Anastomotic Leakage and Enhanced Recovery Pathways After Colorectal Surgery
Anastomotic Leakage and Enhanced Recovery Pathways After Colorectal Surgery
Prospective observational multicenter study on the influence of adherence to enhanced
 recovery pathways on early outcomes (anastomotic leakage, morbidity, mortality, readmission,
 reoperation rates and length of postoperative stay) after elective colorectal surgery in
 Italy.
BACKGROUND

 Anastomotic leakage (AL) is a dreaded major complication after colorectal surgery. The
 overall incidence of anastomotic dehiscence and subsequent leaks is 2 to 7 percent when
 performed by experienced surgeons. The lowest leak rates are found with ileocolic anastomoses
 (1 to 3 percent) and the highest occur with coloanal anastomosis (10 to 20 percent). Leaks
 usually become apparent between five and seven days postoperatively. Almost half of all leaks
 occur after the patient has been discharged, and up to 12 percent occur after postoperative
 day (POD) 30. Late leaks often present insidiously with low-grade fever, prolonged ileus, and
 nonspecific symptoms attributable to other postoperative infectious complications. Small,
 contained leaks present later in the clinical course and may be difficult to distinguish from
 postoperative abscesses by radiologic imaging, making the diagnosis uncertain and
 underreported.

 There is no uniform definition of an anastomotic dehiscence and leak. In a review of 97
 studies, as an example, 56 different definitions of an anastomotic leak were used. The
 majority of reports define an anastomotic leak using clinical signs, radiographic findings,
 and intraoperative findings. The clinical signs include: Pain, Fever, Tachycardia,
 Peritonitis, Feculent drainage, Purulent drainage. The radiographic signs include: Fluid
 collections, Gas containing collections. The intraoperative findings include: Gross enteric
 spillage, Anastomotic disruption.

 Risk factors for a dehiscence and leak are classified according to the site of the
 anastomosis (extraperitoneal or intraperitoneal). A prospective review of 1598 patients
 undergoing 1639 anastomotic procedures for benign or malignant colorectal disease found a
 significantly increased risk of anastomotic leak with extraperitoneal compared with
 intraperitoneal anastomoses (6.6 versus 1.5 percent; 2.4 percent overall).

 Major risk factors for an extraperitoneal AL include: The distance of the anastomosis from
 the anal verge (Patients with a low anterior resection and an anastomosis within 5 cm from
 the anal verge are the highest risk group for an anastomotic leak), Anastomotic ischemia,
 Male gender, Obesity.

 Major risk factors for an intraperitoneal AL include: American Society of Anesthesiologists
 (ASA) score Grade III to V, Emergent surgery, Prolonged operative time, Hand-sewn ileocolic
 anastomosis.

 Controversial, inconclusive, or pertinent negative associations between the following
 variables and AL have been reported: Neoadjuvant radiation therapy, Drains, Protective stoma,
 Hand-sewn colorectal anastomosis, Laparoscopic procedure, Mechanical bowel preparation,
 Nutritional status, Perioperative corticosteroids.

 Enhanced Recovery After Surgery (ERAS) programs for colorectal surgery have been extensively
 studied during the last 20 years. It is now clear that they offer a consistent reduction of
 overall morbidity rates, postoperative length of stay and costs, and that there is a clear
 dose-effect relation between adherence to at least 60-70% of the program items and these
 outcomes. On the other hand, little is known concerning the potential benefit of ERAS
 programs over AL rates or if adherence to specific items of the program may reduce AL rates.

 Therefore, the investigators planned this study to prospectively evaluate AL rates after
 colorectal resections and their interaction with known risk factors and ERAS program items.

 METHODS

 Prospective enrollment from January to December 2019 in 41 Italian surgical centers. All
 patients undergoing elective colorectal surgery with anastomosis will be included in a
 prospective database after having provided a written informed consent. A total of 1,750
 patients is expected based on a mean of 43 cases/year per center.

 Outcome measures

 1. Preoperative risk factors of anastomotic leakage (age, gender, obesity, nutritional
 status, diabetes, cardiovascular disease, chronic liver disease, renal failure,
 inflammatory bowel disease, perioperative steroid therapy, ASA class I-II vs III)

 2. Operative parameters (approach, procedure, anastomotic technique, length of operation,
 disease stage)

 3. ERAS program items (prehabilitation, counseling, nutritional evaluation,
 immuno-nutrition, deep venous thrombosis prophylaxis, antibiotic prophylaxis, bowel
 preparation, preoperative carbohydrates load, standardized anesthesia protocol,
 restrictive i.v. fluid administration, control of body temperature, nausea and vomit
 prophylaxis, multimodal approach to opioid-sparing pain control, restrictive use of
 surgical drains, laparoscopic surgery, removal of nasogastric tubes before reversal of
 anesthesia, early removal of urinary catheter, early mobilization, early oral intake of
 fluids and solids, use of chewing gums and laxatives, intake of protein-rich nutritional
 supplements, prepare for early discharge, audit).

 Endpoints

 1. Anastomotic leakage rate

 2. Minor and major complications

 3. Length of postoperative hospital stay

 4. Readmission and reoperation rates Recorded data and follow-up Potential patient-specific
 and intraoperative risk factors will be recorded: gender, body mass index, nutritional
 status according to the Mini Nutritional Assessment short-form, surgical indication
 (cancer, polyps, chronic inflammatory bowel disease, diverticular disease), preoperative
 albuminemia, use of steroids, renal failure and dialysis, cardiovascular or respiratory
 disease, American Society of Anesthesia class, bowel preparation (decision made by
 operating surgeon), laparoscopy or laparotomy, level of anastomosis and technique
 (mechanical or hand-sewn, intra- or extra-corporeal), operative time, presence of
 drainage, and perioperative blood transfusion(s). During the postoperative period,
 patients will be examined by the attending surgeon daily. Fever (central temperature >
 38 °C), pulse, abdominal signs, bowel movements, volume and aspect of drainage (if
 present) will be recorded daily. The attending surgeon will make any decision for
 complementary exams and imaging according to his own criteria. The rate of any
 complication will be calculated and graded including all leaks (independently of
 clinical significance), wound infection (according to the definitions of the Centers for
 Disease Control and Prevention and wound culture), pneumonia (clinical symptoms, and
 physical and radiological examinations), central line infection (positive blood
 culture), urinary tract infection (positive urine culture with bacterial count ).
 Patients will be followed-up in the outpatient clinic up to 6 weeks after discharge from
 the hospital.

 Main endpoint is anastomotic dehiscence (intended as any deviation from the planned
 postoperative course related to the anastomosis, or presence of pus or enteric contents
 within the drains, presence of abdominal or pelvic collection in the area of the anastomosis
 on postoperative CT scan, performed at the discretion of the attending surgeon, leakage of
 contrast through the anastomosis during enema or evident anastomotic dehiscence at
 reoperation for postoperative peritonitis). Thus, all detected leaks will be considered
 independently of clinical significance. No imaging will be performed routinely in order to
 search for leakage.

 Secondary endpoints are morbidity and mortality rates, postoperative length of stay,
 readmission and reoperation rates.

 After anonymization, all data of each single case will be prospectively uploaded by every
 local investigator on a protected web-based database. Thereafter, all data will be
 incorporated into a spreadsheet (MS Excel) for data analysis, checking for any discrepancy,
 that will be addressed and solved through strict cooperation between chief investigator, data
 manager and participating center.

 Statistical Analysis Quantitative values will be expressed as mean ± standard deviation,
 median and range; categorical data with percentage frequencies. Mean values of duration of
 stay will be compared according to the presence or absence of fistulas using Student's
 two-sided t test (allowing for heterogeneity of variances) or with a non-parametric
 Mann-Whitney test. Both univariate analysis and multivariate analysis will be performed to
 assess risk factors for leakage and overall complications. The odds ratio (OR) will be
 presented followed by its 95% confidence interval (95% CI). For all statistical tests the
 significant level is fixed at p < .05.

 Statistical analyses will be carried out using STATA software (Stata Corp. College Station,
 Texas, USA).

 Sample size Considering that adherence to 70% of the items of an ERAS program determines a
 significant reduction in surgical complications after colorectal surgery, an estimation of
 the OR for AL and ERAS program adherence at 70% of the items is equal to 0.55 (95% c.i.
 0.36-0.87); assuming a maximum error equal to 0.04, the required sample size is n=1,748
 (about 874 cases per arm expected in low vs high adherence to ERAS programs).
Inclusion Criteria:

 1. Patients submitted to laparoscopic/robotic/open/converted ileo-colo-rectal resection
 with anastomosis (both intra- and extra-corporeal), including planned Hartmann's
 reversals.

 2. American Society of Anesthesiologists' (ASA) class I, II or III

 3. Elective or delayed urgency surgery

 4. Patients' written acceptance to be included in the study.

 Exclusion Criteria:

 1. American Society of Anesthesiologists' (ASA) class IV-V

 2. Patients with stoma before or at operation

 3. Simple stoma closure

 4. Transanal procedure

 5. Pregnancy

 6. Hyperthermic intraperitoneal chemotherapy for carcinomatosis.