What Is Known
- Infliximab has become a mainstay of therapy in pediatric Crohn disease.
- Despite medical advances, many children with Crohn disease still require surgery.
- The effect of infliximab on postoperative outcomes in adults is inconclusive and in children is largely unknown.
What Is New
- Treatment with infliximab does not seem to increase postoperative complications in children with Crohn disease.
- Postoperative length of stay is not increased in children treated with infliximab.
- Overall rates of postoperative complications may be lower in children with Crohn disease than in adults.
Crohn disease (CD) is a chronic relapsing and remitting inflammatory condition that occurs in adults and children. During the past decade, significant advances have been made in the treatment of CD with the addition of biologic therapies. Most notably, infliximab (IFX), a biologic therapy that inhibits TNF-α, has become a mainstay of therapy in children with moderate to severe CD (1,2). Despite medical advances, approximately 15% to 45% of children still require abdominal operations to treat their CD within 5 years of their diagnosis (3–5). Because anti-TNF therapies have been associated with opportunistic infections and the effect on wound healing is largely unknown (6), concern exists about the risk of complications associated with operations performed in children treated with IFX.
Data on the effect of perioperative IFX on postoperative complication rates in adults with CD are mixed. Some studies show no difference in complication rates, whereas others demonstrate increased risk of infection or overall complications in patients treated perioperatively with IFX (7–16). Moreover, extrapolation to pediatric patients is difficult given that surgical complication rates in children differ from adults. The risk of IFX therapy in children with CD who require surgical intervention is largely unknown.
The present study compares the postoperative complications in a group of children with CD treated with IFX to those not treated with IFX.
Boston Children's Hospital (BCH) is a 395-bed tertiary care pediatric hospital located in Boston, MA. Following approval from the institutional review board, 2 surgical databases were screened for patients with a diagnosis of CD who underwent bowel resection at BCH from 1977 to 2011. Three reviewers (LZ, CS, and AB) reviewed charts from these patients using a standardized case report form, and any discrepancies in data interpretation were resolved by consensus. Patients were included in the study if they had CD, underwent their initial bowel resection at BCH, had documented history of whether or not they had received IFX before surgery, and were followed for at least 6 months postoperatively. Patients with only perianal surgery, permanent ileostomy, or other bowel surgery (such as appendectomy) were excluded. The most common operation performed was ileocecectomy and choice of operation was dictated by the surgeon. Cases were historically performed through a laparotomy; however, institutional trend has become laparoscopic assisted (LA-1) or single incision laparoscopic (SIL-1) operations. The SIL-1 procedure was performed using a 15-mm TriPort Access System trocar (Olympus, Center Valley, PA) through the umbilicus. The LA-1 was performed with a 10-mm Step umbilical trocar to obtain pneumoperitoneum, followed by two 5-mm laparoscopic ports in the left lower quadrant and suprapubic midline. Once the bowel was mobilized laparoscopically, it was brought out of an enlarged umbilical incision and transected extracorporeally. Patients underwent either hand sewn or stapled extracorporeal anastomosis.
Data extracted included age, sex, disease location, disease severity at presentation, preoperative medical therapy, surgical indication, the type of surgical procedure performed, date of surgery, length of hospital stay, and postoperative complications. Complications were identified during the postoperative inpatient course.
The primary outcome of interest was the effect of IFX therapy on complication rate following bowel resection. A secondary outcome of interest was the effect of IFX therapy on hospital length of stay.
Definition of Terms
Disease location was determined as the maximum extent of macroscopic disease present before surgery as evidenced by colonoscopy and radiographic reports. The Montreal classification was used to classify CD both by disease location and behavior (17). Upper gastrointestinal disease was, however, defined as clinically significant ulceration with jejunal involvement. Disease behavior by Montreal classification included nonstricturing/nonpenetrating (inflammatory disease never complicated—B1), stricturing (occurrence of constant luminal narrowing by radiographic, endoscopic, or surgery with prestenotic dilatation or obstructive signs or symptoms, never penetrating—B2), and penetrating (occurrence of intraabdominal or perianal fistulas, inflammatory masses, and/or abscesses—B3). Complications were defined as any adverse outcome during the postoperative hospital course. Major complications were defined a priori as any infection, abscess, bowel obstruction, anastomotic leak, or any complication requiring reoperation or ICU-level care. The duration between the last administration of IFX and the day of operation was recorded.
Demographic, clinical, and surgical variables were summarized by treatment group (received IFX vs never received IFX before operation) through means and standard deviations for most continuous variables; median and interquartile range for preoperative disease duration; and through proportions for categorical variables. Comparisons across groups were performed via t tests when comparing means, Wilcoxon rank sum tests when comparing medians, and Pearson χ2 tests when comparing proportions (Fisher exact tests were used when comparing proportions with <5 cases in at least 1 cell).
The proportion of patients with postoperative complications was compared between those who were treated with IFX and those never treated with IFX before surgery. Median postoperative length of stay was compared using Mann-Whitney U test. Two-tailed P < 0.05 were considered statistically significant. Statistical analysis was performed using IBM SPSS Statistics (version 21.0, IBM, Armonk, NY). To account for potential confounding effects, we performed multivariate logistic regression analyses. In this analysis, we included variables for age at diagnosis, duration of disease before surgery, whether the subject was on steroids at time of surgery, and year the operation took place. We hypothesized a priori that these variables might independently affect surgical outcomes. Given the possibility that surgical technique and medical management might have changed over time, we repeated both of these analyses including only patients operated on after 2000 (the year that IFX was first used for Crohn patients in our institution).
This review was approved by the BCH institutional review board.
Of the originally reviewed 174 charts, 123 children and young adults who were operated on from 1977 to 2011 met our inclusion criteria. Twenty-six were excluded for inadequate length of follow-up, 9 for missing data, 14 for unrevised skin level ostomies, and 2 for alterative diagnosis. Mean age at time of diagnosis was 13 years (SD = 3, range 6–21). Mean age at time of operation was 16 years (SD = 3, range 9–27). In our surgical cohort, the most common operation was ileocecectomy (82%).
Of the 123 patients, 24 patients received IFX before surgery. Of the 24 patients, 22 (92%) had their operation within 90 days of their last infusion, 20 (83%) had within 60 days of their last infusion, and 12 (50%) had within 30 days of their last infusion. The children received a median of 13 months of total IFX use before having an operation (range 3–84 months).
The patients who had received and had not received IFX before their procedures were compared by age at time of operation, sex, disease behavior, and type of operation. The children who received IFX before having an operation were younger at age of diagnosis and had a longer duration of disease before resection. The IFX group had more diffuse ileocolonic disease (Table 1). The children receiving IFX were also more likely to have required multiple courses of steroids and have received other immunomodulator therapies before their operations (Table 1).
The overall postoperative complication rate was 13%. Major complications among children treated with IFX included an intraabdominal abscess, anastomotic leak, and acute tubular necrosis requiring dialysis. There were 9 major complications in the non-IFX group, including postoperative intraabdominal abscesses (2), phlegmon, systemic inflammatory reaction (culture negative shock), infections (2), bowel obstruction, supraventricular tachycardia, and anastomotic stricture. Minor complications in the IFX group included postoperative fevers and Horner syndrome versus in the non-IFX group, Foley catheter trauma to the bladder and pancytopenia presumed secondary from cephalosporins received perioperatively. Complications categorized by IFX use are illustrated in Table 2.
Of the 20 patients who received IFX within 60 days of surgery, there were 4 postoperative complications (20%). Of the 12 patients who received IFX within 30 days, there were 3 postoperative complications (25%). Timing of IFX infusion within 30 days of surgery is highlighted next to the associated complication in Table 2.
There was no statistically significant difference in complication rate in those patients who received IFX or who did not receive IFX before surgery (21% vs 11%; P = 0.2). There was also no difference in major complications in those patients who received IFX and those who did not receive IFX (13% vs 9%; P = 0.64). Median postoperative length of stay in the cohort was 7 days (interquartile range 5–9 days). There was no statistically significant difference in median length of hospital stay with versus without IFX use (median length of stay 6 vs 7 days, P = 0.93) (Table 3).
Limiting the cohort to the 88 patients operated on or after the year 2000, the total complication rate was 15%. In this group, there was no statistically significant difference in complication rate among those who received IFX or who did not receive IFX before surgery (20% vs 13%; P = 0.33). Median postoperative length of stay in this cohort was 6 days (interquartile range 5–8 days). Among the cohort of patients operated on or after the year 2000, there was no statistically significant difference in median length of hospital stay with and without IFX use (median length of stay 6 days in each cohort; P = 0.41) (Table 4).
Treatment with IFX did not influence postoperative complication rate even after controlling for other variables (age of diagnosis, duration of disease before surgery, use of steroids at time of surgery, and year of operation) by use of multivariate analysis. There was also no difference when limiting the cohort to those operated on after the year 2000 (Table 5).
In this review of a large pediatric IBD surgery cohort, we examined the effect of IFX on postoperative outcomes in children with CD undergoing bowel resection. We found no statistically significant difference in complication rate or postoperative stay among those children treated with IFX perioperatively. The similar complication rate and length of stay occurred even though the children treated with IFX had other risk factors including more diffuse disease location and more frequent steroid courses. In this single-center study, we identified a low overall postoperative complication rate of 13%. A recently published study in children with CD reported a similar overall complication rate of 22% (18). The documented postoperative complication rate in adults with CD is significantly higher ranging from 30% to 70% (14). Adults may have other comorbidities, previous operations, and longer duration of disease, which may influence their underlying surgical risk. This difference in baseline complication rates between adults and children highlights both the difficulty in extrapolating pediatric risk from adult studies and the importance of examining pediatric surgical outcomes.
Previous to the present study, much of the existing data on the risk of IFX on surgical outcomes stemmed from adult studies with conflicting results. For example, Syed et al reported an increase in infectious complications among the 211 adults treated with IFX perioperatively, with no difference in overall complication rates (11). Myrelid et al (8) reported no difference in overall or infectious complications among the 298 patients with CD (mainly an adult cohort which included 43 patients younger than 16 years of age) treated with IFX perioperatively. Other studies have also reported no difference in complication rates among those treated with IFX (12,13,15). Three separate meta-analyses have also been performed with conflicting results. Norgard et al (10) included 2293 subjects (included adults and children) and reported no increase in postoperative complication rate with IFX use. Kopylov et al (14) included 1641 subjects (adults and adolescents) with CD and reported an increase in infectious complications among those treated with IFX perioperatively. Yang et al (16) included 2538 subjects and reported an increase in both the total and infectious complications in adults treated with IFX perioperatively.
Studies evaluating perioperative IFX in pediatric patients with ulcerative colitis are scarce with small sample sizes. A small pediatric review examined the effect of preoperative immunosuppression on postoperative complications following colectomy in children with ulcerative colitis. The study reported that 33 of their 51 subjects had received IFX within 90 days of surgery. These children who received IFX perioperatively had no difference in postoperative complications or length of hospital stay (19). Another group reviewed 11 children with ulcerative colitis who underwent a 3-stage proctocolectomy and pouch reconstruction and found that children treated with preoperative IFX had higher rates of small bowel obstruction but no increased risk of infectious-related complications (20).
We reported a postoperative complication rate in the IFX group of 21% and the non-IFX group of 11% in our cohort of 123 patients. One concern we had in our analysis was that we might be underpowered to detect a difference. Given the low frequency of complications in our sample, we performed a series of power calculations to examine the power to detect a difference in complications based on IFX therapy and the likelihood of a Type II error. We found that our cohort had 80% power to detect a 30% difference in complication rates. Our study did identify a 9% difference in the complication rate between the IFX and non-IFX group. To determine whether this difference is statistically significant, we would require approximately 600 children in the non-IFX group and 130 children in the IFX group. This large sample size is not feasible in smaller cohorts, and suggests that large registries may be needed to detect small differences in outcomes. Furthermore, we observed that patients treated with IFX had greater disease duration, less localized disease, and exposure to more steroid courses and immunomodulators than patients in the non-IFX group. These factors would likely increase the baseline surgical risk of the IFX group independently. Thus, given that the underlying surgical risk of the IFX group is likely higher, a 10% difference in complications between groups is not likely clinically significant.
Our study is also both strengthened and limited by its historical nature. The ability to draw on over 35 years of experience allowed us to investigate IFX and surgical complications in a large pediatric cohort. Given the possibility that changes in surgical technique and medical management could have introduced bias over time, we decided to repeat analysis including only patients operated on after the year 2000 (when IFX was first introduced in our institution) and findings were similar. As this was a retrospective review, we were unable to control for many factors that independently influence operative risk, such as dosing of steroids at time of surgery, nutritional status, immunomodulator therapy. Also, the data collection for some patients predated the Paris classification, so we had to define patients by the Montreal criteria. We performed logistic regression analysis to attempt to control for some of these important factors that may have influenced postoperative outcomes. This analysis did not change our results.
Another benefit of our study was the ability to obtain information on the timing of IFX infusion with respect to surgical date. There were 3 significant complications in our 12 patients who had IFX within 30 days. Timing of IFX infusion is an important clinical factor that has not yet been studied closely and requires a large multicenter study or meta-analysis to further investigate.
In summary, in our review of over 3 decades of pediatric surgical experience, we observe that children with CD who undergo bowel resection and reanastomosis have a low postoperative complication rate. Treatment with IFX preoperatively does not appear to increase postoperative complications in children with CD. Larger multicenter studies involving collaboration among gastroenterology and surgical specialties will be instrumental in confirming these observations.
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