Intestinal surgery is commonly performed in small animal veterinary patients, most often for removal of ingested foreign material.1–3 One of the most devastating postoperative complications of intestinal surgery is leakage at the surgical site, which can result in development of septic peritonitis or generalized sepsis and an increase in the risk of death.4,5 Rates of leakage after intestinal resection and anastomosis in dogs and cats have been reported to range from 11% to 14%.6,7 Factors that increase the risk of anastomotic leakage include the presence of inflammation or infection in the peritoneal cavity, decreased blood flow to the surgical site, hypoproteinemia, poor surgical technique, resection and anastomosis involving portions of the large intestine, and perioperative administration of glucocorticoids (eg, prednisone or prednisolone) or antineoplastic treatments.7,8 Anastomotic leakage requires repeated surgery, which can be associated with increased hospitalization time and increased cost for the animal's owner.
Given the potentially deadly consequences of intestinal leakage, the use of surgical sealants, also referred to as tissue sealants, to strengthen the anastomotic site and reduce the risk of leakage has been investigated extensively in human and laboratory animal medicine.9 The ideal sealant is easy to use, biocompatible, inexpensive, and effective for holding 2 tissue surfaces together in a moist environment. It should also be biodegradable, and its use should be associated with minimal to no adverse effects.9 Potential adverse effects of surgical sealants include inflammation, foreign body reaction, toxicosis (often from breakdown products), delayed healing, and tissue distortion. An example of tissue distortion might be stricture formation secondary to sealant use on an organ that has a lumen.9
Tissue sealants can be categorized as synthetic, biomimetic, and biological types.9 Synthetic sealants include the cyanoacrylate glues, among others. Owing to inflammatory reactions and toxic effects, synthetic sealants are generally not suitable for internal surgical use. Biomimetic sealants have been developed to mimic the properties of natural sealants that are effective in wet environments, such as those produced by marine species or gecko species. Biological sealants include fibrin, collagen, albumin, gelatin, and polysaccharide-based products.9,10 They are biocompatible and are frequently used in people for purposes of general hemostasis in surgical applications, during plastic surgery procedures, and for sealing and preventing pulmonary air leaks, lymphatic fluid leaks, and CSF leaks.9–15
Protein-based biological sealants are compounds that solidify when applied and are attractive options for sealing air and fluid leaks because of their ability to bond even in moist environments.9,16–18 In human medicine, a BA-10G sealanta has been approved for use in aortic surgery in the United States.10,19,20 This sealant has also been shown to increase the ex vivo bursting strength of gastrojejunal anastomoses in fresh porcine tissues.21 Recently, a similar BA-DG sealantb,c became available for veterinary use.22 Results of a study23 indicated that ex vivo leakage pressures of enterotomies in fresh caprine tissues were significantly higher with than those achieved without the use of this sealant. The use of the sealant in dogs or cats has not been reported, to our knowledge.
The purpose of the study reported here was to evaluate the effect of a BA-DG sealant on leakage pressures of intestinal anastomoses in jejunal tissue collected from fresh canine cadavers and to evaluate changes in circumference and cross-sectional area of the anastomotic site after application of the sealant. We hypothesized that the leakage pressures would be significantly higher for sutured intestinal anastomoses with sealant application, compared with those values in a control group of sutured anastomoses with no sealant application. We also hypothesized that the application of the sealant would not significantly alter the outer circumference or the cross-sectional area of the intestine at the site of anastomosis.
Materials and Methods
Samples
Jejunal anastomoses were created in tissue samples obtained from fresh canine cadavers. The intestinal tissue used was obtained from dogs that were euthanized with IV overdoses of barbiturate solution for reasons unrelated to this study. Dogs with a history of gastrointestinal tract disease were excluded. Samples of jejunum from 4 canine cadavers were collected. The 4 cadavers included an approximately 1-year-old castrated male German Shepherd Dog that weighed 32.2 kg (dog 1), an approximately 1-year-old castrated male Labrador Retriever that weighed 42.4 kg (dog 2), a 6-year-old castrated male Chesapeake Bay Retriever that weighed 42 kg (dog 3), and a 12-year-old spayed female Siberian Husky that weighed 17.8 kg (dog 4).
Experimental procedures
The small intestinal tract of each dog was removed immediately after euthanasia, and the jejunum was sectioned into 12-cm-long segments. No gross abnormalities of the gastrointestinal tracts were noted during tissue harvesting from any of the dogs. Anastomoses were created with adjacent segments of jejunum, resulting in 24-cm-long tissue constructs for testing. All anastomoses were hand sutured with 3-0 absorbable, monofilament polydioxanoned suture in a simple interrupted pattern; sutures were placed 2 mm apart and 2 to 3 mm from the cut edge of tissue. The anastomoses were all performed by the same surgeon (LMM) within 12 hours after euthanasia.
The anastomoses were then leak tested with a technique similar to that previously described for testing enterotomies and anastomoses.24 Briefly, the lumen of each tissue construct was filled with tap water from one end with finger occlusion of the other end during filling. Finger occlusion was then applied to both ends to maintain distension of the segment. Gentle digital palpation on either side of the anastomosis was performed and the site was evaluated for leakage. Leakage sites between sutures were repaired with additional placement of simple interrupted sutures as needed, and the leak test was repeated to confirm repair. Any anastomoses that persistently leaked through the suture holes were excluded.
For outer circumference measurements of all constructs, each tissue construct was filled with tap water until visible stretching was noted at the anastomotic site. The circumference of the anastomosis was measured and recorded in centimeters. These measurements were then used to estimate the cross-sectional area of the intestinal lumen with a circle area equation as follows: A = C2/(4π), where A is the cross-sectional area, C is the outer circumference, and r is the radius of the lumen. This equation was derived from the circle area equation (A = πr2) and the circle circumference equation (C = 2πr). Each tissue construct was then submerged and stored in 0.9% NaCl solutione at 4°C for approximately 6 hours prior to pressure testing.
Sets of paired tissue constructs from each dog (ie, total of 12 tissue constructs/group) were tested. Any tissue constructs that developed brown discoloration of the tissue prior to pressure testing were excluded. By use of a random number generator, the remaining constructs were randomly assigned to either the experimental group (application of BA-DG sealant) or the control group (no sealant). The tissue constructs in the sealant group were patted dry with surgical gauze, and approximately 1 mL of sealant was applied circumferentially onto the serosa of the intestine at the anastomosis site to completely coat the suture line and suture holes. The sealant was allowed to polymerize for 2 minutes according to the manufacturer's instructions. The intestinal lumens for the constructs in the sealant group were again distended with water, and the outer circumference of each anastomosis was measured and the cross-sectional area was calculated as previously described.
For pressure testing, each construct in the 2 groups was occluded with Doyen clamps 4 cm from the anastomosis on either side. A 22-gauge needle was attached via IV tubing to a 1-L bag of lactated Ringer solutionf dyed with India ink.g The needle was inserted to the hub at a slight angle, with the tip directed toward the anastomotic site, into the left side of the segment approximately halfway between the Doyen clamp and the anastomotic site. A 22-gauge IV catheter was attached to a pressure transducerh via rigid IV tubing with a 3-way stopcock between the tubing and the transducer. Standard IV tubing was used to attach the pressure transducer to a 1-L bag of undyed lactated Ringer solution that was pressurized to 350 mm Hg by means of a pressure bag. The catheter attached to the pressure transducer was inserted to the hub at a slight angle, with the tip directed toward the anastomotic site, into the right side of the segment approximately halfway between the Doyen clamp and the anastomotic site. The entire tissue construct was then held submerged in a 0.9% NaCl solution bath by an assistant. Prior to testing of each tissue construct, the pressure transducer was flushed and recalibrated. The India ink–dyed lactated Ringer solution was then infused into the lumen of the tissue construct by means of a fluid pump.i The segment was monitored for leakage by 2 observers. Leakage was defined as the first observation of ink leaking from the site. At that point, the infusion was stopped, and the highest pressure reading at the time of leakage was recorded as the leakage pressure (in mm Hg). The site of leakage was also recorded for each construct.
Statistical analysis
A prospective power analysis was performed with previously reported25 mean ± SD leakage pressures of small anastomoses in intestinal segments from canine cadavers with (81.8 ± 6.7 mm Hg) and without (28.0 ± 6.7 mm Hg) serosal patching. It was estimated that a sample size of ≥ 6 tissue constructs/group was necessary to achieve 90% power to detect a significant difference with similar data. Leakage pressure data, circumference data, and cross-sectional area data were tested for normality with a Shapiro-Wilk test. The data distributions were judged to be sufficiently nonnormal such that normal theory-based statistical procedures were inappropriate, and a Wilcoxon rank sum test was used to compare leakage pressures between the 2 groups. The circumference and cross-sectional area of the anastomoses before and after application of the sealant were compared with a Wilcoxon signed rank test. The effect of cadaver on pre- and post-testing measurements was assessed by evaluation of cadaver as a separate level in an ANOVA. Significance was set at a value of P < 0.05. All calculations were performed with commercially available statistical software.j
Results
Twelve paired tissue constructs were tested; 3 pairs were from dog 1, 1 pair was from dog 2, and 4 pairs each were from dogs 3 and 4. There was no significant (all values of P ≥ 0.169) effect of cadaver on the results. During leakage pressure testing, all tissue constructs failed at the suture line. Of the 12 tissue constructs in the sealant group, 9 leaked directly at the site of anastomosis (between sutures) and 3 leaked through a single suture hole. Of the 12 tissue constructs in the no-sealant group, 8 leaked at the site of anastomosis and 4 leaked through a single suture hole. The median leakage pressure of anastomoses without applied surgical sealant was 10.8 mm Hg (range, 4 to 30 mm Hg; Figure 1); median leakage pressure of anastomoses with applied surgical sealant was 24.9 mm Hg (range, 14 to 44 mm). The leakage pressure was significantly (P = 0.002) higher for anastomoses in the sealant group.
Box-and-whisker plots of leakage pressure data for jejunal anastomoses created with fresh tissue specimens from 6 canine cadavers. Immediately after euthanasia, the jejunum from each dog was sectioned into segments; all anastomoses were performed on adjacent segments with 3-0 polydioxanone suture in a simple interrupted pattern. Tissue constructs were randomly assigned to 1 of 2 groups (12 constructs/group). In the experimental group (white box), the anastomoses were completed with application of BA-DG sealant; in the control group (gray box), the anastomoses were completed with no application of the sealant. The anastomoses were then leak tested with a technique similar to that previously described for testing enterotomies and anastomoses.24 For each plot, the horizontal line in each box represents the median; the upper and lower boundaries of the box represent the 75th and 25th percentiles, respectively; the line at the end of the whiskers represents the maximum and minimum values within the data set after the outliers (black circles) have been removed. The median leakage pressure of the control group (no sealant) was 10.8 mm Hg, which was significantly (P = 0.002) lower than the median leakage pressure of the experimental (sealant) group (24.9 mm Hg).
Citation: American Journal of Veterinary Research 79, 12; 10.2460/ajvr.79.12.1335
Box-and-whisker plots of leakage pressure data for jejunal anastomoses created with fresh tissue specimens from 6 canine cadavers. Immediately after euthanasia, the jejunum from each dog was sectioned into segments; all anastomoses were performed on adjacent segments with 3-0 polydioxanone suture in a simple interrupted pattern. Tissue constructs were randomly assigned to 1 of 2 groups (12 constructs/group). In the experimental group (white box), the anastomoses were completed with application of BA-DG sealant; in the control group (gray box), the anastomoses were completed with no application of the sealant. The anastomoses were then leak tested with a technique similar to that previously described for testing enterotomies and anastomoses.24 For each plot, the horizontal line in each box represents the median; the upper and lower boundaries of the box represent the 75th and 25th percentiles, respectively; the line at the end of the whiskers represents the maximum and minimum values within the data set after the outliers (black circles) have been removed. The median leakage pressure of the control group (no sealant) was 10.8 mm Hg, which was significantly (P = 0.002) lower than the median leakage pressure of the experimental (sealant) group (24.9 mm Hg).
Citation: American Journal of Veterinary Research 79, 12; 10.2460/ajvr.79.12.1335
Box-and-whisker plots of leakage pressure data for jejunal anastomoses created with fresh tissue specimens from 6 canine cadavers. Immediately after euthanasia, the jejunum from each dog was sectioned into segments; all anastomoses were performed on adjacent segments with 3-0 polydioxanone suture in a simple interrupted pattern. Tissue constructs were randomly assigned to 1 of 2 groups (12 constructs/group). In the experimental group (white box), the anastomoses were completed with application of BA-DG sealant; in the control group (gray box), the anastomoses were completed with no application of the sealant. The anastomoses were then leak tested with a technique similar to that previously described for testing enterotomies and anastomoses.24 For each plot, the horizontal line in each box represents the median; the upper and lower boundaries of the box represent the 75th and 25th percentiles, respectively; the line at the end of the whiskers represents the maximum and minimum values within the data set after the outliers (black circles) have been removed. The median leakage pressure of the control group (no sealant) was 10.8 mm Hg, which was significantly (P = 0.002) lower than the median leakage pressure of the experimental (sealant) group (24.9 mm Hg).
Citation: American Journal of Veterinary Research 79, 12; 10.2460/ajvr.79.12.1335
For the tissue constructs in the sealant group, the median outer circumference of the distended anastomoses and median cross-sectional area before sealant application were 6.4 cm (range, 5.5 to 7.7 cm) and 3.3 cm2 (range, 2.4 to 4.7 cm2), respectively (Figure 2). After sealant application, the median outer circumference of the distended anastomoses and median cross-sectional area were 6.7 cm (range, 6.3 to 7.7 cm) and 3.6 cm2 (range, 3.2 to 4.7 cm2), respectively. There was no significant difference between outer circumference before and after sealant application (P = 0.054) or between cross-sectional area before and after sealant application (P = 0.077).
Box-and-whisker plots of outer circumference (A) and calculated cross-sectional area (B) for the sealant-treated jejunal anastomoses created with fresh tissue specimens from the 6 canine cadavers in Figure 1. The outer circumference of all anastomoses in the experimental (sealant) group was measured before (gray boxes) and after (white boxes) BA-DG sealant application. For outer circumference measurements, the intestine was filled with tap water until visible stretching was noted at the anastomotic site; the circumference of the anastomosis was measured and recorded in centimeters. These measurements were then used to estimate the cross-sectional area of the intestinal lumen with an equation as follows: A = C2/(4π), where A is the cross-sectional area, C is the outer circumference, and r is the radius of the circle. There was no significant difference in outer circumference (P = 0.054) or cross-sectional area (P = 0.077) before and after sealant application. See Figure 1 for key.
Citation: American Journal of Veterinary Research 79, 12; 10.2460/ajvr.79.12.1335
Box-and-whisker plots of outer circumference (A) and calculated cross-sectional area (B) for the sealant-treated jejunal anastomoses created with fresh tissue specimens from the 6 canine cadavers in Figure 1. The outer circumference of all anastomoses in the experimental (sealant) group was measured before (gray boxes) and after (white boxes) BA-DG sealant application. For outer circumference measurements, the intestine was filled with tap water until visible stretching was noted at the anastomotic site; the circumference of the anastomosis was measured and recorded in centimeters. These measurements were then used to estimate the cross-sectional area of the intestinal lumen with an equation as follows: A = C2/(4π), where A is the cross-sectional area, C is the outer circumference, and r is the radius of the circle. There was no significant difference in outer circumference (P = 0.054) or cross-sectional area (P = 0.077) before and after sealant application. See Figure 1 for key.
Citation: American Journal of Veterinary Research 79, 12; 10.2460/ajvr.79.12.1335
Box-and-whisker plots of outer circumference (A) and calculated cross-sectional area (B) for the sealant-treated jejunal anastomoses created with fresh tissue specimens from the 6 canine cadavers in Figure 1. The outer circumference of all anastomoses in the experimental (sealant) group was measured before (gray boxes) and after (white boxes) BA-DG sealant application. For outer circumference measurements, the intestine was filled with tap water until visible stretching was noted at the anastomotic site; the circumference of the anastomosis was measured and recorded in centimeters. These measurements were then used to estimate the cross-sectional area of the intestinal lumen with an equation as follows: A = C2/(4π), where A is the cross-sectional area, C is the outer circumference, and r is the radius of the circle. There was no significant difference in outer circumference (P = 0.054) or cross-sectional area (P = 0.077) before and after sealant application. See Figure 1 for key.
Citation: American Journal of Veterinary Research 79, 12; 10.2460/ajvr.79.12.1335
Discussion
The results of the present study indicated that leakage pressures of sutured fresh canine cadaveric jejunal anastomoses after BA-DG sealant application were significantly higher than leakage pressures of similar tissue constructs without sealant application, and that application of BA-DG sealant did not significantly alter the circumference and cross-sectional area at the anastomosis site. These findings supported our hypotheses and were in agreement with findings of other in vivo and in vitro studies21,23,26,27 investigating the use of BA-10G sealant for enterotomy closure in rats, pigs, and goats.
In veterinary medicine, the use of surgical sealants is not commonplace, whereas in human medicine it has become a routine part of selected gastrointestinal and vascular surgeries.10,20 A major obstacle for wider implementation is the availability of many different sealants without evidence of a clearly superior sealant under clinical conditions. In addition, their usefulness appears site dependent.28 Recently, a series of tissue sealants approved for human use was systematically compared mechanically, histologically, and immunologically in various studies26,27,29,30 of rats undergoing colonic surgery. In those studies,26,27,29,30 BA-10G sealant was identified as having favorable characteristics for anastomotic augmentation. It is not known whether these findings are valid for other regions of the gastrointestinal tract, for larger animals, or under clinical conditions.
Although an increase in leakage pressures of the jejunal anastomoses after sealant application was identified in the present study of cadaveric tissues, the range of leakage pressures was less than values previously reported as normal intraluminal pressure in canine small intestines during peristalsis (20 to 40 mm Hg).31,32 Other studies of intraluminal leakage pressure of canine cadaver intestinal anastomoses33 and enterotomies34 have also identified lower than expected pressures. It is possible, therefore, that the use of cadaveric tissue leads to changes in the ability of the anastomotic sites to withstand pressure, compared with tissue in vivo. Nevertheless, the results of the present study were consistent with findings of other in vitro and in vivo studies21,23 investigating the effectiveness of BA-10G sealants. In the present study, the leakages in the tissue constructs occurred either at the anastomotic site (between sutures) or through a suture hole in the tissue. It is possible that leakage at an anastomotic site is less likely to occur with a simple continuous suture line because continuous suture lines provide better air- and water-tight seals than do interrupted suture patterns.35 However, both continuous and interrupted suture patterns are used for gastrointestinal anastomoses in veterinary medicine. Future investigations are necessary to determine whether there is a difference in leakage site or leakage pressure for sealant-augmented anastomoses that are created with continuous sutures lines, compared with those that are created with interrupted suture lines.
To our knowledge, there have been no reports of a correlation of immediate postoperative leakage pressure at intestinal anastomotic sites with risk of dehiscence, leakage, or development of septic peritonitis in clinical veterinary patients. However, in situations where surgical technique is compromised (eg, suturing errors), the application of a surgical sealant could lower the risk of leakage at that site. Indeed, other researchers have used porcine cadaveric tissue and demonstrated that BA-10G sealanta could seal an artificially created anastomotic leak.21 The beneficial effect of selected sealants, including BA-10G, was also suggested by results of 2 studies26,27 of rats undergoing colonic surgery with a compromised surgical technique. Cadaveric studies to evaluate the effect of the veterinary BA-DG sealant on canine intestinal anastomotic sites with technical imperfections are warranted.
Undoubtedly, the cause of dehiscence and subsequent leakage at a site of intestinal surgery is multifactorial; some common impediments to healing include inflammation, infection, compromised blood flow to the anastomotic site, location of the anastomosis, systemic hypoproteinemia, administration of glucocorticoids (eg, prednisone or prednisolone) or antineoplastic medications, and surgical technique.7,8 In general, the effects of sealants on healing in these suboptimal conditions have not been studied in depth. However, a study36 of colorectal anastomoses in a contaminated environment in rats revealed that application of fibrin glue, cyanoacrylate sealant, or polyethylene glycol sealant at the anastomotic sites increased the anastomotic bursting strength at 3 days after surgery as well as decreased abscess formation, compared with findings for rats in a control group that did not receive sealant application at the anastomotic sites. In a similar study37 in rats with experimental inflammatory bowel disease, reduced colorectal anastomotic leakage and reduced abscess formation were evident at 3 days after surgery with the use of cyanoacrylate or polyethylene glycol sealant at the anastomotic sites. These data suggest that under clinical conditions, sealants may improve the outcome of anastomotic procedures in a suboptimal healing environment. Future studies evaluating the use of sealants on small intestinal anastomoses in suboptimal environments are needed to determine whether these findings are consistent for small intestinal tissue.
The development of strictures and narrowing of the intestinal lumen are major concerns after gastrointestinal surgery. In the present study, the circumference and outer cross-sectional area of the jejunal anastomotic sites before and after application of the sealant were the same, if not increased. This suggested that the sealant did not shrink following polymerization, thereby causing a narrowing of the tissue construct at the anastomotic site. There has been concern that in the long term, the addition of a surgical sealant may cause an increased inflammatory response and secondary stricture formation, which have been shown to develop with the use of cyanoacrylate sealants on rat colonic anastomoses.38,39 In rats undergoing colonic anastomosis with BA-10G sealant, inflammation and collagen formation were greater at 4 and 8 days after surgery, compared with rats that did not receive application of the BA-10G sealant at the anastomotic site.40 Fibroblast activity and hydroxyproline and collagenase concentrations in the sealant group remained unchanged over the 8-day period, compared with results for the control group.40 Moreover, anastomotic bursting pressures and adhesion formation were significantly increased following sealant application, compared with control group findings. Results of other colonic surgery studies26,27 in rats have confirmed these findings. However, no evidence of stricture formation causing obstruction was reported.26,27,40 The long-term effect of fibrin sealants on tissue deformation and stricture formation of sealed anastomoses is unknown.
Application of BA-10G or BA-DG sealants will cause mixing and crosslinking of bovine albumin and glutaraldehyde components. Over time, this reaction may partially reverse and part of the glutaraldehyde may escape from the polymer and cause an inflammatory reaction in the surrounding tissue. Derivatization of the glutaraldehyde in the BA-DG sealant presumably decreases the amount of free glutaraldehyde that is released from the sealant and thus may reduce the ensuing inflammatory response.22,b Although the long-term effect of this veterinary sealant on secondary stricture and adhesion formation is unknown, we believe that the results of the present study and other in vitro and in vivo studies of surgical sealants justify further evaluation in limited clinical studies of animals at risk for postoperative anastomotic leakage.
Results of the present study indicated that application of the BA-DG sealant to sutured jejunal anastomotic sites in specimens obtained from fresh canine cadavers significantly increases leakage pressure of the anastomoses without any evidence of tissue deformation after application, compared with traditionally sutured jejunal anastomotic sites. Future in vivo studies should be performed to further evaluate the potential benefits and efficacy of tissue sealant use for clinical applications.
Acknowledgments
No third-party funding or support was received in connection with this study or the writing or publication of the manuscript. The authors declare that there were no conflicts of interest.
The authors acknowledge the use of the facilities of the Purdue University Pre-Clinical Research Laboratory, a core facility of the NIH-funded Indiana Clinical & Translational Science Institute. The authors thank Ted Vlahos, Shery Park, Christa Cain, and Robyn McCain for technical assistance.
ABBREVIATIONS
| BA-10G | Bovine albumin crosslinked with 10% glutaraldehyde |
| BA-DG | Bovine albumin–derivatized glutaraldehyde biopolymer |
Footnotes
BioGlue surgical sealant, Cryolife Inc, Kennesaw, Ga.
Kem Schankereli, Avalon Medical, Stillwater, Minn: Personal communication, 2018.
PoliPhase, Avalon Medical, Stillwater, Minn.
PDS II (polydioxanone) suture, Ethicon, Somerville, NJ.
0.9% sodium chloride irrigation USP, Braun, Aschaffenburg, Germany.
Lactated Ringer injection USP, Hospira, Lake Forest, Ill.
Fountain pen India ink, Higgins, Leeds, Mass.
Truwave, Model PX260, 3cm2/60inches, Edwards Life-sciences, Irvine, Calif.
Abbot Plum XL Micro Macro Infusion Pump, Abbot Laboratories, North Chicago, Ill.
STATA SE, version 14.2, StataCorp, College Station, Tex.
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