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Background: This is the fourth updated Enhanced Recovery After Surgery (ERAS ® ) Society guideline presenting a consensus for optimal perioperative care in colorectal surgery and providing graded recommendations for each ERAS item within the ERAS ® protocol., Methods: A wide database search on English literature publications was performed. Studies on each item within the protocol were selected with particular attention paid to meta-analyses, randomised controlled trials and large prospective cohorts and examined, reviewed and graded according to Grading of Recommendations, Assessment, Development and Evaluation (GRADE) system., Results: All recommendations on ERAS ® protocol items are based on best available evidence; good-quality trials; meta-analyses of good-quality trials; or large cohort studies. The level of evidence for the use of each item is presented accordingly., Conclusions: The evidence base and recommendation for items within the multimodal perioperative care pathway are presented by the ERAS ® Society in this comprehensive consensus review.

Histologic evaluation of intestinal wound healing with and without cytostatics was performed in 36 rats. Variables were the relative position of the wound edges in mucosa and muscularis, necrosis, exudate, granulation tissue, granulocytes, macrophages, fibroblasts, restoration of the mucosal epithelium, and repair of the muscularis propria. The relative position of the wound edges in the mucosa and the muscularis in the initial phase of wound healing depended on technique but appeared to improve in the later phases of wound healing. It was not affected by the administration of antineoplastic agents; neither were muscularis repair, epithelial restoration of the mucosa, necrosis, nor exudate. Granulation tissue, fibroblasts and macrophages were present in maximal amounts after 7 days appearing later or showing this maximum at a different moment in time when antineoplastic agents were given. The processes of epithelial and muscularis repair were not influenced by the relative position of the wound edges. Granulation tissue, macrophages, and fibroblasts were the best parameters for measuring the histologic evolution of intestinal wound healing, and the effects of antineoplastic agents upon it.

Collagen degradation is thought to be an integral part of the healing sequence of intestinal anastomoses, but almost nothing is known about the enzyme activities involved. We have studied collagenolytic activities, extracted from 1 day-old intestinal anastomoses in the rat. Using either soluble type I collagen or fibrillar type I or type III collagen as a substrate, activities measured in extracts from anastomotic segments were compared to those in extracts from uninjured intestine, removed at operation: in all cases, the collagenolytic activity in anastomotic extracts was significantly higher. This increase was significantly more pronounced in large bowel than in small bowel. The activities were strongly inhibited by serum and metallo-chelating compounds. Analysis, by means of SDS-polyacrylamide gel electrophoresis, of the reaction products of the degradation of fibrillar type I collagen by the extracts revealed the presence of a multitude of fragments, amongst them TcA fragments characteristic for the activity of mammalian collagenase. Thus, the degradative capacity towards various collagen substrates is enhanced in the anastomotic area during the first postoperative period and a true mammalian collagenase is one of the enzymes present.

The effects of parenteral nutrition on the healing of experimental ileal and colonic anastomoses constructed on the 3rd day of a 5-day cytostatics course were investigated. Intravenous saline alone already reduced weight loss induced by cytostatics while parenteral nutrition almost completely prevented postoperative loss of weight. A negative effect of cytostatics on anastomotic bursting strength was found in the ileum 7 days after operation. Parenteral feeding negated this effect but had no positive effect on anastomotic hydroxyproline content. Thus, parenteral nutrition increases the strength of intestinal anastomoses, constructed during a cytostatics regimen, but intravenous saline alone also appears to have a similar effect.

We investigated the effect of two doses of cytostatics, administered intraperitoneally during 5 consecutive days, on the healing of ileal and colonic anastomoses constructed on the third day. The cytostatics regimen consisted of a combination of 5-fluorouracil, bleomycin and cisplatin at 10, 2 and 0.35 mg kg-1d-1, respectively, or at twice higher doses. The lower dose was similar to that given intravenously in previous experiments. Rats were sacrificed 3 or 7 days after operation. No effects of cytostatics were observed after 3 days, neither on anastomotic bursting pressure nor on hydroxyproline concentration (microgram/mg dry weight) or content (microgram cm-1). Profound effects were seen at 7 days. In the high dose group, bursting pressures in both anastomoses were greatly reduced with respect to the control group. Concurrently, collagen synthesis was severely impaired, as indicated by sustained decreased hydroxyproline concentrations and content. The lower dose of cytostatics showed essentially similar effects on hydroxyproline parameters, but affected anastomotic strength less dramatically. The data indicate that, while intraperitoneal chemotherapy may show less detrimental systemic toxicity and thus allow higher doses, its application as an adjunct to gastrointestinal surgery may be limited because of its severe effects on anastomotic repair.

In order to investigate the influence of sutures on intestinal anastomotic healing, 48 rats underwent both ileal and colonic resection. In 24 rats all intestinal sutures were removed 30 min after anastomotic construction (group 1), while in the remaining animals (group 2) the sutures were left in place. Bursting pressures and collagen (hydroxyproline) levels in anastomotic segments were measured 1, 3, and 7 days after operation. Two lethal ileal dehiscences and 9 anastomotic abscesses (5 ileal and 4 colonic) occurred in group 1, while in group 2 there were 3 ileal anastomotic abscesses. On the first day after operation, bursting pressures were significantly lower in sutureless ileal and colonic than in sutured anastomoses. During the post-operative course, changes in collagen concentrations in ileal and colonic segments did not differ between the groups. Thus, sutures are only essential in providing anastomotic strength during the immediate post-operative period, but do not seem to affect post-operative collagen metabolism.

Salt and acid solubility of collagen are thought to reflect its degree of crosslinking. In order to examine postoperative changes in crosslinking of intestinal collagen, which are of importance to the stability of the intestinal wall, we have investigated the solubility of hydroxyproline in rabbit ileum and colon, both in unwounded intestine and after construction of an anastomosis. Solubility in salt and dilute acid was increased by a sonication procedure. This way, 9% of total hydroxyproline in the unwounded colonic wall was salt soluble and 65% acid soluble. A similar distribution was observed in ileum. Three days after operation the salt-soluble fraction was significantly elevated in samples from the anastomotic area. In colon, this increase also persisted 7 days postoperatively. Comparison of anastomotic samples collected 3 and 7 days after surgery shows a significant decrease in the acid-soluble and a significant increase in the solid fraction. This phenomenon occurs both in ileum and colon. These results indicate that during the first days after operation the integrity of the intestinal wall is weakened not only by a loss of collagen, but also by a changed solubility of the remaining collagen.

Collagen lysis, which always occurs to some extent in the wound area, is thought to be the underlying cause for breakdown of intestinal anastomoses. Therefore, we have studied the loss of collagen around ileal and colonic anastomoses in New Zealand White rabbits during the first 48 hr after operation. In the ileum, significant lysis of collagen in the anastomotic area, as represented by a decreased level of hydroxyproline, occurs from 12 hr postoperatively onward. Maximal loss of hydroxyproline, as compared to preoperative values, is 27% measured 24 hr after operation. In the colon, significant lysis of collagen occurs after 3 hr. The lowest level of hydroxyproline measured during the experimental period is found 48 hr after operation, where the concentration is decreased by 38%. Changes in ileum are restricted to the anastomotic area, while in the colon the decrease in hydroxyproline extends along the intestinal wall, particularly in a proximal direction. The fact that total protein concentrations do not vary significantly indicates that the lowered hydroxyproline levels are specific. Microscopic examination of the wound area shows that the cellular response during the first 24 hr after wounding is restricted to granulocytes. It is suggested that granulocyte collagenase is mainly responsible for the observed lysis of collagen after intestinal anastomosis.

The effects of piroxicam on postoperative changes of collagen--measured as hydroxyproline--concentrations were measured around intestinal anastomoses in rats. Piroxicam, in a dose of 2 mg/kg/day, significantly reduced the decrease of hydroxyproline concentrations around colonic anastomoses during the first 3 days after the operation but also reduced the increase of hydroxyproline concentrations observed at day 7 around ileal anastomoses in the control group. 10 mg piroxicam/kg/day resulted in a 100% lethal peritonitis after the 5th postoperative day. We suggest that piroxicam affects collagen metabolism by inhibiting granulocyte functions.

The changes in collagen, measured as hydroxyproline, concentration around both ileal and colonic anastomoses in germ-free and control rats have been investigated and compared with each other. The germ-free rats were raised, operated on and maintained under completely pyrogen-free conditions. Animals were killed 2, 3 or 7 days after operation. There was a significant reduction in the lowering of hydroxyproline concentrations around the colonic anastomosis of germ-free rats compared with control rats both in the anastomosis at days 2 and 3 (P = 0.04 and P = 0.006 respectively) and in the proximal segment at day 3 (P = 0.03). In ileal anastomoses, significant differences between control and germ-free rats were only found at 7 days. Here, the increase in hydroxyproline concentration observed in control rats was significantly reduced in germ-free rats. These data are taken to support the hypothesis that bacteria affect colonic anastomotic healing by contributing to postoperative collagen degradation.

The effects of bile acid drainage on serum cholesterol levels have been investigated in Watanabe heritable hyperlipidemic rabbits, a unique model for homozygous familial hypercholesterolemia. Cholestyramine medication lowered serum cholesterol concentrations with 38%, while a 33% and a 50% small bowel bypass resulted in a decrease of 56 and 48%, respectively. Cholestyramine treatment after either bypass induced a minor additional fall in serum cholesterol. Ileal bypass and ileal resection were equally effective in reducing serum cholesterol. These results indicate the necessity for further investigation into the potential of bile acid drainage as a therapy in homozygous familial hypercholesterolemia.

Various histological parameters of wound repair have been studied in intestinal anastomoses in the rabbit in order to compare the healing processes in ileum and colon. The sequentional appearance of granulocytes, macrophages and fibroblasts has been studied from 3 h to 7 days after operation. Also, degree of necrosis, formation of capillaries and mucosal repair were analysed semi-quantitatively. Significant differences were observed between ileal and colonic anastomoses with respect to occurrence of granulocytes, necrosis and mucosal repair, particularly 7 days after operation. At that time, granulocytes and necrosis were virtually absent from ileal anastomoses, while mucosal integrity was restored in the majority of cases examined. In contrast, granulocytes and necrosis were still abundantly present in colonic anastomoses and mucosal repair was poor. These results support biochemical evidence that wounds in the ileum heal more rapidly than wounds in the colon. Possibly, the sustained presence of granulocytes, which are a potential source of collagenase activity, is important in this respect. Investigation of the same features of intestinal wound healing in rabbits with peritonitis induced by infection showed similar results and no differences were found between infected and non-infected animals.

The effect of a combination of antineoplastic agents (bleomycin (2 mg/kg/d), 5-fluorouracil (10 mg/kg/d) and cisdiamminedichloroplatinum (0.35 mg/kg/d)), given intravenously, on the healing of colonic anastomoses was investigated in rats. Ninety-six male Wistar rats were divided into four groups. A control group of rats underwent surgery only. The remaining rats were operated either 2 days before, 2 days after or during the 5-day chemotherapy course. In all groups rats were killed after 3, 7 and 21 days. Wound healing of the anastomosis was assessed by measuring the bursting pressures and hydroxyproline contents. Operating in the middle of the 5-day chemotherapy course had the greatest effect on anastomotic healing. This was most apparent on the seventh day postoperatively. When surgery was performed on the second day after the chemotherapy course there was an early delay in wound healing as measured by hydroxyproline content. Seven days postoperatively concentrations were in the same range as those in the control group. Chemotherapy commencing 2 days after surgery did not affect anastomotic healing as compared to the control group. Bursting pressure and hydroxyproline content at the end of the experiment were more or less comparable in all groups.

The healing of both rabbit ileal and colonic infected anastomoses has been investigated. Infection was induced by implanting a capsule with human fecal material in the anastomotic area. Infection did result in lowered bursting pressures, which effect was most pronounced in ileum seven days postoperatively. In general, the average hydroxyproline levels in and around infected anastomoses were lower than the hydroxyproline concentrations measured around noninfected anastomoses. This difference was most significant in the segment proximal to the ileal anastomosis seven days after operation, in the segment distal to the colonic anastomosis three days after operation, and in the segment proximal to the colonic anastomosis seven days after operation. It is concluded that infection interferes with the early stages of the healing sequence in rabbit intestinal anastomoses, profoundly affecting collagen metabolism. Our work does not support recent publications that report an unchanged or even increased wound strength under infected conditions.