Anastomotic Leakage and Enhanced Recovery Pathways After Colorectal Surgery

Colorectal Neoplasms Clinical Trial

— iCral2  

Official title:

Anastomotic Leakage and Enhanced Recovery Pathways After Colorectal Surgery: the Italian ColoRectal Anastomotic Leakage Study Group (iCral 2)

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT03771456
• Other study ID #: 2.0
• Status: Recruiting
• Start date: January 7, 2019
• Est. completion date: December 31, 2019

Study information

• Verified date: December 2018
• Source: Ospedale C & G Mazzoni
• Contact: Marco Catarci, MD FACS
• Phone: 3298610040
• Email: marcocatarci[@]gmail.com
• Is FDA regulated: No
• Study type: Observational

Clinical Trial 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.

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).

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 1748
• Est. completion date: December 31, 2019
• Est. primary completion date: December 31, 2019
• Accepts healthy volunteers: No
• Gender: All
• Age group: N/A and older

Eligibility

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.

Related Conditions & MeSH terms

• Anastomotic Leak
• Colorectal Neoplasms
• Surgery--Complications

Intervention

Procedure:
• Colorectal resections
Colorectal resections

Locations

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

Sponsors (1)

Lead Sponsor	Collaborator
Ospedale C & G Mazzoni

Country where clinical trial is conducted

Italy, 

References & Publications (21)

Boushey R, Williams LJ. Management of anastomotic complications of colorectal surgery. Uptodate 2017.

Bruce J, Krukowski ZH, Al-Khairy G, Russell EM, Park KG. Systematic review of the definition and measurement of anastomotic leak after gastrointestinal surgery. Br J Surg. 2001 Sep;88(9):1157-68. Review. — View Citation

Clavien PA, Barkun J, de Oliveira ML, Vauthey JN, Dindo D, Schulick RD, de Santibañes E, Pekolj J, Slankamenac K, Bassi C, Graf R, Vonlanthen R, Padbury R, Cameron JL, Makuuchi M. The Clavien-Dindo classification of surgical complications: five-year experience. Ann Surg. 2009 Aug;250(2):187-96. doi: 10.1097/SLA.0b013e3181b13ca2. — View Citation

Dietz, DW, Bailey, HR. Postoperative complications. In: ASCRS Textbook of Colon and Rectal Surgery, Church, JM, Beck, DE, Wolff, BG, Fleshman, JW, Pemberton, JH, (Eds), Springer-Verlag New York, LLC, New York 2006. p.141.

Dindo D, Demartines N, Clavien PA. Classification of surgical complications: a new proposal with evaluation in a cohort of 6336 patients and results of a survey. Ann Surg. 2004 Aug;240(2):205-13. — View Citation

ERAS Compliance Group. The Impact of Enhanced Recovery Protocol Compliance on Elective Colorectal Cancer Resection: Results From an International Registry. Ann Surg. 2015 Jun;261(6):1153-9. doi: 10.1097/SLA.0000000000001029. — View Citation

Gustafsson UO, Scott MJ, Schwenk W, Demartines N, Roulin D, Francis N, McNaught CE, Macfie J, Liberman AS, Soop M, Hill A, Kennedy RH, Lobo DN, Fearon K, Ljungqvist O; Enhanced Recovery After Surgery (ERAS) Society, for Perioperative Care; European Society for Clinical Nutrition and Metabolism (ESPEN); International Association for Surgical Metabolism and Nutrition (IASMEN). Guidelines for perioperative care in elective colonic surgery: Enhanced Recovery After Surgery (ERAS(®)) Society recommendations. World J Surg. 2013 Feb;37(2):259-84. doi: 10.1007/s00268-012-1772-0. — View Citation

Horan TC, Gaynes RP, Martone WJ, Jarvis WR, Emori TG. CDC definitions of nosocomial surgical site infections, 1992: a modification of CDC definitions of surgical wound infections. Infect Control Hosp Epidemiol. 1992 Oct;13(10):606-8. — View Citation

Hyman N, Manchester TL, Osler T, Burns B, Cataldo PA. Anastomotic leaks after intestinal anastomosis: it's later than you think. Ann Surg. 2007 Feb;245(2):254-8. — View Citation

Kaiser MJ, Bauer JM, Ramsch C, Uter W, Guigoz Y, Cederholm T, Thomas DR, Anthony P, Charlton KE, Maggio M, Tsai AC, Grathwohl D, Vellas B, Sieber CC; MNA-International Group. Validation of the Mini Nutritional Assessment short-form (MNA-SF): a practical tool for identification of nutritional status. J Nutr Health Aging. 2009 Nov;13(9):782-8. — View Citation

Kingham TP, Pachter HL. Colonic anastomotic leak: risk factors, diagnosis, and treatment. J Am Coll Surg. 2009 Feb;208(2):269-78. doi: 10.1016/j.jamcollsurg.2008.10.015. Epub 2008 Dec 4. Review. — View Citation

Law WI, Chu KW, Ho JW, Chan CW. Risk factors for anastomotic leakage after low anterior resection with total mesorectal excision. Am J Surg. 2000 Feb;179(2):92-6. — View Citation

Lipska MA, Bissett IP, Parry BR, Merrie AE. Anastomotic leakage after lower gastrointestinal anastomosis: men are at a higher risk. ANZ J Surg. 2006 Jul;76(7):579-85. — View Citation

Ljungqvist O, Scott M, Fearon KC. Enhanced Recovery After Surgery: A Review. JAMA Surg. 2017 Mar 1;152(3):292-298. doi: 10.1001/jamasurg.2016.4952. Review. — View Citation

Ljungqvist O, Thanh NX, Nelson G. ERAS-Value based surgery. J Surg Oncol. 2017 Oct;116(5):608-612. doi: 10.1002/jso.24820. Epub 2017 Sep 5. Review. — View Citation

Nelson G, Kiyang LN, Crumley ET, Chuck A, Nguyen T, Faris P, Wasylak T, Basualdo-Hammond C, McKay S, Ljungqvist O, Gramlich LM. Implementation of Enhanced Recovery After Surgery (ERAS) Across a Provincial Healthcare System: The ERAS Alberta Colorectal Surgery Experience. World J Surg. 2016 May;40(5):1092-103. doi: 10.1007/s00268-016-3472-7. — View Citation

Neville A, Lee L, Antonescu I, Mayo NE, Vassiliou MC, Fried GM, Feldman LS. Systematic review of outcomes used to evaluate enhanced recovery after surgery. Br J Surg. 2014 Feb;101(3):159-70. doi: 10.1002/bjs.9324. Review. — View Citation

Park JS, Choi GS, Kim SH, Kim HR, Kim NK, Lee KY, Kang SB, Kim JY, Lee KY, Kim BC, Bae BN, Son GM, Lee SI, Kang H. Multicenter analysis of risk factors for anastomotic leakage after laparoscopic rectal cancer excision: the Korean laparoscopic colorectal surgery study group. Ann Surg. 2013 Apr;257(4):665-71. doi: 10.1097/SLA.0b013e31827b8ed9. — View Citation

Platell C, Barwood N, Dorfmann G, Makin G. The incidence of anastomotic leaks in patients undergoing colorectal surgery. Colorectal Dis. 2007 Jan;9(1):71-9. — View Citation

Skipper A, Ferguson M, Thompson K, Castellanos VH, Porcari J. Nutrition screening tools: an analysis of the evidence. JPEN J Parenter Enteral Nutr. 2012 May;36(3):292-8. doi: 10.1177/0148607111414023. Epub 2011 Nov 1. — View Citation

Slieker JC, Komen N, Mannaerts GH, Karsten TM, Willemsen P, Murawska M, Jeekel J, Lange JF. Long-term and perioperative corticosteroids in anastomotic leakage: a prospective study of 259 left-sided colorectal anastomoses. Arch Surg. 2012 May;147(5):447-52. doi: 10.1001/archsurg.2011.1690. Erratum in: Arch Surg. 2012 Aug;147(8):737. Komen, Niels A P [corrected to Komen, Niels]. — View Citation

* Note: There are 21 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Anastomotic Leakage rate	Rate of any complication related to the anastomosis after colorectal resection	up to 45 days
Secondary	Morbidity rate	Rate of any complication after colorectal resection	up to 45 days
Secondary	Mortality rate	Rate of any death after colorectal resection	up to 45 days
Secondary	Reoperation rate	Rate of any unplanned reoperation	up to 45 days
Secondary	Readmission rate	Rate of any unplanned readmission after discharge	up to 45 days
Secondary	Length of postoperative hospital stay	number of days between primary colorectal resection and discharge	up to 45 days