Early Diagnosis of Anastomotic Leakage After Colorectal Surgery: Italian ColoRectal Anastomotic Leakage Study Group. (iCral)

June 15, 2018 updated by: Marco Catarci, Ospedale C & G Mazzoni

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.

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

Study Overview

Status

Unknown

Conditions

Intervention / Treatment

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).

Study Type

Observational

Enrollment (Anticipated)

1131

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Italy
      • Napoli, Italy, 80100
        • Recruiting
        • SOC Chirurgia Colorettale - Istituto Nazionale dei Tumori - IRCCS Fondazione "G.Pascale" - Napoli
    • AN
      • Jesi, AN, Italy, 60035
        • Recruiting
        • UOC Chirurgia Generale - Jesi - AV5 - ASUR Marche
    • BS
      • Brescia, BS, Italy, 25018
        • Recruiting
        • UOC Chirurgia Generale - Ospedale Montichiari (BS) - ASST Spedali Civili di Brescia
      • Brescia, BS, Italy, 25121
        • Recruiting
        • Clinica Chirurgica, Università di Brescia - UOC Chirurgia Generale 3, ASST Spedali Civili di Brescia - Brescia
    • CN
      • Cuneo, CN, Italy, 12100
        • Recruiting
        • S.C. Chirurgia Generale e Oncologica - Azienda Ospedaliera S. Croce e Carle - Cuneo, Italia
    • FG
      • San Giovanni Rotondo, FG, Italy, 71013
        • Recruiting
        • UOC di Chirurgia Addominale IRCCS Casa Sollievo della Sofferenza - San Giovanni Rotondo - Foggia
        • Contact:
    • FI
      • Prato, FI, Italy, 59100
        • Recruiting
        • UOC Chirurgia Generale e Oncologica - Ospedale S. Stefano - Prato (FI) - ASL Toscana Centro
        • Sub-Investigator:
          • Maddalena Baraghini, MD
    • GE
      • Genova, GE, Italy, 16121
        • Recruiting
        • UOC Chirurgia Generale ad Indirizzo Oncologico - IRCCS San Martino IST - Genova
    • PU
      • Pesaro, PU, Italy, 61121
        • Recruiting
        • SOC Chirurgia Generale, Oncologica e Vascolare - Azienda Ospedaliera Marche Nord - Pesaro
        • Sub-Investigator:
          • MARGHERITA LAMBERTINI, MD
    • RM
      • Albano Laziale, RM, Italy, 00041
        • Recruiting
        • UOC Chirurgia Generale - Ospedale "Regina Apostolorum" Albano Laziale (RM)
        • Contact:
      • Roma, RM, Italy, 00100
        • Recruiting
        • U.O. di Chirurgia Generale e d'Urgenza - Policlinico Casilino - Roma
      • Roma, RM, Italy, 00100
        • Recruiting
        • UOC Chirurgia Generale e Oncologica - Ospedale San Filippo Neri - ASL Roma1
        • Sub-Investigator:
          • RICCARDO ANGELONI, MD
      • Roma, RM, Italy, 00100
        • Recruiting
        • UOS Chirurgia Geriatrica - Policlinico Campus BioMedico - Roma
    • RN
      • Riccione, RN, Italy, 47921
        • Recruiting
        • UOC Chirurgia Generale, Laparoscopica, Toracica -Ospedale "Ceccarini" di Riccione - Area Vasta Romagna
        • Sub-Investigator:
          • ANDREA LUCCHI, MD
    • TN
      • Trento, TN, Italy, 38121
        • Recruiting
        • UOC Chirurgia Generale 1 - Ospedale S. Chiara - APSS Trento
    • TO
      • Pinerolo, TO, Italy, 10064
        • Recruiting
        • UOC Chirurgia Generale - Ospedale "E. Agnelli" di Pinerolo (TO) - ASL TO3
    • VR
      • Negrar, VR, Italy, 37024
        • Recruiting
        • UOC Chirurgia Generale - Ospedale Sacro Cuore Don Calabria Negrar Verona
    • VT
      • Viterbo, VT, Italy, 01100
        • Recruiting
        • UOC Chirurgia Generale Oncologica - Azienda Ospedaliera Belcolle - Viterbo
        • Contact:
        • Sub-Investigator:
          • PIETRO P AMODIO, MD

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

  • Child
  • Adult
  • Older Adult

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

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.

Description

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Observational Models: Cohort
  • Time Perspectives: Prospective

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Anastomotic Leakage
Time Frame: 60 days after operation
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.
60 days after operation

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Operative mortality rates
Time Frame: 60 days after operation
death due to any cause
60 days after operation
Operative morbidity rates
Time Frame: 60 days after operation
Operative morbidity rates, graded according to Clavien-Dindo classification
60 days after operation
Postoperative length of stay
Time Frame: 60 days after operation
postoperative length of stay expressed in day(s)
60 days after operation

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Ospedale C & G Mazzoni

Investigators

  • Study Director: Marco Catarci, MD, ASUR Marche

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

September 4, 2017

Primary Completion (Anticipated)

August 31, 2018

Study Completion (Anticipated)

September 30, 2018

Study Registration Dates

First Submitted

June 4, 2018

First Submitted That Met QC Criteria

June 15, 2018

First Posted (Actual)

June 18, 2018

Study Record Updates

Last Update Posted (Actual)

June 18, 2018

Last Update Submitted That Met QC Criteria

June 15, 2018

Last Verified

June 1, 2018

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 01/2017

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

Undecided

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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