Portal de Periódicos da CAPES

Efficacy of Octreotide in Children With Chronic Gastrointestinal Bleeding

2000; Lippincott Williams & Wilkins; Volume: 30; Issue: 4 Linguagem: Inglês

10.1097/00005176-200004000-00018

1536-4801

Aglaia Zellos, Kathleen B. Schwarz,

Neuroendocrine Tumor Research Advances

Chronic gastrointestinal bleeding in children is an infrequent but frustrating problem for clinicians. Multiple endoscopic and radiologic procedures are sometimes required to determine the origin of bleeding. Occasionally, the source of bleeding is not found during the initial episode, and patients are subjected to the risk and expense of repeated transfusions, diagnostic procedures, and hospital admissions. In selected patients, in whom diagnosis is established, interventions such as endoscopic hemostasis, embolization of selected mesenteric artery branches, and surgery may be successful (1). However, rebleeding may occur in patients with multifocal or cryptogenic lesions. Octreotide, a somatostatin analogue that is thought to decrease splanchnic blood flow (2), has been reported to induce cessation of bleeding in adults with acute variceal hemorrhage (3). It has also been effective in the treatment of chronic gastrointestinal bleeding in adults, secondary to intestinal angiodysplasia (4,5). In children, octreotide administered intravenously has been effective in decreasing acute gastrointestinal bleeding of various causes (6). However, there is limited information regarding the efficacy and safety of octreotide for chronic gastrointestinal bleeding in children. Because somatostatin inhibits the secretion of growth hormone, thyrotropin, glucagon, and insulin (7) and decreases bile flow (8,9), the major theoretical complications of long-term octreotide therapy include decreased linear growth velocity, hypothyroidism, diabetes, and cholestasis. We report the successful management of chronic severe gastrointestinal bleeding in three children with the daily use of subcutaneous octreotide (Sandostatin; Sandoz Pharmaceuticals, Basel Switzerland) for 24 to 50 months without significant side effects and with significant reduction in transfusion requirement and in need for gastrointestinal diagnostic procedures. METHODS The octreotide dosage (4–8 μg/kg per day) was derived from previous reports of pediatric usage (13,14). The hemoglobin concentrations, number of blood transfusions, number of blood units transfused, and number of gastrointestinal diagnostic procedures per year were determined for each patient before and after the treatment. Diagnostic procedures included radiologic studies such as sonography, angiography, and nuclear medicine scans and also upper gastrointestinal endoscopy, colonoscopy, and exploratory laparotomy. All patients were treated with iron (4–6 mg/kg per day) during comparison periods. The two-tailed Student's t-test was used to determine differences in the hemoglobin concentrations before and after treatment with octreotide. Data are expressed as mean ± SEM. P < 0.05 is significant. CASE REPORTS AND RESULTS Patient 1 This 5-year-old girl had a history of jejunal atresia, repaired on the second day of life, requiring 11 cm of jejunal resection. At 4 months of life, Hirschsprung disease was diagnosed, and a subtotal colectomy was performed, followed by a pull-through procedure. Since then, she has required multiple blood transfusions for anemia, associated with guaiac-positive stools. At age 2 years, evaluation with esophagogastroduodenoscopy (EGD), abdominal sonography, abdominal computed tomographic (CT) scan, and superior mesenteric angiography was unrevealing. Colonoscopy revealed rectal inflammation, and she was treated with topical corticosteroids. Laparotomy revealed adhesions that were subsequently lysed. After surgery, abdominal distension developed, and anal sphincterotomy resulted in clinical improvement of the distension, yet guaiac-positive melanotic stools persisted. Blood transfusions were required every 3 to 4 weeks. A trial of no oral intake and total parenteral nutrition did not resolve the melena or the need for weekly transfusions. At age 4 years, re-evaluation for melena at a third institution revealed microcytic anemia with hemoglobin of 3.8 g/dl (normal, 11.7–13.8 g/dl), total iron-binding capacity of 604 mg/dl (normal, 250–450 mg/dl), ferritin of 66 ng/ml (normal, 10–130 ng/dl), consistent with severe iron deficiency anemia, most likely due to gastrointestinal loss. Findings in an EGD examination and celiac axis angiography were normal. Colonoscopy showed mild acute and chronic inflammation at the ileocecal valve and right colon with grossly normal-appearing mucosa. Another laparotomy with intraoperative enteroscopy did not reveal a bleeding site. Blood transfusions were administered, and an esophagogram, abdominal sonogram, and another CT scan were unrevealing. A central venous catheter was placed for frequent transfusions, given in the patient's home. At age 5 years, findings in upper and lower gastrointestinal endoscopies were normal. Because the patient frequently had severe anemia in the absence of severe gastrointestinal bleeding, a tentative diagnosis of Munchausen's by proxy was made, and the patient was placed in foster care. However, guaiac-positive stools and severe iron-deficiency anemia persisted, and the child, with a hematocrit of 15%, was returned to her mother. The child was referred to our emergency department and was admitted. At our institution, physical examination showed a well-appearing girl, with tachycardia and guaiac-positive stools. The abdominal scars were well-healed. Hemoglobin was 5.9 g/dl, mean corpuscular volume (MCV) was 65 fl (normal, 75–87 fl), erythrocyte distribution width was 28% (normal, 11.5–14.5%), erythrocyte sedimentation rate was 10 mm/hr (normal, 4–25 mm/hr), serum iron was less than 10 μg/dl (normal, 50–120 μg/dl), transferrin was 395 mg/dl (normal, 200–400 mg/dl), and transferrin saturation was less than 2% (normal, 20–55%). An esophagogram was normal. Technetium 99 sulfur-colloid bleeding scan and celiac axis angiography showed questionable angiodysplasia involving the right colon. However, a technetium-labeled erythrocyte scan performed with the angiography catheter, which was directed toward the angiodysplastic lesion, was negative. The patient received 4 μg/kg per day of subcutaneous octreotide and 4 mg/kg of body weight of iron-replacement therapy. For 52 months since the inception of octreotide therapy, hemoglobin remained more than 9 g/dl (P = 0.014;Fig. 1). Although stools remained intermittently guaiac positive, the need for gastrointestinal diagnostic procedures per year decreased from seven before octreotide to two after treatment. The administration of blood transfusions decreased from 12 per year to 1.3 per year after treatment.FIG. 1.: Mean hemoglobin concentrations (in grams per decaliter) for each patient before and after treatment with octreotide. For patient 1, hemoglobin concentrations were assessed for 20 months before treatment and for 52 months during treatment with octreotide. For patient 2, hemoglobins were assessed for 20 months before treatment and for 24 months during treatment with octreotide. For patient 3, hemoglobins were assessed for 18 months before treatment and for 28 months during treatment.Patient 2 This 5-year-old girl had biliary atresia and a failed Kasai procedure. Orthotopic liver transplantation had been performed at 19 months of age, using a pediatric donor liver. Ten months after surgery, she began to have multiple episodes of lower gastrointestinal bleeding manifesting as melanotic stools with precipitous declines in hemoglobin (e.g., from 8.5 to 5.5 g/dl). No varices or ulcers were detected in upper endoscopy, but antral specimens showed Helicobacter pylori–associated gastritis. Technetium-labeled erythrocyte scan and Meckel's scan were unremarkable as were Doppler abdominal sonography and colonoscopy. Despite triple antibiotic therapy for H. pylori-—induced gastritis, the patient continued to experience gastrointestinal bleeding. During an episode of massive melena, emergency celiac axis angiography was unremarkable as was another upper endoscopy. Colonoscopy revealed abundant melena originating above the terminal ileum. Exploratory laparotomy demonstrated that the distal half of the small bowel was filled with melanotic contents. The endoscope was inserted through an enterotomy at the origin of the melena, and the entire small bowel and Roux-en-Y were inspected, revealing a single vascular lesion that was resected with externalization of the proximal stoma. The pathology report showed dilated sinusoidal spaces and adjacent small vessels in the small bowel, consistent with arteriovenous malformation. Bloody output was noted from the stoma 1 month later. Findings in another upper endoscopy were unremarkable. Bleeding was thought to be secondary to missed arteriovenous malformations of the small bowel, and the patient was treated with 8 μg/kg per day of subcutaneous octreotide and 4 mg/kg of elemental iron. During the ensuing months, she was free of any bleeding with the exception of a 4-week period when octreotide was discontinued. Her mean hemoglobin during the 24 month follow-up remained at more than 9.5 mg/dl (P = 0.008;Fig. 1). Her requirement for blood transfusions decreased from 9 per year to 0 per year after octreotide. The number of gastrointestinal diagnostic procedures decreased from 11 per year to 0 per year after initiation of octreotide therapy. Patient 3 This 16-year-old boy had spontaneous perforation of the common bile duct on day 2 of life that was surgically repaired. At 8 months after surgery, an intrahepatic abscess developed, and cardiac arrest occurred. Resuscitation was achieved with blood products, presumably contaminated with hepatitis B and C viruses. At age 3 years, he had had variceal bleeding requiring endoscopic sclerotherapy. His clinical course was subsequently complicated by growth stunting, and he was treated with fat-soluble vitamins. Since then, he had had several bile duct strictures requiring stent placement. At age 12 years, abdominal CT revealed intrahepatic bile duct dilatation, intrahepatic stones, and cavernous transformation of the portal vein. A percutaneous transhepatic cholangiogram (PTC) confirmed strictures of the left and right hepatic ducts at the level of the porta hepatis. He underwent intraductal lithotripsy, and multiple PTCs for biliary drainage and intraductal stent placement. Analysis of a percutaneous liver biopsy specimen revealed portal fibrosis without cirrhosis or active hepatitis; hepatitis B surface antigen was identified by immunoperoxidase staining. The patient was well until 14 years of age when lower gastrointestinal bleeding developed (hemoglobin, 5 mg/dl). An EGD revealed esophageal varices, and variceal sclerotherapy was performed. A transjugular intrahepatic portosystemic shunt (TIPS) procedure was not possible because of the cavernous malformation of the portal vein. However, hematochezia persisted, and hemoglobin was 6.5 mg/dl and MCV 73. A Meckel's scan was negative and the parents refused further diagnostic procedures. The patient was treated with 5 μg/kg subcutaneous octreotide per day and 6 mg/kg oral elemental iron. Follow-up hemoglobin after 21 days of therapy was 8.7 mg/dl. During 28 months of follow-up, he had no further rectal bleeding or hematemesis. The number of blood transfusions has decreased from 2 per year to 0 per year, and the number of diagnostic procedures has decreased from 5 per year to 0 per year. Hemoglobin has ranged between 9.3 and 11.3 mg/dl, significantly increased compared with mean hemoglobin before treatment (P = 0.042;Fig. 1). Clinically, end-stage liver disease has developed with ascites and severe growth stunting. Side Effects All patients had normal serum glucose and glycosylated hemoglobin, 1 to 52 months after the initiation of therapy (Table 1). Thyroid function was normal in patient 1 throughout treatment; in patient 3 thyroid-stimulating hormone (TSH) was 1.1 to 1.9 mU/l in the first 24 months but decreased to 0.45 mU/l at 28 months (normal range, 0.5–4.5 mU/l).TABLE 1: Hormonal profile of the three patients with severe occult gastrointestinal bleeding treated with subcutaneous octreotideThe growth and growth velocity curves of all patients are illustrated in Figures 2 and 3. The growth of patient 1 remained at the 10th percentile for age, and growth velocity increased during octreotide therapy. Serum insulin-like growth factor-1 (IGF-1) and IGF-binding protein-3 were normal in patient 1. Although growth velocity in patient 2 was depressed before octreotide treatment, her growth was sustained at the 5th percentile throughout treatment. Data for IGF-1 and IGF-binding protein-3 were not available in patient 2. The growth and growth velocity of patient 3 remained unchanged below the 5th percentile, and IGF-1 and IGF-binding protein 3 were decreased.FIG. 2.: Growth curves of patient 1 (A), patient 2 (B), and patient 3 (C) during treatment with octreotide.FIG. 3.: Growth velocities of patient 1 (A), patient 2 (B), and patient 3 (C) during treatment with octreotide.Costs of Therapy A monthly treatment with 50 μg octreotide daily (which was the average dose our patients received) is US$232.00 which includes the syringes used for the subcutaneous injection. The costs saved on the therapy by the institution are shown in Table 2. The cost is estimated per year per patient on the basis of the cost of therapy at Johns Hopkins Hospital. For instance, a transfusion of 1 unit of blood costs $469.00 (this includes supplies and nursing charges). The cost of diagnostic procedures includes hospital and professional charges.TABLE 2: Annual costs of therapy in the three patients before and after treatment with octreotideDISCUSSION In the pediatric population, experience with prolonged octreotide therapy has been limited to case reports for management of endocrine disorders (10,11), intractable diarrheal states (13,14), and ileostomy diarrhea (15). The drug has also been used in the short-term management of pancreatitis (16), and closure of intestinal fistulas (17). A wide range of daily doses from 1.4 to 20 μg/kg have been used and reportedly have been well tolerated (10–17). Our experience suggests that octreotide may be useful in the management of chronic cryptogenic gastrointestinal bleeding or bleeding secondary to arteriovenous malformation and portal hypertension. Our patients were treated successfully with doses between 4 and 8 μg/kg per day. Cessation of bleeding and increase in hemoglobin were generally seen within the first week of administration. Long-term octreotide therapy in children for indications other than gastrointestinal bleeding has not been associated with adverse effects on renal, hepatic, or pituitary functions (10–15). Similarly in our patients, hyperglycemia was not observed, and the concentrations of glycosylated hemoglobin remained normal. None of the patients had clinical symptoms of gallstones or cholecystitis. Thyroid function also remained normal in patients 1 and 2; however, after 28 months of therapy TSH was decreased in patient 3. Octreotide-treated children with normally functioning thyroid glands have been found by other investigators to have no alteration in their thyroid function (10,14,18). However, long-term administration of octreotide in doses of 50 to 100 μg per day have been shown to inhibit release of TSH in response to thyrotropin-releasing hormone (TRH) without modifying basal levels in healthy subjects (19). Although growth hormone suppression and deceleration of growth velocity have been reported (10,18), these findings were not seen in patient 1. However, in patients 2 and 3, growth was stunted. In patient 2, we suspect that growth stunting was probably caused by corticosteroid therapy after liver transplantation and by her refusal of food. The growth of patient 3 has been compromised by documented chronic fat malabsorption due to cirrhosis and noncompliance with fat-soluble vitamin supplementation. Long-term octreotide therapy may have decreased the growth rate of these patients. Octreotide selectively inhibits growth hormone (GH) secretion and has been used successfully in inhibiting GH secretion in patients with acromegaly (20). However, the inhibitory effects of octreotide on GH may not be immediately observed. Jackson et al. (10) reported that a male infant with nesidioblastosis who was treated with octreotide (50 μg twice daily for 10 months) initially exhibited normal growth despite depressed GH levels and increased IGF-1 levels. However, after 12 months of age, growth tapered off. The serum GH and IGF-1 were markedly suppressed after 14 to 17 months of therapy. Other studies have shown that children with chronic liver disease also have decreased IGF-1 levels (21,22) and demonstrate resistance to the growth-promoting effects of GH despite increased measured GH levels. IGF-binding protein-3 may also be decreased in children with cirrhosis but may increase in response to treatment with GH (22). In these children with persistent hematochezia, use of chronic octreotide resulted in resolution of recurrent anemia, and decreased the need for erythrocyte transfusions, costly diagnostic procedures and further hospital admissions. The therapy was clearly cost effective. Although these cases do not establish the efficacy of octreotide in all cases of occult gastrointestinal bleeding, they provide compelling reasons for a prospective placebo-controlled trial to determine whether there is a valid indication for octreotide in the management of chronic gastrointestinal bleeding in children.