Efficacy of cimetidine for gastric acid suppression in pediatric patients J. L a m b e r t , MD, M. M o b a s s a l e h , MD, a n d R. J. G r a n d , MD From the Division of Gastroenterology and Nutrition, Department of Pediatrics, Boston Floating Hospital, New England Medical Center, Tufts University School of Medicine, Boston, Massachusetts
The efficacy of oral cimetidine for gastric acid suppression in pediatric patients was examined in a double-blind study. Twenty-seven patients with gastroesopha g e a l reflux-related gastrointestinal symptoms, pulmonary symptoms, or both were given randomly determined doses of cimetidine. Response was evaluated by continuous intragastric monitoring with a pH probe. Twenty-three patients were given cimetidine doses of 5, 7.5, and 10 mg/kg; eight of these patients were also given additional doses of 15 mg/kg. Four patients received only 10 and 15 mg/kg, because of previous poor clinical response to the lower dosages. The onset of gastric pH >4 was delayed more than 2 hours in 50% of patients with responses to the 5 m g / k g dose. Of the patients with responses to the 10 m g / k g dose, 75% had showed a rise in gastric pH >4 within 2 hours. With respect to the duration of gastric acid suppression, 70% of patients receiving 5 mg/kg doses and 52% of those receiving 7.5 m g / k g doses did not have a sustained a response for more than 2 hours, whereas 75% of patients receiving 10 mg/kg doses had gastric acid suppression for longer than 2 hours. Of the patients receiving 15 m g / k g doses, 75% had a response for more than 2 hours; 50% of these patients had a response for more than 3 hours. We conclude that r e c o m m e n d e d doses of cimetidine for children may not be optimal for a d e q u a t e gastric acid suppression. (J PEDIATR1992;120:474-8)
Cimetidine is widely used in the treatment of children with acid or peptic disease, gastritis or esophagitis with and without hemorrhage, cystic fibrosis with maldigestion, postoperative hypersecretion after small bowel resection, and gastrointestinal and pulmonary symptoms caused by gastroesophageal reflux. 1-9 However, the ability of recommended doses of cirnetidine to suppress production of gastric acid has not been well studied. In adult patients the dosage, pharmacokinetics, and effiSupported in part by a research fund from Smith Kline and French Laboratories, by Pediatric Gastroenterology Research Training grant No. DK07471 from the National Institutes of Health, and by grant No. RR-00054 from the General Clinical Research Centers program of the Division of Research Resources, National Institutes of Health. Submitted for publication June 25, 1991; accepted Oct. 1, 1991. Reprint requests: Munir Mobassaleh, MD, New England Medical Center, 750 Washington St., Box 213, Boston, MA 02111. 9/25/34121
474
cacy of cimetidine have been established; side effects and complications are well known and infrequent.it The pharmacokinetics of cimetidine in infants and children has been described,l 1-15but the dose of cimetidine necessary for suppression of gastric acid secretion in pediatric patients is not well established; doses ranging between 10 and 40 mg/kg per day have been used. Goudsouzian et al. 16suggested that the optimal dose of cimetidine to raise the pH of the gastric contents to greater than 2.5 is 7.5 mg/kg; at this dose the volume of gastric aspirate was also significantly reduced. Because the criteria for pathologic gastroesophageal reflux include a prolonged period of delayed acid clearance during which esophageal pH is 4. 6, 19 However, the appropriate doses of cimetidine necessary to accomplish this goal in children have not been defined. Furthermore, documentation of gastric acid suppression has not been obtained with continuous intragastric monitoring with a pH probe. The validity of this test for contin-
Volume 120 Number 3
uously measuring gastric pH has been confirmed. 2~ 21 The aim of this study was to identify the dose of cimetidine needed to suppress production of gastric acid in pediatric patients with abnormal gastroesophageal reflux, with intragastric pH-probe monitoring used to assess therapeutic efficacy. METHODS Twenty-seven patients with gastroesophageal reflux-related gastrointestinal symptoms, pulmonary symptoms, or both were examined. Informed consent was obtained from a parent or legal guardian for all patients. Children considered capable of giving consent also signed the patient consent form before entry into the study. All patients had screening laboratory data within normal limits for age. Children who had gastrointestinal, cardiovascular, renal, or hepatic dysfunction were not enrolled in the study. Children were also excluded if they had recently had active viral infections (such as overt symptoms of an upper respiratory tract infection) or had been vaccinated against viral infections within 4 weeks of the study. Patients who were allergic to cimetidine or had received investigational compounds within the 3 months immediately preceding the study were excluded. Patients receiving treatment with H2 blockers, antireflux medications, or both had these withheld for at least 12 hours before initiation of the study. Concomitant medication or supportive therapy that was necessary for the health of the patient (such as diuretics or /3-agonists) and that did not affect the evaluation of the study drug was continued. The patients underwent an overnight esophageal pHprobe study (Beckman model 3550 digital pH meter; Beckman Instruments Inc., Fullerton, Calif.) as part of routine evaluation of gastroesophageal reflux.18 The tip of the probe was placed at 13% of the esophageal length above the gastroesophageal junction according to the formula of Strobel et al. 22 and the position was confirmed by chest radiography. In addition, all patients underwent endoscopic or suction esophageal biopsy2325 to document the presence or absence of esophagitis, as defined by the presence of intraepithelial eosinophils, basal-zone hyperplasia, and elongation of the papillaeto >50% ofmucosal depth. 23 Twenty-threepatients (mean age 4.5 years, range 3 to 14 years) with an abnormal esophageal pH-probe recording (pH 2.5 +_ 4.6 per 24 hours, and total time with pH 3
NR
Cirnetidine 5 23 4 5 2 5 7 7 23 2 4 3 8 6 10 27 2 2 13 7 3 15 12 0 2 3 6 1 Ranitidine 3-6 10 1 2 1 5 1 Patients with poor responseto the lowerdosesreceivedcimetidine15 mg/ kg, ranitidine 3 to 6 mg/kg, or both. EDITOR'SNOTE:Individualpatient data are availablefrom the authors. NR. No response.
40
20
0
N
0
The efficacy of oral cimetidine for gastric acid suppression in pediatric patients was examined in a double-blind study. Twenty-seven patients with gastroesopha g e a l reflux-related gastrointestinal symptoms, pulmonary symptoms, or both were given randomly determined doses of cimetidine. Response was evaluated by continuous intragastric monitoring with a pH probe. Twenty-three patients were given cimetidine doses of 5, 7.5, and 10 mg/kg; eight of these patients were also given additional doses of 15 mg/kg. Four patients received only 10 and 15 mg/kg, because of previous poor clinical response to the lower dosages. The onset of gastric pH >4 was delayed more than 2 hours in 50% of patients with responses to the 5 m g / k g dose. Of the patients with responses to the 10 m g / k g dose, 75% had showed a rise in gastric pH >4 within 2 hours. With respect to the duration of gastric acid suppression, 70% of patients receiving 5 mg/kg doses and 52% of those receiving 7.5 m g / k g doses did not have a sustained a response for more than 2 hours, whereas 75% of patients receiving 10 mg/kg doses had gastric acid suppression for longer than 2 hours. Of the patients receiving 15 m g / k g doses, 75% had a response for more than 2 hours; 50% of these patients had a response for more than 3 hours. We conclude that r e c o m m e n d e d doses of cimetidine for children may not be optimal for a d e q u a t e gastric acid suppression. (J PEDIATR1992;120:474-8)
Cimetidine is widely used in the treatment of children with acid or peptic disease, gastritis or esophagitis with and without hemorrhage, cystic fibrosis with maldigestion, postoperative hypersecretion after small bowel resection, and gastrointestinal and pulmonary symptoms caused by gastroesophageal reflux. 1-9 However, the ability of recommended doses of cirnetidine to suppress production of gastric acid has not been well studied. In adult patients the dosage, pharmacokinetics, and effiSupported in part by a research fund from Smith Kline and French Laboratories, by Pediatric Gastroenterology Research Training grant No. DK07471 from the National Institutes of Health, and by grant No. RR-00054 from the General Clinical Research Centers program of the Division of Research Resources, National Institutes of Health. Submitted for publication June 25, 1991; accepted Oct. 1, 1991. Reprint requests: Munir Mobassaleh, MD, New England Medical Center, 750 Washington St., Box 213, Boston, MA 02111. 9/25/34121
474
cacy of cimetidine have been established; side effects and complications are well known and infrequent.it The pharmacokinetics of cimetidine in infants and children has been described,l 1-15but the dose of cimetidine necessary for suppression of gastric acid secretion in pediatric patients is not well established; doses ranging between 10 and 40 mg/kg per day have been used. Goudsouzian et al. 16suggested that the optimal dose of cimetidine to raise the pH of the gastric contents to greater than 2.5 is 7.5 mg/kg; at this dose the volume of gastric aspirate was also significantly reduced. Because the criteria for pathologic gastroesophageal reflux include a prolonged period of delayed acid clearance during which esophageal pH is 4. 6, 19 However, the appropriate doses of cimetidine necessary to accomplish this goal in children have not been defined. Furthermore, documentation of gastric acid suppression has not been obtained with continuous intragastric monitoring with a pH probe. The validity of this test for contin-
Volume 120 Number 3
uously measuring gastric pH has been confirmed. 2~ 21 The aim of this study was to identify the dose of cimetidine needed to suppress production of gastric acid in pediatric patients with abnormal gastroesophageal reflux, with intragastric pH-probe monitoring used to assess therapeutic efficacy. METHODS Twenty-seven patients with gastroesophageal reflux-related gastrointestinal symptoms, pulmonary symptoms, or both were examined. Informed consent was obtained from a parent or legal guardian for all patients. Children considered capable of giving consent also signed the patient consent form before entry into the study. All patients had screening laboratory data within normal limits for age. Children who had gastrointestinal, cardiovascular, renal, or hepatic dysfunction were not enrolled in the study. Children were also excluded if they had recently had active viral infections (such as overt symptoms of an upper respiratory tract infection) or had been vaccinated against viral infections within 4 weeks of the study. Patients who were allergic to cimetidine or had received investigational compounds within the 3 months immediately preceding the study were excluded. Patients receiving treatment with H2 blockers, antireflux medications, or both had these withheld for at least 12 hours before initiation of the study. Concomitant medication or supportive therapy that was necessary for the health of the patient (such as diuretics or /3-agonists) and that did not affect the evaluation of the study drug was continued. The patients underwent an overnight esophageal pHprobe study (Beckman model 3550 digital pH meter; Beckman Instruments Inc., Fullerton, Calif.) as part of routine evaluation of gastroesophageal reflux.18 The tip of the probe was placed at 13% of the esophageal length above the gastroesophageal junction according to the formula of Strobel et al. 22 and the position was confirmed by chest radiography. In addition, all patients underwent endoscopic or suction esophageal biopsy2325 to document the presence or absence of esophagitis, as defined by the presence of intraepithelial eosinophils, basal-zone hyperplasia, and elongation of the papillaeto >50% ofmucosal depth. 23 Twenty-threepatients (mean age 4.5 years, range 3 to 14 years) with an abnormal esophageal pH-probe recording (pH 2.5 +_ 4.6 per 24 hours, and total time with pH 3
NR
Cirnetidine 5 23 4 5 2 5 7 7 23 2 4 3 8 6 10 27 2 2 13 7 3 15 12 0 2 3 6 1 Ranitidine 3-6 10 1 2 1 5 1 Patients with poor responseto the lowerdosesreceivedcimetidine15 mg/ kg, ranitidine 3 to 6 mg/kg, or both. EDITOR'SNOTE:Individualpatient data are availablefrom the authors. NR. No response.
40
20
0
N
0
