Postoperative use of non-steroidal anti-inflammatory drugs in patients with anastomotic leakage requiring reoperation after colorectal resection: cohort study based on prospective data

Abstract

Objectives To evaluate the effect of postoperative use of non-steroidal anti-inflammatory drugs (NSAIDs) on anastomotic leakage requiring reoperation after colorectal resection.Design Cohort study based on data from a prospective clinical database and electronically registered medical records.Setting Six major colorectal centres in eastern Denmark.Participants 2766 patients (1441 (52%) men) undergoing elective operation for colorectal cancer with colonic or rectal resection and primary anastomosis between 1 January 2006 and 31 December 2009. Median age was 70 years (interquartile range 62-77).Intervention Postoperative use of NSAID (defined as at least two days of NSAID treatment in the first seven days after surgery). Main outcome measuresFrequency of clinical anastomotic leakage verified at reoperation; mortality at 30 days. ResultsOf 2756 patients with available data and included in the final analysis, 1871 (68%) did not receive postoperative NSAID treatment (controls) and 885 (32%) did. In the NSAID group, 655 (74%) patients received ibuprofen and 226 (26%) received diclofenac. Anastomotic leakage verified at reoperation was significantly increased among patients receiving diclofenac and ibuprofen treatment, compared with controls (12.8% and 8.2% v 5.1%; P<0.001). After unadjusted analyses and when compared with controls, more patients had anastomotic leakage after treatment with diclofenac (7.8% (95% confidence interval 3.9% to 12.8%)) and ibuprofen (3.2% (1.0% to 5.7%)). But after multivariate logistic regression analysis, only diclofenac treatment was a risk factor for leakage (odds ratio 7.2 (95% confidence interval 3.8 to 13.4), P<0.001; ibuprofen 1.5 (0.8 to 2.9), P=0.18). Other risk factors for anastomotic leakage were male sex, rectal (v colonic) anastomosis, and blood transfusion. 30 day mortality was comparable in the three groups (diclofenac 1.8% v ibuprofen 4.1% v controls 3.2%; P=0.20).Conclusions Diclofenac treatment could result in an increased proportion of patients with anastomotic leakage after colorectal surgery. Cyclo-oxygenase-2 selective NSAIDs should be used with caution after colorectal resections with primary anastomosis. Large scale, randomised controlled trials are urgently needed. IntroductionWith leakage rates of around 3% after colonic resections and 10% after rectal resections and with mortality rates of up to 32%, 1 2 anastomotic leakage remains a serious challenge for colorectal surgeons worldwide. In the past few years, there has been increased focus on the possible effect of non-steroidal anti-inflammatory drugs (NSAIDs) on the risk of anastomotic leakage. [3][4][5][6] Retrospective studies have shown an association between anastomotic leakage and postoperative treatment with diclofenac and celecoxib, two NSAIDs that are predominantly cyclo-oxygenase-2 selective. [3][4][5] These two drugs have a high and similar affinity for the cyclo-oxygenase-2 enzyme. 7 Several publications focusing on adverse cardiovascular events in non-surgical patients treated with NSAIDs hav...

Experimental study of diclofenac and its biliary metabolites on anastomotic healing

“…COX‐2 inhibition is considered the main feature of systemic diclofenac activity, and could affect essential inflammatory and proliferative pathways8 26. Administration of ‘diclofenac bile’ had little impact on plasma levels of diclofenac through the enterohepatic circulation; thus the effect of diclofenac bile could not be explained by more potent systemic activity.…”

“…However, considering the physiological changes that occur following partial or subtotal colectomy, bile toxicity could be comparably relevant for colorectal anastomoses. Clinical cohort studies2, 3, 4 8 reporting an increased risk of leakage following NSAID administration involved both ileocolic and colorectal anastomoses.…”

“…The main mechanism by which NSAIDs are believed to jeopardize anastomotic healing is the cyclo‐oxygenase (COX) 2 inhibitory action, which may cause suppression of inflammatory, proliferative or proangiogenic pathways relevant for normal wound healing2 8. An alternative explanation could be direct toxicity of intraluminal factors resulting from NSAID treatment (such as drug metabolites and bile products).…”

Management of Postoperative Gastrointestinal Leakage With Autologous Stromal Vascular Fraction

“…When gastrointestinal leakage is detected early, within the first 72 hours, patients have to undergo a second surgery in order to clean and close the leakage site; but this second surgery is still associated with high mortality rates and repeated laparotomies (24%) as stated by Klein. 16 When gastrointestinal leakage is detected late, it is usually managed conservatively using drains, keeping the patient null per os on parenteral nutrition and broad-spectrum antibiotics. There is also need for regular evaluation of the leakage site.…”

The Use of NSAIDs in the Postoperative Period: Advantage and Disadvantages

“…A recent survey study performed on data from Danish Colorectal Cancer Group, has pointed out that the assumption of diclofenac and ibuprofen even for just two days increased the absolute risk of anastomotic leakage of 7.8% after diclofenac and of 3.2% after ibuprofen treatment. However, after a multivariate analysis only diclofenac, definite by authors a COX2inhibitor, resulted in an increased risk of anastomotic leak, concluding that an increased risk has been shown only after COX-2 inhibitors [90].…”