Very Early Colorectal Anastomotic Leakage within 5 Post-operative Days: a More Severe Subtype Needs Relaparatomy

Early anastomotic leakage (AL), usually defined as leakage within 30 post-operative days, represents a severe entity. However, mounting evidence has indicated that majorities of leakage occur within one week after surgery, making late AL rarity. Here we analyzed 101 consecutive colorectal AL, all of which occurred within 30 post-operative days, during Jan 2013 and Dec 2015 in cancer hospital of Fudan University. AL occurring within 5 post-operative days was defined as very early AL (vE-AL). We evaluated risk factors of vE-AL compared with non-vEAL and correlated with post-leakage peritonitis and need of relaparatomy. We found that AL occurred at median time of 7 days after surgery. 23 cases were vE-AL. Reconstruction of post-peritoneum for mid-low rectal carcinoma significantly reduced incidence of vE-AL compared with non-vE-AL (p = 0.042). Patients with vE-AL was associated with presence of peritonitis (p = 0.031), the latter significantly correlated with increased re-operation rate (p = 6.8E-13). Besides, patients with vE-AL trended to correlate with increased re-operation rate after leakage (p = 0.088). In concludsion, vE-AL occurring within 5 post-operative days represents a severe subtype associated with general peritonitis and need of relaparatomy.

relaparatomy after leakage. We demonstrated that reconstruction of post-peritoneum significantly reduced the incidence of vE-AL for mid-low rectal carcinoma (p = 0.042), the latter significantly correlated with presence of general peritonitis (p = 0.031). More percentages of patients with peritonitis received relaparatomy after leakage (p < 0.001). We suggested that 5 post-operative days was optimal cut-point discriminating true early AL cases associated with general peritonitis needing relaparatomy.
Factors Associated with Very Early Anastomotic Leakage. We evaluated clinicopathologic factors associated with very early anastomotic leakage (vE-AL). As was shown in Table 1, reconstruction of post-peritoneum was the only factor significantly associated with reduced incidence of vE-AL (11/57 vs 6/13, p = 0.042) for mid-low rectal carcinoma. Besides, patients receiving neo-adjuvant chemoradiotherapy for mid-low rectal carcinoma trended to have increased incidence of vE-AL (6/14 vs 11/56, p = 0.070). Anastomotic reinforcement trended to correlate with decreased incidence of vE-AL (4/33 vs 19/68, p = 0.075) for colorectal carcinoma.
Factors Influencing Peritonitis after Anastomotic Leakage. General peritonitis was the most severe clinical manifestation and leading cause of death. As was shown in Table 2, very early anastomotic leakage (vE-AL, ≤ 5 post-operative days) was the only significant indicator for general peritonitis (6/23, 26.09% vs 7/78, 8.97%; p = 0.031). Howerer, pre-operative conditions (gender, age, diabetes, anemia, hypo-proteinemia and neo-adjuvant CRT) as well as surgical factors (tumor location, open vs laparoscopy, curative vs palliative) did not significantly affected the incidence of peritonitis. Moreover, some techniques including reinforcement of anastomosis, reconstruction of post-peritoneum and protective soma, which were generally regarded as protective factor to reduce the incidence and severity of anastomotic leakage, did not prevent the presence of peritonitis after leakage.
Factors Associated with Necessity of Relaparatomy after Anastomotic Leakage. As was shown in Table 3, presence of general peritonitis was the only significant indicator for necessity of relaparotomy after anastomotic leakage (12/13 vs 7/86, p = 6.8E-13). Besides, patients with vE-AL (7/22 vs 12/77, p = 0.088) or diabetes (6/19 vs 11/80, p = 0.064) trended to correlate with increased relaparatomy rate after leakage. However, other perioperative clinicopathologic factors had no significant relationship with relaparatomy. Unfortunately, 4 patients died because of this complication. Strikingly, leakage associated death did not mainly occur in high-risk patients including patients with very early leakage (1/4), peritonitis (1/4) or lower rectal carcinoma (1/4). Three leakages of colon anastomoses occurred 7 days after surgery and did not show severe symptoms of peritonitis, which resulted in the loss of opportunity for relaparatomy.

Discussion
Anastomotic leakage (AL) was one of the most important complications after surgery of colorectal carcinoma, which was responsible for prolonged hospital stay, delayed post-operative chemoradiotherapy, increased re-operation and motality rate 19 . Patients with high risk of AL would receive protective stoma during first operation, which was planned to be reversed within 3-6 months. However, these temporary stomas would become permanent due to lower rectal anastomotic stricture following radiotherapy. This would largely reduce quality of life, especially for younger patients. Therefore, understanding the mechanism of AL is of great clinical significance.
Early anastomotic leakage, defined as AL occurring within 30 post-operative days 12,16 , represents a unique entity requiring more aggressive intervention 12,13 and causing elevated motality rate compared with late AL. However, since majorities of AL occurred 5-10 days after surgery, cut-point of 30 post-operative days makes late AL rarity 17 accounting for less than 4 percent of AL cases as indicated by a Korean team reporting 290 AL from 10477 colorectal carcinomas 1 . Therefore, redefinition of early anastomotic leakage with optimal cut-point time may be helpful to distinguish truly lethal cases needing urgent intervention.
In the present study, we demonstrated that very early AL (vE-AL, ≤ 5 post-operative days) was significantly associated with presence of general peritonitis (p = 0.031, Table 2) and trended to correlate with increased urgent relaparatomy rate (p = 0.088, Table 3). This was in accordance with great bodies of evidence demonstrating early AL as severe and lethal complication. Floodeen H et al. 9 reported that early symptomatic AL (diagnosed during initial hospital stay, average 8 post-operative days) performed worse than late AL (diagnosed after discharge, average 22 post-operative days) with regard to oral intake, bowel activity and initial hospital stay. Early AL within 30 days after surgery was associated with increased proportions of patients needing relaparatomy (78.8-89% vs 44-55.4%) 12,13 . Several factors may contribute to this discrepancy. First, early AL was associated with worse local inflammation, determined by elevated levels of inflammatory cytokines (TNF-α , IL-6, IL-12) 20-22 from peritoneal fluid as early as the first post-operative day, as well as systemic inflammation burst in terms of elevated expression of circulating procalcitonin (PCT) and C-reactive protein 23 . This inflammatory stress deteriorates the pre-existed negative-nitrigen nutritional status of the patient, whose oral intake and bowel function has not completely recovered, leading to delayed healing of AL. In turn, worsening of AL accelerates nutritional consumption due to restriction of oral intake. These two processes exacerbate each other in a loop resulting in disease progression. Second, post-operative abdominal adhension is critical for the re-formation of post-peritoneum leading to localization of pelvic inflammation. However, in very early AL cases occurring within 5 days after surgery, abdominal adhension has not substantially formatted, which enables penetration and dissemination of pelvic leaking feces into abdominal cavity leading to severe general peritonitis 11 . This can partly explain why reconstruction of post-peritoneum does not reduce the severity of vE-AL in terms of peritonitis (p = 0.473, Table 2). Therefore, vE-AL might be life-threatening, especially for those atypical elderly cases following chemoradiotherapy 24 . About 1/3 of AL cases might present without symptoms 18 . In this study, one elderly patient undergoing ultra-low rectal anastomosis 5 days after oral capecitabine chemotherapy died of very early AL at the first post-operative day.  This patient behaved, without evident feces drainage or signs of peritonitis, as fever and severe agranulocytosis which rapidly progressed to septic shock within 24 hours before surgical intervention could be applied. Indeed, as the fact that majorities of AL happened at least one week after surgery, very early AL of elderly patients with bluntness physical reaction could be easily underestimated. Delayed diagnosis or persistent conservative therapy was reasonably dangerous. General peritonitis is one of the most severe outcome for AL. Lim SB 25 analyzed 142 AL from 2510 consecutive colorectal carcinomas and found that generalized peritonitis (type I AL) was the most common type (44.7%). Generalized peritonitis was associated with increased re-operation rate, as high as 100% in Rickert A's report (67 AL from 1731 colorectal anastomosis) which demonstrated peritonitis as one of the only two reasons for not preserving the anastomosis 26 . Infected peritonitis also correlated with decreased short term and long term survival of AL patients according to the report by Salvans S et al. 27 that infected peritoneal fluid enhanced cell migration and invasion of colorectal MDA-MB-231/SW620 cell lines in vitro. Two-year disease-free survival of patients with peritoneal infection was significantly lower (77.6% vs 90.6%). In our study, leakage-associated peritonitis was the only significant indicator of relaparatomy (p = 6.8E-13, Table 3). It is noteworthy whether re-operation is attributed to life-threatening peritonitis or the fasioned choice by the surgeon is still unknown. Besides, little evidence has been concluded about short-term outcome of leakage-associated peritonitis according to different choices of conservative or surgical interventions 28 .
In conclusion, we analyzed 101 consecutive colorectal anastomotic leakages and defined AL occurring ≤ 5 post-operative days as very early anastomotic leakage (vE-AL). We found that reconstruction of post-peritoneum for mid-low rectal carcinoma significantly reduced incidence of vE-AL compared with late AL (p = 0.042). Patients with vE-AL was associated with presence of peritonitis (p = 0.031), the latter significantly correlated with increased re-operation rate (p = 6.8E-13). We suggested that 5 post-operative days was optimal cut-point time discriminating truly life-threatening early AL needing urgent relaparatomy.  Definition of Anastomotic Leakage. Anastomotic leakage was defined as a communication between the intra-and extraluminal compartments owing to a defect of the integrity of the intestinal wall at the anastomosis (proposed by the International Study Group of Rectal Cancer, Surgery 2010;147:339-51). Detailed criteria were as follows: (1) apparent discharge of gas/pus/feces from abdominal or pelvic drainage tube; (2) anastomotic defect confirmed by proctoscopy, CT scan using contrast medium or rectal examination (only for lower rectal anastomosis); (3) confirmed during relaparatomy.
Peri-operative Preparation and Surgical Procedure. Bowel preparation, peri-operative administration of antibiotics, enteral nutrition (EN) and/or parenteral nutrition (PN) was comparable for the whole cohort. Oral polyethylene glycol solution was routinely taken the last night before surgery unless patients had symptoms of obstruction or perforation. Human albumin supplementation or blood transfusion was adopted if necessary. Standard Complete Mesocolic Excision (CME) or Total Mesocolic Excision (TME) was carried out as described elsewhere. The anastomosis was carried out using stapler for all the patients. Manual reinforcement sewing was performed when anastomosis was above the peritoneal reflextion.
Statistical analysis. Statistical analysis was performed using SPSS version 22. Comparison of subgroup differences was determined using chi-square test or Mann-whitney U test, as appropriate. Two sided p value of less than 0.05 was considered as statistically significant.