Clinical trial NCT03560180: Early Diagnosis of Anastomotic Leakage After Colorectal Surgery: Italian ColoRectal Anastomotic Leakage Study Group.
Official title: Early Diagnosis of Anastomotic Leakage After Colorectal Surgery: a Prospective Observational Validation Study of the Dutch Leakage Score, Serum Procalcitonin and Serum CRP: the Italian ColoRectal Anastomotic Leakage (iCRAL) Study Group.
Study type: OBSERVATIONAL
Overall status: UNKNOWN
Conditions: Anastomotic Leak
Colorectal Surgery
Keywords: Anastomotic Leak
Colorectal Surgery
Lead sponsor: Ospedale C & G Mazzoni
Sponsor class: OTHER
First posted: 2018-06-18
Enrollment: 1131
Sex: ALL
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: PROBABILITY_SAMPLE
Study population: Prospective enrollment from September 2017 to September 2018 in 19 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.

Brief summary: Prospective evaluation of early diagnosis of anastomotic leak after colorectal resection through evaluation of Dutch leakage score, serum C-reactive protein and serum Procalcitonin

Detailed description: BACKGROUND

Anastomotic leakage 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 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 anastomotic leak 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 anastomotic leak 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 an anastomotic leak have been reported: Neoadjuvant radiation therapy, Drains, Protective stoma, Hand-sewn colorectal anastomosis, Laparoscopic procedure, Mechanical bowel preparation, Nutritional status, Perioperative corticosteroids.

Early diagnosis is crucial to treat patients limiting the related mortality. For this reason several clinical items were proposed in literature to detect anastomotic leakage as soon as possible: fever, pain, tachycardia, peritoneal, purulent or faecal drain, and dynamic ileus. Moreover, also laboratory markers were proposed, such as leukocytosis, serum procalcitonin (PCT) and C-Reactive Protein (CRP). Finally, in 2009 den Dulk et al. proposed a leakage score (DUtch LeaKage, DULK), that consider several items (fever, heart rate, respiratory rate, urinary production, mental status, clinical conditions, signs of ileus, gastric retention, fascial dehiscence, abdominal pain, wound pain, leukocytosis, CRP, increase of urea or creatinine and nutrition status), to give a score, based on which is chosen a therapeutic strategy.

Therefore, we planned this study to prospectively evaluate anastomotic leakage rate after colorectal resections, trying to give a definite answer to the need for clear risk factors, and testing the diagnostic yeald of DULK score and laboratory markers.

METHODS Prospective enrollment from September 2017 to September 2018 in 19 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 1,131 patients is expected based on a mean of 55 cases/year per center.

Outcome measures

1. Preoperative risk factors of anastomotic leakage (age, gender, obesity, state of nutrition, diabetes, cardiovascular, renal failure, inflammatory bowel disease, ASA class I-II vs III)
2. Operative parameters (approach, procedure, anastomotic technique, time of operation, pTNM stage)
3. Leukocyte count, serum CRP, serum procalcitonin and DULK score assessment in 2nd and 3rd postoperative day. Minor and major complications according to Clavien-Dindo classification
4. Anastomotic leakage rate
5. Morbidity-Mortality rates
6. Length of postoperative hospital stay

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, preoperative leukocyte count, CRP, PCT cardiovascular or respiratory disease, American Society of Anesthesia score, 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, surgeon 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. Leucocyte count, CRP, PCT and Dulk score will be measured in the evening before the operation (in addition to albuminemia) and on postoperative days 2, 3, and 6 (optional). 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 according to Clavien-Dindo including all leaks (independently of clinical significance), wound infection, pneumonia, central line infection, urinary tract infection. Urinary tract infection will be diagnosed on the basis of positive urine culture with bacterial count. Central line infection will be diagnosed on the basis of positive blood culture. Superficial and deep incisional infections will be diagnosed according to the definitions of the Centers for Disease Control and Prevention and a culture will be performed. Pneumonia will be diagnosed on the basis of clinical symptoms, and physical and radiological examinations. The surgeons will be blinded to the results of the CRP and PCT assays. Patients will be followed-up in the outpatient clinic up to 6 weeks after discharge from the hospital.

Main outcome 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 outcomes are morbidity and mortality rates, and postoperative length of stay. All data will be prospectively recorded into CRF and transmitted to the coordinating center on a monthly basis. Thereafter, all data will be incorporated into a spreadsheet (MS Excel), 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. Mean values of DULK score, CRP and PCT levels will also be compared 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). Areas under the receiver-operating characteristics (ROC) curve will be calculated. For all statistical tests the significant level is fixed at p \< .05. Multivariate analysis will be performed using logistic models. Statistical analyses will be carried out using STATA software (Stata Corp. College Station, Texas, USA).

Sample size Considering that the ASA grade (I and II vs. III) is mostly significant among risk factors for anastomotic dehiscence, an estimation of the OR for anastomotic dehiscence and ASA grade is equal to 5.6; assuming a confidence interval for the estimation of the OR at 95% and a maximum error equal to 0.04, the required sample size is n=1,062 (about 885 and 177 cases expected in ASA I-II and ASA III, respectively).

Eligibility criteria: Inclusion Criteria:

1. Patients submitted to laparoscopic/robotic/open/converted ileo-colo-rectal resection with anastomosis (both intra- and/or extra-corporeal), including planned Hartmann's reversals.
2. American Society of Anesthesiologists' (ASA) class I, II or III
3. Elective 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. Ongoing infection prior to surgery
7. Hyperthermic intraperitoneal chemotherapy for carcinomatosis

Primary outcomes:
measure: Anastomotic Leakage
timeFrame: 60 days after operation
Secondary outcomes:
measure: Operative mortality rates
timeFrame: 60 days after operation
measure: Operative morbidity rates
timeFrame: 60 days after operation
measure: Postoperative length of stay
timeFrame: 60 days after operation
Other outcomes:
Locations:
city: Jesi
country: Italy
facility: UOC Chirurgia Generale - Jesi - AV5 - ASUR Marche
state: AN
city: Brescia
country: Italy
facility: UOC Chirurgia Generale - Ospedale Montichiari (BS) - ASST Spedali Civili di Brescia
state: BS
city: Brescia
country: Italy
facility: Clinica Chirurgica, Università di Brescia - UOC Chirurgia Generale 3, ASST Spedali Civili di Brescia - 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: San Giovanni Rotondo
country: Italy
facility: UOC di Chirurgia Addominale IRCCS Casa Sollievo della Sofferenza - San Giovanni Rotondo - Foggia
state: FG
city: Prato
country: Italy
facility: UOC Chirurgia Generale e Oncologica - Ospedale S. Stefano - Prato (FI) - ASL Toscana Centro
state: FI
city: Genova
country: Italy
facility: UOC Chirurgia Generale ad Indirizzo Oncologico - IRCCS San Martino IST - Genova
state: GE
city: Pesaro
country: Italy
facility: SOC Chirurgia Generale, Oncologica e Vascolare - Azienda Ospedaliera Marche Nord - Pesaro
state: PU
city: Albano Laziale
country: Italy
facility: UOC Chirurgia Generale - Ospedale "Regina Apostolorum" Albano Laziale (RM)
state: RM
city: Roma
country: Italy
facility: U.O. di Chirurgia Generale e d'Urgenza - Policlinico Casilino - 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 - Policlinico Campus BioMedico - Roma
state: RM
city: Riccione
country: Italy
facility: UOC Chirurgia Generale, Laparoscopica, Toracica -Ospedale "Ceccarini" di Riccione - Area Vasta Romagna
state: RN
city: Trento
country: Italy
facility: UOC Chirurgia Generale 1 - Ospedale S. Chiara - APSS Trento
state: TN
city: Pinerolo
country: Italy
facility: UOC Chirurgia Generale - Ospedale "E. Agnelli" di Pinerolo (TO) - ASL TO3
state: TO
city: Negrar
country: Italy
facility: UOC Chirurgia Generale - Ospedale Sacro Cuore Don Calabria Negrar 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
Study officials:
affiliation: ASUR Marche
name: Marco Catarci, MD
role: STUDY_DIRECTOR
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