Surgical tissue adhesives for preventing pancreatic fistula following pancreatic surgery

Review question

Is surgical tissue adhesive able to reduce postoperative pancreatic fistula after pancreatic surgery?

Background

Postoperative pancreatic fistula is a complication that may follow major surgery for cancer or inflammation of the pancreas, a digestive gland situated at the back of the upper abdomen. The surgery involves disconnecting the pancreas from the nearby gut, and then reconnecting this to allow pancreatic juice containing digestive enzymes to enter the digestive system after surgical removal of the head of the pancreas. The pancreatic stump is often left to heal itself after surgical removal of the tail of the pancreas. A fistula occurs when the reconnection or stump does not heal properly, creating a leak of pancreatic juice from the pancreas to the abdominal tissues. This delays recovery from surgery and often requires further treatment to ensure complete healing. The role of fibrin sealants (surgical tissue adhesives) to reduce postoperative pancreatic fistula after pancreatic surgery is controversial.

Study characteristics

We searched for all relevant, well-conducted studies up to March 2019. We included twelve studies which were divided into three comparisons. First, seven of the twelve studies randomised 860 participants undergoing surgical removal of the tail of the pancreas to either fibrin sealant use (428 participants) or no fibrin sealant use (432 participants) for pancreatic stump closure reinforcement. Second, four studies randomised 393 participants undergoing the 'Whipple' operation (surgical removal of the head of the pancreas) to fibrin sealant use (186 participants) or no fibrin sealant use (207 participants) for pancreatic stump reconstruction reinforcement. Third, two studies randomised 351 participants undergoing the 'Whipple' operation to fibrin sealant use (188 participants) and no fibrin sealant use (163 participants) for pancreatic duct blockage.

Key results

Application of fibrin sealants to pancreatic stump closure reinforcement after surgical removal of the tail of the pancreas

Fibrin sealants may have little to no difference in postoperative pancreatic fistula or postoperative death when fibrin sealants are used on stump closure reinforcement after surgical removal of the tail of the pancreas.

Application of fibrin sealants to pancreatic anastomosis (connection between pancreas and gut) reinforcement after 'Whipple' operation

We are uncertain whether fibrin sealants improve postoperative pancreatic fistula or reduce postoperative death when used for pancreatic anastomosis reinforcement after the 'Whipple' operation.

Application of fibrin sealants to pancreatic duct occlusion (blockage or closure) after 'Whipple' operation

Postoperative pancreatic fistula was not reported in any of the studies. Fibrin sealants may have little to no difference in postoperative death when applied to a pancreatic duct occlusion after the 'Whipple' operation.

Fibrin sealants may have little or no benefit on postoperative pancreatic fistula in people undergoing surgical removal of the tail of the pancreas. We cannot tell from our results whether fibrin sealants have an important effect on postoperative pancreatic fistula after the 'Whipple' operation because the sample size was small and the results were imprecise.

Quality of the evidence

Most of the included studies had some shortcomings in terms of how they were conducted or reported. Overall, the quality of the evidence varied from very low to moderate.

Authors' conclusions: 

Based on the current available evidence, fibrin sealants may have little or no effect on postoperative pancreatic fistula in people undergoing distal pancreatectomy. The effects of fibrin sealants on the prevention of postoperative pancreatic fistula are uncertain in people undergoing pancreaticoduodenectomy.

Read the full abstract...
Background: 

Postoperative pancreatic fistula is one of the most frequent and potentially life-threatening complications following pancreatic resections. Fibrin sealants have been used in some centers to reduce postoperative pancreatic fistula. However, the use of fibrin sealants during pancreatic surgery is controversial. This is an update of a Cochrane Review last published in 2018.

Objectives: 

To assess the safety, effectiveness, and potential adverse effects of fibrin sealants for the prevention of postoperative pancreatic fistula following pancreatic surgery.

Search strategy: 

We searched trial registers and the following biomedical databases: the Cochrane Library (2019, Issue 2), MEDLINE (1946 to 13 March2019), Embase (1980 to 11 March 2019), Science Citation Index Expanded (1900 to 13 March 2019), and Chinese Biomedical Literature Database (CBM) (1978 to 13 March 2019).

Selection criteria: 

We included all randomised controlled trials that compared fibrin sealant (fibrin glue or fibrin sealant patch) versus control (no fibrin sealant or placebo) in people undergoing pancreatic surgery.

Data collection and analysis: 

Two review authors independently identified the trials for inclusion, collected the data, and assessed the risk of bias. We performed the meta-analyses using Review Manager 5. We calculated the risk ratio (RR) for dichotomous outcomes (or a Peto odds ratio (OR) for very rare outcomes), and the mean difference (MD) for continuous outcomes, with 95% confidence intervals (CIs).

Main results: 

We included 12 studies involving 1604 participants in the review.

Application of fibrin sealants to pancreatic stump closure reinforcement after distal pancreatectomy

We included seven studies involving 860 participants: 428 were randomised to the fibrin sealant group and 432 to the control group after distal pancreatectomy. Fibrin sealants may lead to little or no difference in postoperative pancreatic fistula (fibrin sealant 19.3%; control 20.1%; RR 0.96, 95% CI 0.68 to 1.35; 755 participants; four studies; low-quality evidence). Fibrin sealants may also lead to little or no difference in postoperative mortality (0.3% versus 0.5%; Peto OR 0.52, 95% CI 0.05 to 5.03; 804 participants; six studies; low-quality evidence), or overall postoperative morbidity (28.5% versus 23.2%; RR 1.23, 95% CI 0.97 to 1.58; 646 participants; three studies; low-quality evidence). We are uncertain whether fibrin sealants reduce reoperation rate (2.0% versus 3.8%; RR 0.51, 95% CI 0.15 to 1.71; 376 participants; two studies; very low-quality evidence) or length of hospital stay (MD 0.99 days, 95% CI -1.83 to 3.82; 371 participants; two studies; very low-quality evidence). The studies did not report serious adverse events, quality of life, or cost effectiveness.

Application of fibrin sealants to pancreatic anastomosis reinforcement after pancreaticoduodenectomy

We included four studies involving 393 participants: 186 were randomised to the fibrin sealant group and 207 to the control group after pancreaticoduodenectomy. We are uncertain whether fibrin sealants reduce postoperative pancreatic fistula (16.7% versus 11.7%; RR 1.14, 95% CI 0.28 to 4.69; 199 participants; two studies; very low-quality evidence). We are uncertain whether fibrin sealants reduce postoperative mortality (0.5% versus 2.4%; Peto OR 0.26, 95% CI 0.05 to 1.32; 393 participants; four studies; low-quality evidence) or length of hospital stay (MD 0.01 days, 95% CI -3.91 to 3.94; 323 participants; three studies; very low-quality evidence). There is probably little or no difference in overall postoperative morbidity (52.6% versus 50.3%; RR 1.04, 95% CI 0.87 to 1.24; 323 participants; three studies; moderate-quality evidence) between the groups. We are uncertain whether fibrin sealants reduce reoperation rate (5.2% versus 7.7%; RR 0.74, 95% CI 0.33 to 1.66; 323 participants; three studies, very low-quality evidence). The studies did not report serious adverse events, quality of life, or cost effectiveness.

Application of fibrin sealants to pancreatic duct occlusion after pancreaticoduodenectomy

We included two studies involving 351 participants: 188 were randomised to the fibrin sealant group and 163 to the control group after pancreaticoduodenectomy. Fibrin sealants may lead to little or no difference in postoperative mortality (8.4% versus 6.1%; Peto OR 1.41, 95% CI 0.63 to 3.13; 351 participants; two studies; low-quality evidence) or length of hospital stay (median 16 to 17 days versus 17 days; 351 participants; two studies; low-quality evidence). We are uncertain whether fibrin sealants reduce overall postoperative morbidity (32.0% versus 27.6%; RR 1.16, 95% CI 0.67 to 2.02; 351 participants; two studies; very low-quality evidence), or reoperation rate (13.6% versus 16.0%; RR 0.85, 95% CI 0.52 to 1.41; 351 participants; two studies; very low-quality evidence). Serious adverse events were reported in one study (169 participants; low-quality evidence): more participants developed diabetes mellitus when fibrin sealants were applied to pancreatic duct occlusion, both at three months' follow-up (33.7% fibrin sealant group versus 10.8% control group; 29 participants versus 9 participants) and 12 months' follow-up (33.7% fibrin sealant group versus 14.5% control group; 29 participants versus 12 participants). The studies did not report postoperative pancreatic fistula, quality of life, or cost effectiveness.

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