(Radiology. 2000;214:563-567.)
© RSNA, 2000
Effect of Barium Sulfate on Wound Healing in the Gastrointestinal Tract of the Rat1
Kristine L. Shackleton, MD,
Edward T. Stewart, MD,
James D. Henderson, Jr, DVM,
Michael J. Demeure, MD and
Gordon L. Telford, MD
1 From the Departments of Radiology (K.L.S., E.T.S.) and General Surgery (J.D.H., M.J.D., G.L.T.), Froedtert Memorial Lutheran Hospital, 9200 W Wisconsin Ave, Milwaukee, WI 53226-3596; and the Medical Research Service, Zablocki Veterans Affairs Medical Center, Medical College of Wisconsin, Milwaukee (J.D.H., G.L.T). Received February 4, 1999; revision requested April 1; revision received May 14; accepted August 23. Address reprint requests to E.T.S. (e-mail: estewart@mcw.edu).
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Abstract
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PURPOSE: To study the effect of barium sulfate on wound healing in the gastrointestinal tract of the rat.
MATERIALS AND METHODS: Sixty rats weighing approximately 320 g were divided into four groups: Fifteen control rats had gastric, small-bowel, and colonic incisions; 15 rats had gastric incision; 15 rats had small-bowel incision; and 15 rats had colonic incision. Barium sulfate was placed into the incision before closure in all rats except those in the control group, and the effects were documented clinically and histopathologically for 3 months. Autopsy was performed in five rats from each group at 1, 4, and 12 weeks. The incisions in the rats receiving barium sulfate were compared with those in the control rats.
RESULTS: There was no difference in the clinical course (weight gain, activity, and viability) between the control and experimental groups. Early and late autopsy findings and histopathologic grading of healing and inflammatory response were similar for both the control and experimental groups.
CONCLUSION: Under the conditions of this study, the effect of barium sulfate on visceral transmural wound healing in the gastrointestinal tract of the rat was minimal.
Index terms: Animals • Barium • Gastrointestinal tract, surgery, 70.458 • Peritonitis, 70.295
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Introduction
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Surgeons frequently express concerns about complications from gastrointestinal tract surgery in patients receiving intraluminal barium sulfate. These concerns are based on the well-documented deleterious effect of barium sulfate in the peritoneal cavity, especially when associated with fecal contamination (1–3). To our knowledge, however, the implied harmful effect of barium sulfate on intestinal wound healing has not been documented. Our review of the scientific evidence of the effect of barium sulfate on transmural visceral wound healing is limited to the findings of one study in dogs (4).
We performed the current study to evaluate the effect of barium sulfate on transmural incisions in the gastrointestinal tract of the rat. We documented both the acute and the long-term effects on wound healing, information that to our knowledge is not available in the literature.
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MATERIALS AND METHODS
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Our study was composed of 60 Sprague-Dawley rats, with a mean weight of 320 g. The rats were divided into four groups, as follows: Fifteen control rats had linear 1.0-cm incisions in the middle of the greater curvature of the stomach, middle of the small intestine, and ascending colon; 15 rats had a linear 1.0-cm incision in the middle of the greater curvature of the stomach; 15 rats had a linear 1.0-cm incision in the proximal and distal parts of the small bowel; and 15 rats had a linear 1.0-cm incision in the ascending colon. Barium sulfate was placed in the incision before closure in all animals except those in the control group.
The animals fasted for at least 12 hours before and 12 hours after surgery. No antibiotics were administered during the study. Animals were anesthetized with intraperitoneal administration of pentobarbital sodium (Nembutal; Abbott Laboratories, Chicago, Ill; 40 mg per kilogram of body weight). A sterile technique was used. The linear incisions were made by using a scalpel and scissors. The incisions were all transmural and exposed the lumen of the viscera. Barium sulfate was manually placed into the wounds of the experimental animals with a physiologic saline–moistened swab, with care taken to prevent spillage of the barium sulfate into the peritoneal cavity (Fig 1a, 1b). We used this approach because the amount of barium sulfate in each wound could be controlled. Powdered, nonsterile, nonsuspended barium sulfate (EZ-HD; E-Z-Em, Westbury, NY) was used; this product is commonly used for positive-contrast studies of the upper gastrointestinal tract in humans.
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Figure 1a. Photographs illustrate the surgical technique used in barium sulfate-treated ileum. (a) A single loop of ileum is isolated on gauze soaked in saline. (b) After a 1.0-cm linear transmural incision (arrow) is made, barium is placed in the open wound. (c) The wound is closed with interrupted 6-0 silk sutures. Barium (arrow) is seen within the suture line.
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Figure 1b. Photographs illustrate the surgical technique used in barium sulfate-treated ileum. (a) A single loop of ileum is isolated on gauze soaked in saline. (b) After a 1.0-cm linear transmural incision (arrow) is made, barium is placed in the open wound. (c) The wound is closed with interrupted 6-0 silk sutures. Barium (arrow) is seen within the suture line.
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Figure 1c. Photographs illustrate the surgical technique used in barium sulfate-treated ileum. (a) A single loop of ileum is isolated on gauze soaked in saline. (b) After a 1.0-cm linear transmural incision (arrow) is made, barium is placed in the open wound. (c) The wound is closed with interrupted 6-0 silk sutures. Barium (arrow) is seen within the suture line.
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Incisions in the viscera of control and experimental animals were closed with simple interrupted sutures by using 6-0 silk (Ethicon, Somerville, NJ) (Fig 1c). The peritoneal cavity was closed with a running 4-0 braided polyglactin 910 (Vicryl; Ethicon) absorbable suture. The skin was closed with metallic staples, which were removed 1–2 weeks after surgery.
Weights were obtained daily for 1 week and then weekly throughout the study. All animals had access to standard rat chow and water. Morbidity and mortality were recorded. Five animals from each of the four groups were humanely killed with carbon dioxide 1 week, 4 weeks, and 12 weeks after surgery.
At autopsy, three authors (J.D.H., K.L.S., E.T.S.) together examined the abdominal cavity for gross evidence of peritonitis or abscess. The abdominal organs were assessed for the presence of adhesions. The stomach and portions of the small intestine and colon, including the incision sites, were removed en bloc and fixed in 10% neutral buffered formalin. Standard histologic preparations were made from transverse sections at the incision site. Six-micrometer-thick tissue specimens were stained with hematoxylin-eosin.
To quantitate the tissue response, one author (J.D.H.) assigned a tissue morphology score, as follows: 0 indicated normal tissue; 1, fewer than five neutrophils and/or lymphocytes per high-power field on the serosal surface or within the incision and/or focal, vascularized fibroblastic proliferation around barium sulfate crystals; 2, more than five neutrophils and/or lymphocytes per high-power field on the serosal surface or within the incision and/or fibroblastic proliferation and focal aggregation of giant cells in reaction to a foreign body (Fig 2); 3, criteria for a morphology score of 2 plus cellular infiltration into the submucosa and focal necrosis; 4, criteria for a morphology score of 3 plus sloughing of mucosal epithelium (Fig 3); and 5, criteria for a morphology score of 4 plus abscess formation (Fig 4).
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Figure 2. Photomicrograph of a section of stomach obtained 4 weeks after surgery in a rat receiving barium sulfate. Notice the barium sulfate within the wall of the stomach surrounded by fibroblastic proliferation (arrows). The keratinized stratified squamous epithelium is normal in the proximal part of the stomach. The tissue morphology score was 2. (Hematoxylin-eosin stain; original magnification, x40.)
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Figure 3. Photomicrograph of a section of ileum obtained 1 week after surgery in a rat receiving barium sulfate. The barium sulfate in the incision is surrounded by fibroblastic proliferation (solid arrows). There are areas of focal necrosis and sloughing of the mucosa (open arrows). The tissue morphology score was 4. (Hematoxylin-eosin stain; original magnification, x40.)
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Figure 4. Photomicrograph of a section of ileum obtained 1 week after surgery in a rat receiving barium sulfate. Barium sulfate aggregates are surrounded by an abscess (arrows). The tissue morphology score was 5. (Hematoxylin-eosin stain; original magnification, x40.)
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RESULTS
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A minimum of perioperative morbidity occurred with normal activity and food intake and output after postoperative recovery. Weight gain was similar in all groups (Fig 5). There was no mortality in any of the groups.
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Figure 5. Graph shows the daily and weekly mean weights. The mean weights for the control rats and those that received barium sulfate were essentially identical for 3 months. The keys indicate the sites of incision for the study rats.
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Gross Observations
Adhesions (Table) were either viscera-to-viscera, viscera-to–solid organ, or viscera-to-omentum. There was no gross evidence of peritonitis in any of the groups, although macroscopic abscess formation (no culture obtained) was seen in two rats, one with a barium sulfate–treated enterotomy and one control animal, at 1 week.
Microscopic Observations
Figure 6 summarizes the tissue morphology scores obtained 1, 4, and 12 weeks after surgery. Tissue reaction at 1 week in the animals receiving barium sulfate was variable and included infiltration by neutrophils, lymphocytes, and macrophages at the incision site and on the serosal surface. In general, histologic changes were similar in the gastric, small intestine, and colonic surgical sites. Occasionally, submucosal extension of the cellular response, focal necrosis, sloughing of mucosal epithelium, and intramural abscess formation were observed.
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Figure 6. Bar graph shows the mean tissue morphology scores in the stomach, small bowel, and colon 1 week, 4 weeks, and 12 weeks after surgery. (The number of observations is too small for statistical analysis.) Notice the similarity in scores between control rats and those receiving barium sulfate.
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Histologic changes at 4 weeks included accumulation of barium sulfate crystals in macrophages in the muscularis propria. The accumulation was surrounded by fibroblasts, collagen fibers, and proliferating capillaries. Foreign-body giant cells were frequently seen adjacent to silk suture fibers but not surrounding barium sulfate crystals.
Tissue changes 12 weeks after surgery consisted of fibroblasts and dense collagen fibers at the surgical site. Numerous free and phagocytosed barium sulfate crystals were present within the connective tissue matrix. Foreign-body giant cells were observed adjacent to silk suture fibers. Sloughing of mucosal epithelium, focal necrosis, and submucosal infiltration with fibroblasts and inflammatory cells frequently occurred at the surgical sites. No granulomas were present in any group at any interval.
When tissue scores at all sites were averaged, there appeared to be little difference between the control group and the experimental group at 1, 4, or 12 weeks (Fig 7). The number of data points was insufficient for statistical analysis with the Wilcoxon rank sum test and a nonparametric approach.
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Figure 7. Bar graph shows the mean tissue morphology scores. When the tissue morphology scores are averaged, there is little difference between control and experimental groups at 1 week, 4 weeks, and 12 weeks. (The number of observations is too small for statistical analysis.)
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DISCUSSION
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For decades, barium sulfate has been marketed as and widely believed to be the best visceral contrast agent for gastrointestinal radiology. Currently, commercial preparations used for positive-contrast imaging studies vary with regard to the percentage of barium sulfate used and the number of additives. These additives reduce flocculation, improve suspension, and promote desired viscosity. In addition, they optimize the mixing properties of the final suspension. Often, anti-foaming agents and flavorings are added (5). Although these additives have been deemed safe for oral administration by the U.S. Food and Drug Administration, Bethesda, Md, it is possible that they might influence wound healing when placed in body tissues.
Experimental and clinical evidence suggest that the primary effect of barium sulfate outside the tubular viscera is the rapid induction of substantial peritonitis by barium crystals, a condition that is further enhanced by the presence of fecal contamination (1). Zheutlin et al (2) described severe peritoneal reaction with adhesions, nodular aggregates of barium sulfate, and barium granulomas that formed when barium sulfate was injected into the peritoneal cavity. By using data accumulated before 1952, they found a mortality rate of 50% for both medically treated patients and surgically treated patients. Later experimental and clinical study findings revealed benefits of intravenous fluid resuscitation (3,6,7), antibiotics (6,7), surgical intervention (8), and the use of urokinase for the intraoperative removal of adherent intraperitoneal barium sulfate (9).
Findings of a recent retrospective study of patients followed up for 3–17 years showed no substantial morbidity and no episodes of bowel obstruction owing to intraperitoneal barium spillage (10). This same study had a 5% mortality rate for the free intraperitoneal spillage of barium sulfate during the past 20 years.
These improved outcome figures are most likely related to the improvements in medical and surgical treatment and in data gathering. The effect of changing barium sulfate preparations is unknown. None of the studies addressed the question of wound healing clinically or experimentally.
Because of the emphasis on peritonitis related to free spillage of barium sulfate in the peritoneal cavity in the medical literature, surgeons have become overly sensitized to and concerned about the effect of barium on wound healing. The debate between surgeons and radiologists frequently revolves around the use of barium sulfate as a positive-contrast agent in patients examined for possible small-bowel obstruction who might undergo surgery. This debate is fostered by surgeons' concerns about potential toxic reactions if intraluminal barium sulfate spills into the peritoneal cavity and by the implied effect on wound healing after incisions are made in the tubular viscera.
At our institution, many patients have undergone visceral surgery with intraluminal barium sulfate without demonstrable morbidity or mortality. Also, it is highly unlikely that substantial amounts of uncontrolled spill of contrast material in the peritoneal cavity would occur at surgery. To our knowledge, the effects of barium sulfate on wound healing have been documented in only one article in the literature (4); we could find no clinical documentation that transmural wound healing is compromised by the presence of barium sulfate.
Najjar et al (4) documented the minimal deleterious effect of barium sulfate by using the dog as an experimental animal. They describe an inflammatory response, especially by neutrophilic granulocytes, when tissue is exposed to barium sulfate. After the barium sulfate is phagocytosed by macrophages, the inflammatory response decreases dramatically. They describe the formation of granulation tissue, which is rich in fibroblasts, but do not identify granulomas. They studied 20 animals for 30 days.
Maglinte et al (11) studied the effects of barium enema examination when performed immediately and 2 and 6 days after superficial and deep colorectal biopsies in six dogs. Although ulceration was seen in deep biopsy sites when a barium enema examination was performed, the healing of these sites was similar to that seen in control animals. Histologic examination was performed 48 hours after the barium enema study; no barium granulomas were found. There were no examinations of the long-term effects of barium sulfate.
Our investigation was stimulated by the ongoing concern of our surgeons relative to this issue and the paucity of scientific evidence to refute their concerns.
The experimental design of our study was tailored to evaluate the acute and long-term influence of barium sulfate on wound healing in the rat. As seen in the Table, the number of adhesions seen in the control and experimental animals was similar. Viability was essentially identical. All animals gained weight (Fig 5) and remained healthy throughout the experiment.
The ingestion of barium sulfate crystals by macrophages was seen but was not as noticeable as that described by Najjar et al (4). Najjar et al, however, did not indicate the particle sizes of the barium sulfate used in their study. The variability in the size of barium sulfate particles in our study was such that larger crystals were too large to be phagocytosed and were simply surrounded by dense connective tissue; smaller particles were ingested by macrophages (Fig 8).
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Figure 8a. Photomicrographs of a section of ileum obtained 1 week after surgery in a rat receiving barium sulfate. (a) Barium sulfate crystals are identified. Smaller crystals are engulfed by the macrophages (thin arrow), whereas larger crystals are surrounded by macrophages (thick arrow). (b) Same view as a with a polarized light demonstrates the birefringent nature of the barium sulfate crystals. The tissue morphology score was 3. (Hematoxylin-eosin stain; original magnification, x400.)
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Figure 8b. Photomicrographs of a section of ileum obtained 1 week after surgery in a rat receiving barium sulfate. (a) Barium sulfate crystals are identified. Smaller crystals are engulfed by the macrophages (thin arrow), whereas larger crystals are surrounded by macrophages (thick arrow). (b) Same view as a with a polarized light demonstrates the birefringent nature of the barium sulfate crystals. The tissue morphology score was 3. (Hematoxylin-eosin stain; original magnification, x400.)
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The most important finding apparent in Figure 6 is the histologic response during wound healing. Using our scoring system, we can see that the effect of barium sulfate on wound healing is a very benign process. The appearances of the wounds in the control rats and in those receiving barium sulfate were similar. Of interest is the fact that tissue scores tended to improve during the 3 months (Fig 7). Also of importance was the absence of granuloma formation in the rats receiving barium sulfate, which is at variance with some of the descriptions in the literature of the findings in the peritoneal cavity (1,2). The only foreign-body giant cells encountered were those around the suture material in both the experimental and the control groups (Fig 9). No granulomas were seen around the suture material or barium crystals.
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Figure 9. Photomicrograph of a section of colon obtained 4 weeks after surgery in a rat receiving barium sulfate. Foreign-body giant cells (open arrows) are seen adjacent to silk sutures (solid arrows). No granulomas surrounding barium sulfate crystals were identified, and foreign-body giant cells were demonstrated only adjacent to silk sutures. (Hematoxylin-eosin stain; original magnification, x400.)
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Barium sulfate in the wound alone as compared with barium sulfate and intestinal contents in the peritoneal cavity may account for some of this difference in inflammatory response that has been described with barium peritonitis. Our data, however, suggest that the presence of barium sulfate within the wound incites little or no difference in the inflammatory reaction from that seen in control rats. Although the number of observations was too small for statistical analysis, the similarity of the response to wound healing is striking.
A larger group of animals is needed to provide a statistically significant comparison between the control rats and those receiving barium sulfate. Our data, however, support to our knowledge the only available evidence that shows that transmural visceral wound healing is unimpaired by the presence of barium sulfate within an incision. The usual benign course in those patients undergoing surgery while the bowel is exposed to barium sulfate supports our hypothesis. From our observations, it is unlikely that retention of barium sulfate within the lumen of the tubular viscera substantially impairs wound healing; surgeons should not avoid the use of barium sulfate when positive contrast is necessary to establish a proper diagnosis.Practical application: Normal wound healing in the presence of barium sulfate supports the continued use of this contrast agent in the preoperative evaluation of the gastrointestinal tract.
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Acknowledgments
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We thank Mark Kern, PhD, for data analysis and Jan Staedler for manuscript preparation.
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Footnotes
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Author contributions: Guarantors of integrity of entire study, K.L.S., E.T.S.; study concepts, E.T.S.; study design, K.L.S., E.T.S.; definition of intellectual content, all authors; literature research, K.L.S., E.T.S.; experimental studies, all authors; data acquisition, all authors; data analysis, K.L.S., E.T.S., J.D.H.; manuscript preparation, K.L.S., E.T.S.; manuscript editing and review, all authors.
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References
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Cochran DQ, Almond CH, Shucart WA. An experimental study of the effects of barium and intestinal contents on the peritoneal cavity. AJR Am J Roentgenol 1963; 89:883-887.
-
Zheutlin N, Lasser EC, Rigler LG. Clinical studies on effect of barium in the peritoneal cavity following rupture of the colon. Surgery 1952; 32:967-979.[Medline]
-
Nahrwold DL, Isch JH, Benner DA, Miller RE. Effect of fluid administration and operation on the mortality rate in barium peritonitis. Surgery 1971; 70:778-781.[Medline]
-
Najjar FB, Khalil IA, Noltenius H. The effect of barium on intestinal anastomosis. Am J Proct 1973; 24:307-311.
-
Skucas J. Anaphylactoid reactions with gastrointestinal contrast media. AJR Am J Roentgenol 1997; 168:962-964.[Abstract/Free Full Text]
-
Kleinsasser LJ, Warshaw H. Perforation of the sigmoid colon during barium enema: report of a case with review of the literature and experimental study of the effect of barium sulfate injected intraperitoneally. Ann Surg 1952; 135:560-565.
-
Gardiner H, Miller RE. Barium peritonitis: a new therapeutic approach. Am J Surg 1973; 125:350-352.[Medline]
-
Westfall RH, Nelson RH, Musselman MM. Barium peritonitis. Am J Surg 1966; 112:760-763.[Medline]
-
Yamamura M, Nishi M, Furubayashi H, Hioki K, Yamamoto M. Barium peritonitis. Dis Colon Rectum 1985; 28:347-352.[Medline]
-
Ghahremani GG, Gordon GI, Gore RM. Long-term consequences of intraperitoneal barium (abstr). Radiology 1997; 205(P):339.
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Maglinte DDT, Strate RW, Strong RC, et al. The effect of barium enemas and barium sulfate on healing of colorectal biopsy sites. Dis Colon Rectum 1983; 26:595-597.[Medline]
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Abstract
Introduction
