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Practical Limitations of Bioresorbable Membranes in the Prevention of Intra-Abdominal Adhesions

  • 2008 ssat plenary presentation
  • Published:
Journal of Gastrointestinal Surgery Aims and scope

Abstract

Introduction

Intra-abdominal adhesions are a significant source of postoperative morbidity. Bioresorbable barriers composed of hyaluronic acid and carboxymethylcellulose (HA/CMC) reduce adhesion formation by physically separating injured or healing peritoneal surfaces. To assess whether the efficacy of a physical barrier can extend beyond the site of application, we evaluated the effectiveness of an HA/CMC barrier in preventing adhesions distal to the site of placement.

Methods

Adhesions were induced in rats by creating peritoneal ischemic buttons on either side of a midline incision. An HA/CMC barrier (Seprafilm™ Genzyme) was intraoperatively placed either under the midline incision, unilaterally over half the ischemic buttons, or bilaterally over all ischemic buttons. Control buttons received no HA/CMC. On day 7 adhesions were scored. In similar experiments, peritoneal fluid was collected at 24 h to assess the effects of HA/CMC on tissue plasminogen activator activity.

Results

Placement of HA/CMC under the midline incision did not reduce adhesion formation to distal ischemic buttons (72 ± 7%) compared to controls (80 ± 8%). Unilateral placement of HA/CMC significantly (p < 0.05) reduced adhesion formation to those ischemic buttons over which the barrier was applied (35 ± 7%) compared to both contralateral (83 ± 9%) and control (80 ± 8%) ischemic buttons. The bilateral application of HA/CMC also significantly (p < 0.05) reduced adhesion formation to all ischemic buttons compared to controls (22 ± 7% vs. 66 ± 7%, respectively). HA/CMC did not affect peritoneal tPA activity.

Conclusions

Effective adhesion reduction by the physical barrier HA/CMC appears to be limited to the site of application in this rat model. Despite the presence of a bioresorbable membrane at predicted sites of adhesion formation in the peritoneal cavity, adhesions readily form to distal unprotected sites.

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Authors and Affiliations

  1. Department of Surgery, Boston University School of Medicine, 88 East Newton Street, Boston, MA, 02118, USA

    Rizal Lim, Jonathan M. Morrill, Ryan C. Lynch, Karen L. Reed, Adam C. Gower, Susan E. Leeman, Arthur F. Stucchi & James M. Becker

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  1. Rizal Lim
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  2. Jonathan M. Morrill
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  3. Ryan C. Lynch
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  4. Karen L. Reed
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Correspondence to James M. Becker.

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Discussion

Margo Shoup, M.D. (Maywood, IL): I would like to congratulate the authors for trying to tackle a difficult problem that we all face with our patients with adhesion formation in a small bowel obstruction, and we really haven't made much headway in this in the last couple of decades. The authors in this paper attempt to study the effects of HA/CMC, or seprafilm, and neurokinin-1 receptor antagonist. The adhesions were measured at seven days postoperatively and placement of the buttons, and the Tpa was measured 24 hours after laparotomy. And we know that the synergistic effects of NK1RA and seprafilm is evident, but we are not really sure what is going on with the Tpa during all that. So I have a few questions for you.

Have you first looked at dose escalation studies with increasing NK1 receptor antagonists to evaluate the effects on Tpa, because this would clarify whether this is truly the mechanisms through which this is working. Also, you checked the Tpa levels 24 hours after surgery and, like I said, the adhesions at seven days. Have you looked at different time frames for both of these to see if there is more of a correlation? And at this point do you have any information on the status of the soluble seprafilm that is available in Europe, and if so, where do you think this may impact your study?

Thank you.

Rizal Lim, M.D. (Boston, MA): In terms of dose escalation of our antagonist, going back to the original parent compound, it is actually based off of a drug called ezlopitant. When we received this compound as a gift, the doses were actually based on the then maximum recommended dose of 25 mg/kg, which we used. But in earlier studies, as we started off with 5 mg/kg and then went to 10 mg/kg, we saw a progressive increase in adhesion prevention from those two doses.

In terms of the different time frames, looking at adhesions with this model specifically, our personal experience and data we have collected in the past have shown that when we look at adhesion formation beyond 7 days, we haven't really seen much of a difference in terms of severity. The same is true for tPA. In fact, what we have seen in previous studies is that tPA immediately post-op, at least within the rat, drops significantly and hits its nadir at approximately 24 hours and following that period of time begins to slowly rise back towards normal levels. So we chose that simply because it gives us a general idea of what the fibrinolytic activity within the abdomen is doing at its worst case scenario. We have also shown that giving the drug at 24 hours, we can alter that fibrinolytic activity.

And the final question, in terms of the soluble and gel forms of various barrier compounds, I am not firmly sure as to how far the various companies have progressed in terms of getting that approved within the U.S. But some of the implications which it may convey are that currently some of the biggest limitations of using HA/CMC barriers involve its actual application. It is a brittle, stiff material. It is difficult to use in certain cases such as laparoscopy, and I think that progressing to more of a gel type of device would improve its utility.

This work was supported in part, by the Smithwick Endowment Fund to the Department of Surgery at Boston University School of Medicine.

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Lim, R., Morrill, J.M., Lynch, R.C. et al. Practical Limitations of Bioresorbable Membranes in the Prevention of Intra-Abdominal Adhesions. J Gastrointest Surg 13, 35–42 (2009). https://doi.org/10.1007/s11605-008-0724-3

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