The optimal treatment Of Fulminant Clostridium Difficile Colitis: Diverting Loop Ileostomy and Colonic Lavage versus Total Abdominal Colectomy Presented by Paula Ferrada, MD Division of Trauma, Critical Care & Emergency General Surgery July, 2013

Objectives The objective of this study is to determine if a minimally invasive, colon preserving approach could serve as an alternative to total abdominal colectomy (also called subtotal colectomy) in the treatment of fulminant clostridium difficile colitis (FCDC) which is safer and less risky than total colectomy.

Overview A total abdominal colectomy with end ileostomy ( a surgical procedure in which the small intestine is attached to the abdominal wall in order to bypass the large intestine; digestive waste then exits the body through an artificial opening called a stoma) has been advocated as the operation of choice and has been demonstrated to improve survival compared to non- operative management in these critically ill patients. A total abdominal colectomy has many disadvantages. Most importantly, mortality rates continue to range from 35-80%. Additionally, total abdominal colectomy may result in significant morbidity, and many survivors may require an ileostomy for the rest of their lives. The new treatment option that will be tested may change the standard care. Based on a small prospective series from Neal and colleagues [1] we propose an alternative surgical approach for the management of FCDC, which may prove to be a safer and simpler option. Based on the nature of the disease as a bacterial toxin-mediated mucosal inflammatory process with delayed and indirect systemic threats to life, we think that minimally invasive ileal diversion with intraoperative colonic lavage using a high volume polyethylene glycol/electrolyte solution followed by antegrade vancomycin (an antibiotic) enemas and IV flagyl (antibiotic medication) will result in eradication of FCDC while preserving the colon.

Rationales/Treatment Plan This will be a prospective, randomized surgical study 1.)Total abdominal colectomy with ileostomy 2.)Diverting loop ileostomy with colonic lavage The two study groups will be compared using 30-day mortality from day of operation as the primary outcome. Prior to surgery, patients and/or LAR will be informed of which group they have been randomized to, and may withdraw at any time prior to surgery.

Technique 1. Total abdominal colectomy (STANDARD): The surgical approach to the colon in a total abdominal colectomy involves a midline incision. Via the midline incision, the right and left colon are mobilized in the standard fashion. The mesentery of the bowel is ligated, and the proximal colon is transected at the distal ileum. The distal margin is transected at the level of the peritoneal reflection overlying the rectum. An end ileostomy is performed in the right lower quadrant (RLQ) and the abdomen is closed. Maturation of the ileostomy, meaning the end of the ileum is being attached to the skin of the abdominal wall by sutures, is performed after the closure of the abdomen. In the post-operative period, a specific antibiotic regimen will be followed. All patients will receive IV flagyl (antibiotic medication) in the appropriate dosing for 500mg q8 hours for 10 days. Additional antibiotics can be administered at discretion of the clinical team.

Technique (cont.) 2. Diverting loop ileostomy with colonic lavage (INTERVENTION): The surgical approach involves creation of a loop ileostomy after visually assessing the colon to assure viability via either a laparoscopic approach or via a laparotomy. The decision to perform the operation laparoscopically or open is determined by the attending surgeon. For those undergoing a laparoscopic approach an open technique is used to access the abdominal cavity and a 12 mm trocar is placed to inspect the abdomen using a 30 degree 10mm scope. Additional 5mm trocars may be placed under direct visualization to allow for manipulation of the bowel. If the loop is unable to be safely performed laparoscopically, an open loop ileostomy will be performed via midline incision. Intra-operatively, 105 degrees F 8 liters of warmed polyethylene glycol 3350/electrolyte solution [GoLytely®; Braintree Laboratories] will be infused into the colon via the ileostomy, and collected via a rectal drainage tube. Post-operatively, the patients will receive vancomycin flushes [500 mg in 500 ml of 0.9% NaCl; q8 hours for duration of 10 days] via a Malecot catheter [24 French] left in the efferent limb of the ileostomy (Figure 1). Additionally patients will be continued on intravenous metronidazole [500mg q8 hours] for 10 days.

Technique (cont.)

Inclusion Criteria 1.)Adult patients >18 years of age 2.)Able to provide informed consent, or presence of a legally authorized representative able and willing to provide informed consent 3.)Candidates for total abdominal colectomy due to severe, complicated FCDC per consulting surgeon and team providing care 4.)Subjects must meet criteria for operative management of FCDC as below Indications for operative management in patients with severe, complicated CDC (must be a combination of A-D) A. A diagnosis of FCDC as determined by history of ongoing or recent diarrhea and a positive toxin assay for C difficile. B. For patients with no available toxin assay results, there must be either: 1. positive CT abdomen (pancolitis) or 2. positive endoscopy (pseudomembranes)

Inclusion Criteria (Cont.) C. Plus at least 2 of the following criteria: 1. Peritonitis (is an inflammation of the membrane which lines the inside of the abdomen and all of the internal organs) 2. Worsening abdominal distention/pain 3. Sepsis (a bacterial infection in the bloodstream or body tissues) 4. New onset ventilatory failure 5. New or increasing vasopressor requirement 6. Mental status changes 7. Unexplained clinical deterioration 8. Stable elevated leukocytosis (is a condition characterized by an elevated number of white cells in the blood) or leukopenia (reduction of the number of leukocytes in the blood), or worsening leukocytosis, defined as more than 20,000 or less than 3,000 despite appropriate antibiotic therapy for 24 hours 9. Stable or worsening bandemia (the presence of more than 6% of immature neutrophils (band cells) in the blood) (>10%) despite appropriate antibiotic therapy for 24 hours 10. Temperature D. A medical and surgical attending physician of record are in agreement that 2 of the criteria in section C are met.

Exclusion Criteria 1.) Children (<18 years of age) 2.) Allergy or hypersensitivity reaction to study medications: Vancomycin, Metronidazole, GoLytely 3.) Intra-operative evidence of colonic perforation 4.) Intra-operative evidence of colonic necrosis 5.) Pregnancy (this will be ruled out by a urine test at the time of indication for surgery) 6.) Prisoners 7.) Non-English Speaking Subjects

Discontinuation / Withdrawal Adverse event/Serious adverse event Protocol deviation at discretion of sponsor Investigator discretion Subject withdrew consent

Questions? Clinical Issues: –Principal Investigator: Paula Ferrada, MD