Fig. 36.1
Diffuse inflammation with loss of vascular pattern and ulceration, typical of the pattern seen in ulcerative colitis
He continued to do well and infliximab was stopped after the fourth infusion and he remained in remission on 6-MP and mesalamine. Seven months later his lipase was noted to be three times normal and the amylase was twice normal. 6-MP was discontinued. An abdominal ultrasound and a magnetic resonance cholangio-pancreatography were normal. One week later, the lipase was 9 times normal, yet he remained asymptomatic. Mesalamine was stopped at that time. Amylase and lipase began to decrease, but 3 weeks later he began to experience crampy abdominal pain and hematochezia. He was restarted on mesalamine, but within 1 week his amylase and lipase began to rise. Because he was having hematochezia without diarrhea, he was started on corticosteroid enemas and oral prednisone; however, the rectal bleeding continued and his stools increased in frequency and became more watery. He was admitted to the hospital, made NPO and started on intravenous methylprednisolone sodium succinate 20 mg every 12 h. A colonoscopy revealed pancolitis with sparing of the terminal ileum. When he developed fever, ampicillin, gentamicin, and metronidazole were added. He was started on total parenteral nutrition and after 1 week of no response to intravenous corticosteroids, he received an infliximab infusion. His stool output decreased and his abdominal pain subsided, but when he began to advance his diet he became febrile again and he passed greater than one liter of stool daily. His CRP was 20 times normal. He underwent a total colectomy and ileostomy on day 10. He was discharged 6 days later and subsequently returned for ileoanal anastomosis and creation of a pouch.
Discussion
Children with ulcerative colitis are more likely to have pancolitis, whereas disease limited to the left colon and the rectum is more common in adults. About 20% of children at presentation with ulcerative colitis will have severe disease and require intravenous corticosteroids [1]. About 43% of children presenting with ulcerative colitis have mild disease and 57% have moderate to severe disease. At 6 months 90% and 81% of the children with mild and moderate/severe disease, respectively, have resolution of symptoms. After 5 years, 9% of children presenting with mild disease and 26% of children presenting with moderate/severe disease underwent colectomy [2]. At 1 year after diagnosis, 50% of children who were treated within 30 days of diagnosis had a response to steroids, 45% were steroid dependent, and 5% underwent colectomy [1].
Severe ulcerative colitis is defined as more than six bloody stools daily along with evidence of toxicity such as fever, tachycardia, anemia, or an elevated erythrocyte sedimentation rate [3]. Fulminant disease is defined as passing more than ten bowel movements daily, continuous bleeding, toxicity, abdominal tenderness and distension, need for blood transfusions, and evidence for colonic dilatation on a plain film of the abdomen [3]. The management of fulminant colitis is based on controlling gastrointestinal hemorrhage using immunosuppression and avoiding complications of the disease or the therapy [4]. For children with severe disease, initial therapy is often bowel rest and intravenous methylprednisolone at a dose of 2 mg/kg divided every 12 h with a maximum dose of 20 mg every 12 h. Randomized controlled studies in adults suggest that bowel rest is not beneficial and may impact negatively on nutritional status [5], but children often have less abdominal cramping when they are not eating. Although the value of being NPO in promoting healing is not clear, when a child is not fed, one can determine if the amount of blood and stool frequency is truly decreasing without having to factor in the effects of enteral feeding on secretion and motility.
Despite the lack of randomized controlled clinical trials to provide evidence-based guidance for optimal therapy, expert opinion suggests that healing is best achieved by keeping the hematocrit over 30%, the albumin over 30 g/L, and the electrolytes in the normal range. Although not evidence based, in theory, avoiding anemia and hypoalbuminemia may enhance delivery of oxygen to the tissue and improve mucosal blood flow. Normal electrolytes decrease the possibility of stasis related to poor motility. Unlike treating patients with Crohn disease, antibiotics are generally not indicated in ulcerative colitis unless there is evidence for toxicity or fever. Since perforations may be silent in patients on high doses of corticosteroids, any sign of infection should be investigated and treated. If a child does not respond within 3 days with decreasing stool and blood, parenteral nutritional support should be started. Some clinicians increase the dose of methylprednisolone to a maximum dose of 60 mg daily, but again there are no data to suggest that patients who do not respond to 40 mg daily will respond to 60 mg daily. Anecdotal experience suggests that nutrition may enhance mucosal healing and is best achieved initially by placing a PICC line to provide total parenteral nutrition. If by day 5–7, there is no improvement in the volume of bloody diarrhea, consideration of adding a second medication should be discussed with the family.
Although retrospective data suggest that 75% of pediatric patients benefit from 6-MP or azathioprine after tapering off prednisone [6], these immunomodulators require about 3 months to become effective and usually do not play a role in the management of a child with fulminant colitis. For the child with severe colitis, they are effective maintenance medications and may permit the successful taper of corticosteroids. The options for additional therapy for the child who is not responding include cyclosporine, tacrolimus, or infliximab.
Tacrolimus may be given at a dose of 0.1 mg/kg/dose twice daily with subsequent dose adjustment to achieve blood levels of 10–15 ng/mL. In a small retrospective series of 14 children treated with tacrolimus, 69% responded and were discharged. However, at 1 year only 38% had achieved long-term remission [7]. Similar data exist for adults with severe colitis. In a placebo-controlled trial of adults treated with tacrolimus, those patients who were maintained at blood levels 10–15 ng/mL had significant improvement in disease activity, but only 20% achieved clinical remission. The most common side effect was tremor [8].
Intravenous cyclosporine is effective at inducing remission in up to 80% of children with severe colitis, but by 1 year most require colectomy [9]. In adults, the response to cyclosporine after 6 months is as high as 60%, but declines to about half that level after 3–5 years [10–13]. A randomized, controlled trial of two doses of cyclosporine suggest that 2 mg/kg/day was as effective as higher doses and did not have as much toxicity [14]. Patients receiving cyclosporine are at increased risk for infection, lymphoma and other neoplasms, renal insufficiency, seizures, paresthesias, hypertension, hypertrichosis, gingival hyperplasia, headache, hyperkalemia, tremor, and elevated liver function tests [15].
Infliximab is more commonly being used to treat the child with ulcerative colitis who does not respond to corticosteroids. Children who are taking 6-MP have a better response to infliximab [16], but the reports of hepatosplenic T-cell lymphoma in children and adolescents receiving the combination of 6-MP and infliximab are causing clinicians to reevaluate how best to use these medications. Infliximab appears to be less effective in steroid-dependent patients [17] and a recent follow-up report suggests that infliximab is more effective when given to the acutely ill patient compared with the patient on chronic corticosteroids [18]. Similar observations have been made in the adult population in which 83% of adults who were nonsteroid dependent improved with infliximab, while 33% of adults who were steroid dependent responded [19]. Outcome data are limited in children, but a series of nine children who received infliximab were assessed after 2 years and one third were off the medication [20]. Infusion reactions are the most common complication and are usually managed by premedication with diphenhydramine and acetaminophen [21]. A more recent study from the Pediatric Inflammatory Bowel Disease Collaborative Research Group prospectively followed 332 pediatric patients with UC, in whom 51 (16%) received infliximab. In this group of children, at 12 months 38% were no longer taking corticosteroids and were in clinical remission. At 2 years, 21% of the children were not taking corticosteroids and 61% had not had a colectomy [22].
The indications for surgical treatment for fulminant colitis are perforation, toxic megacolon, massive hemorrhage or failure to respond to maximal medical management. Surgical options include abdominal colectomy with ileostomy and Hartmans’s pouch, which is then followed by a mucosectomy, ileal anastomosis, and diverting ileostomy. At a subsequent surgery, the diverting ileostomy is taken down. Alternatively, the abdominal colectomy may be performed with mucosectomy, ileoanal anastomosis, and diverting ileostomy. A second surgery is performed to take down the ileostomy. At some centers, abdominal colectomy with mucosectomy and ileoanal anastomosis may be done as a single operation.
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