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Early timing of single balloon enteroscopy is associated with increased diagnostic yield in patients with overt small bowel bleeding
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Journal of the Formosan Medical Association xxx (xxxx) xxx
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Original Article
Early timing of single balloon enteroscopy is associated with increased diagnostic yield in patients with overt small bowel bleeding Chia-Hung Tu a,b, John Y. Kao c, Ping-Huei Tseng a,b, Yi-Chia Lee a, Tsung-Hsien Chiang a,b, Chien-Chuan Chen a, Hsiu-Po Wang a, Han-Mo Chiu a,*, Ming-Shiang Wu a,b,1 a
Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan c Department of Internal Medicine, University of Michigan Health System, Ann Arbor, MI, Taiwan b
Received 30 July 2018; received in revised form 9 December 2018; accepted 2 January 2019
KEYWORDS Diagnostic yield; Enteroscopy; Gastrointestinal hemorrhage; Timing
Background/purpose: Although performing balloon enteroscopy soon after the onset of small bowel bleeding appeared to enhance diagnostic rate, the optimal timing was unclear. Methods: A retrospective cohort study in a single referral center. Patients with overt, suspected small bowel bleeding who underwent primary single-balloon enteroscopy (SBE) were evaluated to determine the association between procedure timing and diagnostic yield rates. Results: A total of 220 patients were enrolled (47.7% males; mean age, 65.6 18.1 years). They were stratified into four groups based on the timing of SBE: emergency (<24 h after onset or continued bleeding, n Z 64), 24e72 h (n Z 28), 3e7 days (n Z 41), and >7 days (n Z 87). A significant trend of decreasing diagnostic yields was observed across the groups (90.6%, 67.9%, 68.3%, and 44.8%, respectively, P < 0.0001). Diagnostic yield rates were different between emergency and 24e72 h groups (P < 0.0001), and between 3 and 7 days and >7 days groups (P < 0.05), but not between 24 and 72 h and 3e7 days groups (P Z 0.97). In multivariate regression analysis, emergency, 3 days, and 7 days SBEs had greater yield rates than SBEs at later timings. Conclusion: The likelihood of diagnostic yield was highest when SBE was performed during continued bleeding or within 24 h of onset, and gradually declined as waiting time increased. We therefore recommend that SBE should be performed as soon as possible, preferably no later than seven days.
* Corresponding author. Department of Internal Medicine, National Taiwan University Hospital, No. 7, Chung-Shan South Road, Taipei 10002, Taiwan. E-mail addresses: [email protected], [email protected] (H.-M. Chiu), [email protected] (M.-S. Wu). 1 No. 7, Chung-Shan South Road, Taipei, 10002, Taiwan. Fax: þ886 2 23947899. https://doi.org/10.1016/j.jfma.2019.01.003 0929-6646/Copyright ª 2019, Formosan Medical Association. Published by Elsevier Taiwan LLC. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). Please cite this article as: Tu C-H et al., Early timing of single balloon enteroscopy is associated with increased diagnostic yield in patients with overt small bowel bleeding, Journal of the Formosan Medical Association, https://doi.org/10.1016/j.jfma.2019.01.003
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C.-H. Tu et al. Copyright ª 2019, Formosan Medical Association. Published by Elsevier Taiwan LLC. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/bync-nd/4.0/).
Introduction Approximately 80% of patients with suspected small bowel bleeding have a bleeding source outside the reach of regular endoscopies1,2 and often require investigation in the small bowel. As a result of technological advancement, video capsule endoscopy (VCE), double-balloon enteroscopy (DBE), and single-balloon enteroscopy (SBE) are by far the most frequently applied techniques that serve this role. However, the diagnostic yield rates were generally low, regardless of study modality. Previous studies found that 17e62% of VCE, 19e57% of DBE, and 35e59% of SBE procedures failed to specify the source of bleeding.3,4 Unlike screening endoscopy, a negative study in this setting is often unwanted for the time and resource costs, unnecessary risks, and concerns that clinically important lesions will be missed.5e9 The main reasons for negative results are the episodic pattern of small bowel bleeding and possibly the rapid healing of small ulcers.10 Minute bleeder lesions are more likely being overlooked when bleeding stops before endoscopic examination. Therefore, early endoscopy performed during or shortly after bleeding would theoretically increase the chance of locating the bleeder and facilitate the administration of therapeutics.11e15 However, setting up an early enteroscopy is often challenging. Before balloon enteroscopy is deemed necessary, patients have to receive a series of first-line investigations including esophagogastroduodenoscopy (EGD) and/or colonoscopy, imaging studies, repeat endoscopies, push enteroscopy, and often VCE. Therefore, it usually takes several days or a few weeks before a patient is properly referred for deep enteroscopy, either DBE or SBE.1,2,4,10,16,17 Presently, there is a lack of guidance or specific recommendations on the timing of deep enteroscopy for suspected small bowel bleeding. Deep enteroscopy is rarely considered as one of the necessary emergency gastrointestinal procedures. To address this, we hypothesized that the diagnostic yield of deep enteroscopy is greatest on the day of onset of bleeding or during continued bleeding, and decreases as it is performed later. The study aim was to compare the rates of positive diagnosis for deep enteroscopy at different timings by analyzing a large cohort of patients with suspected small bowel bleeding.
Methods Study population Consecutive patients with suspected small bowel bleeding who underwent SBE at the National Taiwan University Hospital from October 2010 to July 2016 were retrospectively evaluated for eligibility. Suspected small bowel bleeding was defined as gastrointestinal bleeding with a
negative EGD and colonoscopy.17 Before SBE, repeated EGD and/or colonoscopy were routinely performed unless they were contra-indicated. Unlike the more widely accepted management that included initial VCE, primary SBE without antecedent VCE was the preferred standard of practice in our cohort because of a favorable insurance coverage. However, either options were provided during evaluation for each individual case. Only overt bleeding with melena and/or hematochezia were included in our analysis, although those with occult bleeding defined as having iron deficiency anemia with positive fecal occult blood tests were excluded.12,18 As we were interested only in those SBEs that were performed without prior diagnostic information regarding the small bowel, patients who underwent VCE or a nuclear bleeding scan prior to SBE were excluded. Those with positive CT findings and required SBE for the purpose of biopsy were also excluded. Clinical data was reviewed and the inclusion of the following variables was checked: comorbidity, medication history, clinical manifestation, transfusion requirement based on hematocrit levels, time of bleeding onset, time of SBE and its finding, therapeutic procedure, SBE-related complication, and follow-up. This study was approved by the institutional research ethics committee of National Taiwan University Hospital (protocol number: 201507082RIND, 20th Aug, 2015) before its commencement.
SBE procedure and timing SBE was performed using a small bowel endoscope (SIF-Q260, Olympus, Tokyo, Japan) assisted with a balloon-mounted splinting tube (ST-SB1), and a standard push-and-pull technique.19 All procedures were performed by a single endoscopist (C. H. T.). The initial route of insertion was based on the appearance of the abnormal stool, as melena prompted antegrade SBE and hematochezia retrograde SBE.14,20 Bowel preparation involved fasting for over 6 h before antegrade SBE, or early morning ingestion of a polyethylene glycol solution (PEG) before retrograde SBE. However the protocol was flexible, particularly for emergency SBE. The timing of SBE was measured as the interval between symptom onset (first passage of blood in stool) and the start of the procedure. Thereby patients were divided into four groups of different time intervals posteindex bleeding: 1) emergency, i.e., within 24 h of onset of bleeding, or continued bleeding on the day of SBE, regardless of onset time; 2) 24e72 h after onset of bleeding; 3) 3e7 days after onset of bleeding; and 4) > 7 days after onset of bleeding.
SBE finding A positive diagnosis was defined as either an SBE finding of visible bleeding, or an inactive lesion likely to be the source of bleeding relevant to bleeding symptoms. Diverticulosis
Please cite this article as: Tu C-H et al., Early timing of single balloon enteroscopy is associated with increased diagnostic yield in patients with overt small bowel bleeding, Journal of the Formosan Medical Association, https://doi.org/10.1016/j.jfma.2019.01.003
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without stigmata of recent hemorrhage was not considered a positive finding. Additionally, the finding of a 0.1 cm angioectasia was not considered significant unless active bleeding was directly visible. Each patient was attached with the procedure data from only a single SBE session, in order to carry out per-patient analyses. For those who had undergone multiple SBE sessions, we selected the one that yielded a positive diagnosis, or the one with the earliest procedure timing if all SBEs were negative.
Statistical analysis The diagnostic yield rates of the four groups of different SBE timings were compared and tested for a trend using chi-square tests, or Fisher’s exact test when necessary. In the regression analyses, SBE timing was re-categorized as emergency vs. non-emergency, 3 days vs. > 3 days, and 7 days vs. > 7 days, thereby analyses were performed separately. The effects of SBE timing and other clinical variables, including age, gender, comorbidity, transfusion requirement, medication, and whether the enteroscopy was first-time, on diagnostic yield were first evaluated using univariate logistic regressions. Subsequent multivariate logistic regressions were performed to evaluate the impact of SBE timing adjusted for those significant clinical variables. All data were analyzed using the IBM Statistical Package for Social Sciences (SPSS version 22; SPSS, Chicago, IL., US.). The significance level was set at P < 0.05.
Results Patients We identified 292 consecutive patients who underwent totally 415 SBE procedures for suspected small bowel bleeding during the study period. Of these, 249 patients (355 SBEs) presented with overt bleeding. Twenty-nine patients were excluded because of prior positive findings on CT (22 patients), VCE (5 patients), or nuclear bleeding scan (1 patient), and undocumented time of bleeding onset (one patient). As a result, 220 patients were eligible for the study (Fig. 1). The mean age was 65.6 18.1 years, and 47.7% of the cohort were male. The most common presenting symptoms were melena (60.9%), followed by hematochezia (23.6%) and mixed bloody stool (15.5%). During the bleeding episode, 68.6% of patients required transfusion, 77.3% had comorbidities, and 23.6% were taking medications that may have potentiated bleeding (e.g., anti-platelet agents, anticoagulants, nonsteroidal anti-inflammatory drugs [NSAID], and steroids. Table 1).
SBE Altogether, 324 SBEs were performed on 220 patients, including 80 patients who had received multiple SBE sessions (Fig. 2). The average number of SBE sessions per patient was 1.47 0.82 (Table 1). Following the selection
Figure 1 Flow diagram illustrating the process of identifying the study cohort. SBE, single-balloon enteroscopy; CT, computed tomography; VCE, video capsule endoscopy.
Table 1
Characteristics of study subjects.
Number of patients Age (year, mean SD) Male Clinical presentation Melena Hematochezia Mixed Comorbidity Heart disease Hypertension End-stage renal disease Cirrhosis Diabetes mellitus Connective tissue disease Malignancy Medication Anti-platelet agent Anti-coagulant NSAID Steroid Transfusion requirement SBE sessions per patient (mean SD, maximum) Positive finding SBE sessions needed to find the bleeding source (mean SD, maximum) Timing of SBEa Emergency (24 h or continued bleeding) >24 and 72 h >3 and 7 days >7 days
220 65.6 18.1 105 (47.7%) 134 (60.9%) 52 (23.6%) 34 (15.5%) 65 (29.6%) 104 (47.3%) 42 (19.1%) 26 (11.8%) 59 (26.8%) 5 (2.3%) 43 (19.6%) 33 (15.0%) 5 (2.3%) 10 (4.6%) 8 (3.6%) 151 (68.6%) 1.47 0.82, 8 144 (65.5%) 1.36 0.82, 8
64 28 41 87
(29.1%) (12.7%) (18.6%) (39.6%)
SBE, single-balloon enteroscopy; NSAID, non-steroidal anti-inflammatory drug. a Interval since the onset of bleeding symptoms.
Please cite this article as: Tu C-H et al., Early timing of single balloon enteroscopy is associated with increased diagnostic yield in patients with overt small bowel bleeding, Journal of the Formosan Medical Association, https://doi.org/10.1016/j.jfma.2019.01.003
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C.-H. Tu et al.
Figure 2 A 61-year old woman presented with recurrent episodes of transient melena associated with severe anemia. She had received three repeated antegrade SBEs in the past 7 months but the bleeding source was not identified. Finally on the fourth SBE, a non-bleeding Dieulafoy’s lesion in the third portion of duodenum was identified (a, b), with inducible bleeding upon probing (c), and was managed with multiple hemoclipping (d). There was no more recurrent bleeding up to 2.5 years of follow-up. SBE, singleballoon enteroscopy.
process described above, only 220 SBE procedure-related data were collected for analyses (Fig. 1). The overall diagnostic yield rate was 65.5%. The most prevalent positive diagnosis was vascular lesion (25.5%), followed by ulcers (18.2%), tumors (9.6%), diverticulum (7.7%), and others (4.6%, including portal hypertensive enteropathy, diffuse petechial hemorrhage secondary to bleeding diathesis, infectious enteritis, unspecified ileitis, Mallory-Weiss tear, Crohn’s disease, and intestinal hookworm infection). In 32 patients the bleeding source was located within reach of EGD or colonoscopy (14.5% of patients, 22.2% of bleeding source). Therapeutic procedures were carried out in 100 (45.5%) patients. The average procedure time was 65.4 29 min for antegrade SBE, and 86.5 35.7 min for retrograde SBE. Major adverse events occurred in two (0.9%) patients, including a delayed perforation secondary to thermocoagulation therapy, and a fatal sepsis in a 93-year-old uremic woman (Table 2).
Timing of SBE Sixty-four (29.1%) patients had received emergency SBE, while 28 (12.7%) had SBE within 24e72 h of the onset of bleeding, 41 (18.6%) within 3e7 days, and 87 (39.6%) after 7 days. Among the four groups, the diagnostic yield rates were 90.6%, 67.9%, 68.3%, and 44.8%, respectively. There was a significant (P < 0.0001) downtrend across the groups (Fig. 3). A similar trend was detected in patients found to
Table 2 Single-balloon enteroscopy for the 220 patients with suspected small bowel bleeding. First-time enteroscopy Routes of insertion Antegrade Retrograde Duration of procedure (minutes, mean SD) Antegrade Retrograde All Insertion depth Antegrade (n Z 142) Proximal jejunum Middle jejunum Distal jejunum and deeper Retrograde (n Z 78) Distal ileum Middle ileum Proximal ileum and deeper Therapeutic procedure Major complications Small bowel perforation Sepsis
80 (57.1%) 142 (64.6%) 78 (35.5%) 65.4 29.0 86.5 35.7 72.8 33.1
12 (8.5%) 42 (29.8%) 67 (47.5%) 14 (18%) 33 (42.3%) 27 (34.6%) 76 (52.4%) 2 (0.9%) 1 1
Please cite this article as: Tu C-H et al., Early timing of single balloon enteroscopy is associated with increased diagnostic yield in patients with overt small bowel bleeding, Journal of the Formosan Medical Association, https://doi.org/10.1016/j.jfma.2019.01.003
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Figure 3 Comparisons of diagnostic yield rates of primary SBE stratified by different procedure timings. SBE, single-balloon enteroscopy. * 24 h after onset or continued bleeding on the day of SBE.
have tumor (n Z 21, P < 0.0001), but not in patients with vascular lesions (n Z 56, P Z 0.10), ulcers (n Z 40, P Z 0.63), diverticulum (n Z 17, P Z 0.18), or other bleeder lesions (n Z 10, P Z 0.21). Comparing between groups, there was a significant difference between the emergency group and the 24e72 h group (P < 0.0001), and between the 3e7 days group and the >7 days group (P < 0.05), but not between the 24e72 h group and the 3e7 days group (P Z 0.97; Fig. 3).
Impact of SBE timing Univariate logistic regression showed that earlier SBE timing was associated with increased diagnostic rate, either emergency SBE (odds ratio [OR] Z 7.87, 95% confidence interval [CI] Z 3.21e19.31; P < 0.0001, vs. nonemergency), SBE within 3 days (OR Z 4.67, 95% CI Z 2.43e8.98; P < 0.0001, vs. > 3 days), or SBE within 7 days (OR Z 4.62, 95% CI Z 2.55e8.36; P < 0.0001, vs. > 7 days, Table 3). For other clinical variables, age (OR Z 1.02 for every 1 year older, 95% CI Z 1.00e1.04; P < 0.01), firsttime SBE (OR Z 4.13, 95% CI Z 2.28e7.45; P < 0.01), and transfusion requirement (OR Z 2.10, 95% CI Z 1.17e3.79; P < 0.05) were also associated with increased diagnostic yield. Whereas gender, heart disease, cirrhosis, end-stage renal disease, diabetes mellitus, connective tissue
disease, malignancy, and medications affecting coagulation were not statistically significant. In subsequent multivariate analysis, the effect of SBE timing was adjusted for age, first-time SBE, and transfusion requirement. Emergency SBE had an adjusted OR (aOR) of 7.47 (95% CI Z 2.90e19.25; P < 0.0001) for a positive diagnosis compared to non-emergency SBE. Likewise, SBE within 3 days had an aOR of 4.61 (95% CI Z 2.26e9.40; P < 0.0001) compared to SBE > 3 days, and SBE within 7 days had an aOR of 4.34 (95% CI Z 2.25e8.36; P < 0.0001) compared to SBE > 7 days (Table 3).
Discussion The study results showed that emergency SBE performed during active bleeding or within 24 h of bleeding onset had a 7.3-times greater chance of finding the bleeding source than SBE performed at a later timeframe. The benefit of earlier SBE was greatest within the first 24 h of bleeding onset, and gradually declined over the following seven days and beyond. However, once bleeding stopped and emergency SBE was not likely, SBE performed as soon as 24e72 h had no clear advantage over SBE performed during 3e7 days. Even if the bleeding had stopped upon admission, scheduling an SBE within seven days was worthwhile, since it would then provide a four-fold greater likelihood of a
Please cite this article as: Tu C-H et al., Early timing of single balloon enteroscopy is associated with increased diagnostic yield in patients with overt small bowel bleeding, Journal of the Formosan Medical Association, https://doi.org/10.1016/j.jfma.2019.01.003
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C.-H. Tu et al. Table 3
Regression analysis of early SBE timing as a predictor of a positive finding (n Z 220).
Regression model according to definition of early timing b
1. Emergency vs. non-emergency 2. 3 days vs. > 3 days 3. 7 days vs. > 7 days
Multivariate analysisa
Univariate analysis OR
95% CI
P value
aOR
95% CI
P value
7.87 4.67 4.62
3.21e19.31 2.43e8.98 2.55e8.36
<0.0001 <1111 0.0001 <0.0001
7.47 4.61 4.34
2.90e19.25 2.26e9.40 2.25e8.36
<0.0001 <0.0001 <0.0001
SBE, single-balloon enteroscopy; OR, odds ratio; CI, confidence interval; aOR, adjusted odds ratio. a In multivariate regression, SBE timing was adjusted for age, first-time enteroscopy, and transfusion requirement. The aOR for age (per 1 year older, 95% CI; P value) was 1.02 (1.00e1.02; 0.049) in model 1, 1.02 (0.99e1.03; 0.07) in model 2, and 1.02 (0.99e1.03; 0.08) in model 3. The first-time enteroscopy aOR was 4.60 (2.36e8.96; <0.01) in model 1, 4.94 (2.54e9.63; <0.01) in model 2, and 4.89 (2.51e9.53; <0.01) in model 3. The transfusion requirement aOR was 1.92 (1.02e3.62; 0.04) in model 1, 1.83 (0.98e3.44; 0.059) in model 2, and 1.62 (0.86e3.06; 0.14) in model 3. b 24 h after onset or continued bleeding on the day of SBE.
positive diagnosis. Based on the results, we recommend that when deep enteroscopy is considered for the evaluation of suspected small bowel bleeding, it would be optimal to carry out the procedure within the first seven days. The optimal timing for enteroscopy has seldom been addressed in clinical guidelines or management algorithms for small bowel bleeding.2,4,16,17 The European Society of Gastrointestinal Endoscopy guidelines suggest that deviceassisted enteroscopy should be done as soon as possible; however, this statement appears as a weak recommendation based on low-quality evidence.21 Although the present study is not the first that looked into the clinical effect of early timing,14,18,20,22e24 it would provide a stronger evidence by enrollment of the largest cohort of patients and so has allowed more precise estimation while adjusting for potential confounding variables. Multiple studies had already shown the diagnostic advantage of early VCEs or DBEs, though the definition of early timing varied among different studies, either 48 h, 3 days, 15 days, or 1 month.11,14,15,20,25 In the same way, the present study also found superior diagnostic rates of early SBE, set at either 24 h, 3 days, or 7 days. However, our results provide additional insight into how diagnostic yield decreases over the first few days of waiting. By sorting the SBE timing based on the levels of urgency, we were able to demonstrate a clear trend of declining diagnostic yield as procedure waiting time increased. Unlike the studies that compared urgent enteroscopy performed within 24 or 72 h with enteroscopy occurring outside of that interval,20,22,23 we extended the set point to seven days. As a result, we can justify whether a deep enteroscopy should still be performed urgently even when 72 h have passed, like the majority of cases. Meanwhile, much fewer studies used SBE as the deep enteroscopy of choice. Nelson et al. reported that in 110 patients with obscure gastrointestinal bleeding, emergency SBE within 24 h was associated with more radiological intervention and shorter hospital stays but without an increase in diagnostic yield.23 Compared to Nelson’s study, the present study design differs in how procedure timing was defined and this should probably the main reason behind the discrepant study results. Unlike most studies that defined the onset of bleeding at the time of hospital presentation or admission,11,15,23,25 we set at the time of first bleeding symptom so that the possible delays in being
seen by a physician (e.g., ease of accessing healthcare, delay due to transition of care) were taken into account. Several pathophysiologic characteristics of the small intestines might have strengthened the association between endoscopic timing and diagnostic sensitivity. For example, Dieulafoy’s lesions and angioectasias are among the most common small bowel bleeders, which are submucosal lesions and require ruptures of both vessel wall and overlying mucosa to produce bleeding. Therefore, bleeding tends to resolve spontaneously in a limited interval that is nevertheless long enough for clot formation, vascular wall repair, and epithelial regrowth; usually a matter of minutes to a few days.26,27 Other leading causes of small bowel bleeding, such as diverticulosis and NSAID enteropathy, also tend to cease bleeding rapidly.28,29 Once bleeding stops, the thin tube structure and unidirectional flow in the small intestine allow limited space for blood or clot retention, and thereby reduce the chance of being visualized. The present study has several strengths. First, the size of our cohort allowed us to conduct comprehensive multivariate analyses. Second, a single operator study largely eliminated the concern of inter-operator variability in endoscopic reading and human skills, although external applicability may be affected. Third, as much as 29% of the patients were able to receive emergency SBE during active bleeding or on the same day of first bleeding symptom. This was essential for prompt stratification of patients and multiple comparative analyses. We achieved this by providing emergency SBE consultation available at any time, and by offering emergency phone call instructions to the patients with negative SBEs but who were at risk of recurrent bleeding. Our study is not without limitations. First, since this study was not a randomized trial, the waiting time for SBE might have been affected by selection bias. For example, the frequency of finding tumor out of all source of bleeding was higher in emergency SBEs but obviously lower in SBEs of >3 days’ delay (Fig. 3), a finding that reflected the likely presence of survivorship bias. It is understandable that patients with more severe overt bleeding will receive more urgent endoscopy, and the acute and brisk lesions could be identified more easily at early enteroscopy. To address this, we conducted multivariate analysis to adjust for potential confounding factors. We did not include patients with
Please cite this article as: Tu C-H et al., Early timing of single balloon enteroscopy is associated with increased diagnostic yield in patients with overt small bowel bleeding, Journal of the Formosan Medical Association, https://doi.org/10.1016/j.jfma.2019.01.003
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Early deep enteroscopy for small bowel bleeding known small bowel findings prior to SBE as a means to minimize channeling bias. For example, physicians may had become more aggressive when active bleeder lesions were found on VCE. Second, since we defined different early timings with reference to symptom onset, recall bias was inevitable. Regarding this, we set multiple time points at shortly after the start of symptoms but no more if the waiting interval was beyond 7 days. Third, the retrospective design and single-center data were susceptible to selection bias. The single operator in this study, as mentioned previously, might have also reduced the generalizability of this study. Lastly, and most importantly, the data source did not provide sufficient information on clinical outcomes correlated to the SBE procedures. For example, rebleeding rates and time free from rebleeding would be more clinically relevant than endoscopic finding as the main study endpoint. Without follow up data, the true benefit generated by a positive SBE finding would remain hypothetical. A future prospective study, ideally a randomized trial, is warranted. Based on the study results, a positive diagnosis is most likely if SBE can be performed immediately after bleeding. More importantly, if performed early enough within the next seven days, it remains at least four times more likely to find the bleeding source compared to a SBE that waits longer. Our findings would justify the intention to perform deep enteroscopy urgently even when seven days have elapsed. Enteroscopy providers, primary care physicians, and secondary referring personnel should acknowledge the importance of timing and expedite their role in the management process as soon as small bowel bleeding is suspected. Further studies are warranted. The benefit of early timing beyond Day 7 remains unclear, and this is nevertheless important as 40% of patients fell into this category in the present study. Whether primary deep enteroscopy deserve a role similar to VCE as the initial option for smallbowel examination will remain questionable until further comparative data and cost-benefit studies emerge.
Conflict of interest The authors have no conflicts of interest relevant to this article.
Disclosure statement This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
Author contributions H.M.C. and M.S.W. conceived the study; C.H.T. and J.Y.K. designed the study; C.H.T., P.H.T., C.C.C., T.H.C., Y.C.L, and H.P.W. carried out the collection, analysis, and interpretation of the data; C.H.T. and J.Y.K. wrote the manuscript; H.M.C. and P.H.T. performed critical revision of the manuscript; M.S.W. granted the final approval of the article. All authors approved the final submission manuscript.
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Appendix A. Supplementary data Supplementary data to this article can be found online at https://doi.org/10.1016/j.jfma.2019.01.003.
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Please cite this article as: Tu C-H et al., Early timing of single balloon enteroscopy is associated with increased diagnostic yield in patients with overt small bowel bleeding, Journal of the Formosan Medical Association, https://doi.org/10.1016/j.jfma.2019.01.003
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8 17. Gerson LB, Fidler JL, Cave DR, Leighton JA. ACG Clinical Guideline: diagnosis and management of small bowel bleeding. Am J Gastroenterol 2015;110:1265e87. 18. Tanaka S, Mitsui K, Yamada Y, Ehara A, Kobayashi T, Seo T, et al. Diagnostic yield of double-balloon endoscopy in patients with obscure GI bleeding. Gastrointest Endosc 2008;68:683e91. 19. Kawamura T, Yasuda K, Tanaka K, Uno K, Ueda M, Sanada K, et al. Clinical evaluation of a newly developed single-balloon enteroscope. Gastrointest Endosc 2008;68:1112e6. 20. Aniwan S, Viriyautsahakul V, Rerknimitr R, Angsuwatcharakon P, Kongkam P, Treeprasertsuk S, et al. Urgent double balloon endoscopy provides higher yields than non-urgent double balloon endoscopy in overt obscure gastrointestinal bleeding. Endosc Int Open 2014;2:E90e5. 21. Pennazio M, Spada C, Eliakim R, Keuchel M, May A, Mulder CJ, et al. Small-bowel capsule endoscopy and device-assisted enteroscopy for diagnosis and treatment of small-bowel disorders: European Society of Gastrointestinal Endoscopy (ESGE) Clinical Guideline. Endoscopy 2015;47:352e76. 22. Monkemuller K, Neumann H, Meyer F, Kuhn R, Malfertheiner P, Fry LC. A retrospective analysis of emergency double-balloon enteroscopy for small-bowel bleeding. Endoscopy 2009;41: 715e7. 23. Nelson KK, Lipka S, Davis-Yadley AH, Rodriguez AC, Doraiswamy V, Rabbanifard R, et al. Timing of single balloon
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enteroscopy: significant or not? Endosc Int Open 2016;4: E761e6. Pinto-Pais T, Pinho R, Rodrigues A, Fernandes C, Ribeiro I, Fraga J, et al. Emergency single-balloon enteroscopy in overt obscure gastrointestinal bleeding: efficacy and safety. United European Gastroenterol J 2014;2:490e6. Goenka MK, Majumder S, Kumar S, Sethy PK, Goenka U. Single center experience of capsule endoscopy in patients with obscure gastrointestinal bleeding. World J Gastroenterol 2011; 17:774e8. Nojkov B, Cappell MS. Gastrointestinal bleeding from Dieulafoy’s lesion: clinical presentation, endoscopic findings, and endoscopic therapy. World J Gastrointest Endosc 2015;7: 295e307. Warkentin TE, Moore JC, Anand SS, Lonn EM, Morgan DG. Gastrointestinal bleeding, angiodysplasia, cardiovascular disease, and acquired von Willebrand syndrome. Transfus Med Rev 2003;17:272e86. Schneider AR, Benz C, Riemann JF. Adverse effects of nonsteroidal anti-inflammatory drugs on the small and large bowel. Endoscopy 1999;31:761e7. Stollman NH, Raskin JB. Diagnosis and management of diverticular disease of the colon in adults. Ad Hoc practice parameters committee of the American College of Gastroenterology. Am J Gastroenterol 1999;94:3110e21.
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Original Article
Early timing of single balloon enteroscopy is associated with increased diagnostic yield in patients with overt small bowel bleeding Chia-Hung Tu a,b, John Y. Kao c, Ping-Huei Tseng a,b, Yi-Chia Lee a, Tsung-Hsien Chiang a,b, Chien-Chuan Chen a, Hsiu-Po Wang a, Han-Mo Chiu a,*, Ming-Shiang Wu a,b,1 a
Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan c Department of Internal Medicine, University of Michigan Health System, Ann Arbor, MI, Taiwan b
Received 30 July 2018; received in revised form 9 December 2018; accepted 2 January 2019
KEYWORDS Diagnostic yield; Enteroscopy; Gastrointestinal hemorrhage; Timing
Background/purpose: Although performing balloon enteroscopy soon after the onset of small bowel bleeding appeared to enhance diagnostic rate, the optimal timing was unclear. Methods: A retrospective cohort study in a single referral center. Patients with overt, suspected small bowel bleeding who underwent primary single-balloon enteroscopy (SBE) were evaluated to determine the association between procedure timing and diagnostic yield rates. Results: A total of 220 patients were enrolled (47.7% males; mean age, 65.6 18.1 years). They were stratified into four groups based on the timing of SBE: emergency (<24 h after onset or continued bleeding, n Z 64), 24e72 h (n Z 28), 3e7 days (n Z 41), and >7 days (n Z 87). A significant trend of decreasing diagnostic yields was observed across the groups (90.6%, 67.9%, 68.3%, and 44.8%, respectively, P < 0.0001). Diagnostic yield rates were different between emergency and 24e72 h groups (P < 0.0001), and between 3 and 7 days and >7 days groups (P < 0.05), but not between 24 and 72 h and 3e7 days groups (P Z 0.97). In multivariate regression analysis, emergency, 3 days, and 7 days SBEs had greater yield rates than SBEs at later timings. Conclusion: The likelihood of diagnostic yield was highest when SBE was performed during continued bleeding or within 24 h of onset, and gradually declined as waiting time increased. We therefore recommend that SBE should be performed as soon as possible, preferably no later than seven days.
* Corresponding author. Department of Internal Medicine, National Taiwan University Hospital, No. 7, Chung-Shan South Road, Taipei 10002, Taiwan. E-mail addresses: [email protected], [email protected] (H.-M. Chiu), [email protected] (M.-S. Wu). 1 No. 7, Chung-Shan South Road, Taipei, 10002, Taiwan. Fax: þ886 2 23947899. https://doi.org/10.1016/j.jfma.2019.01.003 0929-6646/Copyright ª 2019, Formosan Medical Association. Published by Elsevier Taiwan LLC. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). Please cite this article as: Tu C-H et al., Early timing of single balloon enteroscopy is associated with increased diagnostic yield in patients with overt small bowel bleeding, Journal of the Formosan Medical Association, https://doi.org/10.1016/j.jfma.2019.01.003
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C.-H. Tu et al. Copyright ª 2019, Formosan Medical Association. Published by Elsevier Taiwan LLC. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/bync-nd/4.0/).
Introduction Approximately 80% of patients with suspected small bowel bleeding have a bleeding source outside the reach of regular endoscopies1,2 and often require investigation in the small bowel. As a result of technological advancement, video capsule endoscopy (VCE), double-balloon enteroscopy (DBE), and single-balloon enteroscopy (SBE) are by far the most frequently applied techniques that serve this role. However, the diagnostic yield rates were generally low, regardless of study modality. Previous studies found that 17e62% of VCE, 19e57% of DBE, and 35e59% of SBE procedures failed to specify the source of bleeding.3,4 Unlike screening endoscopy, a negative study in this setting is often unwanted for the time and resource costs, unnecessary risks, and concerns that clinically important lesions will be missed.5e9 The main reasons for negative results are the episodic pattern of small bowel bleeding and possibly the rapid healing of small ulcers.10 Minute bleeder lesions are more likely being overlooked when bleeding stops before endoscopic examination. Therefore, early endoscopy performed during or shortly after bleeding would theoretically increase the chance of locating the bleeder and facilitate the administration of therapeutics.11e15 However, setting up an early enteroscopy is often challenging. Before balloon enteroscopy is deemed necessary, patients have to receive a series of first-line investigations including esophagogastroduodenoscopy (EGD) and/or colonoscopy, imaging studies, repeat endoscopies, push enteroscopy, and often VCE. Therefore, it usually takes several days or a few weeks before a patient is properly referred for deep enteroscopy, either DBE or SBE.1,2,4,10,16,17 Presently, there is a lack of guidance or specific recommendations on the timing of deep enteroscopy for suspected small bowel bleeding. Deep enteroscopy is rarely considered as one of the necessary emergency gastrointestinal procedures. To address this, we hypothesized that the diagnostic yield of deep enteroscopy is greatest on the day of onset of bleeding or during continued bleeding, and decreases as it is performed later. The study aim was to compare the rates of positive diagnosis for deep enteroscopy at different timings by analyzing a large cohort of patients with suspected small bowel bleeding.
Methods Study population Consecutive patients with suspected small bowel bleeding who underwent SBE at the National Taiwan University Hospital from October 2010 to July 2016 were retrospectively evaluated for eligibility. Suspected small bowel bleeding was defined as gastrointestinal bleeding with a
negative EGD and colonoscopy.17 Before SBE, repeated EGD and/or colonoscopy were routinely performed unless they were contra-indicated. Unlike the more widely accepted management that included initial VCE, primary SBE without antecedent VCE was the preferred standard of practice in our cohort because of a favorable insurance coverage. However, either options were provided during evaluation for each individual case. Only overt bleeding with melena and/or hematochezia were included in our analysis, although those with occult bleeding defined as having iron deficiency anemia with positive fecal occult blood tests were excluded.12,18 As we were interested only in those SBEs that were performed without prior diagnostic information regarding the small bowel, patients who underwent VCE or a nuclear bleeding scan prior to SBE were excluded. Those with positive CT findings and required SBE for the purpose of biopsy were also excluded. Clinical data was reviewed and the inclusion of the following variables was checked: comorbidity, medication history, clinical manifestation, transfusion requirement based on hematocrit levels, time of bleeding onset, time of SBE and its finding, therapeutic procedure, SBE-related complication, and follow-up. This study was approved by the institutional research ethics committee of National Taiwan University Hospital (protocol number: 201507082RIND, 20th Aug, 2015) before its commencement.
SBE procedure and timing SBE was performed using a small bowel endoscope (SIF-Q260, Olympus, Tokyo, Japan) assisted with a balloon-mounted splinting tube (ST-SB1), and a standard push-and-pull technique.19 All procedures were performed by a single endoscopist (C. H. T.). The initial route of insertion was based on the appearance of the abnormal stool, as melena prompted antegrade SBE and hematochezia retrograde SBE.14,20 Bowel preparation involved fasting for over 6 h before antegrade SBE, or early morning ingestion of a polyethylene glycol solution (PEG) before retrograde SBE. However the protocol was flexible, particularly for emergency SBE. The timing of SBE was measured as the interval between symptom onset (first passage of blood in stool) and the start of the procedure. Thereby patients were divided into four groups of different time intervals posteindex bleeding: 1) emergency, i.e., within 24 h of onset of bleeding, or continued bleeding on the day of SBE, regardless of onset time; 2) 24e72 h after onset of bleeding; 3) 3e7 days after onset of bleeding; and 4) > 7 days after onset of bleeding.
SBE finding A positive diagnosis was defined as either an SBE finding of visible bleeding, or an inactive lesion likely to be the source of bleeding relevant to bleeding symptoms. Diverticulosis
Please cite this article as: Tu C-H et al., Early timing of single balloon enteroscopy is associated with increased diagnostic yield in patients with overt small bowel bleeding, Journal of the Formosan Medical Association, https://doi.org/10.1016/j.jfma.2019.01.003
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without stigmata of recent hemorrhage was not considered a positive finding. Additionally, the finding of a 0.1 cm angioectasia was not considered significant unless active bleeding was directly visible. Each patient was attached with the procedure data from only a single SBE session, in order to carry out per-patient analyses. For those who had undergone multiple SBE sessions, we selected the one that yielded a positive diagnosis, or the one with the earliest procedure timing if all SBEs were negative.
Statistical analysis The diagnostic yield rates of the four groups of different SBE timings were compared and tested for a trend using chi-square tests, or Fisher’s exact test when necessary. In the regression analyses, SBE timing was re-categorized as emergency vs. non-emergency, 3 days vs. > 3 days, and 7 days vs. > 7 days, thereby analyses were performed separately. The effects of SBE timing and other clinical variables, including age, gender, comorbidity, transfusion requirement, medication, and whether the enteroscopy was first-time, on diagnostic yield were first evaluated using univariate logistic regressions. Subsequent multivariate logistic regressions were performed to evaluate the impact of SBE timing adjusted for those significant clinical variables. All data were analyzed using the IBM Statistical Package for Social Sciences (SPSS version 22; SPSS, Chicago, IL., US.). The significance level was set at P < 0.05.
Results Patients We identified 292 consecutive patients who underwent totally 415 SBE procedures for suspected small bowel bleeding during the study period. Of these, 249 patients (355 SBEs) presented with overt bleeding. Twenty-nine patients were excluded because of prior positive findings on CT (22 patients), VCE (5 patients), or nuclear bleeding scan (1 patient), and undocumented time of bleeding onset (one patient). As a result, 220 patients were eligible for the study (Fig. 1). The mean age was 65.6 18.1 years, and 47.7% of the cohort were male. The most common presenting symptoms were melena (60.9%), followed by hematochezia (23.6%) and mixed bloody stool (15.5%). During the bleeding episode, 68.6% of patients required transfusion, 77.3% had comorbidities, and 23.6% were taking medications that may have potentiated bleeding (e.g., anti-platelet agents, anticoagulants, nonsteroidal anti-inflammatory drugs [NSAID], and steroids. Table 1).
SBE Altogether, 324 SBEs were performed on 220 patients, including 80 patients who had received multiple SBE sessions (Fig. 2). The average number of SBE sessions per patient was 1.47 0.82 (Table 1). Following the selection
Figure 1 Flow diagram illustrating the process of identifying the study cohort. SBE, single-balloon enteroscopy; CT, computed tomography; VCE, video capsule endoscopy.
Table 1
Characteristics of study subjects.
Number of patients Age (year, mean SD) Male Clinical presentation Melena Hematochezia Mixed Comorbidity Heart disease Hypertension End-stage renal disease Cirrhosis Diabetes mellitus Connective tissue disease Malignancy Medication Anti-platelet agent Anti-coagulant NSAID Steroid Transfusion requirement SBE sessions per patient (mean SD, maximum) Positive finding SBE sessions needed to find the bleeding source (mean SD, maximum) Timing of SBEa Emergency (24 h or continued bleeding) >24 and 72 h >3 and 7 days >7 days
220 65.6 18.1 105 (47.7%) 134 (60.9%) 52 (23.6%) 34 (15.5%) 65 (29.6%) 104 (47.3%) 42 (19.1%) 26 (11.8%) 59 (26.8%) 5 (2.3%) 43 (19.6%) 33 (15.0%) 5 (2.3%) 10 (4.6%) 8 (3.6%) 151 (68.6%) 1.47 0.82, 8 144 (65.5%) 1.36 0.82, 8
64 28 41 87
(29.1%) (12.7%) (18.6%) (39.6%)
SBE, single-balloon enteroscopy; NSAID, non-steroidal anti-inflammatory drug. a Interval since the onset of bleeding symptoms.
Please cite this article as: Tu C-H et al., Early timing of single balloon enteroscopy is associated with increased diagnostic yield in patients with overt small bowel bleeding, Journal of the Formosan Medical Association, https://doi.org/10.1016/j.jfma.2019.01.003
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Figure 2 A 61-year old woman presented with recurrent episodes of transient melena associated with severe anemia. She had received three repeated antegrade SBEs in the past 7 months but the bleeding source was not identified. Finally on the fourth SBE, a non-bleeding Dieulafoy’s lesion in the third portion of duodenum was identified (a, b), with inducible bleeding upon probing (c), and was managed with multiple hemoclipping (d). There was no more recurrent bleeding up to 2.5 years of follow-up. SBE, singleballoon enteroscopy.
process described above, only 220 SBE procedure-related data were collected for analyses (Fig. 1). The overall diagnostic yield rate was 65.5%. The most prevalent positive diagnosis was vascular lesion (25.5%), followed by ulcers (18.2%), tumors (9.6%), diverticulum (7.7%), and others (4.6%, including portal hypertensive enteropathy, diffuse petechial hemorrhage secondary to bleeding diathesis, infectious enteritis, unspecified ileitis, Mallory-Weiss tear, Crohn’s disease, and intestinal hookworm infection). In 32 patients the bleeding source was located within reach of EGD or colonoscopy (14.5% of patients, 22.2% of bleeding source). Therapeutic procedures were carried out in 100 (45.5%) patients. The average procedure time was 65.4 29 min for antegrade SBE, and 86.5 35.7 min for retrograde SBE. Major adverse events occurred in two (0.9%) patients, including a delayed perforation secondary to thermocoagulation therapy, and a fatal sepsis in a 93-year-old uremic woman (Table 2).
Timing of SBE Sixty-four (29.1%) patients had received emergency SBE, while 28 (12.7%) had SBE within 24e72 h of the onset of bleeding, 41 (18.6%) within 3e7 days, and 87 (39.6%) after 7 days. Among the four groups, the diagnostic yield rates were 90.6%, 67.9%, 68.3%, and 44.8%, respectively. There was a significant (P < 0.0001) downtrend across the groups (Fig. 3). A similar trend was detected in patients found to
Table 2 Single-balloon enteroscopy for the 220 patients with suspected small bowel bleeding. First-time enteroscopy Routes of insertion Antegrade Retrograde Duration of procedure (minutes, mean SD) Antegrade Retrograde All Insertion depth Antegrade (n Z 142) Proximal jejunum Middle jejunum Distal jejunum and deeper Retrograde (n Z 78) Distal ileum Middle ileum Proximal ileum and deeper Therapeutic procedure Major complications Small bowel perforation Sepsis
80 (57.1%) 142 (64.6%) 78 (35.5%) 65.4 29.0 86.5 35.7 72.8 33.1
12 (8.5%) 42 (29.8%) 67 (47.5%) 14 (18%) 33 (42.3%) 27 (34.6%) 76 (52.4%) 2 (0.9%) 1 1
Please cite this article as: Tu C-H et al., Early timing of single balloon enteroscopy is associated with increased diagnostic yield in patients with overt small bowel bleeding, Journal of the Formosan Medical Association, https://doi.org/10.1016/j.jfma.2019.01.003
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Figure 3 Comparisons of diagnostic yield rates of primary SBE stratified by different procedure timings. SBE, single-balloon enteroscopy. * 24 h after onset or continued bleeding on the day of SBE.
have tumor (n Z 21, P < 0.0001), but not in patients with vascular lesions (n Z 56, P Z 0.10), ulcers (n Z 40, P Z 0.63), diverticulum (n Z 17, P Z 0.18), or other bleeder lesions (n Z 10, P Z 0.21). Comparing between groups, there was a significant difference between the emergency group and the 24e72 h group (P < 0.0001), and between the 3e7 days group and the >7 days group (P < 0.05), but not between the 24e72 h group and the 3e7 days group (P Z 0.97; Fig. 3).
Impact of SBE timing Univariate logistic regression showed that earlier SBE timing was associated with increased diagnostic rate, either emergency SBE (odds ratio [OR] Z 7.87, 95% confidence interval [CI] Z 3.21e19.31; P < 0.0001, vs. nonemergency), SBE within 3 days (OR Z 4.67, 95% CI Z 2.43e8.98; P < 0.0001, vs. > 3 days), or SBE within 7 days (OR Z 4.62, 95% CI Z 2.55e8.36; P < 0.0001, vs. > 7 days, Table 3). For other clinical variables, age (OR Z 1.02 for every 1 year older, 95% CI Z 1.00e1.04; P < 0.01), firsttime SBE (OR Z 4.13, 95% CI Z 2.28e7.45; P < 0.01), and transfusion requirement (OR Z 2.10, 95% CI Z 1.17e3.79; P < 0.05) were also associated with increased diagnostic yield. Whereas gender, heart disease, cirrhosis, end-stage renal disease, diabetes mellitus, connective tissue
disease, malignancy, and medications affecting coagulation were not statistically significant. In subsequent multivariate analysis, the effect of SBE timing was adjusted for age, first-time SBE, and transfusion requirement. Emergency SBE had an adjusted OR (aOR) of 7.47 (95% CI Z 2.90e19.25; P < 0.0001) for a positive diagnosis compared to non-emergency SBE. Likewise, SBE within 3 days had an aOR of 4.61 (95% CI Z 2.26e9.40; P < 0.0001) compared to SBE > 3 days, and SBE within 7 days had an aOR of 4.34 (95% CI Z 2.25e8.36; P < 0.0001) compared to SBE > 7 days (Table 3).
Discussion The study results showed that emergency SBE performed during active bleeding or within 24 h of bleeding onset had a 7.3-times greater chance of finding the bleeding source than SBE performed at a later timeframe. The benefit of earlier SBE was greatest within the first 24 h of bleeding onset, and gradually declined over the following seven days and beyond. However, once bleeding stopped and emergency SBE was not likely, SBE performed as soon as 24e72 h had no clear advantage over SBE performed during 3e7 days. Even if the bleeding had stopped upon admission, scheduling an SBE within seven days was worthwhile, since it would then provide a four-fold greater likelihood of a
Please cite this article as: Tu C-H et al., Early timing of single balloon enteroscopy is associated with increased diagnostic yield in patients with overt small bowel bleeding, Journal of the Formosan Medical Association, https://doi.org/10.1016/j.jfma.2019.01.003
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Regression analysis of early SBE timing as a predictor of a positive finding (n Z 220).
Regression model according to definition of early timing b
1. Emergency vs. non-emergency 2. 3 days vs. > 3 days 3. 7 days vs. > 7 days
Multivariate analysisa
Univariate analysis OR
95% CI
P value
aOR
95% CI
P value
7.87 4.67 4.62
3.21e19.31 2.43e8.98 2.55e8.36
<0.0001 <1111 0.0001 <0.0001
7.47 4.61 4.34
2.90e19.25 2.26e9.40 2.25e8.36
<0.0001 <0.0001 <0.0001
SBE, single-balloon enteroscopy; OR, odds ratio; CI, confidence interval; aOR, adjusted odds ratio. a In multivariate regression, SBE timing was adjusted for age, first-time enteroscopy, and transfusion requirement. The aOR for age (per 1 year older, 95% CI; P value) was 1.02 (1.00e1.02; 0.049) in model 1, 1.02 (0.99e1.03; 0.07) in model 2, and 1.02 (0.99e1.03; 0.08) in model 3. The first-time enteroscopy aOR was 4.60 (2.36e8.96; <0.01) in model 1, 4.94 (2.54e9.63; <0.01) in model 2, and 4.89 (2.51e9.53; <0.01) in model 3. The transfusion requirement aOR was 1.92 (1.02e3.62; 0.04) in model 1, 1.83 (0.98e3.44; 0.059) in model 2, and 1.62 (0.86e3.06; 0.14) in model 3. b 24 h after onset or continued bleeding on the day of SBE.
positive diagnosis. Based on the results, we recommend that when deep enteroscopy is considered for the evaluation of suspected small bowel bleeding, it would be optimal to carry out the procedure within the first seven days. The optimal timing for enteroscopy has seldom been addressed in clinical guidelines or management algorithms for small bowel bleeding.2,4,16,17 The European Society of Gastrointestinal Endoscopy guidelines suggest that deviceassisted enteroscopy should be done as soon as possible; however, this statement appears as a weak recommendation based on low-quality evidence.21 Although the present study is not the first that looked into the clinical effect of early timing,14,18,20,22e24 it would provide a stronger evidence by enrollment of the largest cohort of patients and so has allowed more precise estimation while adjusting for potential confounding variables. Multiple studies had already shown the diagnostic advantage of early VCEs or DBEs, though the definition of early timing varied among different studies, either 48 h, 3 days, 15 days, or 1 month.11,14,15,20,25 In the same way, the present study also found superior diagnostic rates of early SBE, set at either 24 h, 3 days, or 7 days. However, our results provide additional insight into how diagnostic yield decreases over the first few days of waiting. By sorting the SBE timing based on the levels of urgency, we were able to demonstrate a clear trend of declining diagnostic yield as procedure waiting time increased. Unlike the studies that compared urgent enteroscopy performed within 24 or 72 h with enteroscopy occurring outside of that interval,20,22,23 we extended the set point to seven days. As a result, we can justify whether a deep enteroscopy should still be performed urgently even when 72 h have passed, like the majority of cases. Meanwhile, much fewer studies used SBE as the deep enteroscopy of choice. Nelson et al. reported that in 110 patients with obscure gastrointestinal bleeding, emergency SBE within 24 h was associated with more radiological intervention and shorter hospital stays but without an increase in diagnostic yield.23 Compared to Nelson’s study, the present study design differs in how procedure timing was defined and this should probably the main reason behind the discrepant study results. Unlike most studies that defined the onset of bleeding at the time of hospital presentation or admission,11,15,23,25 we set at the time of first bleeding symptom so that the possible delays in being
seen by a physician (e.g., ease of accessing healthcare, delay due to transition of care) were taken into account. Several pathophysiologic characteristics of the small intestines might have strengthened the association between endoscopic timing and diagnostic sensitivity. For example, Dieulafoy’s lesions and angioectasias are among the most common small bowel bleeders, which are submucosal lesions and require ruptures of both vessel wall and overlying mucosa to produce bleeding. Therefore, bleeding tends to resolve spontaneously in a limited interval that is nevertheless long enough for clot formation, vascular wall repair, and epithelial regrowth; usually a matter of minutes to a few days.26,27 Other leading causes of small bowel bleeding, such as diverticulosis and NSAID enteropathy, also tend to cease bleeding rapidly.28,29 Once bleeding stops, the thin tube structure and unidirectional flow in the small intestine allow limited space for blood or clot retention, and thereby reduce the chance of being visualized. The present study has several strengths. First, the size of our cohort allowed us to conduct comprehensive multivariate analyses. Second, a single operator study largely eliminated the concern of inter-operator variability in endoscopic reading and human skills, although external applicability may be affected. Third, as much as 29% of the patients were able to receive emergency SBE during active bleeding or on the same day of first bleeding symptom. This was essential for prompt stratification of patients and multiple comparative analyses. We achieved this by providing emergency SBE consultation available at any time, and by offering emergency phone call instructions to the patients with negative SBEs but who were at risk of recurrent bleeding. Our study is not without limitations. First, since this study was not a randomized trial, the waiting time for SBE might have been affected by selection bias. For example, the frequency of finding tumor out of all source of bleeding was higher in emergency SBEs but obviously lower in SBEs of >3 days’ delay (Fig. 3), a finding that reflected the likely presence of survivorship bias. It is understandable that patients with more severe overt bleeding will receive more urgent endoscopy, and the acute and brisk lesions could be identified more easily at early enteroscopy. To address this, we conducted multivariate analysis to adjust for potential confounding factors. We did not include patients with
Please cite this article as: Tu C-H et al., Early timing of single balloon enteroscopy is associated with increased diagnostic yield in patients with overt small bowel bleeding, Journal of the Formosan Medical Association, https://doi.org/10.1016/j.jfma.2019.01.003
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Early deep enteroscopy for small bowel bleeding known small bowel findings prior to SBE as a means to minimize channeling bias. For example, physicians may had become more aggressive when active bleeder lesions were found on VCE. Second, since we defined different early timings with reference to symptom onset, recall bias was inevitable. Regarding this, we set multiple time points at shortly after the start of symptoms but no more if the waiting interval was beyond 7 days. Third, the retrospective design and single-center data were susceptible to selection bias. The single operator in this study, as mentioned previously, might have also reduced the generalizability of this study. Lastly, and most importantly, the data source did not provide sufficient information on clinical outcomes correlated to the SBE procedures. For example, rebleeding rates and time free from rebleeding would be more clinically relevant than endoscopic finding as the main study endpoint. Without follow up data, the true benefit generated by a positive SBE finding would remain hypothetical. A future prospective study, ideally a randomized trial, is warranted. Based on the study results, a positive diagnosis is most likely if SBE can be performed immediately after bleeding. More importantly, if performed early enough within the next seven days, it remains at least four times more likely to find the bleeding source compared to a SBE that waits longer. Our findings would justify the intention to perform deep enteroscopy urgently even when seven days have elapsed. Enteroscopy providers, primary care physicians, and secondary referring personnel should acknowledge the importance of timing and expedite their role in the management process as soon as small bowel bleeding is suspected. Further studies are warranted. The benefit of early timing beyond Day 7 remains unclear, and this is nevertheless important as 40% of patients fell into this category in the present study. Whether primary deep enteroscopy deserve a role similar to VCE as the initial option for smallbowel examination will remain questionable until further comparative data and cost-benefit studies emerge.
Conflict of interest The authors have no conflicts of interest relevant to this article.
Disclosure statement This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
Author contributions H.M.C. and M.S.W. conceived the study; C.H.T. and J.Y.K. designed the study; C.H.T., P.H.T., C.C.C., T.H.C., Y.C.L, and H.P.W. carried out the collection, analysis, and interpretation of the data; C.H.T. and J.Y.K. wrote the manuscript; H.M.C. and P.H.T. performed critical revision of the manuscript; M.S.W. granted the final approval of the article. All authors approved the final submission manuscript.
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Appendix A. Supplementary data Supplementary data to this article can be found online at https://doi.org/10.1016/j.jfma.2019.01.003.
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Please cite this article as: Tu C-H et al., Early timing of single balloon enteroscopy is associated with increased diagnostic yield in patients with overt small bowel bleeding, Journal of the Formosan Medical Association, https://doi.org/10.1016/j.jfma.2019.01.003