Use of Octreotide for the Treatment of Severe Gastrointestinal Bleeding in Children

Severe gastrointestinal bleeding (SGIB) is an infrequent but potentially life-threatening problem in childhood (1,2). Although treatment is often limited to supportive medical care, continued bleeding is an indication for therapeutic endoscopic hemostasis, angiographic embolization, or surgical intervention (3-5). Some patients may not be suitable candidates for or may continue to hemorrhage despite these interventions (4,5). Pharmacologic intervention has therefore been advocated(1,4-6). Vasopressin has been successful, but the incidence of side effects has hampered its use(1). Recently, octreotide, a somatostatin analogue(6), has been shown in adults to be effective in the control of bleeding esophageal varices (4,6), angiodysplasia (7), or SGIB from multiple sites(3). In children, octreotide has been successfully used in secretory diarrhea, in pancreatic and intestinal fistulas, or in the treatment of endocrine disorders (8). Octreotide is safe and has no major side effects (8); it may therefore represent a viable alternative for pharmacologic therapy in children with SGIB. We report our initial experience using octreotide as primary or adjunctive therapy in children with SGIB. MATERIALS AND METHODS Records of all patients with SGIB who received octreotide at the Children's Hospital in Boston from 1993-1995 were reviewed retrospectively. Severe gastrointestinal bleeding was defined as hemorrhage associated with a decrease in systolic blood pressure of more than 20 mmHg and or an acute (<12-hour) decrease in hemoglobin of more than 2 g/dl (2). Patients with cirrhosis were classified, using the Child-Pugh classification(9). Octreotide was administered in patients with SGIB who had lesions that were not amenable to or in which endoscopic therapy had failed, who were too unstable for intervention, who had arterial bleeding (Dieulafoy's lesion[10]), or who had known varices undergoing stabilization before endoscopic therapy. Octreotide (Sandoz Pharmaceutical, Rueil-Malmaison, France) was administered by intravenous bolus in a 5-minute period, followed by continuous infusion. Patients 2, 3, 4, and 5 received the adult dose, a 50-μg bolus followed by 50 μg/hr (3,4,6). Patients 1 and 6 received a dose of 1-2 μg/kg bolus, followed by 1 μg/kg per hour. The continuous infusion was increased every 8 hours if there was no reduction in the bleeding. Patient 7 received an initial bolus of 2 μg/kg, followed by 1-μg/kg boluses every 8 hours. The octreotide dose was tapered by one-half every 12 hours when there was no active bleeding for 24 hours and was stopped when it reached one-quarter of the initial dose. In patient 1, the octreotide was not tapered, but was left unchanged until the patient extracorporeal membrane oxygenation (ECMO) was discontinued. The following outcomes were analyzed: Cessation of bleeding: absence of bleeding for 24 hours and stabilization of vital signs and hemoglobin without further transfusion requirement. Rebleeding: recurrence of bright red blood in the nasogastric tube or rectum or melena with deterioration of vital signs not related to any other factor (4). Change in blood transfusion requirement: measured by the difference in packed red blood cell (PRBC) requirement during the 48-hour period before administration of octreotide, and the entire period during administration. Blood requirements before and after octreotide were compared by paredt- tests. Values are expressed as mean ± SE. RESULTS Seven patients were included (Table 1). All were acutely ill at the time of octreotide administration, four were referred from other hospitals, and vasopressin and endoscopic therapy had been tried before in five patients. Their mean age was 9 ± 5.4 (range, 2-18) years. Table 2 shows the main treatment characteristics. The mean initial bolus administered was 1.66 ± 0.27 μg/kg, and the mean constant infusion was 2.06 ± 0.86 μg/kg per hour. Bleeding stopped during therapy in six (86%) patients in a mean time of 40 ± 8 hours(median, 36 hours). There was a significant reduction in packed red blood cell requirement after octreotide initiation from 28.4 ± 5.9 ml/kg (0.62± 0.1 ml/kg per hour) before treatment to 10.8 ± 7.3 ml/kg(0.097 ± 0.09 ml/kg per hour) after treatment (p < 0.05 by paired t-test). The patient with arterial bleeding did not improve and required surgical intervention. The only side effect noted was hyperglycemia in patient 2. Her blood sugar increased to 600 mg/dl (333 mmol/l) on day 4 of octreotide administration. At that point, she was receiving 5 μg/kg per hour, and the bleeding had been controlled. She was also receiving a pulse of high-dose steroids to treat rejection of her liver graft. The hyperglycemia was controlled with insulin, and the octreotide was tapered to 2.5 μg/kg per hour. After 72 hours, the insulin was discontinued without complication. Bleeding recurred in two patients (2 and 5) after the octreotide was discontinued. Octreotide was reinstated, and the bleeding was successfully controlled. In patient 2, the rebleeding occurred 3 days later and stopped within 24 hours of octreotide administration. She remained hemodynamically stable after the octreotide was withdrawn. One and a half months later, severe graft rejection developed, and she required a second liver transplant. In patient 5, successful esophageal band ligation was accomplished during the initial endoscopy. He had recurrence of the bleeding 5 days after the octreotide was withdrawn. Octreotide was reinstated. A new endoscopic examination failed to reveal the exact site of the bleeding, and esophageal varices in the distal esophagus were again ligated. He had no further evidence of bleeding, and the octreotide was tapered for 5 days, without recurrence. A liver transplant was performed 2 weeks later, and he had no more evidence of bleeding. DISCUSSION Octreotide effectively controlled nonarterial SGIB in this group of critically ill children. All patients were actively bleeding, and most had lesions in which endoscopic intervention had not been effective or their underlying medical condition precluded more aggressive intervention. Octreotide was effective in children with active variceal bleeding, as results of controlled trials in adults have shown(4-6,11). Although the role of octreotide in the treatment of patients with diffuse mucosal lesions is less well established (3,6), it was very effective in the patient with hemorrhagic gastritis on ECMO (patient 1) who had been bleeding for 2 weeks before drug therapy was initiated. Octreotide had no effect on arterial bleeding in patient 3, not an unexpected finding, in that octreotide primarily reduces collateral splanchnic and hepatic blood flow (6,12). Octreotide was also used in a critically ill intubated patient with end-stage Alagille syndrome and portal hypertension, who had recently undergone a reoperation for tetralogy of Fallot, in whom endoscopy was not feasible because of cardiovascular instability. The patient had significant bleeding for 8 days, and even though the exact source was unknown, the bleeding stopped soon after octreotide was administered. Although octreotide has been used to treat other pediatric conditions(e.g., secretory diarrhea, pancreatic and intestinal fistulas) with doses ranging from 2 to 20 μg/kg per day (8), no pediatric dose has been tested for the treatment of gastrointestinal bleeding. From results in this study, it is not possible to determine the dose at which octreotide becomes effective. It seems that a 1-μg/kg bolus followed by a constant infusion of 1 μg/kg per hour may be an initial dose that could be increased as needed without major side effects. Although octreotide was generally given by continuous infusion, subcutaneous injections every 8 hours was recently reported to yield good results in one patient (7) for management of chronic bleeding related to angiodysplasia of the small intestine(7). No adverse side effects were associated with octreotide therapy.(6,8,12). This contrasts sharply with the serious complications seen with vasopressin(1,11). The only side effect of octreotide was hyperglycemia that required insulin administration in one patient. It is unclear whether the hyperglycemia was related only to the octreotide, in that the patient was also under stress from rejection of a liver graft and was simultaneously receiving a pulse of high-dose steroids. However, hyperglycemia has been associated with octreotide administration (6) and patients must be closely monitored for development of this side effect. Given the lack of control subjects, it is difficult to prove that the control of the bleeding was related to the administration of octreotide and not to the natural history of the disease. For example, patients 5 and 6 received octreotide early, in preparation for therapeutic endoscopy. Although their bleeding was controlled, it may have stopped spontaneously without octreotide. In the other patients, however, there was uncontrolled bleeding for days to weeks, with ongoing blood loss at the time octreotide therapy was initiated. Cessation of bleeding shortly thereafter supports the notion that octreotide was an effective therapy. Furthermore, findings in controlled studies in adults have clearly demonstrated its efficacy for the pharmacologic control of variceal hemorrhage (5,6). We recognize that a controlled trial in children may be very important, but the number of heterogenous pediatric patients with SGIB makes even a multicenter trial difficult. It is our impression that data taken from the adult controlled studies, combined together with our limited clinical experience, demonstrate the value of octreotide for the treatment of SGIB in children. We conclude that octreotide appears safe and effective in controlling nonarterial SGIB in children. It may also represent an important adjunct in the initial treatment of patients with SGIB and known portal hypertension who are admitted to institutions in which there is no endoscopic expertise and require stabilization before transfer to centers providing endoscopic services. Clearly, additional experience is required to identify predictors of response and to determine appropriate dose range and routes of delivery. Acknowledgment: The authors thank Lorena Klaes for her help in gathering data for this report. This work was supported in part by the National Institutes of Health, Bethesda, Maryland (grant T32-DK 07703).