Historically the radiologic diagnosis for acute overt GI bleeding has been performed using Technetium 99m-labeled (99mTc) RBC scintigraphy and conventional angiography. Promising initial results have led to increasing utilization of CTA. Given that the small bowel is the source of GI bleeding only in a minority of cases, most reported studies on 99mTc-labeled RBC scintigraphy, conventional angiography, and CTA have included upper GI, small bowel, and colonic data.
Most studies using CT to evaluate GI bleeding are performed during multiple phases of contrast enhancement with one of the phases occurring during the arterial phase of enhancement. When performed with oral contrast, this is referred to as multiphasic CTE. When no oral contrast is administered, the technique has been termed multiphasic CT or CTA. Multiphasic CT or CTA is usually performed to detect the site of active bleeding in cases of acute overt bleeding, which can occur sporadically or in the setting of small bowel bleeding. CTA has been shown to be able to detect bleeding rates as slow as 0.3 ml/min compared with 0.5–1.0 ml/min for conventional angiography and 0.2 ml/min for 99mTc tagged RBC scintigraphy.
A meta-analysis of 9 studies with 198 patients showed CTA had a pooled sensitivity of 89% and specificity of 85% in diagnosing acute GI bleeding throughout the GI tract (164). Several of these studies showed detection by CTA which were negative by other techniques. CT is widely available and can be performed rapidly during the time of bleeding, which may aid in detection compared with other techniques. CT has also been shown to localize accurately the site of bleeding (165). Other studies have shown sensitivities of 79–94% and specificity of 95–100% for detecting active bleeding throughout the GI tract (165, 166, 167). In a study of 113 consecutive patients with active GI bleeding, CTA was positive in 80/113 (70.8%), all of which were confirmed. Negative studies were seen in 33 patients (29.2%). Out of 33, 27 of these negative cases did not require further intervention (168).
In a retrospective analysis of 31 patients with overt suspected small bowel bleeding, CT had a yield of 45% (86% tumor yield and 33% non-tumor yield) compared with 94% for double-balloon endoscopy. CT detected 1 of 7 ulcers, 6 of 7 tumors, and both angioectasias seen at DBE. In addition, CT was able to provide correct guidance for DBE in 100% of cases (169).
CTA can also be used to help triage patients for further management. In one study, 64/86 CT angiograms were negative and 92% of these patients required no further intervention. There were no cases with a negative CTA that had a subsequent positive conventional angiogram within 24 h (166). Therefore, some have recommended watchful waiting in cases with a negative CTA as the bleeding rate may be low or intermittent and conventional angiography rarely shows an additional site of bleeding. Factors predictive for a positive conventional angiogram following a positive CTA include non-diverticular etiologies and lower hemoglobin levels and should be performed soon after the CTA to enhance detection (170).
CTA has some limitations however. To detect contrast extravasation, the patient must be actively bleeding at the time of the scan. The findings of blood within the lumen or sentinel clot may help to localize the source if the bleeding is subtle or absent. If no active bleeding or source is identified at the time of the CTA additional workup may be necessary. In elderly patients with decreased renal function, the administration of the intravenous contrast for CT may increase the risk of renal complications if subsequent conventional angiography is required.
There is a wide range of reported sensitivities (33–93%), specificity (30–95%), diagnostic yields (26–87%), and localization accuracy (19–100%) for scintigraphy throughout the GI tract (164, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180). Because bleeding is intermittent, scintigraphy may be helpful in identifying the site of bleeding when other diagnostic tests have been negative (180, 181, 182).
Because of the large variations in the reported diagnostic yield, sensitivity, accuracy in localization, and correlation of outcomes combined with the inability to characterize the source of bleeding, there is considerable controversy on the use of scintigraphy for acute overt GI bleeding (183).
In younger patients with ongoing overt bleeding and negative evaluation with VCE, CTE, or other testing modalities, consideration should be made for testing with a 99mTc-pertechnetate scan for detection of Meckel’s diverticulum (184). Ectopic gastric mucosa can be seen in 10–60% of Meckel’s diverticulae (172, 185). The results of 99mTc-labeled pertechnitate scans can be varied and are dependent on the quantity and functional quality of the heterotopic gastric mucosa (186). The diagnostic yields from these scans appear to be highest when performed in children. Sensitivities have ranged from 50 to 90% with specificities from 9 to 95% (172, 185, 186, 187). There are several false positives that occur related to uptake in ulcers, inflammatory lesion, arteriovenous malformations, obstruction, intussusceptions, and ectopic gastric mucosa in other lesions such as duplication cysts (172, 185). False negatives can occur with anatomic or physiologic cause or other inflammation such as ectopic pancreatic mucosa, which can be present in up to 74% of diverticula (186).
As with scintigraphy, conventional angiography has been used for many years in patients with active GI bleeding, especially in those who may be more hemodynamically unstable. An advantage of angiography is the ability to perform therapeutic intervention with transarterial embolization at the time of diagnosis and angiography is not hampered by impaired visualization of the source by intraluminal blood. Limitations of angiography include the need for higher rates of bleeding (0.5–1.0 ml/min) for detection and the risk of complications (including renal failure, thromboembolic events, and more commonly infections or bleeding at the catheter site) that can occur in up to 10% (183, 188). Data from multiple studies assessing results throughout the GI tract show yields for angiography in the range of 20–77% with a mean near 50% (181, 182, 189, 190, 191).
Predictors of positive angiography include hemodynamic instability, particularly in those who require transfusion of ≥5 U to achieve hemodynamic stability (191). A positive yield was shown to increase to 87% with more massive GI bleeding. Angiographic yields are highest when the patient is actively bleeding with minimal delay from presentation (192).
Patients with a negative tagged RBC scan implying a slow bleeding rate or a negative CT angiogram are unlikely to have a positive conventional angiogram (166). In patients with a positive CT angiogram, those with non-diverticular etiologies and lower hemoglobin were more likely to have a subsequent positive conventional angiogram (170).
For small vascular abnormalities that require surgical intervention, placement of a catheter in the vessel supplying the vascular abnormality and dye staining can assist with intraoperative localization.
Previously, provocative angiography using hemodilution agents, vasodilators, anticoagulants, and thrombolytics has been performed in cases of GI bleeding with normal conventional angiography with good results and low complications rates (193). However, because of varied results in clinical practice and newer sensitive techniques, provocative angiography is rarely used today. Provocative angiography may be considered when all other diagnostic techniques have been unrevealing.
Throughout the years, catheter-based intervention has shown significant advances with transition from vasopressin infusion to superselective transarterial embolization, resulting in improved results and decreased complications. In 15 studies from 1992 to 2006, consisting of 309 patients and using superselective transarterial embolization, there was an 82% success rate, 95% overall clinical success rate, 76% 30-day success rate, and rebleed rate of 12% (194). However, the majority of these cases were performed for bleeding sources outside of the small bowel.
In a retrospective review of 107 angiograms during 83 episodes of bleeding, angiography effectively identified the site of bleeding in 48% of patients and allowed embolization in 45%. Embolization achieved clinical success in 76% of patients but repeat embolization was associated with a high rate of complications. The overall mortality was 7%, with four deaths because of rebleeding and two deaths because of a medical comorbidity (190).
This section will focus primarily on the treatment of vascular abnormalities in the small intestine. The treatment of bleeding from Crohn’s disease, polyposis syndromes, and small intestinal neoplasms is beyond the scope of this guideline.
Evidence from randomized controlled clinical trials as to how best to treat small bowel bleeding has been very limited. Data from the precapsule era on angioectasias found in the stomach and colon demonstrated that non-bleeding lesions were not treated, whereas those actively bleeding were treated endoscopically (196). Angioectasias in the stomach and colon may be markers for small bowel angioectasia. Despite endoscopic therapy, the recurrence rate after treatment of vascular lesions has ranged from 20 to nearly 50%.
Data regarding efficacy of endoscopic therapy for small bowel vascular lesions were limited to studies using push enteroscopy and surgical intervention before 2001. Despite ongoing usage of push enteroscopy with heater probe therapy (197, 198) and introduction of deep enteroscopy after 2004, rebleeding rates from vascular lesions have not declined significantly. In the era before deep enteroscopy, most angioectasia in the stomach and/or colon were treated with tools including monopolar and bipolar probes that provided electrocoagulation, or neodymium yttrium-aluminum-Garnet laser that provided tissue coagulation. Since 2001, argon plasma coagulation has been primarily used as the treatment of choice.
As a general statement, the outcomes associated with treatment of small bowel sources of bleeding have been disappointing and there has been a paucity of data regarding outcomes after treatment of small bowel angioectasia. To date, there have not been any published trials comparing endoscopic therapy of angioectasia compared with sham therapy or trials where only actively bleeding lesions or lesions of a certain size are treated compared with therapy for all visualized lesions. Given these limitations, recurrence of bleeding has been used as a surrogate as to the effectiveness of treatment. Even this strategy is limited because we know little of whether there are subsets of vascular lesions in the small intestine that do benefit from therapy. Two randomized controlled studies demonstrated lack of benefit of either intervention, VCE vs. radiology (199), or by hormonal therapy (200) compared with placebo. The placebo arm in both studies demonstrated the natural history of bleeding from angioectasia. In the radiology study vs. VCE, the rebleeding rate was 30% in those studied by capsule vs. 24% investigated by radiology, a nonsignificant difference. Similarly, the rebleeding rate in the study using hormonal therapy vs. placebo showed a nonsignificant 7% difference after a mean of 412 days of follow-up.
There have been several studies looking at the recurrence of bleeding after endoscopic treatment of vascular lesions in the small intestine as a measure of its effectiveness. The most recent was of a retrospective cohort study carried out at a French tertiary-referral center between January 2004 and December 2007. Of 261 patients who presented with suspected small bowel bleeding, 129 of 133 (97%) patients with small bowel vascular lesions were successfully treated with argon plasma coagulation (using DBE). At 36 months, rebleeding occurred in 45/98 (46%) patients (201). A second study involved 274 patients who had undergone DBE at two different centers between 2004 and 2006 (14). At 12 months, 43% of 101 patients reported no further overt bleeding, 23% reported recurrent overt bleeding, and 35% reported ongoing iron and/or transfusion requirements. Of the 85 patients who were interviewed at at a mean of 30 months, 50 (59%) reported no overt bleeding or iron/transfusion needs, 20 (24%) reported further overt bleeding, and 15 (18%) reported ongoing iron and transfusion requirements. A recent meta-analysis of 14 studies including 623 subjects with small bowel angioectasia treated with endoscopic therapy demonstrated a pooled rebleeding rate of 34% (95% CI: 27–42%) after a mean of 22±13 months. This rebleeding rate increased to 45% when the 341 patients with small bowel angioectasia were analyzed (202).
Risk factors for recurrent bleeding from small bowel angioectasia have included the number of vascular lesions (13, 201, 203), age over 65 years (204, 205), presence of lesions in the jejunum (205), presence of cardiac valvular disease (65, 201), chronic renal disease (65, 204, 206), usage of anticoagulant medication (47), and need for transfusion.
Heyde’s syndrome is a controversial association between the presence of aortic stenosis and angioectasia, thought to be secondary to an acquired type 2 von Willebrand deficiency (207, 208). In support of this relationship is the fact that some patients with aortic stenosis have demonstrated resolution of GIB after aortic valve replacement (202). Patients with left ventricular assist devices have also been demonstrated to be at risk for angioectasia and recurrent bleeding, again secondary to an acquired von-Willebrand deficiency syndrome (209). Pilot studies have demonstrated that decreased levels of von Willebrand factor are predictive of recurrent bleeding from small bowel angioectasia in patients with left ventricular assist devices (210).
Supportive care with iron given orally or intravenously is a mainstay of treatment for mild small intestinal bleeding (211). This not only helps maintain an adequate level of hemoglobin, but in more severe cases help reduce the frequency of transfusion. In more severe bleeding, transfusion of packed RBCs is an essential element of treatment, particularly when mechanistic and medical methods fail.
Although anticoagulation has been associated with an increased risk of recurrent bleeding (47), there is no prospective data showing that withdrawal of anticoagulation therapy is beneficial. In a 2009 assessing 162 patients with small bowel bleeding, risk factors for recurrent bleeding after DBE included the presence of small bowel vascular disorders and comorbid conditions, but not the usage of anticoagulants or antiplatelet therapy (65). Another follow-up study in 2010 demonstrated that transfusional requirements, number, and type of vascular lesions were predictors for recurrent bleeding, but not anticoagulant usage (212). There is no data that cessation of antiplatelet therapy reduces the risk for recurrent bleeding.
Specific medical treatment for small bowel bleeding is poorly developed. Hormonal therapy has not been shown to be helpful. Thalidomide and octreotide have been shown to have some benefit.
There have been several trials of hormonal therapy, all in the pre-capsule era. Thus, the precise nature of what was treated was largely unknown with respect to the small intestine. The proposed mechanism of action for these agents included shortening of the bleeding time contributing to an effect on hemostasis (213). However, other studies suggested that these agents may instead increase plasma fibrinolysis and lead to recurrent bleeding (214). A prospective randomized double-blind placebo-controlled crossover study performed in Belgium in 1990 created enthusiasm for hormonal treatment. This was a small study with 10 patients; it demonstrated a 78% reduction in transfusion in the patient’s treated with ethinyl estradiol 50 μg and norethisterone 1 mg daily for 6 months compared with those treated with placebo. Only one patient on the drug required transfusion compared with all on the placebo. The majority of patients had chronic renal failure or von Willebrand’s disease (215), factors that may not be representative of typical angioectasia patients. A multicenter double-blind randomized study, in Spain, of the use of hormonal therapy vs. placebo in patients with GI angioectasia, showed no benefit after a year of treatment. The hormonal therapy used was ethinyl estradiol 0.01 mg plus norethisterone 2.0 mg or placebo daily for at least 1 year. There were 35 patients in the placebo group and 33 in the treatment group. Failure rates for the treatment and placebo groups were 39% and 46%, respectively, a nonsignificant difference (200, 216). There was no difference in the number of bleeding episodes or transfusion requirements over a mean period of 412±255 days (range 1–3 years). Serious adverse event occurred in both groups—one pulmonary thromboembolic event in each group. One patient died of an ischemic stroke in the placebo group and there was one stroke in the treatment group. One-third of the women in the treatment group had menorrhagia in response to the hormonal treatment.
Interest in the use of somatostatin analogs for treating angioectasia started in 1999 (216). The proposed mechanism of action for these agents has included reduction of bleeding by the inhibition of angiogenesis, decrease in splanchnic flow, increase in vascular resistance, and improved platelet aggregation (218). A number of case reports were followed by a systematic review in 2010 (219) demonstrating a significant reduction in the need for blood products in 62 patients from three small studies. Following this systematic review, Bon et al. (220) reported response rates for a further 15 patients with angiodyplasias in the stomach (n=6), small intestine (n=9), and colon (n=3). These were consecutive patients who had been bleeding for at least 6 months and had endoscopic evaluation with upper endoscopy, colonoscopy, and VCE, radiological examination with abdominal CT, and, in some cases, DBE. Most had comorbid diseases listed by Nardone et al. (216) as independent co-factors for rebleeding and some were on anticoagulation. Those with refractory bleeding, defined as patients requiring >5 U of blood within 3 months after conventional treatment, were given depot octreotide LAR intramuscularly monthly or Lanreotide 90 mg monthly for a mean of 12 months (range 6–36 months). Transfusion requirements during treatment decreased to 2 (range 0–14) vs. 10 (6–24) in the period before treatment (P<0.001). The number of patients experiencing a bleeding episode also decreased to 20% in the treatment group compared with 73% in the pretreatment phase (p=0.001).
Thalidomide, a drug with a tragic past, has made a resurgence owing to its properties as an antiangiogenic agent, possibly by its inhibition by vascular endothelial growth factor (222). It is also an antitumor necrosis factor agent and an immune modulator.
There have been several small case studies and one good sized randomized open-label controlled trial that included a variety of vascular malformations throughout the GI tract, but predominantly in the small intestine (223). Patients enrolled in the randomized open-label controlled trial were required to have at least six or more bleeding episodes (measured by positive immunoassay fecal occult blood test) and received either 25 mg (four times a day) of thalidomide or 100 mg of iron daily for 4 months, with at least a 12-month follow-up. The primary end point, defined as the proportion of patients showing a reduction of bleeding episodes by ≥50%, was met in 20/28 (71%) of patients on thalidomide compared with 1/27 (4%) of those on iron supplementation (p<0.001). Adverse events including fatigue, constipation, and somnolence were reported by 73% of the thalidomide group and 34% of the iron cohort. Levels of vascular endothelial growth factor were consistently and significantly lower in the thalidomide group.
The benefit of thalidomide for patients with small bowel angioectasia failing endoscopic therapy was demonstrated in 9/12 (75%) patients in a study published in 2012 where patients received daily doses of 200 mg for 4 months (224). The mean hemoglobin concentration before treatment was 6.5 g/dl and at the end of treatment was 12.1 g/dl. Three patients were withdrawn from the study because of adverse side effects.
This modality is covered in the section on radiological diagnosis.
Surgical treatment for small intestinal bleeding is generally regarded as a last resort or for patients requiring lysis of adhesions in order to perform successful deep enteroscopy. In the pre-enteroscopic era, a right hemicolectomy was performed as the treatment of choice for recurrent GI bleeding, presumed to originate from right-sided diverticulosis as the source of bleeding (225). Subsequently, surgical treatment of small intestinal bleeding has been guided by IOE where possible or by a combination of VCE deep enteroscopy and/or angiographic techniques (129, 226). In a report by Hartmann et al. (226), 47 consecutive patients with suspected small bowel bleeding had a negative conventional work-up followed by VCE studies. These patients then underwent IOE via an enterotomy; the endoscopist was blind to the results of the prior VCE study. A bleeding source was identified on IOE in 73% of all cases. Diagnostic yields were 100% for patients with ongoing overt bleeding, 70% in overt previous bleeding, and 50% in occult bleeding with an overall mortality rate of 2%. An interesting combined radiological and surgical option has been recently re-reported involving angiographic localization of small bowel vascular lesions (227). The angiographic catheter is left in place and the patient is transferred to the operating room. At laparotomy, methylene blue is injected via the angiographic catheter. The dye highlights the vasculature and mesentery related to the intestinal lesion, making it easy for the surgeon to resect the relevant segment of small intestine. Surgery displays excellent results with discrete lesions such as tumors or localized arteriovascular malformations. More diffuse lesions, such as multiple angioectasias, are usually treated endoscopically at the time of operation. As the treatment is the same as that delivered at deep or push enteroscopy, rebleeding rates can be anticipated to be similar, but there is no long-term follow-up data.
For patients with Heyde’s syndrome (aortic stenosis and angioectasia), a recent meta-analysis suggested a reduced bleeding risk after aortic valve replacement based on data from two studies (pooled event rate of 0.16 for rebleeding events (95% CI: 0.05–0.38).(202)
The occurrence of small bowel bleeding remains a relatively uncommon event. A significant percentage of patients with suspected small bowel bleeding will have sources of bleeding detected upon repeat upper and lower endoscopic examinations. The remainder of the patients will likely demonstrate sources of bleeding in the small bowel on VCE, deep enteroscopy or CTE studies. Given the efficacy of these new imaging modalities, the prior classification of “obscure GI bleeding” should be reserved for patients in whom a bleeding source cannot be demonstrated after an extensive evaluation. Small bowel angiodysplastic lesions remain the most common cause of small bowel bleeding, and despite endoscopic therapy, demonstrate high recurrence rates. Medical therapy with somatostatin analogs or antiangiogenic agents may be an option for refractory patients. Surgical therapy should be reserved for patients requiring lysis of adhesions for successful deep enteroscopy, and aortic valve replacement should be considered for patients with Heyde’s syndrome.
(1) Hemorrhage, gastrointestinal/ or “gastrointestinal hemorrhage*”.mp. or “gastrointestinal haemorrhage*”.mp. or melena.mp. or hematoemisis.mp. or hematochez*.mp. or haematochez*.mp. [mp=title, abstract, original title, name of substance word, subject heading word, keyword heading word, protocol supplementary concept word, rare disease supplementary concept word, unique identifier]
(2) 1 and (obscure or ogib*).mp. [mp=title, abstract, original title, name of substance word, subject heading word, keyword heading word, protocol supplementary concept word, rare disease supplementary concept word, unique identifier]
(3) 1 and overt.mp. and occult.mp. [mp=title, abstract, original title, name of substance word, subject heading word, keyword heading word, protocol supplementary concept word, rare disease supplementary concept word, unique identifier]
(4) 2 or 3
(5) exp intestine, small/bs, pa, ra, ri or exp duodenal diseases/pa, co, di, et, ra, ri, eh, ep or exp ileal diseases/pa, co, di, et, ra, ri, eh, ep or exp jejunal diseases/pa, co, di, et, ra, ri, eh, ep
(6) 1 and 5
(7) 6 and (obscure or occult or overt).mp. [mp=title, abstract, original title, name of substance word, subject heading word, keyword heading word, protocol supplementary concept word, rare disease supplementary concept word, unique identifier]
(8) 4 or 7
(9) anemia, iron deficiency/ or ida.tw. or localiz*.mp. or localis*.mp. or visuali*.mp. or fobt.mp. or occult blood/ or “occult blood”.mp. or missed.mp. or diagnostic errors/ or diagnosis, differential/ [mp=title, abstract, original title, name of substance word, subject heading word, keyword heading word, protocol supplementary concept word, rare disease supplementary concept word, unique identifier]
(10) 6 and 9
(11) 8 or 10
(12) avms.mp. or meckels diverticulum/ or vascular diseases/ra, di, ri or dieulafoy*.mp. or telangiectasia*.mp. or ectasia*.mp. or hemangioma*.mp. or haemangioma*.mp. or angiodysplasi*.mp. [mp=title, abstract, original title, name of substance word, subject heading word, keyword heading word, protocol supplementary concept word, rare disease supplementary concept word, unique identifier]
(13) lvad*.mp. or heart assist devices/ or “osler weber”.mp. or “blue rubber”.mp. or erosion*.mp. or willebrand*.mp. or crohn*.mp. [mp=title, abstract, original title, name of substance word, subject heading word, keyword heading word, protocol supplementary concept word, rare disease supplementary concept word, unique identifier]
(14) 6 and (12 or 13)
(15) exp anticoagulants/ or exp fibrinolytic agents/ or exp platelet aggregation inhibitors/
(16) (exp anticoagulants/ae or exp fibrinolytic agents/ae or exp platelet aggregation inhibitors/ae) and 6
(17) 11 or 14 or 16
(18)…l/ 17 lg=en and hu=y and yr=1980–2014
(19) exp Gastrointestinal Hemorrhage/ci, cl, di, dh, dt, ec, ep, eh, et, mo, pa, pp, pc, ra, ri, rh, su, th, us [Chemically Induced, Classification, Diagnosis, Diet Therapy, Drug Therapy, Economics, Epidemiology, Ethnology, Etiology, Mortality, Pathology, Physiopathology, Prevention & Control, Radiography, Radionuclide Imaging, Rehabilitation, Surgery, Therapy, Ultrasonography]
(20) 18 and 19
(21) 18 and (esophagoduodenoscop*.mp. or endoscopy/ or exp endoscopy, gastrointestinal/ or capsule endoscopy/ or dbe.mp. or “double balloon”.mp. or enteroscop*.mp. or duodenoscopy/ or esophagoscopy/ or gastroscopy/ or colonoscopy/) [mp=title, abstract, original title, name of substance word, subject heading word, keyword heading word, protocol supplementary concept word, rare disease supplementary concept word, unique identifier]
(22). exp angiography/ or exp radiographic image enhancement/ or exp radiographic image interpretation, computer-assisted/ or exp radiography, abdominal/ or exp radionuclide imaging/ or exp tomography/
(23) diagnostic imaging/ or exp magnetic resonance imaging/
(24) “tagged red blood”.mp. or erythrocytes/ri [mp=title, abstract, original title, name of substance word, subject heading word, keyword heading word, protocol supplementary concept word, rare disease supplementary concept word, unique identifier]
(25) exp Radionuclide Imaging/
(26) 18 and (22 or 23 or 24 or 25)
(27) exp diagnostic imaging/ae, st, ut, ed
(28) 18 and 27
(29) 18 and (education*.tw. or train*.mp. or simulat*.mp.) [mp=title, abstract, original title, name of substance word, subject heading word, keyword heading word, protocol supplementary concept word, rare disease supplementary concept word, unique identifier]
(30) 18 and clinical competence/
(31) 28 or 29 or 30
(32) 20 or 26 or 28 or 31
(33) 18 and manag*.mp. [mp=title, abstract, original title, name of substance word, subject heading word, keyword heading word, protocol supplementary concept word, rare disease supplementary concept word, unique identifier]
(34) 18 and (rebleed* or recurr* or yield* or algorithm* or repeat*).mp. [mp=title, abstract, original title, name of substance word, subject heading word, keyword heading word, protocol supplementary concept word, rare disease supplementary concept word, unique identifier]
(35) exp endoscopy/ed, st
(36) 18 and 35
(37) 31 or 36
(38) 32 or 33 or 34 or 37
(39) remove duplicates from 38
(40) 39 and (longitudinal studies/ or follow-up studies/ or cohort*.mp. or series.mp. or prospective*.mp. or retrospective*.mp.) [mp=title, abstract, original title, name of substance word, subject heading word, keyword heading word, protocol supplementary concept word, rare disease supplementary concept word, unique identifier]
(41) limit 39 to (clinical trial, all or clinical trial, phase i or clinical trial, phase ii or clinical trial, phase iii or clinical trial, phase iv or clinical trial or comparative study or controlled clinical trial or evaluation studies or meta analysis or multicenter study or observational study or pragmatic clinical trial or practice guideline or randomized controlled trial or “review” or systematic reviews or validation studies)
(42) exp case-control studies/ or exp cohort studies/ or exp cross-sectional studies/ or exp feasibility studies/ or exp intervention studies/ or exp pilot projects/
(43) 39 and 42
(44) 40 or 41 or 43
(1) hemorrhage, gastrointestinal/ or “gastrointestinal hemorrhage*”.mp. or “gastrointestinal haemorrhage*”.mp. or melena.mp. or hematoemisis.mp. or hematochez*.mp. or haematochez*.mp. [mp=title, abstract, subject headings, heading word, drug trade name, original title, device manufacturer, drug manufacturer, device trade name, keyword]
(2) 1 and (obscure or ogib*).mp. [mp=title, abstract, subject headings, heading word, drug trade name, original title, device manufacturer, drug manufacturer, device trade name, keyword]
(3) 1 and overt.mp. and occult.mp. [mp=title, abstract, subject headings, heading word, drug trade name, original title, device manufacturer, drug manufacturer, device trade name, keyword]
(4) 2 or 3
(5) anemia, iron deficiency/ or ida.tw. or localiz*.mp. or localis*.mp. or visuali*.mp. or fobt.mp. or occult blood/ or “occult blood”.mp. or missed.mp. or diagnostic errors/ or diagnosis, differential/ [mp=title, abstract, subject headings, heading word, drug trade name, original title, device manufacturer, drug manufacturer, device trade name, keyword]
(6) avms.mp. or meckels diverticulum/ or vascular diseases/ra, di, ri or dieulafoy*.mp. or telangiectasia*.mp. or ectasia*.mp. or hemangioma*.mp. or haemangioma*.mp. or angiodysplasi*.mp. [mp=title, abstract, subject headings, heading word, drug trade name, original title, device manufacturer, drug manufacturer, device trade name, keyword]
(7) lvad*.mp. or heart assist devices/ or “osler weber”.mp. or “blue rubber”.mp. or erosion*.mp. or willebrand*.mp. or crohn*.mp. [mp=title, abstract, subject headings, heading word, drug trade name, original title, device manufacturer, drug manufacturer, device trade name, keyword]
(8) exp anticoagulants/ or exp fibrinolytic agents/ or exp platelet aggregation inhibitors/
(9) exp angiography/ or exp radiographic image enhancement/ or exp radiographic image interpretation, computer-assisted/ or exp radiography, abdominal/ or exp radionuclide imaging/ or exp tomography/
(10) diagnostic imaging/ or exp magnetic resonance imaging/
(11) “tagged red blood”.mp. or erythrocytes/ri [mp=title, abstract, subject headings, heading word, drug trade name, original title, device manufacturer, drug manufacturer, device trade name, keyword]
(12) exp Radionuclide Imaging/
(13) exp case control study/ or exp case study/ or exp clinical trial/ or exp “clinical trial (topic)”/ or exp intervention study/ or exp longitudinal study/ or exp major clinical study/ or exp prospective study/ or exp retrospective study/
(15) 1 and 14
(16) 15 and (obscure or ogib* or occult or overt).mp. [mp=title, abstract, subject headings, heading word, drug trade name, original title, device manufacturer, drug manufacturer, device trade name, keyword]
(17) 4 or 16
(18) 13 and 17
(19) exp cohort analysis/ or exp correlational study/ or exp cross-sectional study/ or exp evidence based practice/ or exp practice guideline/
(20) 17 and 19
(21) 18 or 20
(22) remove duplicates from 21
(23) exp gastrointestinal hemorrhage/co, di, dm, ep, et, pc, si, su, th [Complication, Diagnosis, Disease Management, Epidemiology, Etiology, Prevention, Side Effect, Surgery, Therapy]
(24) 22 and 23
(25) exp diagnostic accuracy/ or exp diagnostic error/ or exp diagnostic reasoning/ or exp diagnostic test accuracy study/ or exp diagnostic value/ or exp differential diagnosis/ or exp endoscopy/
(26) 23 and 25
(27) 17 and 26
(28) (13 or 19) and 27
(29) 24 or 28
(TITLE-ABS-KEY((obscure OR occult OR overt OR active OR suspect* OR unknown OR acute) AND (gi OR gastrointestinal* OR intestinal) AND (bleed* OR rebleed* OR hemorrhag* OR haemorrhag*) AND (ct OR tomogra* OR enterography OR angiography OR mdct OR endoscop* OR enteroscop* OR imag*)) ANDPUBYEAR>1979) AND (performance OR useful* OR value OR important OR plan* OR suggest* OR diagnos* OR accura* OR missed) AND NOT (PMID(1* OR 2* OR3* OR 4* OR 5* OR 6* OR 7* OR 8* OR 9*)) AND (EXCLUDE(DOCTYPE, “ch”) OR EXCLUDE(DOCTYPE, “ip”) OR EXCLUDE(DOCTYPE, “sh”) OR EXCLUDE(DOCTYPE, “no”) OR EXCLUDE (DOCTYPE, “le”) OR EXCLUDE(DOCTYPE, “bk”)) AND (LIMIT-TO(LANGUAGE, “English”)) 1150
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