Attenuation of postoperative adhesions using a modeled manual therapy

Abstract

Postoperative adhesions are pathological attachments that develop between abdominopelvic structures following surgery. Considered unavoidable and ubiquitous, postoperative adhesions lead to bowel obstructions, infertility, pain, and reoperations. As such, they represent a substantial health care challenge. Despite over a century of research, no preventive treatment exists. We hypothesized that postoperative adhesions develop from a lack of movement of the abdominopelvic organs in the immediate postoperative period while rendered immobile by surgery and opiates, and tested whether manual therapy would prevent their development. In a modified rat cecal abrasion model, rats were allocated to receive treatment with manual therapy or not, and their resulting adhesions were quantified. We also characterized macrophage phenotype. In separate experiments we tested the safety of the treatment on a strictureplasty model, and also the efficacy of the treatment following adhesiolysis. We show that the treatment led to reduced frequency and size of cohesive adhesions, but not other types of adhesions, such as those involving intraperitoneal fatty structures. This effect was associated with a delay in the appearance of trophic macrophages. The treatment did not inhibit healing or induce undesirable complications following strictureplasty. Our results support that that maintained movements of damaged structures in the immediate postoperative period has potential to act as an effective preventive for attenuating cohesive postoperative adhesion development. Our findings lay the groundwork for further research, including mechanical and pharmacologic approaches to maintain movements during healing.

Fig 1. Experimental methods.

A. To create the cecal hinge, the abraded cecum was stitched in two places (arrows) to appose a 1 cm X 2 cm area where the peritoneum had been removed. B. Quantification of the primary adhesion. The free cecum was cut from the adhesion area, the contents removed, and the edges trimmed. The adhesion was outlined and the area recorded. C. Completed strictureplasty surgery. D. The intestinal segment 7 days following strictureplasty was instrumented and inflated until suture failure. The sutures can be seen beneath the fatpad adhesion that encased the suture line. E. Sample trace of intraluminal pressure. The first dip (arrow) was associated with mesothelial splitting at a different site from the suture line. This sample withstood a pressure of 179 mmHg.

Fig 2. Representative postoperative adhesions seen in the cecal hinge model.

Images A-C were taken from the same rat in the 4-day treatment group. A. Greater omentum to cecum (C, in all panels), the extent indicated by a bracket. B. Left adnexal fatpad (*) is adherent to the cecum. In this rat there was no primary adhesion, which can be appreciated by the fold in the tissue between the abdominal wall and the cecum. C. Cohesive adhesion between the small intestine and the cecum (arrow). D. Band-like adhesion between the mesentery of the small intestine and the cecum.

Fig 3. Modeled manual therapy attenuated or prevented primary postoperative adhesions.

A. Areas of primary adhesions (means ± SEM; * p < 0.05). B. The proportion of rats with primary adhesion formation was lower than untreated rats (Fischer’s exact test, * = p < 0.0001). Numbers per group are indicated within bars.

Fig 4. Ratings of necropsy videos (not including primary adhesion).

There were no differences between treated and untreated groups in rated parameters of non-primary postoperative adhesions (n = 7 per group; means ± SEM). There were numerous differences over time, representing the natural biology of postoperative adhesions (Table 2).

Fig 5. Effects of surgery and buprenorphine on fecal pellet discharge.

A. Surgery and 1 dose of buprenorphine immediately after surgery (beginning of Epoch 1) led to reduced fecal pellet discharge 20 to 24 hours after administration. B. Surgery and 3 doses of buprenorphine immediately after surgery (beginning of Epoch 1) led to reduced fecal pellet discharge from 12 to 24 hours after administration. The observed differences between doses were not statistically significant, and there was no effect of treatment under either condition. Shaded area represents 7:00 PM– 7:00 AM. Baseline data in both panels are from rats from the 3-dose group, taken the week before surgeries. n = 14/group at each Epoch, means ± SEM.

Fig 6. Relative expression of M1 or M2 markers by intraperitoneal macrophages.

Intraperitoneal macrophages were isolated by peritoneal lavage at postoperative days specified in the X-axes. Cells were stained with anti-CD11b to positively identify monocyte lineage cells and anti-HIS48 to exclude neutrophils. Expression levels of the indicated markers (A) arginase, (B) CD163, (C) CD86, (D) iNOS are depicted as fold changes normalized to expression by intraperitoneal macrophages isolated from naïve rats. n = 7/group, means ± SEM. * p<0.05 post hoc test.

Fig 7. Ratings of necropsy videos 7 days following adhesiolysis.

There were no differences between treated (n = 15) and untreated (n = 12) rats in adhesion parameters following adhesiolysis (means ± SEM). These results are comparable to those reported in Fig 4.

Fig 8. Strictureplasty burst strengths.

While the variability of the burst strengths was greater following treatment (untreated n = 6, treated n = 7, means ± SEM), the means were not.