considered in the setting of ongoing overt bleeding and negative VCE, deep enteroscopy, and/or CT examination (condi-tional recommendation, very low level of evidence).

22. In younger patients with ongoing overt bleeding and normal testing with capsule endoscopy and enterography examinations, a Meckels scan should beperformed (conditional recommendation, very low level of evidence).

Treatment and outcomes

23. If a source of bleeding is found by VCE and/or deep enteroscopy in the small intestine that is associated with signicant ongoing anemia or active bleed-ing, then the patient should be managed with endoscopic therapy (strong recommendation, low level of evidence).

24. If after appropriate small bowel investigation no source of bleeding is found, the patient should be managed conservatively with oral iron or by intrave-nous infusion as is dictated by the severity and persistence of the associated iron-deciency anemia. In this context, a small vascular lesion found oncapsule endoscopy does not always need treatment (strong recommendation, very low level of evidence).

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Guidelines for Small Bowel Bleeding


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and telangiectasia. Te ull literature search strategy is demon-strated in the Appendix .

o evaluate the level o evidence and strength o recommenda-tions, we used the Grading o Recommendations Assessment,Development, and Evaluation (GRADE) system ( 3). Te level oevidence could range rom high (implying that urther researchwas unlikely to change the authors con dence in the estimate othe effect) to moderate ( urther research would be likely to havean impact on the con dence in the estimate o effect), low ( ur-ther research would be expected to have an important impact on

the con dence in the estimate o the effect and would be likely tochange the estimate), or very low (any estimate o effect is veryuncertain). Te strength o a recommendation was graded asstrong when the desirable effects o an intervention clearly out-weigh the undesirable effects and as conditional when there isuncertainty about the trade-offs. We pre erentially used meta-anal-yses or systematic reviews when available, ollowed by clinical trialsand retrospective cohort studies. o determine the level o evi-dence, we entered data rom the papers o highest evidence into theGRADE program (accessible at http: // www.gradepro.org ). Te rec-ommendation statements rom this guideline are shown in Table 1 .Summary statements, when listed, are designed to be descriptive innature without associated evidence-based ratings.

Denition of overt or occult small bowel bleeding Summary statements 1. A source o small bowel bleeding should be considered in

patients with overt or occult GI hemorrhage afer per or-mance o a normal upper and lower endoscopic examination.

2. Patients should be classi ed as having small bowel bleedingi a source o bleeding is identi ed distal to the ampulla oVater and/or proximal to the ileocecal valve.

3. Afer normal upper and lower endoscopic examinations andbe ore per ormance o capsule endoscopy, patients should beclassi ed as having potential small bowel bleeding.

4. Overt small bowel bleeding re ers to patients presentingwith either melena or hematochezia with a source obleeding identi ed in the small intestine. Te term occultsmall bowel bleeding can be reserved or patients presentingwith iron-de ciency anemia with or without guaiac-positivestools who are ound to have a small bowel source obleeding.

5. Te term obscure GI bleeding should be reserved orpatients not ound to have a source o bleeding afer per or-mance o standard upper and lower endoscopic examina-

tions, small bowel evaluation with VCE and/or enteroscopy,and radiographic testing.

Te traditional de nition o OGIB be ore the introduction oVCE and deep enteroscopy included patients with overt or occultGI bleeding who underwent normal upper and lower endoscopicexaminations in addition to a small bowel series that did notreveal a source o bleeding. Patients with overt obscure bleedingwere de ned as patients presenting with either hematochezia ormelena, whereas patients with occult obscure bleeding were classi-

ed based on the presence o a positive ecal occult blood test withor without iron-de ciency anemia.

With the introduction o VCE in the United States in 2001 anddeep enteroscopy in 2004, the majority (~75%) o patients previ-ously classi ed as having obscure bleeding were ound to havesources o bleeding identi ed in the small intestine ( 4). Te diag-nostic yield included any causes o bleeding detected distal to theampulla o Vater or proximal to the ileocecal valve by any testingmodality including push enteroscopy, ileoscopy, deep enteroscopy,VCE, angiography, or an enterography examination. We wouldthere ore propose that patients with small bowel sources identi edbe classi ed as having small bowel bleeding, reserving the priorterm o OGIB or patients without a source o bleeding identi edafer comprehensive evaluation o the small bowel as described inthe sections below.

Table 1 . Recommendation statements

25. If bleeding persists in either of the above situations with worsening anemia, a further diagnostic workup should include a repeated upper and lowerendoscopy, video capsule examination, deep enteroscopy, CT or MRI enterography as is appropriate for the clinical situation and availability ofinvestigative devices (strong recommendation, low level of evidence).

26. If bleeding persists or recurs or a lesion cannot be localized consideration may be given to medical treatment with iron, somostatin analogs, orantiangiogenic therapy (strong recommendation, moderate level of evidence).

27. Anticoagulation and/or antiplatelet therapy should be discontinued if possible in patients with small bowel hemorrhage (conditional recommendation,very low level of evidence).

28. Surgical intervention in massive small bowel bleeding may be useful, but is greatly aided with presurgical localization of the site of bleeding by markingthe lesion with a tattoo (strong recommendation, low level of evidence).

29. Intraoperative enteroscopy should be available at the time of the surgical procedure to provide assistance to localize the source of bleeding and toperform endoscopic therapy (conditional recommendation, low level of evidence).

30. Patients with Heydes syndrome (aortic stenosis and angioectasia) and ongoing bleeding should undergo aortic valve replacement (conditionalrecommendation, moderate level of evidence).

31. For patients with recurrence of small bowel bleeding, endoscopic management can be considered depending on the patients clinical course andresponse to prior therapy (conditional recommendation, moderate level of evidence).

CTA, CT angiography; CTE, computed tomographic enterography; MRI, magnetic resonance imaging; VCE, video capsule endoscopy.


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Brisk/massive suspectedsmall bowel bleeding

Stabilize patient

Red cell scan or CTangiography

Angiography

Embolization

Positive

Positive

Specific managemententeroscopy vs surgery andintraoperative enteroscopy

Negative

Negative

Unstable

Figure 2 . Algorithm for brisk or massive suspected small bowel bleeding. CT, computed tomography.

Sub-acute ongoingsmall bowel bleeding

Stabilize patient

Consider VCE vs CTE

Proceed to deep endoscopy

Treat accordingly

Consider RBC scan and orangiography or surgery intraoperative endoscopy

Negative

Negative

Positive

Positive

Figure 3 . Algorithm for sub-acute ongoing suspected small bowel bleeding. CTE, computed tomographic enterography; RBC, red blood cell; VCE, videocapsule endoscopy.

Suspected small bowel bleeding

Occult Overt

Repeat endoscopy ifwarranted

CTE/MRE VCE

Further evaluationwarranted

Observation/iron supplements Consider repeat endoscopy/VCE/Meckelsscan/surgeryintraoperative enteroscopy

Possible obstruction No obstruction

Specific management:push or deep enteroscopy

surgery intraoperativeenteroscopy

Negative

PositiveNegative

Positive

YesNo

Negative

Treat accordingly

Positive

NegativeNegativeno obstruction

Proceed with smallbowel evaluation

Figure 1 . Algorithm for suspected small bowel bleeding. CTE, computed tomographic enterography; MRE, magnetic resonance enterography; VCE, videocapsule endoscopy.


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Epidemiology and natural history of small bowel bleeding Summary statements 1. Te type o lesion responsible or small bowel bleeding is

dependent on patient age but not gender or ethnicity.2. Small bowel angioectasia are the most common cause osmall bowel bleeding.

3. Risk actors or angioectasia include advancing age, presenceo aortic stenosis, chronic renal ailure, lef ventricular assistdevices, and other hereditary disorders.

4. Risk actors or recurrent small bowel bleeding rom angi-oectasia include number o lesions, advanced age, presence ocomorbid conditions, and anticoagulant therapy.

Prevalence and etiology of small bowel bleeding . Te prevalenceo small bowel lesions has been estimated to be ~510% in patientspresenting with GI bleeding ( 1,2). Details pertaining to the clinicalpresentation are critically important in the determination o theetiology. A history o a bleeding diathesis as with von Willebranddisease and medication usage including aspirin, nonsteroidalanti-in ammatory drugs, anticoagulants, and/or other antiplate-let agents also can lend clues to the diagnosis. Knowledge o co-morbidities such as valvular heart disease and prior procedures/surgeries such as liver biopsy, liver transplantation, abdominalaortic aneurysm repair, or bowel resection again can be very help-

ul. Common causes o small bowel bleeding are listed in Table2 and are ound in ~75% o patients with suspected small bowelbleeding (5). Based on a 2008 meta-analysis combining data romWestern and Asian countries and reporting yields on both VCE

and double-balloon enteroscopy (DBE) ( 4), the prevalence o smallbowel vascular lesions based on 10 studies was 24% or both VCE(N =371) and DBE (N =364). For in ammatory ndings, the yieldwas 18% or VCE (N =343) and 16% or DBE (N =336), and theyield was 11% or mass lesions (VCE,N =343 and DBE, N =336).An analysis comparing diagnostic yields rom Western comparedto Asian countries demonstrated that patients undergoing DBEin Asian countries were more likely to have neoplastic ndings,whereas angioectasia were more common in Western countries.

Age has been known to be a determinant or the type o smallbowel pathology detected. Patients under the age o 40 years are morelikely to have in ammatory bowel disease or Meckels diverticulum.Small bowel neoplasms (e.g., GI stromal cell tumor, lymphoma,carcinoid, adenocarcinoma, or other polypoid lesions) and Dieu-la oys lesions can occur in both younger and older patient cohorts(611). Angioectasia, other vascular lesions, and ulcers secondaryto anti-in ammatory agents are more likely in patients over theage o 40 years. Data regarding ethnicity and small bowel ndings

has not been extensively published to date.

Differences in ndings between patients with overt or occultsmall bowel bleeding . Studies using VCE and deep enteroscopyhave demonstrated higher diagnostic yields or patients withovert bleeding compared with patients with occult bleeding. Forpatients with prior overt bleeding, the diagnostic yield was lessthan that or current overt bleeders, and decreased substantiallywith time. In a 2004 study by Pennazio et al. (12) o 100 patientsundergoing VCE, the diagnostic yield was 92% or patients withovert bleeding, 44% or occult bleeders, 67% or patients with pri-or overt bleeding who were studied within 1014 days, and 33%

at 34 weeks postbleeding episode. In a 2010 study o 200 patientswith bleeding undergoing DBE, the diagnostic yield was 77% orovert bleeding, 67% or patients with occult hemorrhage, and 59%

or patients with prior overt bleeding ( 13). In addition to higher diagnostic yields or patients with overt

bleeding, recurrence rates may be higher in patients presentingwith overt bleeding. In a multicenter US study assessing long-termoutcomes post-DBE, recurrence o overt bleeding occurred in34% o patients presenting with overt hemorrhage compared with13% o patients with occult bleeding at 12 months postprocedure(P =0.06) (14). Tese recurrence rates, however, were not signi -cant at 30 months o ollow-up (27% vs. 20%,P =NS).

Rare causes and non-small bowel sources of bleeding . Rarecauses o small bowel bleeding are shown in Table 2 . Patientswith disorders associated with portal hypertension and/or withendoscopic evidence o varices or portal hypertension have alsodemonstrated portal hypertensive changes in the small bowel onVCE or enteroscopy studies ( 15). Other rare causes o bleeding

rom the small bowel have included Kaposis sarcoma associatedwith acquired immunode ciency syndrome, PlummerVinsonsyndrome, pseudoxanthoma elasticum, EhlersDanlos syndrome,HenochSchoenlein purpura, neuro bromatosis, malignantatrophic papulosis, and other inherited polyposis syndromes. A

amily history o polyposis syndromes may provide important

Table 2 . Causes of small bowel bleeding

Common causes Rare causes

Under age 40 years Over age 40 years HenochSchoenlein purpura

Inammatory bowel

disease

Angioectasia Small bowel varices and/or

portal hypertensive enteropathyDieulafoys lesions Dieulafoys lesions Amyloidosis

Neoplasia Neoplasia Blue rubber bleb nevussyndrome

Meckels diverticulum NSAID ulcers Pseudoxanthoma elasticum

Polyposis syndromes OslerWeberRendu syndrome

Kaposis sarcoma with AIDS

PlummerVinson syndrome

EhlersDanlos syndrome

Inherited polyposis syndromes(FAP, PeutzJeghers)

Malignant atrophic papulosisHematobilia

Aorto-enteric stula

Hemosuccus entericus

FAP, familial adenomatous polyposis; NSAID, nonsteroidal anti-inammatorydrug.


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clues to the underlying etiology o small bowel bleeding. Physicalexamination, including a detailed dermatological evaluation, mayalso be use ul in the diagnosis o systemic syndromes, includinghereditary hemorrhagic telangiectasia and blue-rubber bleb ne- vus syndrome. Uncommon non-small bowel sources o obscureGI bleeding not shown in the table have included hematobilia,hemosuccus pancreatitis, and aortoenteric stulae.

Prior clinical guidelines have listed celiac disease as a cause osmall bowel bleeding (16), but there is emerging evidence thatceliac disease leads to iron-de ciency anemia because o malab-sorption and not because o the presence o occult GI bleeding(17). Although complications associated with celiac disease such asulcerative jejunitis, lymphoma, and/or adenocarcinoma can causebleeding rom the small intestine, the entity o celiac disease is nolonger listed as a cause o small bowel bleeding.

Diagnosis of small bowel bleeding (Figure 1 ) Recommendations

1. Second-look upper endoscopy should be considered in caseso recurrent hematemesis, melena, or a previously incompleteexam (strong recommendation, low level o evidence).

2. Second-look colonoscopy should be considered in the settingo recurrent hematochezia or i a lower source is suspected(conditional recommendation, very low level o evidence).

3. I the second-look examinations are normal, the next stepshould be a small bowel evaluation (strong recommendation,moderate level o evidence).

4. Push enteroscopy can be per ormed as a second-look exami-nation in the evaluation o suspected small bowel bleeding(conditional recommendation, moderate level o evidence).

5. VCE should be considered a rst-line procedure or smallbowel (SB) evaluation afer upper and lower GI sources havebeen excluded, including second-look endoscopy when indi-cated (strong recommendation, moderate level o evidence).

6. Owing to the lower detection rate o lesions in the duodenumand proximal jejunum with VCE, push enteroscopy shouldbe per ormed i proximal lesions are suspected (strong rec-ommendation, very low level o evidence).

7. otal deep enteroscopy should be attempted i there is astrong suspicion o a small bowel lesion based on clinicalpresentation or abnormal VCE study (strong recommenda-tion, moderate level o evidence).

8. Any method o deep enteroscopy can be used when endoscopicevaluation and therapy is required based on similar diagnosticyields (strong recommendation, high level o evidence).

9. Intraoperative enteroscopy (IOE) is a highly sensitive but invasive diagnostic and effective therapeutic procedure. Its usageshould be limited to scenarios where enteroscopy cannot beper ormed, such as patients with prior surgeries and intestinaladhesions (strong recommendation, low level o evidence).

10. VCE should be per ormed be ore deep enteroscopy toincrease diagnostic yield. Initial deep enteroscopy can beconsidered in cases o massive hemorrhage or when VCEis contraindicated (strong recommendation, high level oevidence).

Te main limitations o SB evaluation in the past were related toits length (>6 m) and limited intubation with conventional endos-copy; these shortcomings have been largely overcome by recentadvances in endoscopic technology, including VCE, deep enter-oscopy (including DBE, SB enteroscopy, and spiral enteroscopy),and radiologic modalities including C enterography (C E) andMR enterography. Tese new advances, as well as the capacity tosuccess ully per orm endoscopic therapeutic interventions, haveled to signi cant improvement in the management o patients withsmall bowel bleeding, and a decline in invasive surgical procedures(IOE, laparoscopy, and exploratory laparotomy) ( 1821).

Second-look endoscopy Most small intestinal bleeding is undramatic in presentation andeither presents as stable overt or occult bleeding. Te prior litera-ture demonstrated that a high percentage o patients designatedas having potential small bowel bleeding were ound to havemissed bleeding sources within reach o conventional upper and

lower endoscopy including diagnostic yields ranging rom 2 to25% in patients undergoing repeat esophagogastroduodenoscopyand 6 to 23% on repeat colonoscopy ( 2224). More recent stud-ies using DBE and capsule endoscopy have also con rmed these

ndings (2530). Most overt bleeding can be evaluated rst with a second-look

procedure to exclude upper and lower bleeding that can be readilyreached with a standard endoscope. Instead o repeating an upperendoscopy, a push enteroscopy may be per ormed to examine thedistal duodenum and proximal jejunum. During the colonoscopy,every effort should be made to intubate the terminal ileum to vis-ualize the ileal mucosa and to inspect or blood coming rom a

more proximal location o the small intestine. For expediency owork up, it is sometimes appropriate to use VCE as the rst-linetest afer having had a negative upper endoscopy and colonoscopy.In act, one study did not show that second-look endoscopy wascost effective (31). However, the distal duodenum and proximal jejunum would still need to be examined unless the VCE revealsthe source o the suspected small bowel bleeding.

Push enteroscopy Push enteroscopy is an extended upper endoscopy per ormedwith a long endoscope such as a pediatric colonoscope ( 32) orwith a commercially available push enteroscope, which is typi-cally 250 cm in length. Push enteroscopy allows only limited eval-uation o the proximal SB, ~70 cm distal to the ligament o reitz.Push enteroscopy using a colonoscope typically can be passed4560 cm beyond the ligament o reitz (33). When push enteros-copy is carried out with the variable stiffness design, it reaches adeeper distance o nearly 90 cm (34). Te diagnostic yield o pushenteroscopy is reported to range rom 3 to 70%, with the major-ity o SB ndings being vascular lesions (16,3538). Interestingly,most o the lesions diagnosed on push enteroscopy have been

ound in locations accessible to standard esophagogastroduoden-oscopy, emphasizing the importance o second-look endoscopy(22,39). When a dedicated push enteroscope is used, it may beper ormed with an overtube designed to reduce looping in the


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improved to 60% i a dual camera capsule is used (63). Nonethe-less, VCE does miss clinically important duodenal and proximal jejunal lesions (6467), and thus cannot be solely relied upon orexclusion o bleeding lesions in these areas. However, there arestudies to suggest that repeat VCE may be o bene t and increasethe diagnostic yield, even when the rst study is negative ( 6870).A prospective study again showed that repeat VCE may be bene -cial, particularly when the bleeding changes rom occult to overt orthere is a hemoglobin drop 4 g/dl ( 71).

VCE is very well tolerated by patients (72). Its main complicationis capsule retention, which may occur in roughly 1.5% o patientsundergoing evaluations or potential small bowel bleeding sources(73). VCE, however, may be complicated by retention in up to 13%in Crohns disease patients, which limits its use in patients withsuspected obstruction or strictures until patency is documented(74,75). Screening SB radiographs have not been able to eliminatethis problem, although the patency capsule may be use ul ( 76).Te most serious complication reported with VCE is per oration,

which ortunately has been exceedingly rare ( 77).

Deep enteroscopy Balloon-assisted enteroscopy . Balloon-assisted enteroscopy usesthe principle o push and pull enteroscopy, and includes DBE andSBE as described urther below (78). As the name suggests, botho the balloon enteroscopes have an overtube, with balloons attheir distal ends. Te DBE uses a balloon on the end o the scopeand the overtube. Te SBE works by using the tip o the scopeas an anchor along with the single balloon. Te balloons on theDBE and overtube are composed o latex, whereas the balloon onthe SBE overtube is made o silicone. Tere ore, or patients with

latex allergy, SBE should be per ormed. Te enteroscope in bothsystems has a working length o 200 cm with an outer diameter o9.4 mm. Te overtube is 140 cm in length.

Te technique o balloon-assisted enteroscopy involves a serieso steps called advancement cycles, described below. Balloon-assisted enteroscopy can be per ormed via the oral and rectalapproach. It has been mainly studied in adults between the ageso 18 and 70 years but appears to be sa e in the elderly population(over 70 years in age), as well as in children ( 79,80).

Double-balloon enteroscopy DBE was rst described in 2001 by Yamamoto et al. (81). Teequipment has been available or clinical use in the United Statessince 2004. DBE allows deeper intubation o the SB comparedwith tradtional endoscopes. It can be advanced a distance o~240360 cm distal to the pylorus with the oral approach and102140 cm proximal to the ileocecal valve with the rectalapproach. Tis compares to a distance o 90150 cm with thepush enteroscope and 5080 cm with ileoscopy ( 51,82). It has theadditional advantage over VCE o both diagnostic and therapeu-tic capabilities, including biopsies, tattoo, hemostasis, polypec-tomy, dilation, and oreign body removal (including retainedcapsules) (8385). Te 2.8 mm accessory channel allows passageo virtually all standard-caliber, through-the-scope, diagnosticand therapeutic instruments ( 86).

stomach and stiffen the enteroscope or deeper passage ( 40).Although the use o an overtube may allow or deeper SB intuba-tion up to 150 cm, it does not appear to increase the diagnosticyield o the test (41). Te main disadvantages o this exam includelooping o the enteroscope and patient discom ort. Its role is cur-rently limited to endoscopic therapeutics in those patients whohave only proximal SB lesions detected on VCE. Although it hasonly a limited range, push enteroscopy is an ideal second-lookprocedure because o the ability to examine the distal duodenumand proximal jejunum, a SB segment that is not always well seenwith VCE.

Endoscopic visualization of the small intestine Video capsule endoscopy . Introduced or clinical use in the UnitedStates in 2001, VCE is now available throughout the world. Tereare now our VCE plat orms, with three available or clinical usein the United States. Te VCE measures 2611 mm 2 , and has thecapacity to take images at the rate o 2 rames/s, over an 812 h

period. Images are transmitted to a recording device, and can bedownloaded and viewed on a computer station with the appro-priate sofware. Capsule endoscopy allows noninvasive evaluationo the entire SB in 7990% o patients, with a diagnostic yield o3883% in patients with suspected small bowel bleeding ( 42). Temain utility o this test lies in its high positive (9497%) and nega-tive predictive value (83100%) in the evaluation o GI bleeding(12,43). Findings on VCE leading to endoscopic or surgical intervention or a change in medical management have been reportedin 3787% o patients (12,44). In addition, 5066% o patientshave been reported to remain trans usion ree without recurrentbleed at ollow-up, afer undergoing VCE-directed interventions

(43,45). Te rebleeding rate ranges rom 6 to 27% in patients whohave had a negative capsule study ( 4648). Te yield o VCE may be in uenced by multiple actors, with

a higher likelihood o positive ndings in patients with a hemo-globin 6 months), morethan one episode o bleeding, overt as compared with occult bleed-ing (60% vs. 46%), and per ormance o VCE within 2 weeks o thebleeding episode (91% vs. 34%) (4952). Tere is also evidencethat VCE within 48 to 72 h o overt suspected small bowel bleedinghas the greatest yield or lesion detection (5355). A more recentstudy con rmed that overt bleeding was the strongest predictoro a positive capsule study, but male sex, age >60 years, and in-patient status were also independent predictors ( 56). Other risk

actors or a positive capsule include cardiac and renal comorbidi-ties. Although usually per ormed or intermittent overt bleeding,at least one study suggests that it may be use ul in the emergencysituation o severe overt suspected small bowel hemorrhage ( 57).

Te main limitations o VCE include lack o therapeutic capa-bilities, inability to control its movement through the GI tract, andthe diffi culty in localizing the lesion. Te other limitations o VCEinclude a lack o speci city with 14% incidental ndings in healthy volunteers ( 58) and a 1036% alse-negative rate (59,60). Finally,VCE ails to identi y the major papilla in a majority o cases (61,62)and there ore may miss important duodenal lesions because orapid transit through the duodenal loop. Tis de ciency may be


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o per orm DBE, the enteroscope and overtube are introducedinto the small bowel typically past the ampulla, and the balloon onthe overtube is in ated. Te enteroscope is then urther advancedinto the small bowel. Te balloon on the DBE enteroscope is thenin ated. Te overtube is subsequently advanced over the entero-scope. Now both overtube and enteroscope are drawn back (withboth balloons in ated on DBE), which allows the small bowel toplicate over the enteroscope. By repeating this series o steps, alonger distance can be traversed as compared with conventionalendoscopy.

Te diagnostic yield o DBE ranges rom 60 to 80% in patientswith suspected small bowel bleeding and other SB disorders. Suc-cess ul per ormance o endoscopic therapeutic interventions hasbeen reported in 4073% o patients (51,87,88). A more recentstudy con rms these earlier ndings ( 89). DBE has generally beenused or small bowel evaluation in the chronic stable or mildlyto moderately active bleeding situation because o its small suc-tion channel. However, a small recent study actually suggests that

emergency DBE is technically easible and may acilitate the diag-nosis and management o patients with massive overt small bowelhemorrhage ( 90). A more recent study also suggests that urgentDBE is better than non-urgent DBE and is associated with a lowerrecurrent bleeding rate ( 91). In addition, one study suggests thatrepeat DBE rom the same direction may also be bene cial, par-ticularly i the patient had a prior positive DBE ( 92).

otal enteroscopy with DBE is de ned as complete evaluationo the small bowel either with a single approach or combined oraland rectal approach. Te decision to per orm total enteroscopy isusually dependent on the discretion o the endoscopist, degree oclinical suspicion or a small bowel lesion, and inability to detect

the lesion using a single approach. Despite the best attempts o theendoscopist, total enteroscopy may not be easible in all patients,with a reported success rate ranging rom 16 to 86% ( 81,93). Aprospective, randomized study demonstrated that DBE had a sig-ni cantly higher total enteroscopy rate than SBE ( 94).

Te main limitations o DBE include its invasive nature, pro-longed procedure time, and requirement or additional personnel.Te reported complication rate or diagnostic procedures is 0.8%,and up to 4% i therapeutics such as electrocoagulation, polypec-tomy, or dilation are per ormed. Te main complications reportedwith this technique are ileus, pancreatitis, and per oration, usu-ally associated with large polypectomies ( 51,84,95). Pancreatitisis the most common complication o the peroral diagnostic DBE,occurring in at least 0.3% o patients (95). Per oration appearsto be more common in patients with intestinal anastomosis andSB polypectomy (96,97). Postprocedure bloating and abdominalpain were once a common occurrence, but they have been rarelyreported by patients as the use o carbon dioxide as the insuffl at-ing gas because o rapid diffusion o the gas across the intestinalmucosa (98,99). A recent large prospective database suggested anoverall complication rate o 1.2% (100).

Single-balloon enteroscopy wo years afer the launch o the commercially available double-balloon system, SBE was introduced. Te theory and technique

o SBE are very similar to that o DBE; the key difference beingthat there is no balloon on the end o the enteroscope with SBE.During the reduction maneuver with SBE, the overtube balloon isin ated and the distal end o the enteroscope hooked over a oldas the SBE does not have a distal balloon.

Even the dimensions o the enteroscope and the overtubes are virtually identical to those o DBE. Te overtube balloon is madeo a silicone material rather than latex. SBEs have a stiff shaf andthe enteroscope can be easily removed and reinserted through theovertube. Its caliber is similar to that o a standard upper endo-scope but with more than twice its length (200 cm). Hence, mostendoscopic diagnostic and therapeutic maneuvers are possible toper orm with the SBEs.

A preliminary report o 78 SBE procedures per ormed in 41patients, o whom 12 had small bowel bleeding, ound that SBEallowed evaluation o the SB in a sa e and effective manner, includ-ing per ormance o total enteroscopy (25%; 6/24). Te diagnos-tic yield in patients with suspected small bowel bleeding sources

was 33% (4/12 patients), and therapeutics such as argon plasmacoagulation could be success ully per ormed (20). Another studyevaluated 20 patients with suspected SB disorders, and ound adiagnostic yield o 60% using SBE (101). More recent studies have

ound diagnostic yields between 65 and 74% (102104). SBE alsoappears to be associated with improved outcomes ( 105). A pro-spective study on 105 patients who underwent at least one oralSBE procedure ound no complications related to the diagnosticprocedures ( 106). One per oration occurred afer stricture dila-tion. Prospective, sequential amylase testing be ore and afer SBEshowed 16% o patients developed elevation o serum amylase butwithout any overt clinical evidence o acute pancreatitis. At this

time, it appears that SBE is equivalent to DBE or the evaluation osmall bowel bleeding sources (107,108).

Spiral enteroscopy Spiral enteroscopy consists o a unique overtube with an outerraised spiral ridge at its distal end through which an SBE or a DBEcan be inserted. It is used or enteroscopy via the oral route andcan be used only with enteroscopes


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recommended as the third test o choice in patients with suspect-ed small bowel bleeding, who have had a negative esophagogas-troduodenoscopy and colonoscopy.

DBE compared with push enteroscopy and VCE . A study by Mayet al. (85), which compared DBE to push enteroscopy in 52 pa-tients with suspected small bowel bleeding, ound that DBE notonly allowed a greater depth o intubation (230 vs. 80 cm) but alsohad a higher yield or small bowel ndings (73% vs. 44%). Fur-thermore, DBE acilitated detection o additional lesions in thedistal small bowel in patients who had positive ndings on pushenteroscopy.

Several studies have compared the yield o VCE with DBE, buthave shown inconsistent results because o their small sample size.A meta-analysis o 11 studies that compared these modalities inpatients with SB disease (majority with suspected small bowelbleeding) showed a comparable diagnostic yield (60% vs. 57%;incremental yield o 3%) or all SB ndings. Te yield with the tests

was also similar or vascular, in ammatory, and neoplastic lesions(4). Another meta-analysis o eight studies also ound no differencein diagnostic yield between the two tests or the evaluation o SBdisease (odds ratio 1.21, 95% con dence interval (CI): 0.642.29)).In patients with small bowel bleeding, VCE had a higher yield ascompared with DBE using a single approach (odds ratio 1.61, 95%CI: 1.072.43), but a signi cantly lower yield as compared withDBE using a combined antegrade and retrograde approach (oddsratio 0.12, 95% CI: 0.030.52) (133). Tis nding rein orces theimportance o total enteroscopy with DBE in patients with highclinical suspicion or an SB lesion. Another meta-analysis similarlyshowed comparable diagnostic yields, and also suggested that the

diagnostic yield improves i per ormed in patients with a positivecapsule study (134). wo more recent meta-analyses again con rmthe similarity in diagnostic yields between VCE and DBE ( 89,135).

VCE has been reported to be use ul as a screening tool be oreDBE in patients with suspected small bowel bleeding. Tis approacho a targeted DBE has been reported to increase both the diag-nostic (7393%) and therapeutic yield (5773%) o the test ( 136).Furthermore, VCE transit times have been ound use ul in guidingthe optimal route o DBE. Owing to deeper intubation o the smallbowel and a higher success rate with the oral approach, this is thepre erred route or lesions suspected to lie within the proximal 75%o the small bowel, whereas the rectal route is used or more distallesions. Because o the high negative predictive value o VCE, theapproach o VCE-guided DBE allows avoidance o DBE in patientswith a low pretest probability or SB ndings (137139).

However, the concept o CE-guided DBE may not be applicablein all patients. VCE has a alse-negative rate o 11% or all SB nd-ings, and more importantly, up to 19% or neoplasms. Additional

ndings on repeat VCE have been detected in up to 75% o patientswith suspected small bowel bleeding, thereby leading to a changein management in 62% ( 69). Tere have also been reports o neo-plasms missed on VCE and subsequently diagnosed at DBE ( 140).Hence, in patients with a negative VCE, in whom there is a highclinical suspicion or an SB lesion, DBE should still be pursued,including consideration or total enteroscopy ( 4).

yield o the initial cases o spiral enteroscopy has been reportedto be only 33% (122). Since that time, a more recent prospectivestudy suggested that the diagnostic yield in patients with a positivecapsule study was 57% (119). Furthermore, a prospective cohortstudy also ound that spiral enteroscopy leads to improved out-comes in terms o trans usion requirements, iron supplementa-tion, and additional therapeutic procedures ( 123). Tere is also anovertube or a rectal approach that can be used or limited ileos-copy. Questions have been raised about some sa ety concerns withregards to bowel trauma and diffi culty in rapid removal duringan emergency. However, there had been no major complicationreported in the early literature ( 120). In a series o 75 patients, 12%o had a sore throat, 27% had super cial mucosal trauma, and 7%had moderate esophageal trauma that did not require any intervention. In a retrospective registry study involving 1750 patients,the rate o severe complications was reported to be 0.34%, with asmall bowel per oration rate o 0.27% (118). In the rst 850 casesreported in the literature with spiral enteroscopy, there were no

serious complications ( 124).

Intraoperative enteroscopy IOE involves evaluation o the SB at laparotomy, and may beper ormed orally, rectally, or via an enterotomy, wherein thescope is inserted through a surgical incision in the SB ( 125).Upper endoscopes, colonoscopes, push enteroscopes, and thenewer balloon-assisted scopes have all been used in IOE. Tismay be the most reliable method to achieve a complete smallbowel evaluation but it is highly invasive. Although the diagnos-tic yield o IOE has been reported to range rom 58 to 88% (126),rebleeding may occur in up to 60% o patients ( 127130). Major

complications o IOE include serosal tears, avulsion o mesen-teric vessels, and prolonged ileus ( 130). In addition, the proce-dure has a high mortality rate o 17%. Owing to these reasons,IOE should be reserved only or those patients who present withrecurrent bleeds requiring multiple trans usions or hospitaliza-tions afer a comprehensive negative evaluation with VCE anddeep enteroscopy or or patients in whom deep enteroscopycannot be per ormed without lysis o adhesions (131).

Comparison of endoscopic modalities in suspected smallbowel bleeding Capsule endoscopy compared with push enteroscopy and smallbowel follow-through . Multiple retrospective and prospectivestudies have ound VCE to be superior to both push enteroscopyand small bowel series in the evaluation o patients with suspectedsmall bowel bleeding. A meta-analysis o studies that comparedVCE and push enteroscopy showed that VCE had an incrementalyield o 30% (yield 56% vs. 26%) or clinically signi cant ndingsin patients with small bowel bleeding sources. Similarly, VCE hadan incremental yield o 36% over small bowel series (yield 42% vs. 6%) (132). Te number needed to test with VCE was three,to establish one additional diagnosis. Based on subanalysis o thedata, VCE had a higher yield or both vascular and in ammatorylesions. VCE has hence largely replaced push enteroscopy andsmall bowel series in the evaluation o the SB, and is currently


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Te indications or DBE in patients with suspected smallbowel bleeding is broad, and include patients who have a posi-tive VCE, both or tissue diagnosis and therapeutics; patients inwhom VCE is contraindicated; patients with a negative VCE, buthigh clinical suspicion or SB lesion; and in patients with activebleeding.

Spiral enteroscopy compared with DBE . In a small prospective,cross-over, single-center trial comparing oral DBE to spiral en-teroscopy in patients with suspected small bowel vascular mal-

ormations, the mean insertion time was signi cantly quicker orspiral enteroscopy (43 vs. 65 min; P =0.007). However, more im-portantly, the depth o insertion was signi cantly greater or DBE(310 vs. 250 cm; P =0.004) (141). A more recent prospective study

ound them to be similar in terms o insertion time and distance,as well as o diagnostic and therapeutic yield (142).

Cost-effectiveness analysis . A cost-effectiveness analysis that

compared various diagnostic modalities (push enteroscopy, DBE,VCE-guided DBE, angiography, and IOE) ound that DBE wasnot only the most cost-effective approach in the evaluation oovert small bowel bleeding but also had the highest success rate

or bleeding cessation. However, the investigators concluded thatVCE-guided DBE may be associated with better long-term out-comes as compared with the initial DBE approach, because odecreased risk or complications and appropriate utilization oendoscopic resources ( 143).

Diagnosis using radiographic techniques

Recommendations 1. Barium studies should not be per ormed in the evaluation

o small bowel bleeding (strong recommendation, high levelevidence).

2. C E should be per ormed in patients with suspected smallbowel bleeding and negative capsule endoscopy because ohigher sensitivity or the detection o mural-based smallbowel masses, superior capability to locate small bowelmasses, and ability to guide subsequent deep enteroscopy.(strong recommendation, low level o evidence).

3. C is pre erred over MR imaging or the evaluation osuspected small bowel bleeding. MR can be considered inpatients with contraindications or C or to avoid radiationexposure in younger patients (conditional recommendation, very low level o evidence).

4. C E could be considered be ore VCE in the setting o estab-lished in ammatory bowel disease, prior radiation therapy,previous small bowel surgery, and/or suspected small bowelstenosis (strong recommendation, very low level o evi-dence).

5. In patients with suspected small bowel bleeding and negativeVCE examination, C E should be per ormed i there is highclinical suspicion or a small bowel source despite the per or-mance o a prior standard C o the abdomen (conditionalrecommendation, very low level o evidence).

Usage of abdominal imaging . As mentioned previously,barium examinations o the small bowel have had low yields(317%) or detecting abnormalities in the setting o suspectedsmall bowel bleeding (132,144146), and there ore are notrecommended in the evaluation o patients with suspected smallbowel bleeding.

Cross-sectional imaging techniques optimized or imaging thesmall bowel have a larger role in small bowel imaging and haveshown improved per ormance over routine C ( 147). Advantageso these techniques include the ability to see all bowel loops withoutsuperimposition and the visualization o extraluminal structures(148,149). Imaging can be per ormed using either enterographytechnique, which requires ingestion o large volumes o contrastmedium, or enteroclysis with direct administration o enteric uidby a nasoenteric tube. Enteroclysis provides superior small boweldistension; however, it is not as well tolerated or widely used ( 150).Te uid administered should be a neutral contrast or near waterdensity to improve detection o hyperenhancing abnormalities

or bleeding. Tese optimized small bowel techniques can be per-ormed using C or MR. C is more widely used in the setting

o GI bleeding because o the superior temporal and spatial reso-lution compared with MR and is more widely available. Imagesobtained during multiple phases o enhancement likely improvesdetection and characterization o the site and cause o GI bleed-ing (151156). Overt bleeding can be detected using multiphasicC without enterography technique (C angiography (C A)).Patients with overt bleeding may not be able to drink oral contrastor may be hemodynamically unstable. In addition, the oral con-trast may dilute the contrast extravasation and make subtle activebleeding more diffi cult to detect. In stable patients with suspected

small bowel bleeding, enterography with enteric contrast improvesdetection o intraluminal masses, which may be the cause obleeding.

Multiple studies have demonstrated that the yields or imagingtechniques are higher in the setting o overt bleeding comparedwith patients with occult bleeding ( 151,156159).

CT enterography . In a meta-analysis o 18 studies, C E had apooled yield o 40% compared with 53% or VCE (160). Otherstudies have shown similar yields or C E (151,156,158,159).

Several studies have shown that VCE has higher yields ordetecting vascular and in ammatory lesion compared with C E(144,160,161). However, some studies have shown that C E candetect vascular and in ammatory abnormalities, which may bemissed on VCE (154). Te detection o subtle vascular abnormali-ties at C E may be in uenced by technique and experience.

An advantage o C E over VCE is the improved detection osmall bowel masses, especially those that are mural-based. Ina study by Huprich et al. (154), C E detected 9/9 small boweltumors, whereas VCE only detected 3/9 o the lesions.

Tere ore, C E and VCE are complementary examinations. Ina study o 30 patients with negative C E, subsequent VCE waspositive in 57% (161). In another study o 52 patients with non-diagnostic VCE, subsequent C E had a 50% positive yield in thosepatients with overt small bowel bleeding ( 151). Because o the


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small number o studies regarding MR enterography ( 150,162),this exam is not routinely recommended in lieu o C E, but canbe considered in patients aged


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Scintigraphy 99m c-labeled RBC scintigraphy has been used in the evalua-tion o overt acute GI bleeding or many years. Advantages oscintigraphy include the ability to detect lower rates obleeding and the ability to per orm delayed imaging that canimprove detection o intermittent or delayed bleeding ( 171).Detection o bleeding at angiography may be enhanced bytiming the angiogram to evidence o active bleeding at scintig-raphy. Tere ore, the examination must be closely monitored sothat the patient can be taken quickly to angiography. Limitationso scintigraphy include the reported variability in localizationo bleeding, which may be more diffi cult in the oregut andsmall bowel (172), and the inability to characterize the source obleeding.

Tere is a wide range o reported sensitivities (3393%), speci-city (3095%), diagnostic yields (2687%), and localization

accuracy (19100%) or scintigraphy throughout the GI tract(164,171180). Because bleeding is intermittent, scintigraphy may

be help ul in identi ying the site o bleeding when other diagnostictests have been negative ( 180182).

Negative scintigraphy may also be an indicator o better out-comes (175). In some studies, many o the patients with negativescans may stop bleeding spontaneously and need no urther treat-ment, whereas those with positive scans may need intervention(175,176).

Because o the large variations in the reported diagnostic yield,sensitivity, accuracy in localization, and correlation o outcomescombined with the inability to characterize the source o bleed-ing, there is considerable controversy on the use o scintigraphy oracute overt GI bleeding ( 183).

In younger patients with ongoing overt bleeding and negativeevaluation with VCE, C E, or other testing modalities, consid-eration should be made or testing with a 99m c-pertechnetatescan or detection o Meckels diverticulum (184). Ectopic gastricmucosa can be seen in 1060% o Meckels diverticulae (172,185).Te results o 99m c-labeled pertechnitate scans can be varied andare dependent on the quantity and unctional quality o the het-erotopic gastric mucosa ( 186). Te diagnostic yields rom thesescans appear to be highest when per ormed in children. Sensi-tivities have ranged rom 50 to 90% with speci cities rom 9 to95% (172,185187). Tere are several alse positives that occurrelated to uptake in ulcers, in ammatory lesion, arteriovenousmal ormations, obstruction, intussusceptions, and ectopic gastricmucosa in other lesions such as duplication cysts ( 172,185). Falsenegatives can occur with anatomic or physiologic cause or otherin ammation such as ectopic pancreatic mucosa, which can bepresent in up to 74% o diverticula (186).

Angiography As with scintigraphy, conventional angiography has been used ormany years in patients with active GI bleeding, especially in thosewho may be more hemodynamically unstable. An advantage oangiography is the ability to per orm therapeutic interventionwith transarterial embolization at the time o diagnosis and angi-ography is not hampered by impaired visualization o the source

by intraluminal blood. Limitations o angiography include theneed or higher rates o bleeding (0.51.0 ml/min) or detectionand the risk o complications (including renal ailure, thrombo-embolic events, and more commonly in ections or bleeding at thecatheter site) that can occur in up to 10% ( 183,188). Data rommultiple studies assessing results throughout the GI tract showyields or angiography in the range o 2077% with a mean near50% (181,182,189191).

Predictors o positive angiography include hemodynamic insta-bility, particularly in those who require trans usion o 5 U toachieve hemodynamic stability ( 191). A positive yield was shownto increase to 87% with more massive GI bleeding. Angiographicyields are highest when the patient is actively bleeding with mini-mal delay rom presentation (192).

Patients with a negative tagged RBC scan implying a slow bleed-ing rate or a negative C angiogram are unlikely to have a positiveconventional angiogram ( 166). In patients with a positive C angi-ogram, those with non-diverticular etiologies and lower hemo-

globin were more likely to have a subsequent positive conventionalangiogram ( 170).

For small vascular abnormalities that require surgical interven-tion, placement o a catheter in the vessel supplying the vascularabnormality and dye staining can assist with intraoperative locali-zation.

Previously, provocative angiography using hemodilutionagents, vasodilators, anticoagulants, and thrombolytics hasbeen per ormed in cases o GI bleeding with normalconventional angiography with good results and low com-plications rates ( 193). However, because o varied results inclinical practice and newer sensitive techniques, provocative

angiography is rarely used today. Provocative angiography maybe considered when all other diagnostic techniques have beenunrevealing.

Treatment with angiography Troughout the years, catheter-based intervention has shownsigni cant advances with transition rom vasopressin in usion tosuperselective transarterial embolization, resulting in improvedresults and decreased complications. In 15 studies rom 1992 to2006, consisting o 309 patients and using superselective trans-arterial embolization, there was an 82% success rate, 95% overallclinical success rate, 76% 30-day success rate, and rebleed rate o12% (194). However, the majority o these cases were per ormed

or bleeding sources outside o the small bowel. In a recent retrospective study o 70 patients, Hongsakul

et al. (195) had a 99% technical success rate, 71% primaryclinical success rate, and 79% secondary clinical success rateafer repeat embolization. Bowel in arction was seen in 4%,with the majority o the cases involving bleeding sources out-side o the small bowel. Predictors o ailure to achieve 30-dayhemostasis include hemoglobin


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in 48% o patients and allowed embolization in 45%. Embolizationachieved clinical success in 76% o patients but repeat embolizationwas associated with a high rate o complications. Te overall mortal-ity was 7%, with our deaths because o rebleeding and two deathsbecause o a medical comorbidity (190).

Treatment and outcomes Recommendations 1. I a source o bleeding is ound by VCE and/or deep enteros-

copy in the small intestine that is associated with signi cantongoing anemia or active bleeding, then the patient shouldbe managed with endoscopic therapy (strong recommenda-tion, low level o evidence).

2. I afer appropriate small bowel investigation no source obleeding is ound, the patient should be managed conserva-tively with oral iron or by intravenous in usion as is dictatedby the severity and persistence o the associated iron-de ciency anemia. In this context, a small vascular lesion

ound on capsule endoscopy does not always need treatment(strong recommendation, very low level evidence).

3. I bleeding persists in either o the above situations withworsening anemia, a urther diagnostic workup shouldinclude a repeated upper and lower endoscopy, VCE, deepenteroscopy, C , or MRI enterography as is appropriate orthe clinical situation and availability o investigative devices(strong recommendation, low level evidence).

4. I bleeding persists or recurs or a lesion cannot belocalized consideration may be given to medical treatmentwith iron, somostatin analogs, or antiangiogenic therapy(strong recommendation, moderate level evidence).

5. Anticoagulation and/or antiplatelet therapy should bediscontinued i possible in patients with small bowelhemorrhage (conditional recommendation, very low levelevidence).

6. Surgical intervention in massive small bowel bleeding maybe use ul, but is greatly aided with presurgical localization othe bleeding site by marking the lesion with a tattoo (strongrecommendation, low level evidence).

7. IOE should be available at the time o the surgical procedureto provide assistance to localize the source o bleeding and toper orm endoscopic therapy (conditional recommendation,low level o evidence).

8. Patients with Heydes syndrome (aortic stenosis and angi-oectasia) and ongoing bleeding should undergo aortic valvereplacement (conditional recommendation, moderate level oevidence).

9. For patients with recurrence o small bowel bleeding,endoscopic management can be considered depending onthe patients clinical course and response to prior therapy(conditional recommendation, moderate level o evidence).

Tis section will ocus primarily on the treatment o vascularabnormalities in the small intestine. Te treatment o bleeding

rom Crohns disease, polyposis syndromes, and small intestinalneoplasms is beyond the scope o this guideline.

Treatment of small bowel vascular lesions Evidence rom randomized controlled clinical trials as to how bestto treat small bowel bleeding has been very limited. Data rom theprecapsule era on angioectasias ound in the stomach and colondemonstrated that non-bleeding lesions were not treated, whereasthose actively bleeding were treated endoscopically ( 196). Angi-oectasias in the stomach and colon may be markers or smallbowel angioectasia. Despite endoscopic therapy, the recurrencerate afer treatment o vascular lesions has ranged rom 20 tonearly 50%.

Endoscopic therapy Data regarding effi cacy o endoscopic therapy or small bowel vas-cular lesions were limited to studies using push enteroscopy andsurgical intervention be ore 2001. Despite ongoing usage o pushenteroscopy with heater probe therapy ( 197,198) and introduc-tion o deep enteroscopy afer 2004, rebleeding rates rom vascu-lar lesions have not declined signi cantly. In the era be ore deep

enteroscopy, most angioectasia in the stomach and/or colon weretreated with tools including monopolar and bipolar probes thatprovided electrocoagulation, or neodymium yttrium-aluminum-Garnet laser that provided tissue coagulation. Since 2001, argonplasma coagulation has been primarily used as the treatment ochoice.

As a general statement, the outcomes associated with treatmento small bowel sources o bleeding have been disappointing andthere has been a paucity o data regarding outcomes afer treat-ment o small bowel angioectasia. o date, there have not been anypublished trials comparing endoscopic therapy o angioectasiacompared with sham therapy or trials where only actively bleed-

ing lesions or lesions o a certain size are treated compared withtherapy or all visualized lesions. Given these limitations, recur-rence o bleeding has been used as a surrogate as to the effective-ness o treatment. Even this strategy is limited because we knowlittle o whether there are subsets o vascular lesions in the smallintestine that do bene t rom therapy. wo randomized controlledstudies demonstrated lack o bene t o either intervention, VCE vs. radiology (199), or by hormonal therapy ( 200) compared withplacebo. Te placebo arm in both studies demonstrated the naturalhistory o bleeding rom angioectasia. In the radiology study vs.VCE, the rebleeding rate was 30% in those studied by capsule vs.24% investigated by radiology, a nonsigni cant difference. Simi-larly, the rebleeding rate in the study using hormonal therapy vs.placebo showed a nonsigni cant 7% difference afer a mean o 412days o ollow-up.

Tere have been several studies looking at the recurrence obleeding afer endoscopic treatment o vascular lesions in the smallintestine as a measure o its effectiveness. Te most recent was o aretrospective cohort study carried out at a French tertiary-re erralcenter between January 2004 and December 2007. O 261 patientswho presented with suspected small bowel bleeding, 129 o 133(97%) patients with small bowel vascular lesions were success ullytreated with argon plasma coagulation (using DBE). At 36 months,rebleeding occurred in 45/98 (46%) patients ( 201). A second studyinvolved 274 patients who had undergone DBE at two different


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centers between 2004 and 2006 ( 14). At 12 months, 43% o 101patients reported no urther overt bleeding, 23% reported recur-rent overt bleeding, and 35% reported ongoing iron and/or trans u-sion requirements. O the 85 patients who were interviewed at at amean o 30 months, 50 (59%) reported no overt bleeding or iron/trans usion needs, 20 (24%) reported urther overt bleeding, and15 (18%) reported ongoing iron and trans usion requirements. Arecent meta-analysis o 14 studies including 623 subjects with smallbowel angioectasia treated with endoscopic therapy demonstrateda pooled rebleeding rate o 34% (95% CI: 2742%) afer a mean o2213 months. Tis rebleeding rate increased to 45% when the 341patients with small bowel angioectasia were analyzed ( 202).

Risk actors or recurrent bleeding rom small bowel angioectasiahave included the number o vascular lesions ( 13,201,203), ageover 65 years (204,205), presence o lesions in the jejunum ( 205),presence o cardiac valvular disease (65,201), chronic renal disease(65,204,206), usage o anticoagulant medication ( 47), and need ortrans usion.

Heydes syndrome is a controversial association betweenthe presence o aortic stenosis and angioectasia, thought tobe secondary to an acquired type 2 von Willebrand de ciency(207,208). In support o this relationship is the act that somepatients with aortic stenosis have demonstrated resolution o GIBafer aortic valve replacement ( 202). Patients with lef ventricularassist devices have also been demonstrated to be at risk or angi-oectasia and recurrent bleeding, again secondary to an acquired von-Willebrand de ciency syndrome ( 209). Pilot studies havedemonstrated that decreased levels o von Willebrand actor arepredictive o recurrent bleeding rom small bowel angioectasia inpatients with lef ventricular assist devices ( 210).

Medical treatment of small bowel bleeding Supportive care with iron given orally or intravenously is a main-stay o treatment or mild small intestinal bleeding (211). Tis notonly helps maintain an adequate level o hemoglobin, but in moresevere cases help reduce the requency o trans usion. In moresevere bleeding, trans usion o packed RBCs is an essential ele-ment o treatment, particularly when mechanistic and medicalmethods ail.

Although anticoagulation has been associated with an increasedrisk o recurrent bleeding (47), there is no prospective data show-ing that withdrawal o anticoagulation therapy is bene cial. In a2009 assessing 162 patients with small bowel bleeding, risk ac-tors or recurrent bleeding afer DBE included the presence osmall bowel vascular disorders and comorbid conditions, but notthe usage o anticoagulants or antiplatelet therapy ( 65). Another

ollow-up study in 2010 demonstrated that trans usional require-ments, number, and type o vascular lesions were predictors orrecurrent bleeding, but not anticoagulant usage ( 212). Tere isno data that cessation o antiplatelet therapy reduces the risk orrecurrent bleeding.

Speci c medical treatment or small bowel bleeding is poorlydeveloped. Hormonal therapy has not been shown to be help-

ul. Talidomide and octreotide have been shown to have somebene t.

Hormonal therapy Tere have been several trials o hormonal therapy, all in thepre-capsule era. Tus, the precise nature o what was treatedwas largely unknown with respect to the small intestine. Teproposed mechanism o action or these agents included short-ening o the bleeding time contributing to an effect on hemo-stasis (213). However, other studies suggested that these agentsmay instead increase plasma brinolysis and lead to recurrentbleeding (214). A prospective randomized double-blind placebo-controlled crossover study per ormed in Belgium in 1990 cre-ated enthusiasm or hormonal treatment. Tis was a small studywith 10 patients; it demonstrated a 78% reduction in trans usionin the patients treated with ethinyl estradiol 50 g and nore-thisterone 1 mg daily or 6 months compared with those treatedwith placebo. Only one patient on the drug required trans usioncompared with all on the placebo. Te majority o patients hadchronic renal ailure or von Willebrands disease ( 215), actorsthat may not be representative o typical angioectasia patients. A

multicenter double-blind randomized study, in Spain, o the useo hormonal therapy vs. placebo in patients with GI angioectasia,showed no bene t afer a year o treatment. Te hormonal therapyused was ethinyl estradiol 0.01 mg plus norethisterone 2.0 mg orplacebo daily or at least 1 year. Tere were 35 patients in the pla-cebo group and 33 in the treatment group. Failure rates or thetreatment and placebo groups were 39% and 46%, respectively,a nonsigni cant difference ( 200,216). Tere was no difference inthe number o bleeding episodes or trans usion requirements overa mean period o 412255 days (range 13 years). Serious adverseevent occurred in both groupsone pulmonary thromboembolicevent in each group. One patient died o an ischemic stroke in the

placebo group and there was one stroke in the treatment group.One-third o the women in the treatment group had menorrhagiain response to the hormonal treatment.

In an earlier study by Lewis et al. (217), 30 o 64 patients withsmall bowel angioectasia received 510 mg o norethynodrel eitherwith mestranol 0.0750.15 mg 24 patients or in conjunction withconjugated estrogens 0.625 mg (six patients), whereas the otherhal o the cohort did not receive any urther treatment. In theuntreated group, 15 o 34 (44%) required no urther therapy com-pared with 15 o 30 (50%) o the treated group o a mean o 16months ( p =0.8). In summary, hormonal therapy does not appearto have a role in the treatment o small bowel bleeding.

Somatostatin analogs Interest in the use o somatostatin analogs or treating angioec-tasia started in 1999 ( 216). Te proposed mechanism o action

or these agents has included reduction o bleeding by the inhi-bition o angiogenesis, decrease in splanchnic ow, increase in vascular resistance, and improved platelet aggregation ( 218). Anumber o case reports were ollowed by a systematic reviewin 2010 (219) demonstrating a signi cant reduction in theneed or blood products in 62 patients rom three small stud-ies. Following this systematic review, Bon et al. (220) reportedresponse rates or a urther 15 patients with angiodyplasias in thestomach ( n =6), small intestine ( n =9), and colon ( n =3). Tese


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concentration be ore treatment was 6.5 g/dl and at the end o treat-ment was 12.1 g/dl. Tree patients were withdrawn rom the studybecause o adverse side effects.

Radiological treatment Tis modality is covered in the section on radiological diagnosis.

Surgical treatment Surgical treatment or small intestinal bleeding is generallyregarded as a last resort or or patients requiring lysis o adhesionsin order to per orm success ul deep enteroscopy. In the pre-ent-eroscopic era, a right hemicolectomy was per ormed as the treat-ment o choice or recurrent GI bleeding, presumed to originate

rom right-sided diverticulosis as the source o bleeding ( 225).Subsequently, surgical treatment o small intestinal bleeding hasbeen guided by IOE where possible or by a combination o VCEdeep enteroscopy and/or angiographic techniques ( 129,226). In areport by Hartmann et al. (226), 47 consecutive patients with sus-

pected small bowel bleeding had a negative conventional work-up ollowed by VCE studies. Tese patients then underwent IOE via an enterotomy; the endoscopist was blind to the results o theprior VCE study. A bleeding source was identi ed on IOE in 73%o all cases. Diagnostic yields were 100% or patients with ongo-ing overt bleeding, 70% in overt previous bleeding, and 50% inoccult bleeding with an overall mortality rate o 2%. An interest-ing combined radiological and surgical option has been recentlyre-reported involving angiographic localization o small bowel vascular lesions ( 227). Te angiographic catheter is lef in placeand the patient is trans erred to the operating room. At laparot-omy, methylene blue is injected via the angiographic catheter. Te

dye highlights the vasculature and mesentery related to the intes-tinal lesion, making it easy or the surgeon to resect the relevantsegment o small intestine. Surgery displays excellent results withdiscrete lesions such as tumors or localized arteriovascular mal-

ormations. More diffuse lesions, such as multiple angioectasias,are usually treated endoscopically at the time o operation. As thetreatment is the same as that delivered at deep or push enteros-copy, rebleeding rates can be anticipated to be similar, but there isno long-term ollow-up data.

For patients with Heydes syndrome (aortic stenosis and angi-oectasia), a recent meta-analysis suggested a reduced bleedingrisk afer aortic valve replacement based on data rom two stud-ies (pooled event rate o 0.16 or rebleeding events (95% CI: 0.050.38).(202)

CONCLUSION Te occurrence o small bowel bleeding remains a relativelyuncommon event. A signi cant percentage o patients withsuspected small bowel bleeding will have sources o bleedingdetected upon repeat upper and lower endoscopic examinations.Te remainder o the patients will likely demonstrate sources obleeding in the small bowel on VCE, deep enteroscopy or C Estudies. Given the effi cacy o these new imaging modalities, theprior classi cation o obscure GI bleeding should be reserved

were consecutive patients who had been bleeding or at least 6months and had endoscopic evaluation with upper endoscopy,colonoscopy, and VCE, radiological examination with abdominalC , and, in some cases, DBE. Most had comorbid diseases listedby Nardone et al. (216) as independent co- actors or rebleedingand some were on anticoagulation. Tose with re ractory bleed-ing, de ned as patients requiring >5 U o blood within 3 monthsafer conventional treatment, were given depot octreotide LARintramuscularly monthly or Lanreotide 90 mg monthly or amean o 12 months (range 636 months). rans usion require-ments during treatment decreased to 2 (range 014) vs. 10 (624)in the period be ore treatment ( P


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or patients in whom a bleeding source cannot be demonstratedafer an extensive evaluation. Small bowel angiodysplastic lesionsremain the most common cause o small bowel bleeding, anddespite endoscopic therapy, demonstrate high recurrence rates.Medical therapy with somatostatin analogs or antiangiogenicagents may be an option or re ractory patients. Surgical therapyshould be reserved or patients requiring lysis o adhesions orsuccess ul deep enteroscopy, and aortic valve replacement shouldbe considered or patients with Heydes syndrome.

CONFLICT OF INTERESTGuarantor of the article: Lauren B. Gerson, MD, MSc, FACG. Speci c author contributions: All authors were involved in writingthe manuscript and providing critical revision o the manuscript orimportant intellectual content. Financial support: Leighton: P zer; Fidler: Beekley Medical; Cave:Capsovision and Olympus okyo. Potential competing interests: Gerson has served as a consultant

to Capsovision, Intromedic, Covidien, Given Imaging, and Fujinon.Leighton has served as a consultant to Olympus, Fujinon, Covidien,and Given Imaging. Cave has served as a consultant to Olympus

okyo and Covidien.

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66. Bar-Meir S. Video capsule endoscopy or double-balloon enteroscopy: arethey equivalent? Gastrointest Endosc 2009 ;69:875

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