International consensus statement regarding the use of animal models for research on anastomoses in the lower gastrointestinal tract

Purpose This project aimed to reach consensus on the most appropriate animal models and outcome measures in research on anastomoses in the lower gastrointestinal tract (GIT). The physiology of anastomotic healing remains an important research topic in gastrointestinal surgery. Recent results from experimental studies are limited with regard to comparability and clinical translation. Methods PubMed and EMBASE were searched for experimental studies investigating anastomotic healing in the lower GIT published between January 1, 2000 and December 31, 2014 to assess currently used models. All corresponding authors were invited for a Delphi-based analysis that consisted of two online survey rounds followed by a final online recommendation survey to reach consensus on the discussed topics. Results Two hundred seventy-seven original articles were retrieved and 167 articles were included in the systematic review. Mice, rats, rabbits, pigs, and dogs are currently being used as animal models, with a large variety in surgical techniques and outcome measures. Forty-four corresponding authors participated in the Delphi analysis. In the first two rounds, 39/44 and 35/39 participants completed the survey. In the final meeting, 35 experts reached consensus on 76/122 items in six categories. Mouse, rat, and pig are considered appropriate animal models; rabbit and dog should be abandoned in research regarding bowel anastomoses. ARRIVE guidelines should be followed more strictly. Conclusions Consensus was reached on several recommendations for the use of animal models and outcome measurements in research on anastomoses of the lower GIT. Future research should take these suggestions into account to facilitate comparison and clinical translation of results. Electronic supplementary material The online version of this article (doi:10.1007/s00384-016-2550-5) contains supplementary material, which is available to authorized users.


The use of animal models for research on anastomoses in the lower gastrointestinal tract
Example questions 1. *Example 1: How appropriate is it to include the following subjects as vegetables?
Please note that you will be asked the same question under "fruits". Additional remarks on why a certain subject should be considered a vegetable or other comments 2. *Example 2: How appropriate is it to include the following subjects as fruits? We saw in literature that the most used animal model for anastomotic healing was by far the rat (65%). Other animals used were pigs (15%), rabbits (10%), mice (5%) and dogs (5%). Use of the rat as an animal is practical, since the animals are easy to handle and not very expensive, however a rat might not represent a true clinical model due to its resistance to intra-abdominal infection. Therefore, it was suggested by Pommergaard et al that a mouse is a more clinical model for colorectal anastomotic leakage. Other authors suggest that the pig is most translational to the human setting, but pigs are expensive and not very easy to handle. The following questions regard the reasons why to choose a certain animal for research on anastomoses in the lower gastrointestinal tract. Please provide arguments for the animal model of your choice (rat, pig, rabbit, mouse or dog)/additional remarks Research on intestinal anastomoses is carried out for several purposes: investigating the healing process, reducing anastomotic leakage with specific interventions or evaluation of new techniques.

The use of animal models for research on anastomoses in the lower gastrointestinal tract
6. Based on the purpose of observational research concerning anastomotic healing: How appropriate is the following model for research on anastomoses in the lower gastrointestinal tract? It was evident that not all anastomoses were made in the same parts of the lower gastrointestinal tract. We excluded all anastomoses made from stomach-small intestine and anastomoses performed in the pancreatic-biliary tract. The most used anastomotic site was the colon (ascending 15%, transverse 20%, descending 32%, sigmoid 14%); however which part of the colon was not always evident (1% unknown). In addition, anastomoses were made in the small intestine (22%) and rectum (8%) as well. Some authors performed transection only, while others chose to resect a part of the bowel to reflect the human setting. Furthermore, laparoscopy was performed in a few cases, while the majority of the animal experiments was performed as open surgery.

Location in the lower gastrointestinal tract & type of surgery
10. How appropriate is it to perform an anastomosis in the following part to study anastomoses in the lower gastrointestinal tract? Reasons for choosing a specific part of the intestine/additional remarks 11. How appropriate is it to perform an anastomosis in the following fashion to study anastomoses in the lower gastrointestinal tract? Why is a certain evaluation method considered appropriate/other important evaluations/additional remarks 13. Adhesions towards the anastomotic site are commonly observed. These adhesions can be scored regarding both quantitative and qualitative aspects of adhesions.How appropriate is it to use the following scoring system to score adhesions around the anastomosis in animal research on anastomoses in the lower gastrointestinal tract? Why is a certain scoring system considered appropriate/other adhesion scoring systems/additional remarks In order to define anastomotic healing, histological evaluation is often performed. The following question will regard different stainings and scoring mechanisms for this purpose.

Mechanical & Biochemical outcome measures
16. How appropriate is it to use the following method as a measure for anastomotic healing in animal research on anastomoses in the lower gastrointestinal tract? Other analyses (please specify which analyzing methods) Please provide arguments on why you consider this appropriate or specify which method you used The following section focuses on specific details of the experiments and animal welfare. Often, these items are not reported in scientific papers, while it can provide significant information. Using an anastomotic leakage model may cause severe discomfort for the animals and some researchers use this as an outcome measure. The following questions are about the appropriateness of using and reporting animal welfare assessments as well as reporting details about the experiments. If you consider any other items appropriate regarding animal welfare, please specify/any additional remarks.

The use of animal models for research on anastomoses in the lower gastrointestinal tract
We are also interested in who performes animal research on anastomoses in the lower gastrointestinal tract. The following questions will focus on characteristics of researchers.

The use of animal models for research on anastomoses in the lower gastrointestinal tract
Researchers' characteristics 18. How many animals did you operate on?