A novel food-based foam as oral contrast agent with negative Hounsfield units for demarcation of small bowel loops on abdominal CT: tolerability and bowel distension in 25 volunteers

Abstract

Background

Diseases of the bowel are not always displayed on conventional abdominal computed tomography (CT). The studied oral contrast agent aims to improve this.

Purpose

To investigate whether the use of a novel oral contrast for abdominal CT enables the same diagnostic advantages as seen in magnetic resonance imaging (MRI).

Material and Methods

Twenty-five consented volunteers drank up to 1400 mL of a stable, drinkable foam. Comments on acceptance and side effects were noted immediately and 24 h later. Foam palatability was documented through interviews, and distribution in the small bowel by Hounsfield units from the CT software. The CT results were compared with age- and sex-matched controls, pretreated according to routine. A non-enhanced abdominal CT protocol of lowest possible radiation dose was used. External referees evaluated all data obtained.

Results

Foam was considered odd to swallow, and fullness was reported by all volunteers after 950 mL. Five had difficulties in drinking the last 320 mL and two abstained from it. All adverse symptoms were mild. The distribution in the small bowel was on par with standard agents. Foam density revealed stability with intraluminal values of around –550 HU from stomach to terminal ileum, satisfying the requirement of a great bowel lumen-to-wall contrast. External reviewers re-evaluated all our data, and one predicted the foam to offer a potential for improved diagnostics.

Conclusion

A CT true-negative bowel filling agent was formulated, with high acceptance, few side effects, and a potential to mimic T1-weighted MRI images.

Keywords

Imaging computed tomography small bowel oral contrast negative Hounsfield Units

Introduction

Patients referred for examination with computed tomography (CT) of the abdomen are, as a rule, prepared with an oral liquid contrast medium (CM) for demarcating loops of small bowel (SB) from the abdominal and pelvic organs (1). Most oral CM are based on iodine (2), which results in an intraluminal appearance with positive Hounsfield Units (HU). Other options include slightly osmotic solutions based on either polyethylene glycol (3,4), sorbitol, or Mannitol (5,6), keeping water in the SB and creating luminal densities near that of water, i.e. around 10–20 HU, hence denominated as neutral CM. The rationale behind a neutral solution is to increase attenuation difference between the SB wall and lumen, further increased by an intravenous (i.v.) iodine CM (7). The amplified difference between the SB wall and lumen will improve the diagnostics of the mucosal lining and of lesions in the bowel wall and its proximity. This knowledge is implemented in CT protocols aimed at pancreatic cancer (8). A high attenuation difference between lumen and mucosal lining is also a prerequisite for virtual three-dimensional (3D) presentation, similar to CT colonoscopy (9).

An intensified SB wall is currently depicted on images acquired with magnetic resonance imaging (MRI) technique (10). On T1-weighted (T1W) MRI sequences, the SB lumen appears dark. After administration of i.v. gadolinium contrast, the SB wall enhances and contrasts to the lumen, particularly in a case with inflammatory bowel disease (IBD) and facilitates and improves diagnostics (11,12). Unfortunately, the availability of MRI equipment is rather limited compared to that of CT, and is therefore mostly reserved for young patients with IBD, for those who need repeated imaging, and for those with complicated diseases of the SB. In addition, MRI is more suited for examining dedicated parts of the abdomen, i.e. with focus on various organ systems, whereas abdominal CT is well suited for examining the entire abdomen in seconds, often including the thorax as well.

Thus, most patients with abdominal problems, including those with problems allegedly emanating from the SB, who need imaging are referred for abdominal CT. It would therefore be desirable to present CT images with a dark SB lumen, not least for the clinically silent SB lesion to be unveiled. A “black” bowel lumen would be advantageous in all patients for abdominal CT. Interestingly enough, scientists have been eager to pursue this idea since the 1980s (see reference lists of patents). Furthermore, radiologists have for decades expressed a wish for a negative gut contrast in order to improve diagnostics and tested several agents based on fat and bubbles (13 –17). Many of these bowel-filling agents have been denominated as being negative although measuring with positive HU (18). Still, the use of a neutral oral CM, with HU of around that of water, have been established in clinical routine due to improved CT diagnostics (19,20).

The aim of the present series was to ascertain whether a foam-based contrast agent would provide bowel loops with a black lumen, from pylorus to cecum. Additional aims included acceptance of the novel agent by the patient, no serious side effects, and that the diagnostic reading of abdominal CT would not be hampered.

Material and Methods

We tested an entirely food-based substance for filling the SB, Lumentin™ 60 (L60), henceforth referred to as “the foam.” It measures –500 HU to –600 HU on CT images. It is a dispersion of micro air bubbles in an aqueous phase, defined as a 60% air content containing 1% egg albumen, 0.25% stabilizer, 0.25% flavor, and buffer to withstand various pH conditions of the gastrointestinal tract (Table 1). To ascertain whether the buffers used had no influence on serum electrolytes, venous blood samples of 2 mL were retrieved before and 1 h after ingestion of the foam.

Table 1.

The composition of the novel, entirely food-based contrast agent with true-negative HU on CT, with 60% air content (150 mL of air per 100 g of dispersion).

Substances	g/100g
Water	97.2
Egg albumen powder	1.0
Disodium phosphate	1.0
Monopotassium phosphate	0.3
Xanthan gum	0.2
Flavor	0.2

CT, computed tomography; HU, Hounsfield unit.

The test substance was whipped from 550 mL to 1.3–1.4 L of foam. Foam stability was assessed by determining air content by weight, bubble size by optical microscopy, and signs of separation (liquid drainage) by the naked eye.

Twenty-five healthy volunteers were recruited (aged > 45 years). Written informed consent was obtained. They had nil by mouth 4 h before being admitted 1 h before the CT examination. Four cups of foam were ingested in 45–60 min, to a maximum of 1400 mL. The abdominal CT examination was initiated after drinking. An abdominal protocol without i.v. iodine CM was chosen, with the lowest possible radiation dose, i.e. tube kilovoltage of 120 kV and a reference mAs of 40. The volunteers were positioned supine.

The volunteers each had an abdominal CT examination and were followed up by phone 24 h later. Side effects were spontaneously reported and answers to open questions were noted.

Two radiologists, specialized in abdominal radiology, read the images on workstations. The length of the SB was divided into six regions. Eleven big luminal 6-mm regions of interest (ROI) were plotted for HU measurements. Stable values of intraluminal HU_mean were interpreted as signs of foam homogeneity, whereas a wide SD was a sign of foam inhomogeneity.

Linear extension and local distension of the foam were assessed using a 9-point Likert scale, from “none” (grade 1) to “excellent” (grade 9) (21,22). Grade 5 corresponded to a bowel segment that was “half filled.” Grades in between allow for modifications in either direction.

The study was approved by the Institutional Review Board/local Ethical Committee (Dnr. 2015/912) and Institute of Radiation Protection (SSF02015-048). We accomplished our first clinical series of abdominal CT examinations in healthy volunteers

In addition, the Ethical Committee gave permission to collect age- and gender-matched controls from our patient files, i.e. one for each of two routinely used bowel filling mixtures: iodine based (10% Omnipaque® 350 mg I/mL) and polyethylene glycol (MoviPrep®), and external referees to audit this series. The volumes ingested by the control groups, respectively, were 0.8 L and 1 L in liquid volume.

Four experts in gastrointestinal radiology were invited: two domestics in the mid-term of the project and two from abroad at the study termination.

Results

The foam showed in vitro stability for at least 1 h 5 min, i.e. visually there was no sign of separation or liquid drainage. Air content and bubble size remained unaffected.

Thirteen women were recruited (mean age = 60 years) and 12 men (mean age = 62.5 years). The age range for both genders was 52–71 years.

The amount of foam ingested was in the range of 0.9–1.5 L (mean = 1.3 ± 0.2 L). The time of drinking was in the range of 20–72 min (mean = 49 ± 15 min). The mean time from last swallow of foam and start of CT examination was 12 ± 9 min.

The taste and foamy consistency were deemed acceptable by all. Six volunteers remarked difficulties with the last, fourth cup, two of whom refrained from drinking after having had 0.9 L.

Registered side effects (Table 2) were mild (15), with no need to intervene: abdominal distension was reported by four volunteers, eructation by seven, nausea by three, and flatulence by two during and two others after drinking. Two volunteers mentioned single episodes of loose stools in the morning. Night sleep and daily eating habits were not influenced.

Table 2.

Number of treated individuals with related adverse effects by preferred term (MedDRA) and severity after treatment with the preliminary formulation L60. (n, N = 25).

	During the intake				After intake within 24 h*
Adverse effects	Mild	Moderate	Severe	Total	Mild
Abdominal discomfort	1	–	–	1	–
Abdominal distension^†	3	1	–	4	–
Diarrhea^‡	–	–	–	–	2
Eructation	5	2	–	7	–
Flatulence	2	–	–	2	2
Nausea	2	1	–	3	–

*Only mild symptoms were reported after 24 h.

^†The code abdominal distension includes both fullness and distension.

^‡Single episodes of “loose morning motion” were reports, not diarrhea.

The axial extension and the local distension of the three bowel filling contrast materials for each of six parts of the SB is evident from Tables 3 and 4.

Table 3.

Assessment of extension (Ext) and distension (Dist) of three bowel-filling contrast media in the proximal half of the small bowel.

	Duodenum		Jejunum		Proximal ileum
	Ext	Dist	Ext	Dist	Ext	Dist
L60 (n = 25)
Min	2	2	2	2	2	2
Median	4.00	3.00	4.00	4.00	5.00	4.00
Max	8	7	7	7	8	8
Mean	4.24	3.16	4.48	4.44	5.36	5.00
Std	2.13	1.46	1.45	1.23	1.75	1.80
Omnipaque® (n = 25)
Min	1	1	1	1	1	1
Median	3.00	3.00	4.00	4.00	6.00	5.00
Max	7	7	7	7	7	7
Mean	3.52	3.00	4.00	3.60	5.40	4.56
Std	1.92	1.63	1.55	1.50	1.96	1.66
MoviPrep® (n = 25)
Min	2	2	3	2	4	3
Median	4.00	3.00	5.00	4.00	6.00	5.00
Max	6	7	7	6	8	7
Mean	3.92	3.40	4.80	4.24	5.76	4.80
Std	1.29	1.32	1.26	1.27	1.05	1.08

A scale of nine was used. Omnipaque® is an iodine-based contrast and MoviPrep® is based on polyethylene glycol. L60 stands for the new HU-negative agent.

Table 4.

Assessment of extension (Ext) and distension (Dist) of three bowel-filling contrast media in the distal half of the small bowel.

	Mid	Ileum	Distal	Ileum	Terminal	Ileum
	Ext	Dist	Ext	Dist	Ext	Dist
L60 (n = 25)
Min	5	3	4	4	2	2
Median	6.00	5.00	5.00	5.00	6.00	5.00
Max	9	9	9	8	9	8
Mean	6.16	5.92	5.68	5.36	5.72	5.08
Std	1.18	1.47	1.31	1.08	1.65	1.55
Omnipaque® (n = 25)
Min	3	3	1	1	1	1
Median	7.00	6.00	7.00	5.00	3.00	3.00
Max	7	7	7	7	7	7
Mean	6.56	5.64	5.72	4.88	3.92	3.12
Std	1.00	1.22	1.97	1.86	2.72	2.09
MoviPrep® (n = 25)
Min	4	3	3	3	1	1
Median	7.00	5.00	7.00	5.00	6.00	5.00
Max	8	7	8	7	7	7
Mean	6.40	5.32	6.36	5.20	5.56	4.48
Std	0.91	1.14	1.04	1.26	1.39	1.29

Omnipaque® is an iodine-based contrast and Moviprep® based on polyethylene glycol.

No in vivo foam degradation, i.e. neither separation nor bubble formation, was evident from the CT images. Given the mean values of HU (ROIs of 6 mm) per segment indicate axial foam stability. The range of HU increases down the gastrointestinal tract, indicative of bowel content of solids and gas left behind (Table 5).

Table 5.

Mean intra luminal ROI values from seven parts of the gastrointestinal tract.

Part of bowel	Mean HU	Range HU	Comments*
Stomach	–566	–560 to –600	n = 25
Duodenum	–530	–490 to –650	n = 17
Jejunum	–560	–490 to –650	n = 24
Proximal ileum	–530	–477 to –530	n = 24
Mid ileum	–570	–491 to –700	n = 25
Distal ileum	–570	–425 to –700	n = 25
Terminal ileum	–540	–470 to –650	n = 20

Figures denote negative Hounsfield units. A region of interest was et to 6 mm in diameter. Range denotes the highest and lowest HU recorded per segment.

*n corresponds to number of volunteers in whom the new, HU-negative foam (L60) filling was sufficient for HU measuring.

The feathery aspect of the jejunal mucosa, and the anatomy of folds in the distal and terminal parts of the ileum, was obvious on moderately well-distended loops with each of the three oral-filling agents. With increasing bowel distension, mucosal folds were still depicted on par in profile, while on images with well distended bowels, folds were only discernible in coronal view when filled with foam (Fig. 1–3).

Blood samples for testing sodium, potassium, calcium, and phosphate, before and 1 h after the ingestion of the foam, revealed results within normal ranges in all but two volunteers. Serum phosphate increased from 1.2 mmol/L before to 2.2 and 2.4 mmol/L after drinking, exceeding the normal upper limit of 1.5 mmol/L with 0.7 to 0.9 mmol/L, respectively. At the follow-up interviews 24 h later, both testified to their wellbeing and refrained from further interventions. All four external reviewers corroborated our results.

Discussion

In the present study, an entirely food-based, drinkable foam showed the unique quality to fill and mark the SB lumen in hundreds of negative HU, somewhere in between those of fat and gas, i.e. displayed in black on an abdominal window setting and white on inverted images (Figs. 1 and 2). On a lung window setting, the formulation is shown in gray, readily discernible from any natural, intra-, or extra-luminal gas. Thus, the formulation will never cause confusion with medical conditions causing accumulation of either gas or fluid.

Fig. 1.

Images from a volunteer examined with abdominal computed tomography after per-oral pretreatment with the new negative, food-based contrast mixture. (a) Abdominal window setting, (b) lung window setting, and (c) inverted image.

Fig. 2.

The mean intraluminal value of the foam was in the range of–400 HU to –700 HU. The extreme values may be explained by foregoing bowel solids incorporated into the foam by peristalsis, and endogenous gas being pushed ahead towards distal segments (Table 5). The mean HU values of the foam itself were stable throughout the gastrointestinal tract with no indication of separation.

It is indicated in this first study that the HU-negative foam is at least as good as currently used filling agents in demarcating loops of bowel. It offers both unprecedented bowel wall-to-lumen contrast and visualizes mucosal folds well against the “black” lumen (Fig. 3).

Fig. 3.

Mucosal folds depicted in the coronal view after filling loops of the small bowel with the new negative contrast agent. (a) Lung window setting and b) (abdominal window of the same image.

To get an understanding of how well the new foam performed, the local ethics committee granted us the right to compare it with our two clinically used bowel filling agents, one being a 10% solution of iodine (350 mg I/mL) and the other polyethylene glycol (ca. 10 HU). To minimize any influence of medical conditions on comparing bowel filling, we excluded emergency patients and those with suspected bowel obstruction or inflammation. Whether the results were affected by the different liquid volumes ingested is not known. The volume 1.3–1.4 L of foam was based on the assumption that this amount would be possible for most adults to ingest within 1 h (27). Moreover, beverages of equal volumes containing sugar alcohols are probably superior to alternative agents, i.e. other things than volumes also matter (23). In 25 healthy volunteers, the foam provided luminal distention on par with or slightly better than the routinely used one (6). The good outcome of distension by the foam must be verified in patients.

Other scientists have researched the possibility of decreasing intraluminal HU below zero to improve visualization of the bowel wall and detectability of any mucosal abnormality (17). They dispersed stabilized microbubbles in a polymeric solution into a foam which acted as a negative CM. However, the present study is the first to clearly show how it compares to other existing oral regimes in a clinical setting.

Other groups have also shown oral bowel filling contrasts with HU around that of water, demonstrating it to be advantageous to positive oral CM for evaluating inflammatory bowel diseases with abdominal CT (23). Obviously, high signals that stand out from a complex, low-signal background, will attract the observer’s attention, for instance a bowel wall with positive HU against intraluminal density of around 20 HU. This difference is augmented when a SB lesion, rich in blood supply, is present (24). Hence, it is fair to assume that an improved difference in contrast density between an iodine-enhanced SB wall and a true Hounsfield-negative bowel lumen will be advantageous, a difference incidentally achieved today when endogenous gas distends a loop of bowel.

In T1W MRI, intrinsically high contrast is achieved between the lumen and the SB wall, and therefore MRI many times serves as the first technique of choice in imaging SB diseases. Both inflammatory lesions and most tumors of the SB are hyperemic and stand out bright against a dark lumen on T1W sequences (9). Even the odd, asymptomatic SB lesion, such as a small carcinoid, can be seen (25). By using the present food-based oral agent, it may be possible to achieve similar advantages with CT. With the CT technique used today, SB examinations are performed with a Hounsfield-neutral beverage to improve the mucosa-to-lumen difference in contrast (26), thereby facilitating diagnostic evaluation of type and severity of disease. However, SB lesions poor in vascularity will stand out less well.

A less favorable effect seen was retention of foam in the stomach. The reason for administering the last cup was to ascertain a good filling of the duodenum and jejunum, which was not initially achieved. The last volunteers were therefore given time to rest in right lateral decubitus for some minutes before the CT examination with improved filling of these segments. An even distribution of the foam from pylorus to the cecum failed in some volunteers, mostly explained by peristaltic contractions, but an irregular intake might be another reason. Ongoing product development includes optimization of the luminal filling, patient acceptability without hampering the favorable profile of side effects.

All volunteers felt various degrees of satisfaction at the end of the intake. Eleven volunteers had no problems while drinking. Side effects were related to the large volume ingested, i.e. saturation and fullness, and to the consistency of the foam. No negative influence on intake of meals after the examination was reported. Only two volunteers commented on a single bowel movement that was unusually loose. Three complained of nausea, two with only mild and transient symptoms. The third had to stop drinking after 700 mL. When asked, others reported on burping and some flatulence, but deemed unobtrusive. Four participants had very mild symptoms such as flatulence and loose stool. Most of the adverse effects were commented by the volunteers to be very mild and probably variations of normality. Walking around during intake made drinking easier and mitigated symptoms. Immediately after the test, and at the follow-up interview, all volunteers stated a normal food intake and undisturbed sleep at night.

The external experts verified our results and expressed their view that radiologists in general would have no objections to read abdominal CT examinations with “black” bowels. Three of them anticipated that the test substance had potential to facilitate diagnostics of SB lesions. Affirmation of this prospect is pending and will be dealt with in forthcoming patient studies.

Another possible method of examination is virtual endoscopy using the present oral contrast agent. Work in progress is promising enabled by the large difference in HU between the lumen and mucosa.

In conclusion, for the first time, a per-oral, true HU-negative contrast agent has been tested in humans. It is a food-based foam with a unique roentgenographic character with distribution throughout the SB and HU in between those of fat and gas. It is stable with approval of taste, consistency, and drinkability. Side effects were few, mild, and transient, and the results encourage further studies.

Footnotes

Declaration of conflicting interests

The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: IA, OB, LC-D and TF are together minor shareholders in Lument AB.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This research work was partly funded by Grants from Vinnova, from Torsten & Karin Almén’s research fund, and by Lument AB, Lund, Sweden.

List of patents

1. Peter W. Field: “Negative contrast agent” CA1116084 (1982).

2. Hasegawa Hideo et al.: X-ray contrast composition for digestive tract JPH06228013 (1994).

3. Unger Evan C. “Stabilized homogeneous suspensions as computed tomography contrast agents” US5736121 (1998).

4. Unger Evan C. “Gaseous precursor filled microspheres as magnetic resonance imaging contrast agent” US5922304 (1999).

5. Unger Evan C. “Method of computed tomography using fluorinated gas-filled lipid microspheres as contrast agents” US6117414 (2000).

6. Unger Evan C. “Method of computed tomography using fluorinated gas-filled lipid microspheres as contrast agents” US6117414 (2000).

7. Wei Xiaohui et al. “CT negative contrast medium of aqueous matrix for digestive tract and the preparation method thereof”. EP2050470 (2009) or US2010166668 (2010).

8. Wei Xiaohui et al. “Aqueous negative contrast medium for CT imaging of the gastrointestinal tract and the preparation method thereof”. US8747812 (2014) or WO2007131390 (2007) or CN2006001063 (2006).

9. Hong Suk; Soo Won Seo. “Contrast composition containing x-ray contrast agent and air bubble promoting agent, and preparation method therefore” KR2014005968 (2014) or WO2015002485 (2014).

10. Xiaohui Wei; Jianrong Xu; Yuhong Xu. “Aqueous negative contrast medium for CT imaging of the gastrointestinal tract and the preparation method thereof” US8747812 (2014); CN2006001063 (2006); WO200713139 (2007).

11. Xiaohui Wei; Jianrong Xu; Yuhong Xu. “CT negative contrast medium of aqueous matrix for digestive tract and the preparation method there of” US2010166668 (2010).

ORCID iD

Peter Leander

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