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World J Gastroenterol. Sep 21, 2014; 20(35): 12637-12648
Published online Sep 21, 2014. doi: 10.3748/wjg.v20.i35.12637
Pharmacological interventions for improved colonic anastomotic healing: A meta-analysis
Mari Nanna Øines, Peter-Martin Krarup, Lars Nannestad Jorgensen, Magnus Sven Ågren
Mari Nanna Øines, Peter-Martin Krarup, Lars Nannestad Jorgensen, Magnus Sven Ågren, Digestive Disease Center, Bispebjerg Hospital, University of Copenhagen, DK-2400 Copenhagen NV, Denmark
Magnus Sven Ågren, Copenhagen Wound Healing Center, Bispebjerg Hospital, University of Copenhagen, DK-2400 Copenhagen NV, Denmark
Magnus Sven Ågren, Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, DK-2200 Copenhagen, Denmark
Author contributions: Øines MN performed the literature search, collected and analyzed the data and drafted the article; Krarup PM designed the study and performed the literature search and the statistical analyses; Jorgensen LN designed the study and analyzed the data; Ågren MS designed the study, analyzed the data and edited the manuscript.
Correspondence to: Magnus Sven Ågren, Professor, Digestive Disease Center, Bispebjerg Hospital, University of Copenhagen, Bispebjerg Bakke 23, DK-2400 Copenhagen NV, Denmark.
Telephone: +45-35316493 Fax: +45-35313911
Received: January 28, 2014
Revised: April 10, 2014
Accepted: May 12, 2014
Published online: September 21, 2014

AIM: To identify pharmaceuticals for the prophylaxis of anastomotic leakage (AL), we systematically reviewed studies on anastomosis repair after colorectal surgery.

METHODS: We searched PubMed and EMBASE for articles published between January 1975 and December 2012. We included studies in English with the primary purpose of promoting healing of anastomoses made in the colon or rectum under uncomplicated conditions. We excluded studies on adverse events from interventions, nutritional interventions or in situ physical supporting biomaterials. The primary outcome was biomechanical strength or AL. We performed meta-analyses on therapeutic agents investigated by three or more independent research groups using the same outcome. The DerSimonian-Laird method for random effects was applied with P < 0.05.

RESULTS: Of the 56 different therapeutic agents assessed, 7 met our inclusion criteria for the meta-analysis. The prostacyclin analog iloprost increased the weighted mean of the early bursting pressure of colonic anastomoses in male rats by 60 mmHg (95%CI: 30-89) vs the controls, and the immunosuppressant tacrolimus increased this value by 29 mmHg (95%CI: 4-53) vs the controls. Erythropoietin showed an enhancement of bursting pressure by 45 mmHg (95%CI: 14-76). The anabolic compound growth hormone augmented the anastomotic strength by 21 mmHg (95%CI: 7-35), possibly via the up-regulation of insulin-like growth factor-1, as this growth factor increased the bursting pressure by 61 mmHg (95%CI: 43-79) via increased collagen deposition. Hyperbaric oxygen therapy increased the bursting pressure by 24 mmHg (95%CI: 13-34). Broad-spectrum matrix metalloproteinase inhibitors increased the bursting pressure by 48 mmHg (95%CI: 31-66) on postoperative days 3-4. In the only human study, the AL incidence was not significantly reduced in the 103 colorectal patients treated with aprotinin (11.7%) compared with the 113 placebo-treated patients (9.7%).

CONCLUSION: This systematic review identified only one randomized clinical trial and seven therapeutic agents from pre-clinical models that could be explored further for the prophylaxis of AL after colorectal surgery.

Keywords: Anastomotic healing, Colorectal surgery, Experimental, Breaking strength, Bursting pressure, Collagen, Meta-analysis

Core tip: Anastomotic leakage after colorectal surgery is an ongoing challenge and results in high morbidity and mortality. Currently, there is no pharmaceutical compound specifically indicated for the improvement of anastomotic healing. This situation is remarkable considering the many interventions that have been assessed under experimental conditions. This study reviewed 56 therapeutic agents investigated in 75 separate studies. Iloprost, tacrolimus, erythropoietin, growth hormone, insulin-like growth factor-1, hyperbaric oxygen and matrix metalloproteinase inhibitor therapies reproducibly improved anastomosis stability in experimental models. These therapies, alone or in combination, should be explored further.