Applications in Contrast Imaging

Clinical Utility of Barium Sulfate Products: Formulation Determines Appropriate Use

Steven Sireci, MD

Supported by an educational grant from Bracco Diagnostics, Inc. 2 APPLICATIONS IN CONTRAST IMAGING

CE Information Clinical Utility of Barium Sulfate Products: Formulation Determines Appropriate Use

Summary

Barium-containing contrast media contain barium sulfate (BaSO4), as well as a number of additives. The BaSO4 provides radiodensity (ie, radio-opacity) and physical density (g/mL) to the suspension. Depending on the intended use of the contrast, the specific combination

of additives provide other useful properties, including: BaSO4 particle suspension; mucosal coating; viscosity and texture; sweetness; filling and laxative effects; preservation; foaming prevention; and flavoring.Here we describe the purpose of each ingredient and additive found

in BaSO4 contrast media products currently available for fluoroscopic and radiographic examinations. In addition, we review the role of these products in anatomic radiographic evaluation of the gastrointestinal (GI) tract and in evaluation of the physiology of swallowing. Finally, we review barium preparations used in computed tomography (CT) applications.

Learning Objectives At the conclusion of this activity, participants should be able to:

• Explain the role that BaSO4 plays in barium-containing contrast media;

• Review the purpose of each ingredient/additive found in BaSO4 contrast media products available for fluoroscopic and radiographic examinations; • Describe the formulation of barium products that are appropriate for single- and double-contrast anatomic radiographic evaluation of the gastrointestinal (GI) tract; • Summar ize qualities of the barium-containing contrast media used in evaluation of swallowing that make them most appropriate for that application; and, • State the properties of barium-containing contrast media used in computed tomography (CT) applications.

Author

Steven Sireci, MD, is Head of Medical Services – Americas, Global Medical & Regulatory Affairs, Bracco Diagnostics Inc., Monroe Township, NJ, USA.

Financial disclosure for Dr. Sireci includes: Employee of Bracco Diagnostics, Inc., which manufactures barium sulfate products for diagnostic imaging. He has no non-financial relationships to disclose

Obtaining Credits

Instructions Accreditation Period To earn CE credit, participants must complete Release: July 1, 2021 this activity during the accreditation period and Expiration: June 30, 2023 follow these instructions. Accreditation 1. Review this article in its entirety. This article confers 0.75 ARRT Category A Continuing Education 2. Visit appliedradiology.org/aici. credit, which will be awarded upon completion of an online post test. 3. Login or create an account. The entire text of this supplement, learning objectives, and the post 4. Add activity to your account. test are available at appliedradiology.org/aici. 5. Complete the post test. 6. Complete the evaluation. Commercial Support 7. Print your certificate. This program was supported through an educational grant from Bracco Diagnostics, Inc. APPLICATIONS IN CONTRAST IMAGING 3

Clinical Utility of Barium Sulfate Products: Formulation Determines Appropriate Use

arium (Ba) is an alkaline earth metal Bfound in the second column of the A B periodic table.1 In pure form, it is a soft, silvery-white metal with a slight golden shade.1 Based on its atomic number (56), barium is excellent for blocking X-rays of the energies used in medical imaging. However, barium is too reactive to exist as a pure metal in nature1 and, therefore, cannot be administered in pure form for the purposes of medical imaging. FIGURE 1. (A) Barium sulfate salt; (B) barium sulfate chemical formula. Barium sulfate (BaSO4) is a com- mon, stable, inorganic, insoluble mineral tract and in evaluation of the physiology modified barium swallow study [MBSS] salt, used industrially as a filler for rubber, of swallowing. Finally, we review barium to evaluate swallowing physiology, in plastics, and resins2 (Figure 1). Although preparations used in CT applications. which precise viscosities are critical). difficult to dissolve in water, BaSO4 can Finally, additives are included to ensure be suspended in water with the help Barium Sulfate Formulations for that BaSO4 products are palatable, readily of additives, providing radiodensity (ie, Radiographic Procedures eliminated, non-foaming, and long-last- radio-opacity) and physical density (g/ BaSO4 itself is inert and not ab- ing. Here we review the additives that mL) to the suspension. Concentrated sorbed from the GI tract. It is present in provide each of these properties, to pro- suspensions ranging from 40% up to contrast media to provide radio-opac- vide a better understanding of how they

240% weight-to-volume (w/v) can be ity, which is determined by the BaSO4 contribute to clinical utility of the var- used in fluoroscopy and radiography for concentration, and physical density. It ious barium-containing contrast media a variety of clinical applications. To use has no pharmacologic effects, nor can (Tables 1 and 2).

BaSO4 for computed tomography (CT), it cause an allergic reaction. However, a technology that has a very exquisite if BaSO4 leaks from the GI lumen, it can Emulsifiers/Stabilizers/Dispersants discrimination of radiodensities, the sus- cause mediastinitis, peritonitis, or retro- Since BaSO4 is not soluble in water, pension has to be greatly diluted, to ap- peritonitis.3 Importantly, these adverse in order for it to be used as a contrast proximately 2% w/v. Preparations in that clinical events result from a severe medium, emulsifiers, stabilizers, and low concentration range are made and granulomatous reaction,4 and therefore dispersants must be added to main- sold for several specialized abdominal are distinct from the concepts of both tain smooth BaSO4 particle suspension, CT imaging procedures. “hypersensitivity” and “toxicity.” along with pH regulators to maintain

In addition to BaSO4, barium-con- Additives present in BaSO4 contrast suspension efficacy. One of these is taining contrast media have a number media formulations include emulsifiers, carboxymethyl-cellulose sodium, a of additional ingredients (almost all stabilizers, and dispersants to keep the negatively charged polymer that coats common food additives) that provide BaSO4 particles smoothly suspended in BaSO4 particles. At low concentrations, the important physicochemical proper- water, without which the BaSO4 parti- carboxymethyl-cellulose sodium helps ties of each product. Here we describe cles would simply sink to the bottom to suspend the particles in water via the purpose of each ingredient/additive and clump. Mucosal-coating thickeners electrostatic repulsion. Other emul- found in BaSO4 contrast media products provide stickiness, while non-coating sifiers/stabilizers/dispersants include currently available for fluoroscopic and thickeners increase viscosity. Inclusion/ sodium citrate, a dispersant that also radiographic examinations. In addition, exclusion of such thickeners is essen- helps regulate pH, and polysorbate 80, we review the role of these barium prod- tial, as mucosal coating is vital for some a surfactant that also is anti-foaming. ucts in both the anatomic radiographic applications (eg, double-contrast GI im- These 3 multi-purpose additives are evaluation of the gastrointestinal (GI) aging), while detrimental to others (eg, present in many BaSO4 preparations. 4 APPLICATIONS IN CONTRAST IMAGING

Table 1. Properties and Ingredients of Barium Products Used for Anatomic Procedures SC UGI SC UGI DC UGI SMALL BOWEL BARIUM ENEMAS PASTE (for esophagus (powder) (powder) DC: ~100% w/v or rectum)

BaSO4 CONCENTRATION ~60% w/v ~60-120% w/v ~240% w/v ~25% w/v SC: ~50% w/v ~60% w/w EMULSIFIERS/STABILIZERS/DISPERSANTS Carboxymethyl-cellulose (low conc.) X Sodium citrate X X X X X X Polysorbate 80 X X X X X MUCOSAL COATING/THICKENERS Acacia gum X X X Tragacanth gum X Carboxymethyl-cellulose (high conc.) X NON-COATING THICKENERS Xanthan gum X X X X Carrageenan X X X X Pectin X Methylcellulose X SWEETENERS/TEXTURIZERS Glycerin X SWEETENERS/LAXATIVES Sorbitol X X X X X X SOLVENT Propylene glycol X OTHERS Preservatives X X X X Conc.=concentration; DC=double contrast; SC=single contrast; UGI=upper gastrointestinal; w/v=weight/volume.

Table 2. Properties and Ingredients of Barium Products Used for MBSS THIN LIQUID (powder) NECTAR THIN HONEY HONEY PUDDING

BaSO4 CONCENTRATION 40% w/v 40% w/v 40% w/v 40% w/v 40% w/v reconstituted VISCOSITY (cPs) <15 300 1500 3000 5000 EMULSIFIERS/STABILIZERS/DISPERSANTS Carboxymethyl-cellulose (low conc.) X X X X Sodium citrate X X X X Polysorbate 80 X X X X X NON-COATING THICKENERS Xanthan gum X X X X Carboxymethyl-cellulose (medium conc.) X Modified corn starch X X SWEETENERS/TEXTURIZERS Glycerin X X X X Maltodextrin X X X SWEETENERS/LAXATIVES Xylitol X X X X X Sorbitol X OTHERS Preservatives X X X X Conc.=concentration; cPs=centipoise; MBSS=modified barium swallow study. APPLICATIONS IN CONTRAST IMAGING 5

Mucosal-coating and Non-coating sion and speeding transit time through order to see these structures, the muco- Thickeners the GI tract; at least one of them will be sal lining must get a thin, even coating of

Mucosal coating is achieved by found in all BaSO4 preparations. Sweet- a high-density, sticky BaSO4 preparation increasing the stickiness of the barium eners can also act as texturizers and/or while the lumen is filled with air or gas. product. Additives that increase sticki- thickeners, creating a food-like texture (Table 1) Therefore, the BaSO4 contrast ness include the plant saps acacia gum (“mouthfeel”) and increasing viscosity. agent must contain a sticky gum (eg, (aka, gum arabic, the sap of the acacia Glycerol also functions as a surfactant. acacia gum) for mucosal coating, and be tree) and, to a lesser degree, tragacanth highly radiodense (100-240% w/v). gum (the sap of the astragalus gummifer Others On the other hand, single-contrast shrub). Electrostatic forces can also pro- Other important additives in- upper GI imaging is used to see general vide mucosal coating, and this can be clude: anti-foaming agents, such as anatomy and anatomic lesions. The GI achieved by adding high concentrations simethicone and polysorbate 80, to structures must be filled with contrast, of carboxymethyl-cellulose sodium. ensure that the product doesn’t get which is typically not problematic in These additives also perform more than bubbly when shaken; pH regulators, in- AP or mildly oblique projections, owing one role: all 3 serve as thickeners, in- cluding citric acid, sodium citrate, HCl, to relatively little overlapping of upper creasing viscosity; acacia gum and car- and KCl, to maintain proper acid/base GI structures in those projections. boxymethyl-cellulose help suspend the balance for successful suspension; and Therefore, for this exam, the lumen

BaSO4 particles. preservatives such as sodium benzoate, must be filled with a well-mixed, mod- Non-coating thickeners increase potassium sorbate, methylparaben, and erate-density (60-120% w/v) solution of viscosity, but not stickiness, of the bar- propylparaben to increase the shelf life a non-sticky (ie, no sticky gums) BaSO4 ium product; therefore, they do not of liquid BaSO4 preparations. preparation. result in mucosal coating. Products con- Preservatives are not added to Small bowel follow-through (SBFT) taining non-coating thickeners are suit- powdered BaSO4 preparations, which examination or enteroclysis (direct able for the MBSS and single-contrast should be used shortly after reconsti- contrast administration into the small anatomic imaging, for which mucosal tution, based on manufacturer’s recom- bowel) can be done as a single- or dou- coating is undesirable. Non-coating mendations. Further additives include ble-contrast procedure. The main chal- thickeners include xanthan gum, a bac- flavorants such as ethyl maltol, ethyl lenge is to fill and “see through” a long terial polysaccharide; carrageenan, a sul- vanillin, natural/artificial fruit flavors, stretch of heavily overlapped bowel fated polysaccharide from red seaweed; and saccharin, and the nontoxic sol- loops. So, the barium contrast must pro- pectin, a heteropolysaccharide from vent propylene glycol to help mix a vide significant substance and should plant cell walls; modified corn starch powdered preparation with water. be of relatively low concentration. In (which is also anti-sticking/anti-caking), addition, some mucosal coating may and methylcellulose, which are plant-fi- be helpful. Therefore, the formulation Imaging with BaSO4 Preparations ber molecules bound to -CH3 moieties. Anatomic Radiographic should consist of non-sticky thickeners/ Unlike the broader ranges of viscosity Evaluation of the GI Tract fillers (such as methylcellulose, xanthan, acceptable in anatomic imaging of the Anatomic evaluation of the GI tract or carrageenan) and a small amount of GI tract, the viscosities of the barium with barium products includes single- sticky gum, and be of low radiodensity products used in the MBSS are tightly and double-contrast upper GI (UGI) (<25% w/v). controlled and highly standardized, with examinations (esophagus, stomach, For a double-contrast barium increasing amounts of non-sticky thick- and duodenum), as well as evaluation enema, the anatomic consideration is eners present in correspondingly more of the small bowel, colon, and rectum capacious bowel loops with some over- viscous preparations. (Figure 2). The purpose of these exams lapping, especially on oblique views of is to identify and characterize anatomic the sigmoid and splenic flexures. The Sweeteners/Texturizers/Laxatives lesions such as tumor, inflammation, ob- primary barium contrast requirement is

BaSO4 contrast agents should be struction, malformation, and others with mucosal coating (filling is achieved with palatable; thus, they require sweeteners, an opacifying contrast agent that can ei- insufflated air); however, too much stick- such as glycerin (aka, glycerol, a polyol), ther coat or fill the lumen. BaSO4 prod- iness may interfere with instilling the maltodextrin (a variable short-chain ucts used for all these applications must coating all the way to the cecum. There- polysaccharide of glucose), and xylitol have high physical and radiographic fore, the barium preparation has a mod- and sorbitol (poorly digestible sugar al- density, ranging from 24% to 240% w/v. erate concentration of sticky gum, and a cohols). Of note, such sweeteners play Double-contrast UGI imaging is moderate radiodensity (100% w/v). other important roles. Xylitol and sorbi- used to reveal detail of the GI tract’s For the single-contrast barium tol are also osmotic laxatives that hold mucosal inner lining to reveal ulcers, enema, filling is the priority, and over- water in the bowel, maintaining suspen- polyps, inflammatory patterns, etc. In lapping loops can be a considerable 6 APPLICATIONS IN CONTRAST IMAGING

Evaluating Swallowing Physiology A B The MBSS, also known as the vid- eofluoroscopic swallow study (VFSS), is a real-time fluoroscopic radiologic exam used to assess the physiology of swallowing (Figure 3). Its purpose is to obtain a systematic and reproducible assessment of the structure and func- tion of the swallowing mechanism, and determine compensatory strategies for any abnormalities. This is a single-con-

trast examination, so the BaSO4 prepa- rations must contain a low-to-moderate radiodensity (40% w/v). (Table 2) Per-

haps more importantly for BaSO4 prepa- rations for the MBSS/VFSS, a consistent selection of standardized viscosities must be available. Typical consistencies include thin liquid, nectar, thin honey, honey, puree/pudding, and solid. More- C D over, these viscosities must be achieved with non-sticky starches and sugars-- -no acacia or tragacanth gum, to avoid mucosal coating. Finally, they must be agreeable and food-like, providing adequate “mouthfeel,” or texture, and include sweetness and flavoring for palatability. Note that carboxymethyl-cellulose is present as a thickener in all liquid

BaSO4 preparations used for the MBSS. However, the low concentrations found in these liquid preparations are not suf-

ficient to provide BaSO4 particles with enough electrostatic attraction to ad- here to the inner lining of the GI tract, so there is no coating effect. When car- boxymethyl-cellulose is added in a con- centration sufficient to create a pudding for MBSS, the electrostatic attraction to FIGURE 2. Representative images from (A) a double-contrast upper gastrointestinal (UGI) the GI inner lining is counteracted by examination (Image previously published in: Iyer R et al. Cancer Imaging. 2004;4:125-132.); other additives. (B) a single-contrast UGI examination (Image courtesy of: Jo Ann Puntil-Sheltman, SLP, Why can’t “regular” GI barium Intermountain St. George Regional Hospital, UT); (C) a small-bowel follow-through (SBFT) ex- products suitable for single-contrast amination (Image courtesy of: Marc S. Levine, MD), and (D) a double-contrast barium enema imaging be used for the MBSS? Be- (Image previously published in: Baldwin M et al. Appl Radiol. 2012;41: 29-35.) cause these products lack the precise, problem. The barium preparation relatively low. The contrast, moreover, standardized viscosities that the MBSS should have non-sticky thickeners and must imitate the consistency of normal products possess. During development, fillers such as xanthan or carrageenan, feces so it can be retained in the rec- the viscosity of each MBSS barium and low radiodensity (50% w/v). tum. Consequently, the barium prepa- product, from thin liquid to pudding, When performing defecography, ration should be a paste, which can be was selected to best reveal physio- the primary anatomic consideration is attained with a high concentration of logic deficiencies in the swallowing that the rectum may be capacious, and carboxymethyl-cellulose, and be of rel- mechanism. The use of these products therefore, the radiodensity should be atively low radiodensity (60% w/v). is critical to performing an accurate, APPLICATIONS IN CONTRAST IMAGING 7

low BaSO4 concentration (40% w/v) and 0.1% w/v concentration; include natural have no sticky gums, both of which gum to provide substance; and contain assist in clearance. Iodinated contrast sorbitol to maintain filling and promote media are also not recommended for bowel transit. the MBSS. Ionic high-osmolar contrast media (HOCM), if aspirated, may cause Conclusions life-threatening pulmonary edema.3 Barium sulfate provides barium-con- Nonionic low-osmolar CM (LOCM), taining contrast agents with two specific while much safer to aspirate by them- properties: radiodensity and physical selves, are all “thin liquids;” therefore, for density. Radiodensity, determined by

a full swallowing evaluation, they would the BaSO4 concentration, is adjusted for have to be mixed with various foods/ the imaging technology, technique, and food additives, whose viscosities are not structure(s) of interest. All other ingredi- standardized, and would be nonsterile ents provide the other useful properties

and possibly dangerous to aspirate. present in BaSO4 products: BaSO4 particle suspension; mucosal coating; viscosity Barium Preparations for CT and texture, which are both important Three CT applications utilize for MBSS preparations; sweetness; filling barium contrast: bowel marking, for and laxative effect; preservation; foaming standard CT of the abdomen/pelvis; prevention; and flavoring. Selecting the

FIGURE 3. Representative image from a tagging residual solid stool, for CT colo- right BaSO4 product for the right exam modified barium swallow study (MBSS) nography (CTC; residual liquid stool is requires an understanding of the body (Image courtesy of: Jo Ann Puntil-Sheltman, tagged with iodinated CM); and bowel structures being imaged and the diseases SLP, Intermountain St. George Regional distention at near-water density, for CT being evaluated. Each imaging technol- Hospital, UT). enterography (CTE). ogy and clinical application carries not 5 reproducible MBSS; they also improve The function of barium preparations only its own optimal BaSO4 concentra- patient safety, increase efficiency, and for standard CT of the abdomen/pelvis tion or concentration range, but also an reduce waste. Simply diluting standard is to mark bowel loops in order to dis- optimal combination of additives that

BaSO4 preparations for the MBSS does tinguish them from adjacent structures permit evaluation of the anatomy and/ not eliminate mucosal coating, creates such as vessels, tumors, and nodes. BaSO4 or function of interest. different (and possibly excessively low) preparations for standard CT should: be radiodensities, creates unknown viscos- at 2% w/v concentration, which is suffi- References ities, and dilutes the helpfulness of the cient to reveal enhancement; be highly 1. National Center for Biotechnology Information. additives in unpredictable, and likely palatable for patient compliance; and PubChem Periodic Table of Elements. Barium (El- ement). Available at: https://pubchem.ncbi.nlm.nih. unfavorable, ways. contain sorbitol to maintain filling and gov/element/56. Accessed February 7, 2021. An oft-stated concern with the promote bowel transit. 2. Miller-Keane Encyclopedia & Dictionary of Med- icine, Nursing & Allied Health. Revised Reprint, 7th MBSS is aspiration of BaSO4 preparations. Barium preparations for CTC are 3 Edition, Elsevier, Amsterdam. Per the ACR Manual on Contrast Media, used to tag residual solid stool fragments 3. American College of Radiology (ACR) Commit- tee on Drugs and Contrast Media. ACR Manual on aspirated barium contrast agent is usu- to distinguish them from polyps. BaSO4 ally mobilized proximally by the ciliary preparations for this application should: Contrast Media, 2020. Available at: https://www.acr. org/-/media/ACR/files/clinical-resources/contrast_ action of normal bronchial epithelium. be at 40% w/v concentration; contain media.pdf. Accessed February 7, 2021. However, damaged epithelium from carboxymethyl-cellulose (for tagging); 4. Goldner RD, Adams DO. The structure of mono- bronchial disease delays this process. If be highly palatable; and come packaged nuclear phagocytes differentiating in vivo. III. The ef- fect of particulate foreign substances. Am J Pathol. not completely expectorated, retained and labeled for home use. 1977;89:335-350.

BaSO4 particles can remain indefinitely Barium-containing contrast for 5. Hazelwood RJ, Armeson KE, Hill EG, Bonilha HS, and may cause inflammation. As is true CTE is used to distend bowel loops at Martin-Harris B. Identification of Swallowing Tasks From a Modified Barium Swallow Study That Opti- for any liquid, high-volume aspiration near-water density, facilitating the assess- mize the Detection of Physiological Impairment. J of barium-containing contrast can lead ment of IV contrast-enhanced bowel Speech Lang Hear Res. 2017;60:1855-1863. to acute respiratory distress or pneu- wall for involvement with inflammatory 6. Gelfand DW. Complications of gastrointes- tinal radiologic procedures: I. Complications of 6 O monia. To minimize risk, preparations bowel disease. For this application, BaS 4 routine fluoroscopic studies. Gastrointest Radiol. approved for the MBSS have a relatively preparations should: be at no more than 1980;5:293-315.. 8 APPLICATIONS IN CONTRAST IMAGING

Supported by an educational grant from Bracco Diagnostics, Inc.