Clinical trial NCT03593252: Bowel Preparation in Elective Pediatric Colorectal Surgery
Official title: Pre-Operative Mechanical Bowel Preparation And Prophylactic Oral Antibiotics For Pediatric Patients Undergoing Elective Colorectal Surgery: A Feasibility Randomized Controlled Trial
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: NA
Conditions: Colostomy
Hirschsprung Disease - Pull Through
Necrotizing Enterocolitis
Inflammatory Bowel Diseases
Meconium Ileus
Bowel Obstruction
Elective Surgery
Lead sponsor: McMaster University
Sponsor class: OTHER
Collaborators: name: McMaster Pediatric Surgery Rresearch Collaborative (MPSRC)
First posted: 2018-07-20
Enrollment: 81
Sex: ALL
Minimum age (years): 3
Maximum age (years): 18
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Patients will be randomized to the following study arms:

1. Combination bowel prep: Mechanical preparation and oral non-absorbable antibiotics + standard care.
2. Oral antibiotics + standard care.
3. No preparation, with standard care. \*Standard care (all groups):

   * Nil per os (NPO) prior to general anesthesia

     * Solids until 8 hours prior to surgery, formula until 6 hours, breast milk until 4 hours, clear fluids until 2 hours
   * Prophylactic IV antibiotics

     * Cefazolin (30mg/kg) and metronidazole (15mg/kg) within 60 minutes of incision
     * Re-dosing if procedure exceeds 4 hours
     * In case of beta-lactam allergy allergy, clindamycin 5mg/kg and gentamicin 7mg/kg will be used.
Primary purpose: PREVENTION

Brief summary: Infections after elective intestinal surgery remain a significant burden for patients and for the health care system. The cost of treating a single surgical site infection is estimated at approximately $27,000. In adult patients, there is good evidence that the combination of oral antibiotics and mechanical bowel preparation is effective at reducing infections after intestinal surgery. In children, the body of evidence is much weaker. In this population, little evidence exists for oral antibiotics reducing infections and no data exists as to the effect of combining antibiotics with mechanical bowel preparation (such as polyethylene glycol (PEG)). The goal of the proposed study is to examine the effects of oral antibiotics with and without the combined use of mechanical bowel preparation on the rate of post-operative infectious complications in children aged 6 months to 18 years. This will be compared to the institution's current standard of care, which is to abstain from any type of mechanical bowel preparations or oral antibiotic administration before intestinal surgery.

Detailed description: Background:

A Cochrane review of randomized controlled trials of MBP use in adults showed no difference in the rate of wound infection or anastomotic leak in colon or rectal procedures with MBP compared to no preparation (Guenaga, Matos, \& Wille-Jorgensen, 2011). Two recent systematic reviews and meta-analyses support those findings. Lok and colleagues (2018) identified two randomized controlled trials and four retrospective reviews for patient \<21 years, looking at preoperative MBP and its effect on the incidence postoperative complications, including anastomotic leak, wound infection, and intra-abdominal infection (Janssen Lok M 2018). Overall, MBP before colorectal surgery did not significantly decrease the incidence of post-operative outcomes. This was consistent with findings from a systematic review in mechanical bowel preparation in pediatric population. The review showed that the risk of developing a post-operative infection was 10.1% in patients who received MBP compared to 9.1% in patients who did not receive MBP, resulting in no statistically significant difference difference (risk difference of -0.03% (95% CI, -0.09% - 0.03%)) (Zwart 2018).

With regards to OA alone, the adult literature showed promising results in favour of the OA. In a Cochrane review on antimicrobial prophylaxis in colorectal surgery, the addition of OA to the intravenous antibiotics was found to reduce surgical wound infection (RR 0.56, 95% CI 0.43 to 0.74) (Nelson, Gladman, \& Barbateskovic, 2014).

There are fewer studies in the pediatric population on the subject, they contain fewer patients and are mainly retrospective in nature. In a multi-center retrospective study, Serrurier et al. (2012), reviewed outcomes in children who underwent colostomy closure, and found higher rates of wound infection (14% vs. 6%, p=0.04) and a longer hospital length of stay in children who received MBP. In a retrospective cohort study including 1581 pediatric patients from PHIS database, post-operative complications were found to be highest in the no preparation group compared to combination prep and OA alone (23.3%, 15.9%, and 14.2% respectively; p=0.002) (Ares 2018). One study compared MBP alone versus MBP with OA in children undergoing colostomy closure post anorectal malformation repair and found no difference in overall SSI rates (MBP+OA: 13% (7/53) versus MBP alone: 17% (7/12) p=0.64) (Breckler, Rescorla, \& Billmire, 2010). The authors found that the use of MBP alone was associated with a greater risk of wound infection (14% vs. 6%, p=0.04) and a longer hospital stay. Evidence to support the sole use of oral antibiotics versus in combination with MBP is lacking, particularly in the pediatric literature, with more studies being required to address this question.

One recent meta-analysis including adults assessed 8458 adult patients (38 clinical trials), comparing 4 groups of different bowel preparation: MBP with OA, OA only, MBP only, and no preparation. The primary outcome was the total rate of incisional and organ/space SSIs. Results showed that only MBP with OA versus MBP alone was associated with a statistically significant reduction in SSI rates. The use of OA without MBP was not associated with a statistically significant reduction in SSI rates when compared to any other group. The authors concluded that MBP with OA was associated with the lowest risk of SSI, followed by OA only (Toh et al., 2018).

It remains unclear whether the addition of MBP to OA in pediatric population affects the rate of post-operative infectious complications positively or negatively. The current study is therefore needed to build on the work conducted in the adult literature to determine best practices for the pediatric population.

Purpose:

This is a pilot study to check the feasibility of conducting a randomized controlled trial to assess the efficacy of oral nonabsorbable antibiotics, with or without mechanical bowel preparation, in reducing the rate of post-operative infectious complications occurring within 30 days post-operatively in children and adolescents (aged 6 months to 18 years) undergoing elective colon or rectal surgery.

Post-operative complications include: surgical site infections (incisional, organ-space, and anatomic leak), length of hospital stay, readmission, post-operative use of therapeutic antibiotics, re-operation, occurrence of electrolyte disturbances (in case MBP was used), and occurrence of C. difficile infection.

Eligibility criteria: Inclusion Criteria:

1. Pediatric patients aged three months to eighteen years being treated by the Pediatric General Surgery service at McMaster Children's Hospital.
2. Undergoing elective colorectal surgery.
3. Parents or legal guardian able to give free and informed consent.

Exclusion Criteria:

1. Non-elective surgery
2. Procedures that would not require mechanical bowel preparation:

   1. Colorectal resection with an existing diverting small bowel ostomy.
   2. Completion proctectomy - Ileal Pouch Anal Anasotmosis (IPAA)
   3. Closure of small bowel ostomy (e.g. ileostomy)
3. Mechanical bowel obstruction
4. Known hypersensitivity to laxatives or oral antibiotics (neomycin and metronidazole)
5. Contraindication to oral antibiotics
6. Patients on long-term antibiotics for other reasons
7. Congestive heart failure
8. Renal insufficiency
9. Other medical conditions precluding the use of either oral antibiotics or mechanical bowel preparation
10. Co-enrolment in another intervention trial

Primary outcomes:
measure: Feasibility (no. enrolled)
timeFrame: From randomization to 30 days post-operatively
measure: rate of post-randomization exclusions
timeFrame: From randomization to 30 days post-operatively
measure: Protocol deviations
timeFrame: From randomization to 30 days post-operatively
measure: Adverse events
timeFrame: From randomization to 30 days post-operatively
measure: Incomplete follow-up
timeFrame: From randomization to 30 days post-operatively
Secondary outcomes:
measure: Superficial Incisional surgical site infection (SSI)
timeFrame: 30 days post-operatively.
measure: Deep incisional surgical site infection (SSI)
timeFrame: 30 days post-operatively.
measure: Organ space - Surgical site infection (SSI)
timeFrame: 30 days post-operatively.
measure: Anastomotic leak - Surgical site infection (SSI)
timeFrame: 30 days post-operatively.
measure: Length of hospital stay
timeFrame: 30 days post-operatively.
measure: Time to full enteric feed.
timeFrame: 30 days post-operatively.
measure: Re-admission
timeFrame: 30 days post-operatively.
measure: Re-operation
timeFrame: 30 days post-operatively.
measure: Electrolyte disturbance
timeFrame: On day of surgery
measure: Electrolyte disturbance
timeFrame: On day of surgery
measure: Clostridium difficile infection
timeFrame: 30 days post-operatively.
Other outcomes:
Locations:
Study officials:
affiliation: McMaster Children's Hospital
name: Lisa VanHouwelingen, MD, MPH, FRCSC
role: PRINCIPAL_INVESTIGATOR
References:
citation: Breckler FD, Rescorla FJ, Billmire DF. Wound infection after colostomy closure for imperforate anus in children: utility of preoperative oral antibiotics. J Pediatr Surg. 2010 Jul;45(7):1509-13. doi: 10.1016/j.jpedsurg.2009.10.054.
citation: Guenaga KF, Matos D, Wille-Jorgensen P. Mechanical bowel preparation for elective colorectal surgery. Cochrane Database Syst Rev. 2011 Sep 7;2011(9):CD001544. doi: 10.1002/14651858.CD001544.pub4.
citation: Julious, S. A. (2005). Sample size of 12 per group rule of thumb for a pilot study. Pharmaceutical Statistics, 4, 287-291.
citation: Nelson RL, Gladman E, Barbateskovic M. Antimicrobial prophylaxis for colorectal surgery. Cochrane Database Syst Rev. 2014 May 9;2014(5):CD001181. doi: 10.1002/14651858.CD001181.pub4.
citation: Rangel SJ, Islam S, St Peter SD, Goldin AB, Abdullah F, Downard CD, Saito JM, Blakely ML, Puligandla PS, Dasgupta R, Austin M, Chen LE, Renaud E, Arca MJ, Calkins CM. Prevention of infectious complications after elective colorectal surgery in children: an American Pediatric Surgical Association Outcomes and Clinical Trials Committee comprehensive review. J Pediatr Surg. 2015 Jan;50(1):192-200. doi: 10.1016/j.jpedsurg.2014.11.028. Epub 2014 Nov 12.
citation: Serrurier K, Liu J, Breckler F, Khozeimeh N, Billmire D, Gingalewski C, Gollin G. A multicenter evaluation of the role of mechanical bowel preparation in pediatric colostomy takedown. J Pediatr Surg. 2012 Jan;47(1):190-3. doi: 10.1016/j.jpedsurg.2011.10.044.
citation: Smith RL, Bohl JK, McElearney ST, Friel CM, Barclay MM, Sawyer RG, Foley EF. Wound infection after elective colorectal resection. Ann Surg. 2004 May;239(5):599-605; discussion 605-7. doi: 10.1097/01.sla.0000124292.21605.99.
citation: Koullouros M, Khan N, Aly EH. The role of oral antibiotics prophylaxis in prevention of surgical site infection in colorectal surgery. Int J Colorectal Dis. 2017 Jan;32(1):1-18. doi: 10.1007/s00384-016-2662-y. Epub 2016 Oct 24.
citation: Janssen Lok M, Miyake H, O'Connell JS, Seo S, Pierro A. The value of mechanical bowel preparation prior to pediatric colorectal surgery: a systematic review and meta-analysis. Pediatr Surg Int. 2018 Dec;34(12):1305-1320. doi: 10.1007/s00383-018-4345-y. Epub 2018 Oct 20.
citation: Zwart K, Van Ginkel DJ, Hulsker CCC, Witvliet MJ, Van Herwaarden-Lindeboom MYA. Does Mechanical Bowel Preparation Reduce the Risk of Developing Infectious Complications in Pediatric Colorectal Surgery? A Systematic Review and Meta-Analysis. J Pediatr. 2018 Dec;203:288-293.e1. doi: 10.1016/j.jpeds.2018.07.057. Epub 2018 Sep 12.
citation: Ares GJ, Helenowski I, Hunter CJ, Madonna M, Reynolds M, Lautz T. Effect of preadmission bowel preparation on outcomes of elective colorectal procedures in young children. J Pediatr Surg. 2018 Apr;53(4):704-707. doi: 10.1016/j.jpedsurg.2017.03.060. Epub 2017 Mar 30.
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citation: Toh JWT, Phan K, Hitos K, Pathma-Nathan N, El-Khoury T, Richardson AJ, Morgan G, Engel A, Ctercteko G. Association of Mechanical Bowel Preparation and Oral Antibiotics Before Elective Colorectal Surgery With Surgical Site Infection: A Network Meta-analysis. JAMA Netw Open. 2018 Oct 5;1(6):e183226. doi: 10.1001/jamanetworkopen.2018.3226.
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