Medical therapy for severe ulcerative colitis (UC) in children often includes the use of high-dose corticosteroids, immunomodulatory agents such as thiopurines and calcineurin inhibitors, and antitumor necrosis factor-α agents such as infliximab (1–4). Despite the use of these medications, up to 25% of children require colectomy within 5 years of diagnosis (5,6).
Recently, there has been concern raised, largely in adult patients, that postoperative complications following surgery for UC are more common in those patients receiving intense immunosuppression preoperatively, particularly with infliximab used in combination with other therapies (7,8). There is a paucity of information on potential adverse effects of infliximab therapy on postoperative course in pediatric patients undergoing colectomy and ileal pouch anal anastomosis (IPAA). Therefore, the aim of our study was to determine whether preoperative immunosuppression affects postoperative outcomes in children undergoing colectomy for UC or inflammatory bowel disease unspecified (IBD-U), with specific attention to the use of infliximab.
All of the pediatric patients who underwent colectomy from 1996 through 2010 at Connecticut Children's Medical Center for UC or IBD-U were identified through databases maintained by the Division of Digestive Diseases, the Division of Pediatric Surgery, and a private surgeon's office. The diagnoses of UC or IBD-U were made by accepted clinical, endoscopic, and histopathologic criteria (9). A comprehensive review of each patient's hospital and ambulatory medical records was made to extract the following information: diagnosis; age at diagnosis; sex; disease extent at diagnosis; age at colectomy; exposure within 30 days of surgery to corticosteroids, calcineurin inhibitors, thiopurines, and within 90 days of colectomy to infliximab; indication for colectomy; and surgical details including staging, length between stages, and open or laparoscopic colectomy. Length of initial hospitalization and nonelective readmission within 30 days were noted. Complications were considered early if they occurred within 60 days of the initial colectomy stage and late if they occurred from 61 days to 1 year. Early complications were further divided into infectious and noninfectious complications. Infectious complications included sepsis, wound infections, pelvic abscess, and other infections. Noninfectious complications were small bowel obstruction (SBO), nonelective readmission within 30 days, and prolonged (>10 days) initial hospitalization. At 1 year the presence or absence of pouchitis was considered a late complication. The definition of pouchitis was made by standard criteria (10).
Indications for surgery were categorized as fulminant colitis if patients were admitted for a flare of their symptoms for which they did not respond to medical therapy and required colectomy during same hospitalization, or chronic medically refractory colitis in those children with a planned colectomy after failed outpatient therapy. Disease extent at diagnosis was recorded as left sided if distal to splenic flexure, and as pancolitis if disease extended proximal to the splenic flexure and usually to the cecum. Surgical details including open or laparoscopic-assisted subtotal colectomy, staging of colectomy, and time between stages were collected. A 2-stage procedure was either total proctocolectomy with pouch reconstruction and loop ileostomy followed by reversal of the ileostomy or total abdominal colectomy with end ileostomy followed by completion proctectomy and pouch reconstruction without an ileostomy. A 3-stage procedure was total abdominal colectomy with end ileostomy, then completion proctectomy with pouch reconstruction and loop ileostomy, and finally ileostomy takedown. No patient underwent proctocolectomy with pouch reconstruction as a 1-stage procedure.
Data are expressed as frequency and percent or mean ± standard deviation (median, range). Group differences were evaluated using t tests or nonparametric analogues for continuously distributed variables and exact tests for categorical variables. A significance level of 0.05 was used for all of the tests.
A total of 51 patients were identified during the study period who underwent colectomy for UC (n = 45) or IBD-U (n = 6). The demographic features of these subjects are shown in Table 1. Of patients who had a colectomy, all had follow-up data available for 3 months following their initial operation and 41 (84%) had follow-up data at 1 year available.
Immunosuppressive Medication Exposure
Preoperative medical therapies are shown in Table 2. Nearly all of the patients (88%) were exposed to corticosteroids and half (51%) to immunomodulators within 30 days of surgery. For those patients taking corticosteroids, the dosage was converted to prednisone equivalents with a mean of 0.62 ± 0.42 mg · kg−1 · day−1 (median 0.62, range 0.04–1.77). Within 30 days, 33 of 51 (65%) patients were exposed to infliximab. The most common combinations of medications were corticosteroids and infliximab (29%) followed by corticosteroids, immunomodulators, and infliximab (28%). Monotherapy with corticosteroids, immunomodulators, or infliximab and use of calcineurin inhibitors were less frequent. One patient did not have any medication exposure in the month before surgery.
Most patients received intravenous second- or third-generation cephalosporin and metronidazole immediately before surgery. There was no consistent regimen of oral antibiotics or bowel cleansing before surgery.
A total of 47 (92%) of our patients eventually underwent total abdominal colectomy with IPAA, whereas 4 remained with permanent ileostomy. Initial laparoscopic-assisted colectomy was performed in 29 (57%).
Of the patients with IPAA, 37 were done in 2 stages and 10 were done in 2 stages. Ten of the patients with a 2-stage procedure had a primary pouch and 27 patients had a secondary pouch. Of the 10 patients with a primary pouch, none were exposed to infliximab within 30 days of colectomy and 1 was exposed to infliximab between 31 and 90 days of the colectomy. Of the 4 children who did not have IPAA, 2 were subsequently found to have Crohn disease and elected not to have IPAA and 2 were patient choice.
The duration of hospitalization after the initial operation in all of the patients was 9.5 ± 5.75 days (7, 5–36). In patients exposed to infliximab, the duration of initial hospitalization was 8.55 ± 4.32 days compared with those without exposure with a duration of 11.39 ± 7.41 days (P = 0.09). The mean time from stage 1 to stage 2 was 3.1 ± 1.3 months (2.88, 1–7.8, n = 47), followed by 1.8 ± 0.5 months (1.8, 1.4–2.8, n = 10) between stage 2 and 3. Time from stage 1 to 2 was 3.08 ± 0.97 months in those patients exposed to infliximab and 3.15 ± 1.82 months in those patients not exposed to infliximab (P = 0.89).
Early postoperative complications are seen in Table 3. The most common noninfectious early complication was SBO, occurring in 10 patients (19%). Seven patients (14%) required nonelective readmission: SBO in 4 patients and 1 patient each had sepsis, an abscess, and deep vein thrombosis. Three of the 10 patients with SBO required surgical intervention. Infectious complications included wound infection in 8% and intraabdominal abscess in 6%.
The relation of early postoperative complications to specific preoperative immunosuppressive regimens is shown in Table 4. Of the 33 patients exposed to infliximab, 4 patients (12%) experienced an infectious complication and 7 patients (21%) experienced a noninfectious complication, including 3 patients who have experienced both types of complications. Of the 18 patients without exposure to infliximab therapy, 4 patients (22%) experienced an infectious complication and 7 patients (39%) experienced a noninfectious complication. When comparing those patients with and without exposure to infliximab, there was no difference in percentage or patients experiencing infectious or noninfectious complications (Fig. 1).
In the 29 patients with laparoscopic-assisted surgery, 8 patients (27.5%) developed a complication: 4 (50%) had infectious complications (sepsis, abscess, urinary tract infection) and 4 had noninfectious complications. In the 22 patients with an open colectomy, 10 patients (45%) developed a complication: 4 (40%) had infectious complications (wound infection, abscess) and 6 urinary tract infection (60%) patients had noninfectious complications.
The relation between serum albumin or prealbumin levels checked in the immediate preoperative period and postoperative complications was examined in those patients for whom these values were available. There was no difference in mean serum albumin levels between those patients with (3.43 ± 0.68, n = 18) and without (3.39 ± 0.73, n = 23) a complication. Likewise, the mean serum prealbumin levels in those patients with a complication (19.08 ± 7.39, n = 12) were similar to those without a complication (14.86 ± 8.30, n = 7).
Our data demonstrate that intense immunosuppression is common in the period before colectomy for almost all of the pediatric patients with severe UC or IBD-U. Virtually all of our patients were receiving corticosteroids, and the majority were also receiving immunomodulators, infliximab, or both. In those patients receiving immunomodulators and/or infliximab, we did not observe an increase in the number of infectious complications in the postoperative period compared with patients not receiving these medications. Moreover, the duration of postcolectomy hospitalization was similar in patients exposed to or not exposed to infliximab.
A recent report looked at a group of 31 pediatric patients undergoing colectomy and the possible relation of preoperative immunosuppression to postoperative course. In that group of patients, no relation was noted between preoperative 5-aminosalicylic acid, thiopurines, or corticosteroids and early (within 30 days) complications (11); however, in that series no patients had received infliximab. Another pediatric retrospective study presented in abstract form looked at complications post-IPAA in patients who had been treated with infliximab (n = 11) and demonstrated that these patients experienced nearly twice the amount of complications compared with patients who were not treated with infliximab (n = 27) (12).
Adult studies have shown an increase in complications following colectomy in patients with UC who were exposed to infliximab (7,13); however, these studies have the same confounding variable of multiple immunosuppressive drug combinations and inability to control for infliximab alone. Also, infliximab itself is a marker of more severe disease, and is only given to those patients who fail other immunosuppressive regimens.
A potential surrogate marker for immediate postoperative difficulty is length of hospitalization following colectomy. The group of patients in our study cohort who received infliximab preoperatively did not experience a significant difference in length of hospitalization after first stage of their procedure compared with those who did not. Our study also failed to identify a significant difference in the length of time between stage 1 and 2 in those patients who did and did not receive infliximab.
Surgical decision on whether to proceed with construction of a pouch at the time of colectomy may be influenced by the patient's present condition, present medication exposure, and surgeon preference as to what is considered the ideal or safest approach. In our series the observation that among the 10 patients who underwent pouch creation (with diverting ileostomy) at the time of colectomy only 1 had infliximab exposure indicates that the lack of preoperative biological agent exposure may well have influenced practice.
The main limitation of our study was the number of patients. It is possible that a larger series may be required to detect a difference in postoperative complications between infliximab-treated and not treated groups; however, if one presumed a difference in complication rates of 20% between the 2 groups, then to achieve adequate power a total of 187 patients in each group would be needed.
In summary, the relative infrequency of serious postoperative complications seen in our patient population despite intense preoperative immunosuppression is reassuring. There was no signal that infliximab given in the preoperative period influenced postoperative course. Larger multicenter studies will be required to confirm our observations and more carefully examine the role of all of the preoperative immunosuppressive agents and their respective roles affecting postoperative course.
1. Hyams JS, Lerer T, Griffiths A, et al. Outcome following infliximab therapy in children with ulcerative colitis. Am J Gastroenterol
2. Hyams J, Markowitz J, Lerer T, et al. The natural history of corticosteroid therapy for ulcerative colitis in children. Clin Gastroenterol Hepatol
3. Hyams JS, Lerer T, Mack D, et al. Outcome following thiopurine use in children with ulcerative colitis: a prospective multicenter registry study. Am J Gastroenterol
4. Turner D, Travis SP, Griffiths AM, et al. Consensus for managing acute severe ulcerative colitis in children: a systematic review and joint statement from ECCO, ESPGHAN, and the Porto IBD Working Group of ESPGHAN. Am J Gastroenterol
5. Hyams JS, Davis P, Grancher K, et al. Clinical outcome of ulcerative colitis in children. J Pediatr
6. Gower-Rousseau C, Dauchet L, Vernier-Massouille G, et al. The natural history of pediatric ulcerative colitis: a population-based cohort study. Am J Gastroenterol
7. Selvasekar CR, Cima RR, Larson DW, et al. Effect of infliximab on short-term complications in patients undergoing operation for chronic ulcerative colitis. J Am Coll Surg
8. Schluender SJ, Ippoliti A, Dubinsky M, et al. Does infliximab influence surgical morbidity of ileal pouch-anal anastomosis in patients with ulcerative colitis? Dis Colon Rectum
9. Bousvaros A, Antonioli DA, Colletti RB, et al. Differentiating ulcerative colitis from Crohn disease in children and young adults: report of a working group of the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition and the Crohn's and Colitis Foundation of America. J Pediatr Gastroenterol Nutr
10. Shen B. Impact of preoperative infliximab use on postoperative infectious complications in ulcerative colitis: the price we have to pay? Inflamm Bowel Dis
11. Patton D, Gupta N, Wojcicki JM, et al. Postoperative outcome of colectomy for pediatric patients with ulcerative colitis. J Pediatr Gastroenterol Nutr
12. Kennedy R, Potter DD, Moir C, et al. Pediatric Chronic ulcerative colitis: does infliximab increase post-IPAA complications? J Pediatr Surg
13. Mor IJ, Vogel JD, da Luz Moreira A, et al. Infliximab in ulcerative colitis is associated with an increased risk of postoperative complications after restorative proctocolectomy. Dis Colon Rectum
Keywords:Copyright 2012 by ESPGHAN and NASPGHAN
children; immunosuppression; infliximab; surgery; ulcerative colitis