Systematic review
Systematic review of experimental studies on intestinal anastomosis S. T. K. Yauw1 , K. E. Wever1,2 , A. Hoesseini1 , M. Ritskes-Hoitinga2 and H. van Goor1 1 Department
of Surgery, Radboud University Medical Centre, and 2 Systematic Review Centre for Laboratory Animal Experimentation (SYRCLE), Central Animal Laboratory, Radboud University, Nijmegen, The Netherlands Correspondence to: Mr S. T. K. Yauw, Radboud University Medical Centre, Department of Surgery, Geert-Grooteplein zuid 10, Internal Post 618, 6525 GA Nijmegen, The Netherlands (e-mail: [email protected])
Background: The contribution of animal research to a reduction in clinical intestinal anastomotic leakage
is unknown, despite numerous experimental studies. In view of the current societal call to replace, reduce and refine animal experiments, this study examined the quality of animal research related to anastomotic healing and leakage. Methods: Animal studies on intestinal anastomotic healing were retrieved systematically from PubMed and Embase. Study objective, conclusion and animal model were recorded. Reporting quality and internal validity (reporting of randomization and blinding) were assessed. Results: A total of 1342 studies were identified, with a rising publication rate. The objectives of most studies were therapeutic interventions (64⋅8 per cent) and identification of risk factors (27⋅5 per cent). Of 350 articles studying experimental therapies, 298 (85⋅1 per cent) reported a positive effect on anastomotic healing. On average, 44⋅7 per cent of relevant study characteristics were not reported, in particular details on anastomotic complications (31⋅6 per cent), use of antibiotics (75⋅7 per cent), sterile surgery (83⋅4 per cent) and postoperative analgesia (91⋅4 per cent). The proportion of studies with randomization, blinding of surgery and blinding of primary outcome assessment has increased in the past two decades but remains insufficient, being included in only 62⋅4, 4⋅9 and 8⋅5 per cent of publications respectively. Animal models varied widely in terms of species, method to compromise healing, intestinal segment and outcome measures used. Conclusion: Animal research on anastomotic leakage is of poor quality and still increasing, contrary to societal aims. Reporting and study quality must improve if results are to impact on patients. Presented in part to the Tenth Academic Surgical Congress of the Society of University Surgeons and Association for Academic Surgery, Las Vegas, Nevada, USA, February 2015 Paper accepted 18 December 2014 Published online 2 April 2015 in Wiley Online Library (www.bjs.co.uk). DOI: 10.1002/bjs.9776
Introduction
Worldwide, intestinal resection and anastomosis are performed annually in over a million people with colorectal cancer, inflammatory bowel disease, complicated diverticulitis and morbid obesity1 – 3 . Despite improvements in technique, anastomotic devices and perioperative care, an intestinal anastomosis has a 3–14 per cent risk of leakage4,5 . This postoperative complication often results in severe morbidity, with a consequent mortality rate of up to 18 per cent6 – 8 . Many risk factors have been identified from clinical studies4,9 . Male sex, low colorectal anastomosis, preoperative chemoradiation, advanced tumour stage, immunosuppression, perioperative bleeding and multiple © 2015 BJS Society Ltd Published by John Wiley & Sons Ltd
staple firings have all been associated with increased leak rates4,9,10 . Animal models have been used extensively to study causality and underlying pathophysiological mechanisms11,12 , as well as the assessment of techniques and products that reinforce the anastomosis or improve healing13,14 . The study of anastomotic failure in animals involves moderate to severe animal discomfort, dedicated human effort and considerable cost. This has led to a European directive that animal experiments need to be replaced, reduced and refined whenever possible15,16 . Owing to its complex physiology, the process of anastomotic healing is presently considered too complicated to mimic in vitro. To reduce BJS 2015; 102: 726–734
Experimental studies on intestinal anastomosis
Records identified through PubMed n = 3412
727
Records identified through Embase n = 4173
Excluded (duplicates) n = 3058
Article title/abstract screened n = 4527 Excluded n = 2784 Duplicate data n = 4 Abstract, poster or review n = 188 Human study n = 253 In vitro/ex vivo study n = 43 Not a study of intestinal anastomosis n = 1212 Study of intestinal transplants n = 152 Not a prospective experiment n = 195 Outcome unrelated to anastomotic patency n = 737 Full-text articles assessed n = 1743
Full-text articles included n = 1342 Fig. 1
Excluded n = 401 Full text unretrievable n = 138 No translation possible n = 16 Duplicate data n = 48 Abstract, poster or review n = 102 Human study n = 2 In vitro/ex vivo study n = 11 Not a study of intestinal anastomosis n = 23 Not a prospective experiment n = 5 Outcome unrelated to anastomotic patency n = 39 Use of enterotomy n = 17
PRISMA flow diagram of study selection
and refine animal experiments, it is necessary to perform a systematic review of the existing literature regarding methodology and quality, to see how experimental models and designs might be improved or standardized. The aim of the present systematic review was to investigate study characteristics and the quality of animal research on intestinal anastomotic healing.
Methods
Search and study inclusion This review is reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guideline17 . A prespecified protocol was used for the study selection and extraction of study characteristics (available through https://www.radboudumc.nl/syrcle). A systematic search was conducted in the PubMed version of MEDLINE and the OvidSP version of Embase on 4 April 2014, by using different synonyms, Medical subject headings (MesH) and Emtree terms (for PubMed and Embase respectively) to cover any study on intestinal anastomoses (Table S1, supporting information)18 . © 2015 BJS Society Ltd Published by John Wiley & Sons Ltd
To limit the results to animal studies, a specifically designed and validated filter was used for both databases (Table S1, supporting information)19,20 . Selection was made by screening the title and abstract of all results. Every title or abstract was screened by two authors. Disagreement was resolved by discussion. Experimental studies in which the healing of an anastomosis of the small bowel or colon was investigated in an in vivo animal model were included. All duplicates, abstracts, posters and review articles, all studies in human, in vitro or ex vivo studies, all studies on other types of anastomosis (for example vascular, urological, biliary, gastrojejunal, oesophagojejunal), intestinal transplants, studies reporting outcomes not related to anastomotic healing (such as cancer recurrence) and those in which enterotomy was performed rather than anastomosis were excluded. Articles selected through title and abstract screening were then subjected to full-text screening (using the same inclusion criteria) and simultaneous data extraction by one of the authors. Full-text retrieval was attempted through online searching, by consulting Dutch and German university libraries, and by e-mail to the corresponding author. Articles in all languages except Japanese were included. www.bjs.co.uk
BJS 2015; 102: 726–734
728
S. T. K. Yauw, K. E. Wever, A. Hoesseini, M. Ritskes-Hoitinga and H. van Goor
600 100 Animal model presentation 75
% of studies
400 300 200
Study of physiology 50
Risk factor identification
25
100 0
Therapeutic trial
4
9 Ap ril 2
01
00
9 00
10
to
20 20
10 20
a
–2
99
9 –1
98 90 19
80
–1 19
19
Systematic review of experimental studies on intestinal anastomosis S. T. K. Yauw1 , K. E. Wever1,2 , A. Hoesseini1 , M. Ritskes-Hoitinga2 and H. van Goor1 1 Department
of Surgery, Radboud University Medical Centre, and 2 Systematic Review Centre for Laboratory Animal Experimentation (SYRCLE), Central Animal Laboratory, Radboud University, Nijmegen, The Netherlands Correspondence to: Mr S. T. K. Yauw, Radboud University Medical Centre, Department of Surgery, Geert-Grooteplein zuid 10, Internal Post 618, 6525 GA Nijmegen, The Netherlands (e-mail: [email protected])
Background: The contribution of animal research to a reduction in clinical intestinal anastomotic leakage
is unknown, despite numerous experimental studies. In view of the current societal call to replace, reduce and refine animal experiments, this study examined the quality of animal research related to anastomotic healing and leakage. Methods: Animal studies on intestinal anastomotic healing were retrieved systematically from PubMed and Embase. Study objective, conclusion and animal model were recorded. Reporting quality and internal validity (reporting of randomization and blinding) were assessed. Results: A total of 1342 studies were identified, with a rising publication rate. The objectives of most studies were therapeutic interventions (64⋅8 per cent) and identification of risk factors (27⋅5 per cent). Of 350 articles studying experimental therapies, 298 (85⋅1 per cent) reported a positive effect on anastomotic healing. On average, 44⋅7 per cent of relevant study characteristics were not reported, in particular details on anastomotic complications (31⋅6 per cent), use of antibiotics (75⋅7 per cent), sterile surgery (83⋅4 per cent) and postoperative analgesia (91⋅4 per cent). The proportion of studies with randomization, blinding of surgery and blinding of primary outcome assessment has increased in the past two decades but remains insufficient, being included in only 62⋅4, 4⋅9 and 8⋅5 per cent of publications respectively. Animal models varied widely in terms of species, method to compromise healing, intestinal segment and outcome measures used. Conclusion: Animal research on anastomotic leakage is of poor quality and still increasing, contrary to societal aims. Reporting and study quality must improve if results are to impact on patients. Presented in part to the Tenth Academic Surgical Congress of the Society of University Surgeons and Association for Academic Surgery, Las Vegas, Nevada, USA, February 2015 Paper accepted 18 December 2014 Published online 2 April 2015 in Wiley Online Library (www.bjs.co.uk). DOI: 10.1002/bjs.9776
Introduction
Worldwide, intestinal resection and anastomosis are performed annually in over a million people with colorectal cancer, inflammatory bowel disease, complicated diverticulitis and morbid obesity1 – 3 . Despite improvements in technique, anastomotic devices and perioperative care, an intestinal anastomosis has a 3–14 per cent risk of leakage4,5 . This postoperative complication often results in severe morbidity, with a consequent mortality rate of up to 18 per cent6 – 8 . Many risk factors have been identified from clinical studies4,9 . Male sex, low colorectal anastomosis, preoperative chemoradiation, advanced tumour stage, immunosuppression, perioperative bleeding and multiple © 2015 BJS Society Ltd Published by John Wiley & Sons Ltd
staple firings have all been associated with increased leak rates4,9,10 . Animal models have been used extensively to study causality and underlying pathophysiological mechanisms11,12 , as well as the assessment of techniques and products that reinforce the anastomosis or improve healing13,14 . The study of anastomotic failure in animals involves moderate to severe animal discomfort, dedicated human effort and considerable cost. This has led to a European directive that animal experiments need to be replaced, reduced and refined whenever possible15,16 . Owing to its complex physiology, the process of anastomotic healing is presently considered too complicated to mimic in vitro. To reduce BJS 2015; 102: 726–734
Experimental studies on intestinal anastomosis
Records identified through PubMed n = 3412
727
Records identified through Embase n = 4173
Excluded (duplicates) n = 3058
Article title/abstract screened n = 4527 Excluded n = 2784 Duplicate data n = 4 Abstract, poster or review n = 188 Human study n = 253 In vitro/ex vivo study n = 43 Not a study of intestinal anastomosis n = 1212 Study of intestinal transplants n = 152 Not a prospective experiment n = 195 Outcome unrelated to anastomotic patency n = 737 Full-text articles assessed n = 1743
Full-text articles included n = 1342 Fig. 1
Excluded n = 401 Full text unretrievable n = 138 No translation possible n = 16 Duplicate data n = 48 Abstract, poster or review n = 102 Human study n = 2 In vitro/ex vivo study n = 11 Not a study of intestinal anastomosis n = 23 Not a prospective experiment n = 5 Outcome unrelated to anastomotic patency n = 39 Use of enterotomy n = 17
PRISMA flow diagram of study selection
and refine animal experiments, it is necessary to perform a systematic review of the existing literature regarding methodology and quality, to see how experimental models and designs might be improved or standardized. The aim of the present systematic review was to investigate study characteristics and the quality of animal research on intestinal anastomotic healing.
Methods
Search and study inclusion This review is reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guideline17 . A prespecified protocol was used for the study selection and extraction of study characteristics (available through https://www.radboudumc.nl/syrcle). A systematic search was conducted in the PubMed version of MEDLINE and the OvidSP version of Embase on 4 April 2014, by using different synonyms, Medical subject headings (MesH) and Emtree terms (for PubMed and Embase respectively) to cover any study on intestinal anastomoses (Table S1, supporting information)18 . © 2015 BJS Society Ltd Published by John Wiley & Sons Ltd
To limit the results to animal studies, a specifically designed and validated filter was used for both databases (Table S1, supporting information)19,20 . Selection was made by screening the title and abstract of all results. Every title or abstract was screened by two authors. Disagreement was resolved by discussion. Experimental studies in which the healing of an anastomosis of the small bowel or colon was investigated in an in vivo animal model were included. All duplicates, abstracts, posters and review articles, all studies in human, in vitro or ex vivo studies, all studies on other types of anastomosis (for example vascular, urological, biliary, gastrojejunal, oesophagojejunal), intestinal transplants, studies reporting outcomes not related to anastomotic healing (such as cancer recurrence) and those in which enterotomy was performed rather than anastomosis were excluded. Articles selected through title and abstract screening were then subjected to full-text screening (using the same inclusion criteria) and simultaneous data extraction by one of the authors. Full-text retrieval was attempted through online searching, by consulting Dutch and German university libraries, and by e-mail to the corresponding author. Articles in all languages except Japanese were included. www.bjs.co.uk
BJS 2015; 102: 726–734
728
S. T. K. Yauw, K. E. Wever, A. Hoesseini, M. Ritskes-Hoitinga and H. van Goor
600 100 Animal model presentation 75
% of studies
400 300 200
Study of physiology 50
Risk factor identification
25
100 0
Therapeutic trial
4
9 Ap ril 2
01
00
9 00
10
to
20 20
10 20
a
–2
99
9 –1
98 90 19
80
–1 19
19
