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Tardive dyskinesia associated with use of metoclopramide in a child
Volume 121 Number 6
9. Vailas GN, Brouillett RT, Scott JP, Shkonik A, Conway J, Wiringa K. Neonatal aortic thrombosis: recent experience. J PEDIATR 1986;109:101-8. 10. Zaritsky A, Chernow B. Use of catecholamines in pediatrics. J PEDIATR 1984;105:341-50. 11. Bogaert MG. Clinical pharmacokinetics of glyceryl trinitrate following the use of systemic and topical preparations. Clin Pharmacokinet 1987;12:1-11. 12. Herker JF, Lewis GBH, Stanley H. Nitroglycerine ointment as an aid to venipuncture. Lancet 1983;1:332-3.
Clinical and laboratory observations
983
13. Gibbs NM, Oh TE. Nitroglycerine ointment for dopamine-induced peripheral digital ischemia. Lancet 1983;2:290. 14. Rohrich R J, Cherry GW, Spira M. Enhancement of skin-flap survival using nitroglycerin ointment. Plast Reconstr Surg 1984;73:943-8. 15. Franks AG. Topical glyceryl trinitrate as adjunctive treatment in Raynaud's disease. Lancet 1982;1:76-7. 16. Irazuzta J, McManus ML. Use of topically applied nitroglycerin in the treatment of purpura fulminans. J PEDIATR 1990;117:993-5.
Tardive dyskinesia associated with use of m e t o c l o p r a m i d e in a child Philip E. P u t n a m , MD, Susan R. O r e n s t e i n , MD, Henry B. Wessel, MD, a n d R o b e r t M. S t o w e , MD From the Departments of Pediatrics and Neurology, Divisions of Pediatric Gastroenterology and Pediatric Neurology, Children's Hospital of Pittsburgh and University of Pittsburgh School of Medicine, and the Psychiatry Service, Highland Drive Veterans Administration Medical Center, Pittsburgh, Pennsylvania
Tardive dyskinesia is a chronic, often permanent, movement disorder that has been reported in elderly patients receiving metoclopramide. We describe an 8-year-old boy with tardive dyskinesia that d e v e l o p e d when he received metoclopramide as part of therapy for gastroesophageal reflux and erosive esophagitis. (J PEDIATR1992;121:983-5)
Metoclopramide is a substituted benzamide used as a prokinetic agent to promote upper gastrointestinal tract motility, and as an antiemetic. Its mechanisms of action, although incompletely understood, are mediated in part via antagonism of peripheral and central dopamine receptors.l Antagonism of dopamine receptors in the chemoreceptor trigger zone in the brain stem accounts for the antiemetic properties of the drug. Unfortunately, side effects are also a consequence of dopamine antagonism within the central nervous system. 2 These effects are often dose related and may include mild anxiety, nervousness, fatigue, dystonic reactions, parkinsonism, or akathisia. Tardive dyskinesia, the most distressing and debilitating of the potential extrapyramidal effects, has been reported in adults receiving Presented at a poster session of the 1991 Annual Meeting of the North American Society for Pediatric Gastroenterology and Nutrition, Chicago, IlL, Nov. 1, 1991. Submitted for publication Nov. 15, 1991; accepted July 7, 1992. Reprint requests: Philip E. Putnam, MD, Children's Hospital of Pittsburgh, 3705 Fifth Ave., Pittsburgh, PA 15213.
9/26/40814
metoclopramide 36 but not in children, to our knowledge. As a result, there has been the perception among pediatric practitioners, who commonly employ metoclopramide in the treatment of patients with gastroesophageal reflux or chemotherapy-induced vomiting, that tardive dyskinesia does not develop in children as a consequence of the drug's use.
We report a case of tardive dyskinesia that developed in a child treated with metoclopramide for gastroesophageal reflux. CASE REPORT A 5-year-old boy was seen for evaluation of epigastric abdominal pain and vomiting of several months' duration. He had been born with an omphalocele, which was repaired shortly after birth. Subsequently a duodenojejunostomy was performed for duodenal stenosis and poor gastric emptying. An upper gastrointestinal tract radiographic series with barium disclosed no cause for the child's pain. Esophagogastroduodenoscopy revealed severe erosive distal esophagitis. An eosinophilic infiltrate underlying necrotic epithelium and fibrinopurulent exudate without fungal elements were seen on biopsy. Treatment was instituted with metoclopramide, 0.1 mg/kg per
984
Clinical and laboratory observations
The Journal of Pediatrics December 1992
[:iguro. Examples of a few of the facial contortions exhibited during spontaneous conversation for a period of less than 5 minutes.
dose given four times a day, eimetidine, 7.5 mg/kg per dose given four times a day, and antacids, with resolution of the pain and vomiting. Follow-up endoscopy after 1 month of treatment showed healing esophageal ulceration, but after 5 months endoscopy again revealed diffusely ulcerated esophageal mucosa. A Thal fundoplication, necessitated by the patient's congenital and surgical organ rearrangements, was performed, and the duodenojejunostomy was converted to a Roux-en-Y gastrojejunostomy to improve gastric emptying. Metoclopramide therapy was discontinued after surgery. Despite the fundoplication, the patient continued to retch occasionally. His symptoms progressed, and he again began to vomit. When the child reached 8 years of age, metoclopramide therapy was empirically restarted by his pediatrician because of the vomiting. After a single 10 nag dose (0.4 mg/kg per dose), an acute dystonic reaction developed, with torticollis, oculogyric spasms, and facial grimacing. The dose was immediately decreased to 5 mg because of the reaction. The acute manifestations of the dystonic reaction abated, but the child continued to have involuntary facial movements. Because there was no improvement in his vomiting after 1 month, endoscopy with biopsy was performed. Eroded esophageal mucosa was again seen at the gastroesophageal junction. Sucralfate, 1 gm four times a day as a slurry, was added to the patient's therapeutic regimen. Three months later the esophagus was much improved at endoscopy. The metoclopramide dose was decreased to 0.1 mg/kg per dose four times a day for the next 3 months. This therapy was then discontinued because of the movement disorder and deterioration of the boy's school performance. The facial movements, initially attributed to "habit spasms," were present throughout the 71/2months that metoclopramide was used and have persisted since the medication was discontinued 15 months ago. No treatment has been'~t~tempted. There has been a gradual decrease in the frequency of the movements overall, but they remain prominent during stressful periods. The boy is able to suppress them only briefly by pursing his lips. His school achievement has been unusually variable, ranging from periods of near
failure to others during which his performance was exemplary, all within the same academic year. The patient has taken no other medications that are known to be associated with tardive dyskinesia and has no prior history of neurologic symptoms. There is no family history of tics, movement disorders, or other neurologic diseases. Physical examination reveals a cooperative boy whose weight and height are at the 15th percentile. The general physical findings are unremarkable apart from healed surgical scars on the abdominal wall. He frequently has involuntary choreiform facial movements, which are characterized by grimacing and jaw stretching resembling a yawn (as shown in the Figure). Tongue protrusion, head jerking, head turning, and eye rolling occur less often. There are no associated involuntary vocalizations or choreiform movements of the limbs or trunk. The remainder of neurologic examination findings are normal. DISCUSSION Tardive dyskinesia is a drug-induced m o v e m e n t disorder t h a t follows ~xposure (usually chronic) to neuroleptic and antidopaminergic drugs. 7, 8 It is characterized by repetitive, stereotyped involuntary movements of the head, lips, tongue, and jaw, and less frequently of the trunk, extremities, and even d i a p h r a g m ) T h e lower one t h i r d of the face is most commonly affected. This disorder m a y resolve with discontinuation of t r e a t m e n t with the offending agent, b u t in up to S0% of patients the s y n d r o m e appears to be chronic and irreversible. 10 T r e a t m e n t is generally not effective, a l t h o u g h several medications have been tried, including anticholinergics, reserpine, tetrabenazine, vitamin E, lithium, levodopa, a-methyldopa, and even metoclopramide. 11q3 T h e nature, persistence, and consistency, with time, of the movements exhibited by our patient are characteristic of
Volume 121 Number 6
tardive dyskinesia. Several features make Tourette syndrome or another tic disorder unlikely, including the temporal relationship between the initiation of therapy with metoelopramide and the onset of symptoms, the persistence of the remarkably stereotyped orofacial movements after discontinuation of treatment, the speed and choreiform quality of the movements, the absence of involuntary vocalizations or other classic motor tics (e.g., shoulder shrugging, finger snapping, sniffing), and the patient's inability to suppress them. These features, coupled with the lack of other findings on neurologic examination and the gradual (albeit modest) improvement with time, persuaded us that no other evaluation was required. Because the mechanism by which tardive dyskinesia develops is incompletely understood, it remains unclear whether the unusually high initial dose, the duration of therapy, or the continuation of treatment despite the emergence of involuntary movements contributed to the development of tardive dyskinesia in this case. Metoclopramide is the only substituted benzamide prokinetie drug currently available in the United States. The manufacturer does not recommend use of metoclopramide in children (except to facilitate small bowel intubation). Nevertheless, it is widely employed in infants and children as a prokinetic agent for the treatment of gastroesophageal reflux. The generally accepted dosage for treatment of pediatric gastroesophageal reflux is 0.1 to 0.15 mg/kg per dose four times a day. 1315 Dosages as high as 0.3 mg/kg per dose are employed by some authors 16 despite the increased risk of side effects. That there are few reports linking metoclopramide to chronic movement disorders in children suggests that the risk is small. However, permanent tardive dyskinesia, the manifestation of that risk, is devastating to patients and their families. Therefore a knowledge of the potential side effects and careful monitoring of children receiving the drug are crucial. For the majority of patients, the benefits of metoclopramide use probably outweigh the risks. However, the risk of chronic neurologic sequelae from its use exists, even in children.
Clinical and laboratory observations
985
REFERENCES
1. Harrington RA, Hamilton CW, Brogden RN, Linkewich JA, RomanldewiczJA, Heel RC. Metoclopramide:an updated review of its pharmacological properties and clinical use. Drugs 1983;25:451-94. 2. Miller LG, Jankovic J. Metoclopramide-induced movement disorders: clinical findingswith a reviewof the literature. Arch Intern Med 1989;149:2486-92. 3. Wiholm BE, Mortimer O, Boethias G, Haggstrom JE. Tardive dyskinesia associated with metoclopramide. BMJ 1984;288: 545-7. 4. LavyS, Melamed E, Penchas S. Tardive dyskinesiaassociated with metoclopramide. BMJ 1978;1(6105):77-8. 5. Breitbart W. Tardive dyskinesia associated with high-dose intravenous metoclopramide. N Engl J Med 1986;315:518-9. 6. Stanley M, Rotrosen J, Lautin A, Wazer D, Gershon S. Tardive dyskinesia and metoclopramide. Lancet 1979;2:1190. 7. Klawans HL, Goetz CG, Perlik S. Tardive dyskinesia:review and update. Am J Psychiatry 1980;137:900-8. 8. Fahn S. Tardive dyskinesia. In: Merritt's textbook of neurology. 8th ed. Rowland LP, ed. Philadelphia: Lea & Feibiger: 1989:673-6. 9. Goetz CG, Klawans HL. Tardive dyskinesia. Neurol Clin 1984;2:605-14. 10. Cummings JL, Wirshing WC. Recognition and differential diagnosisof tardive dyskinesia.Int J Psychiatry Med 1989;19: 133-44. 11. Bateman DN, Dutta DK, McClelland HA, Rawlins MD. The effect of metoclopramide and haloperidol on tardive dyskinesia. Proc Br J Pharmacol 1979;66:475P-6P. l 2. Lohr JB, Cadet JL, Lohr MA, et al. Vitamin E in the treatment of tardive dyskinesia: the possible involvement of free radical mechanisms. Schizophr Bull 1986;14:291-6. 13. Kearns GL, Butler HL, Lane JK, Carchman SH, Wright GJ. Metoclopramide pharmacokinetics and pharmacodynamicsin infants with gastroesophageal reflux. J Pediatr Gastroenterol Nutr 1988;7:823-9. 14. Bateman DN, Craft AW, Nicholson E, Pearson ADJ. Dystonic reactions and the pharmacokinetics of metoclopramidein children. Br J Clin Pharmacol 1983;15:557-9. 15. Leung AKC, Lai PCW. Use of metoclopramide for the treatment of gastroesophageal reflux in infants and children. Curr Ther Res 1984;36:911-5. 16. Hyams JS, Leichtner AM, Zamett LO, Waiters JK. Effect of metoclopramide on prolonged intraesophageal pH testing in infants with gastroesophageal reflux. J Pediatr Gastroenterol Nutr 1986;5:716-20.
9. Vailas GN, Brouillett RT, Scott JP, Shkonik A, Conway J, Wiringa K. Neonatal aortic thrombosis: recent experience. J PEDIATR 1986;109:101-8. 10. Zaritsky A, Chernow B. Use of catecholamines in pediatrics. J PEDIATR 1984;105:341-50. 11. Bogaert MG. Clinical pharmacokinetics of glyceryl trinitrate following the use of systemic and topical preparations. Clin Pharmacokinet 1987;12:1-11. 12. Herker JF, Lewis GBH, Stanley H. Nitroglycerine ointment as an aid to venipuncture. Lancet 1983;1:332-3.
Clinical and laboratory observations
983
13. Gibbs NM, Oh TE. Nitroglycerine ointment for dopamine-induced peripheral digital ischemia. Lancet 1983;2:290. 14. Rohrich R J, Cherry GW, Spira M. Enhancement of skin-flap survival using nitroglycerin ointment. Plast Reconstr Surg 1984;73:943-8. 15. Franks AG. Topical glyceryl trinitrate as adjunctive treatment in Raynaud's disease. Lancet 1982;1:76-7. 16. Irazuzta J, McManus ML. Use of topically applied nitroglycerin in the treatment of purpura fulminans. J PEDIATR 1990;117:993-5.
Tardive dyskinesia associated with use of m e t o c l o p r a m i d e in a child Philip E. P u t n a m , MD, Susan R. O r e n s t e i n , MD, Henry B. Wessel, MD, a n d R o b e r t M. S t o w e , MD From the Departments of Pediatrics and Neurology, Divisions of Pediatric Gastroenterology and Pediatric Neurology, Children's Hospital of Pittsburgh and University of Pittsburgh School of Medicine, and the Psychiatry Service, Highland Drive Veterans Administration Medical Center, Pittsburgh, Pennsylvania
Tardive dyskinesia is a chronic, often permanent, movement disorder that has been reported in elderly patients receiving metoclopramide. We describe an 8-year-old boy with tardive dyskinesia that d e v e l o p e d when he received metoclopramide as part of therapy for gastroesophageal reflux and erosive esophagitis. (J PEDIATR1992;121:983-5)
Metoclopramide is a substituted benzamide used as a prokinetic agent to promote upper gastrointestinal tract motility, and as an antiemetic. Its mechanisms of action, although incompletely understood, are mediated in part via antagonism of peripheral and central dopamine receptors.l Antagonism of dopamine receptors in the chemoreceptor trigger zone in the brain stem accounts for the antiemetic properties of the drug. Unfortunately, side effects are also a consequence of dopamine antagonism within the central nervous system. 2 These effects are often dose related and may include mild anxiety, nervousness, fatigue, dystonic reactions, parkinsonism, or akathisia. Tardive dyskinesia, the most distressing and debilitating of the potential extrapyramidal effects, has been reported in adults receiving Presented at a poster session of the 1991 Annual Meeting of the North American Society for Pediatric Gastroenterology and Nutrition, Chicago, IlL, Nov. 1, 1991. Submitted for publication Nov. 15, 1991; accepted July 7, 1992. Reprint requests: Philip E. Putnam, MD, Children's Hospital of Pittsburgh, 3705 Fifth Ave., Pittsburgh, PA 15213.
9/26/40814
metoclopramide 36 but not in children, to our knowledge. As a result, there has been the perception among pediatric practitioners, who commonly employ metoclopramide in the treatment of patients with gastroesophageal reflux or chemotherapy-induced vomiting, that tardive dyskinesia does not develop in children as a consequence of the drug's use.
We report a case of tardive dyskinesia that developed in a child treated with metoclopramide for gastroesophageal reflux. CASE REPORT A 5-year-old boy was seen for evaluation of epigastric abdominal pain and vomiting of several months' duration. He had been born with an omphalocele, which was repaired shortly after birth. Subsequently a duodenojejunostomy was performed for duodenal stenosis and poor gastric emptying. An upper gastrointestinal tract radiographic series with barium disclosed no cause for the child's pain. Esophagogastroduodenoscopy revealed severe erosive distal esophagitis. An eosinophilic infiltrate underlying necrotic epithelium and fibrinopurulent exudate without fungal elements were seen on biopsy. Treatment was instituted with metoclopramide, 0.1 mg/kg per
984
Clinical and laboratory observations
The Journal of Pediatrics December 1992
[:iguro. Examples of a few of the facial contortions exhibited during spontaneous conversation for a period of less than 5 minutes.
dose given four times a day, eimetidine, 7.5 mg/kg per dose given four times a day, and antacids, with resolution of the pain and vomiting. Follow-up endoscopy after 1 month of treatment showed healing esophageal ulceration, but after 5 months endoscopy again revealed diffusely ulcerated esophageal mucosa. A Thal fundoplication, necessitated by the patient's congenital and surgical organ rearrangements, was performed, and the duodenojejunostomy was converted to a Roux-en-Y gastrojejunostomy to improve gastric emptying. Metoclopramide therapy was discontinued after surgery. Despite the fundoplication, the patient continued to retch occasionally. His symptoms progressed, and he again began to vomit. When the child reached 8 years of age, metoclopramide therapy was empirically restarted by his pediatrician because of the vomiting. After a single 10 nag dose (0.4 mg/kg per dose), an acute dystonic reaction developed, with torticollis, oculogyric spasms, and facial grimacing. The dose was immediately decreased to 5 mg because of the reaction. The acute manifestations of the dystonic reaction abated, but the child continued to have involuntary facial movements. Because there was no improvement in his vomiting after 1 month, endoscopy with biopsy was performed. Eroded esophageal mucosa was again seen at the gastroesophageal junction. Sucralfate, 1 gm four times a day as a slurry, was added to the patient's therapeutic regimen. Three months later the esophagus was much improved at endoscopy. The metoclopramide dose was decreased to 0.1 mg/kg per dose four times a day for the next 3 months. This therapy was then discontinued because of the movement disorder and deterioration of the boy's school performance. The facial movements, initially attributed to "habit spasms," were present throughout the 71/2months that metoclopramide was used and have persisted since the medication was discontinued 15 months ago. No treatment has been'~t~tempted. There has been a gradual decrease in the frequency of the movements overall, but they remain prominent during stressful periods. The boy is able to suppress them only briefly by pursing his lips. His school achievement has been unusually variable, ranging from periods of near
failure to others during which his performance was exemplary, all within the same academic year. The patient has taken no other medications that are known to be associated with tardive dyskinesia and has no prior history of neurologic symptoms. There is no family history of tics, movement disorders, or other neurologic diseases. Physical examination reveals a cooperative boy whose weight and height are at the 15th percentile. The general physical findings are unremarkable apart from healed surgical scars on the abdominal wall. He frequently has involuntary choreiform facial movements, which are characterized by grimacing and jaw stretching resembling a yawn (as shown in the Figure). Tongue protrusion, head jerking, head turning, and eye rolling occur less often. There are no associated involuntary vocalizations or choreiform movements of the limbs or trunk. The remainder of neurologic examination findings are normal. DISCUSSION Tardive dyskinesia is a drug-induced m o v e m e n t disorder t h a t follows ~xposure (usually chronic) to neuroleptic and antidopaminergic drugs. 7, 8 It is characterized by repetitive, stereotyped involuntary movements of the head, lips, tongue, and jaw, and less frequently of the trunk, extremities, and even d i a p h r a g m ) T h e lower one t h i r d of the face is most commonly affected. This disorder m a y resolve with discontinuation of t r e a t m e n t with the offending agent, b u t in up to S0% of patients the s y n d r o m e appears to be chronic and irreversible. 10 T r e a t m e n t is generally not effective, a l t h o u g h several medications have been tried, including anticholinergics, reserpine, tetrabenazine, vitamin E, lithium, levodopa, a-methyldopa, and even metoclopramide. 11q3 T h e nature, persistence, and consistency, with time, of the movements exhibited by our patient are characteristic of
Volume 121 Number 6
tardive dyskinesia. Several features make Tourette syndrome or another tic disorder unlikely, including the temporal relationship between the initiation of therapy with metoelopramide and the onset of symptoms, the persistence of the remarkably stereotyped orofacial movements after discontinuation of treatment, the speed and choreiform quality of the movements, the absence of involuntary vocalizations or other classic motor tics (e.g., shoulder shrugging, finger snapping, sniffing), and the patient's inability to suppress them. These features, coupled with the lack of other findings on neurologic examination and the gradual (albeit modest) improvement with time, persuaded us that no other evaluation was required. Because the mechanism by which tardive dyskinesia develops is incompletely understood, it remains unclear whether the unusually high initial dose, the duration of therapy, or the continuation of treatment despite the emergence of involuntary movements contributed to the development of tardive dyskinesia in this case. Metoclopramide is the only substituted benzamide prokinetie drug currently available in the United States. The manufacturer does not recommend use of metoclopramide in children (except to facilitate small bowel intubation). Nevertheless, it is widely employed in infants and children as a prokinetic agent for the treatment of gastroesophageal reflux. The generally accepted dosage for treatment of pediatric gastroesophageal reflux is 0.1 to 0.15 mg/kg per dose four times a day. 1315 Dosages as high as 0.3 mg/kg per dose are employed by some authors 16 despite the increased risk of side effects. That there are few reports linking metoclopramide to chronic movement disorders in children suggests that the risk is small. However, permanent tardive dyskinesia, the manifestation of that risk, is devastating to patients and their families. Therefore a knowledge of the potential side effects and careful monitoring of children receiving the drug are crucial. For the majority of patients, the benefits of metoclopramide use probably outweigh the risks. However, the risk of chronic neurologic sequelae from its use exists, even in children.
Clinical and laboratory observations
985
REFERENCES
1. Harrington RA, Hamilton CW, Brogden RN, Linkewich JA, RomanldewiczJA, Heel RC. Metoclopramide:an updated review of its pharmacological properties and clinical use. Drugs 1983;25:451-94. 2. Miller LG, Jankovic J. Metoclopramide-induced movement disorders: clinical findingswith a reviewof the literature. Arch Intern Med 1989;149:2486-92. 3. Wiholm BE, Mortimer O, Boethias G, Haggstrom JE. Tardive dyskinesia associated with metoclopramide. BMJ 1984;288: 545-7. 4. LavyS, Melamed E, Penchas S. Tardive dyskinesiaassociated with metoclopramide. BMJ 1978;1(6105):77-8. 5. Breitbart W. Tardive dyskinesia associated with high-dose intravenous metoclopramide. N Engl J Med 1986;315:518-9. 6. Stanley M, Rotrosen J, Lautin A, Wazer D, Gershon S. Tardive dyskinesia and metoclopramide. Lancet 1979;2:1190. 7. Klawans HL, Goetz CG, Perlik S. Tardive dyskinesia:review and update. Am J Psychiatry 1980;137:900-8. 8. Fahn S. Tardive dyskinesia. In: Merritt's textbook of neurology. 8th ed. Rowland LP, ed. Philadelphia: Lea & Feibiger: 1989:673-6. 9. Goetz CG, Klawans HL. Tardive dyskinesia. Neurol Clin 1984;2:605-14. 10. Cummings JL, Wirshing WC. Recognition and differential diagnosisof tardive dyskinesia.Int J Psychiatry Med 1989;19: 133-44. 11. Bateman DN, Dutta DK, McClelland HA, Rawlins MD. The effect of metoclopramide and haloperidol on tardive dyskinesia. Proc Br J Pharmacol 1979;66:475P-6P. l 2. Lohr JB, Cadet JL, Lohr MA, et al. Vitamin E in the treatment of tardive dyskinesia: the possible involvement of free radical mechanisms. Schizophr Bull 1986;14:291-6. 13. Kearns GL, Butler HL, Lane JK, Carchman SH, Wright GJ. Metoclopramide pharmacokinetics and pharmacodynamicsin infants with gastroesophageal reflux. J Pediatr Gastroenterol Nutr 1988;7:823-9. 14. Bateman DN, Craft AW, Nicholson E, Pearson ADJ. Dystonic reactions and the pharmacokinetics of metoclopramidein children. Br J Clin Pharmacol 1983;15:557-9. 15. Leung AKC, Lai PCW. Use of metoclopramide for the treatment of gastroesophageal reflux in infants and children. Curr Ther Res 1984;36:911-5. 16. Hyams JS, Leichtner AM, Zamett LO, Waiters JK. Effect of metoclopramide on prolonged intraesophageal pH testing in infants with gastroesophageal reflux. J Pediatr Gastroenterol Nutr 1986;5:716-20.