Clinical trial NCT03771456: Anastomotic Leakage and Enhanced Recovery Pathways After Colorectal Surgery
Official title: Anastomotic Leakage and Enhanced Recovery Pathways After Colorectal Surgery: the Italian ColoRectal Anastomotic Leakage Study Group (iCral 2)
Study type: OBSERVATIONAL
Overall status: UNKNOWN
Conditions: Colorectal Neoplasms
Anastomotic Leak
Surgery--Complications
Lead sponsor: Ospedale C & G Mazzoni
Sponsor class: OTHER
First posted: 2018-12-11
Enrollment: 1748
Sex: ALL
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: Any patient submitted to elective colorectal resection with anastomosis

Brief summary: 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.

Detailed description: 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).

Eligibility criteria: 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.

Primary outcomes:
measure: Anastomotic Leakage rate
timeFrame: up to 45 days
Secondary outcomes:
measure: Morbidity rate
timeFrame: up to 45 days
measure: Mortality rate
timeFrame: up to 45 days
measure: Reoperation rate
timeFrame: up to 45 days
measure: Readmission rate
timeFrame: up to 45 days
measure: Length of postoperative hospital stay
timeFrame: up to 45 days
Other outcomes:
Locations:
city: Fabriano
country: Italy
facility: UOC Chirurgia Generale - Ospedale Profili - Fabriano (AN) - ASUR MARCHE AV2
state: AN
city: Jesi
country: Italy
facility: UOC Chirurgia Generale - Ospedale "C. Urbani" Jesi - AV2 - ASUR Marche
state: AN
city: Aosta
country: Italy
facility: UOC Chirurgia Generale e d'Urgenza - Ospedale Regionale "U. Parini" - Aosta
state: AO
city: Ascoli Piceno
country: Italy
facility: UOC Chirurgia Generale - Ascoli Piceno - AV5 - ASUR Marche
state: AP
city: San Benedetto Del Tronto
country: Italy
facility: UOC Chirurgia Generale - San Benedetto del Tronto (AP) - AV5 - ASUR Marche
state: AP
city: L'Aquila
country: Italy
facility: UOC Chirurgia Generale Universitaria - Ospedale San Salvatore - L'Aquila
state: AQ
city: Avellino
country: Italy
facility: UOC Chirurgia Oncologica - AORN San Giuseppe Moscati - Avellino
state: AV
city: Brescia
country: Italy
facility: Clinica Chirurgica, Università di Brescia - UOC Chirurgia Generale 3, ASST Spedali Civili di Brescia - Brescia
state: BS
city: Montichiari
country: Italy
facility: UOC Chirurgia Generale - Ospedale Montichiari (BS) - ASST Spedali Civili di Brescia
state: BS
city: Cuneo
country: Italy
facility: S.C. Chirurgia Generale e Oncologica - Azienda Ospedaliera S. Croce e Carle - Cuneo, Italia
state: CN
city: Ferrara
country: Italy
facility: UOC Chirurgia Generale 1 - Chirurgia laparoscopica - Università di Ferrara
state: FE
city: San Giovanni Rotondo
country: Italy
facility: UOC di Chirurgia Addominale IRCCS Casa Sollievo della Sofferenza - San Giovanni Rotondo - Foggia
state: FG
city: Firenze
country: Italy
facility: UOC Chirurgia Generale - Ospedale S. Maria Annunziata - Firenze - ASL Toscana Centro
state: FI
city: Genova
country: Italy
facility: UOC Chirurgia Generale ad Indirizzo Oncologico - IRCCS San Martino IST - Genova
state: GE
city: Crotone
country: Italy
facility: UOC Chirurgia Generale - Ospedale"San Giovanni di Dio", ASP di Crotone (KR)
state: KR
city: Tricase
country: Italy
facility: UOC Chirurgia Generale e d'Urgenza - Ospedale Cardinale Panico - Tricase (LE)
state: LE
city: Sesto San Giovanni
country: Italy
facility: UOC Chirurgia Generale - ASST Nord - Sesto San Giovanni (MI)
state: MI
city: Esine
country: Italy
facility: UOC Chirurgia Generale - Ospedale di Esine (BS) - ASST Valcamonica
state: NS
city: Pescara
country: Italy
facility: UOC Chirurgia Generale e D'Urgenza - Pescara
state: PE
city: Foligno
country: Italy
facility: UOC Chirurgia Generale - Foligno (PG) - USL UMBRIA 2
state: PG
city: Pesaro
country: Italy
facility: SC Chirurgia Generale e Oncologica - AO Marche Nord - Pesaro
state: PU
city: Ragusa
country: Italy
facility: UOC Chirurgia Generale - Ragusa
state: RG
city: Albano Laziale
country: Italy
facility: UOC Chirurgia Generale - Ospedale "Regina Apostolorum" Albano Laziale (RM)
state: RM
city: Roma
country: Italy
facility: UOC Chirurgia Generale e d'Urgenza - Policlinico Casilino - Roma
state: RM
city: Roma
country: Italy
facility: UOC Chirurgia Generale e D'Urgenza . Azienda Ospedaliera San Camillo Forlanini Roma
state: RM
city: Roma
country: Italy
facility: UOC Chirurgia Generale e Oncologica - Ospedale San Filippo Neri - ASL Roma1
state: RM
city: Roma
country: Italy
facility: UOS Chirurgia Geriatrica - Università Campus BioMedico - Roma
state: RM
city: Roma
country: Italy
facility: UOSD Chirurgia Mininvasiva e dell'Apparato Digerente - Università Tor Vergata - Roma
state: RM
city: Riccione
country: Italy
facility: UOC Chirurgia Generale, Ospedale "Ceccarini" di Riccione (RN)
state: RN
city: Rimini
country: Italy
facility: UOC Chirurgia Generale e d'urgenza, Rimini, Novafeltria, Santarcangelo
state: RN
city: La Spezia
country: Italy
facility: UOC Chirurgia Generale I - Ospedale di La Spezia - ASL5 Spezzino
state: SP
city: Trento
country: Italy
facility: UOC Chirurgia Generale 1 - Ospedale S. Chiara - APSS Trento
state: TN
city: Trento
country: Italy
facility: UOC Chirurgia Generale e Mininvasiva, Ospedale San Camillo di Trento
state: TN
city: Pinerolo
country: Italy
facility: UOC Chirurgia Generale - Ospedale "E. Agnelli" di Pinerolo (TO) - ASL TO3
state: TO
city: Conegliano
country: Italy
facility: UOC Chirurgia Generale - Conegliano Veneto (TV) AULSS2 Marca trevigiana
state: TV
city: Negrar
country: Italy
facility: UOC Chirurgia Generale - Ospedale Sacro Cuore Don Calabria Negrar Verona
state: VR
city: Verona
country: Italy
facility: U.O.C. di Chirurgia Generale e dell'Esofago e Stomaco - AOUI di Verona
state: VR
city: Verona
country: Italy
facility: UOC Chirurgia Generale Epatobiliare - AOUI Verona
state: VR
city: Viterbo
country: Italy
facility: UOC Chirurgia Generale Oncologica - Azienda Ospedaliera Belcolle - Viterbo
state: VT
city: Napoli
country: Italy
facility: SOC Chirurgia Colorettale - Istituto Nazionale dei Tumori - IRCCS Fondazione "G.Pascale" - Napoli
city: Pozzuoli
country: Italy
facility: UOC Chirurgia Generale - Pozzuoli (NA) - ASL Napoli2 nord
Study officials:
affiliation: Ospedale C & G Mazzoni - Ascoli Piceno
name: Marco Catarci, MD FACS
role: STUDY_CHAIR
affiliation: Ospedale C & G Mazzoni - Ascoli Piceno
name: Gianluca Guercioni, MD
role: PRINCIPAL_INVESTIGATOR
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