Effect of Diclofenac on Cyclooxygenase-2 Levels and Early Breaking Strength of Experimental Colonic Anastomoses and Skin Incisions
Recently, there has been a focus on the effect of the nonsteroidal anti-inflammatory drugs on the anastomotic leakage rate after colorectal surgery. An experimental, randomized, placebo-controlled prospective study on 32 male Wistar rats was carried out. We examined the effect of diclofenac 4 mg/kg/day on the cyclooxygenase-2 (COX-2) enzyme in the anastomotic tissue and on the breaking strength of anastomotic and incisional wounds. The operation was performed with colonic resection and hand-sewn anastomosis. After 3 days, the rats were sacrificed and the breaking strength and the COX-2 content of the anastomosis were measured. There was a significantly reduced level of COX-2 in the rats treated with diclofenac (p = 0.001); no significant differences in any of the breaking strength measurements and no significant correlation between COX-2 levels and breaking strength of the anastomotic or incisional wounds could be found (p = 0.073 and p = 0.727). This study for the first time showed that a diclofenac dose of 4 mg/kg/24 h was sufficient to reduce the level of COX-2 enzymes in the anastomotic tissue in rats. This inhibition of the inflammatory response did not lead to reduced breaking strength of either anastomotic or incisional wounds. Whether there is a detrimental effect of COX inhibition on colorectal anastomoses in the clinical setting remains controversial.
[Show abstract] [Hide abstract] ABSTRACT: In a recent article, Gorissen et al report on 795 patients with primary colorectal anastomosis operated on during the period 2008-2010 for different colorectal conditions at two centres. The leakage rate was significantly higher among patients who were administered non-steroidal anti-inflammatory drugs (NSAIDs) in the perioperative course. A dose-response relationship could also be traced, where longer NSAID use yielded a higher risk of anastomotic breakdown. However, as this study is observational in design, confounding by indication may be present and there is also a risk of residual confounding from unmeasured covariates. Moreover, the question whether different affinity for the cyclooxygenase enzyme is important in different NSAIDs seems to be largely unanswered. The results, conclusions and clinical relevance of the aforementioned study, including the possible effects of different types of NSAIDs, are discussed. While acknowledging that this study represents the best attempt so far in establishing the causal relationship between perioperative NSAID use and anastomotic leakage, the need for further research in this important area is underlined.0Comments 5Citations
- "However, the positive effects of selective COX-2 inhibition have subsequently been questioned, as any lesser rate of gastrointestinal adverse effects may have been outweighed by negative effects such as increased risk of cardiovascular events  . As regards to colorectal surgery, recent retrospective clinical studies have also indicated a negative effect on anastomotic healing121314 , as well as some, but not all, experimental investigations151617 . In these studies, COX-2 inhibitors in particular have been implicated, as these have been compared unfavourably with mostly COX-1 selective compounds; more specifically, the use of celecoxib and diclofenac compared to ibuprofen seemed to be associated with high leakage rates121314 . "
- [Show abstract] [Hide abstract] ABSTRACT: Anastomotic dehiscence remains an important challenge for colorectal surgeons worldwide. Extensive research focused on performing a safe anastomosis is conducted with rats being the most used model when examining colorectal anastomoses. In daily clinical practice resorbable sutures are used when hand-sewn anastomoses are performed. However, in the experimental studies examining colorectal anastomoses, non-resorbable sutures have predominantly been used. The aim of this study was to compare a rapidly resorbable suture with a non-resorbable suture in experimental colorectal anastomoses. This was an experimental, prospective, case-control study using forty male Wistar rats. A colonic anastomosis was performed in a standardized fashion with either rapidly resorbable or non-resorbable suture. On the seventh postoperative day, the animals were sacrificed and the breaking strength of the anastomoses was measured. No suffering or poor wellbeing of the animals was registered. No animals died or were prematurely sacrificed. At tissue harvesting, no anastomotic leaks or signs of peritonitis were registered. The breaking strengths of the anastomoses were comparable in the two groups (median 2.175 (range 1.479-2.880) Newton vs. 2.267 (1.290-4.042) Newton (P = 0.256) for resorbable and non-resorbable sutures, respectively). We found no significant correlations between pre- to postoperative weight-loss and anastomotic strength. Non-resorbable suture was comparable with rapidly resorbable suture with regards to breaking strength of an experimental colonic anastomosis. Thus, absorbable suture can be used in experimental studies which then more easily can be compared to clinical practice.0Comments 2Citations
- [Show abstract] [Hide abstract] ABSTRACT: Analgesic regimes to avoid opioid-related adverse effects have been recommended in gastrointestinal surgery. Non-steroidal anti-inflammatory drugs (NSAIDs) are an important component of opioid sparing regimes in that these drugs indirectly reduce pain by inhibiting inflammation. Although beneficial for most surgical patients, animal studies and recent clinical studies suggest a harmful effect on new intestinal anastomoses by increasing the rate of leakage. NSAIDs may indirectly disturb anastomotic healing by inhibiting inflammation as an integrated part of the wound healing process in an early, critical phase after surgery. A literature review based on a structured search in PubMed of clinical and experimental studies investigating the effects of NSAIDs on anastomotic healing and leakage rates after intestinal surgery, as well as proposed mechanisms and effects studied in animal models. Three recent observational cohort studies (accumulated n = 882) indicate an increased rate of anastomotic leakages (15-21%) associated with cyclooxygenase-2 (COX-2) selective NSAIDs after intestinal surgery compared to the leakage rates in controls or historical cohorts (1-4%). Three prospective studies on related topics contain relevant data on NSAIDs and are compared to these studies. Several experimental animal studies support an increased risk for anastomotic leakage with the use of NSAIDs. The reported effects of NSAIDs on anastomotic healing suggest an increased risk for leakage. A better understanding of the complex interactions of NSAID-induced inhibition on anastomotic healing is a prerequisite for the safe use of NSAIDs. Until more data are available, a careful use of NSAIDs may be warranted in gastrointestinal anastomotic surgery.0Comments 18Citations