Absent postprandial duodenal motility in a child with cystic fibrosis

GASTROENTEROLOGY 1986;90:1274-9

CASE

REPORTS

Absent Post randial Duodenal Motility in a Child Wit R Cystic Fibrosis Correction of the Symptoms and Manometric Abnormality With Cisapride PAUL E. HYMAN Department of Pediatrics, Harbor-UCLA Medical Center, Torrance, California

A 1%mo-old boy with cystic fibrosis presented with a lifelong history offeeding problems and constipation, and an 8-mo history of episodes of repeated retching, diaphoresis, dehydration, and somnolence after eating. Tests of esophageal motility and gastric emptying of a 5% glucose meal were normal. Antroduodenal pressure recordings during fasting demonstrated the presence of all phases of the interdigestive motor complex. After consumption of a 240-ml complex liquid meal, however, the contractile pattern that generally accompanies eating was absent and gastric emptying was markedly delayed. When bethanechol or metoclopramide was given 10 min before the complex liquid meal, there was a paucity of contractile activity, gastric emptying was slow, and symptoms of lethargy, diaphoresis, and retching were present. When cisapride was given, there was frequent irregular contractile activity, faster gastric emptying, and no symptoms of lethargy. During the past year treatment with cisapride has been a requirement in order to prevent recurrence of the symptoms. Antroduodenal pressure studies proved helpful in the identification of a treatable manometric abnormality that was associated with symptoms of delayed gastric emptying. Symptoms of intestinal obstruction occur frequently in children with cystic fibrosis. Park and Grand (1) Received March 7, 1985. Accepted October 29, 1985. Address requests for reprints to: Paul E. Hyman, M.D., HarborUCLA Medical Center, 1000 West Carson Street, C-l Trailer, Torrance, California 90509. This research was supported in part by National Institutes of Health General Clinical Research Center grant RR 00425. The author thanks Roxanne Hecht, M.D. and Joan H. Kurtz, M.D. for referral of the patient; William J. Snape, Jr., M.D. for helpful criticism; and Diane Warpack and Rose Thompson for expert secretarial assistance. 0 1986 by the American Gastroenterological Association 0016~5085/86/$3.50

have applied the term “distal intestinal obstruction syndrome” to a spectrum of clinical conditions including (a) abdominal pain due to constipation or fecal impaction, (b) palpable cecal masses, and (c) complete obstruction of the bowel by puttylike fecal material (also known as “meconium ileus equivalent”). The mechanisms responsible for the symptoms probably include inspissated intestinal secretions, decreased pancreatic secretions, undigested food residues, and intraluminal dehydration. Abnormal patterns of gastrointestinal motility may also play a role, but have not been described in patients with cystic fibrosis. This report describes a gastrointestinal motility disorder in a child with cystic fibrosis. The abnormality was apparent only after meals. A new prokinetic drug, cisapride, corrected both the symptoms and manometric evidence of the disorder.

Case Report A 1%mo-old white boy with cystic fibrosis was transferred to Harbor-UCLA Medical Center for evaluation of a gastrointestinal motility disorder. He was born at term; birth weight was 3.2 kg. The first months of his life were complicated by recurrent regurgitation of feedings, colic, and constipation. He required hospitalizations for dehydration secondary to vomiting at 8, 9, and 10 mo of age. During the second admission for dehydration a diagnosis of cystic fibrosis was established, based on a sweat chloride value of 115 mEq/L. Thereafter he was treated with oral pancreatic enzymes and vitamin supplements, and chest physiotherapy. During the third admission vomiting persisted, and total parenteral nutrition was required. The abdomen was distended, and successful spontaneous defecation was infrequent: mineral oil and acetylcysteine (Mucomyst, Mead Johnson & Co., Evansville, Ind.) enemas were administered. Normal gastrointestinal anatomy was shown in radiologic studies that included upper gastrointestinal series with small bowel follow-through and a barium enema with reflux into the terminal ileum. Upper

May 1986

gastrointestinal panendoscopy was normal. Intraesophageal pH monitoring studies demonstrated abnormal periods of gastroesophageal reflux. A trial of medical management for the recurrent emesis, including upright posture after feedings and metoclopramide therapy, was unsuccessful. The patient underwent a Nissen fundoplication and gastrostomy. Within 3 wk oral feedings were initiated, and the patient was discharged. He remained well for 3 wk before returning with the symptoms that were characteristic throughout the remainder of the course. The patient developed repeated retching and gagging, pallor, abdominal distention, intense diaphoresis, and lethargy or somnolence, but without emesis, diarrhea, or altered blood pressure. Episodes persisted for several hours to several days. Laboratory evaluations during these episodes revealed evidence of dehydration, but no abnormalities in serum glucose or amylase. When he was permitted to regulate his own oral intake, the infant remained asymptomatic, but ingested only 50% of his fluid and caloric requirements. When additional enteral feedings were forced by mouth or added through the gastrostomy at mealtimes, the symptoms recurred. The patient was asymptomatic during periods when 100% of his alimentation was provided by a continuous drip through the gastrostomy. Recurring episodes were the basis for 3 mo of hospitalization prior to transfer. The admitting physical examination was remarkable for skin which was intensely diaphoretic and cool. A gastrostomy stoma was apparent, and the remainder of the examination was normal. His weight (11.26 kg), height (81.4 cm], and head circumference (47.7 cm) were all in the 25th percentile for age. Blood pressure was 80150, without postural hypotension. Admission laboratory values were as follows: sodium 139 mEq/L, potassium 3.1 mEq/L, chloride 95 mEq/L, bicarbonate 29 mEq/L, blood urea nitrogen 12 mgidl, creatinine 0.5 mg/dl, glucose 96 mg/dl, and hematocrit 34%. Intradermal injection of histamine resulted in a normal wheal and flare response.

Methods All studies were performed without sedation. Esophageal manometry was performed using a quadruplelumen polyvinyl tube assembly (individual OD 1.2 mm) with pressure-sensing orifices perfused with distilled, deionized water at 0.5 ml/min by a low-compliance pneumatic-hydraulic capillary infusion system with a response of >800 mmHg/s. Pressures were transmitted to transducers (Statham Instruments, Inc., Oxnard, Calif.) connected to an amplifying recording system (Beckman Instruments, Inc., Mountainside, N.J.). The station pull-through technique was used to determine lower esophageal sphincter pressure using the mean pressure obtained from the three distal, radially oriented orifices, which were 1 cm apart. Peristaltic sequences were assessed utilizing the fourth orifice, which was 5 cm above the next proximal port, and the two most distal orifices. The basal and postmeal gastric fractional emptying rate [the percentage of the gastric contents leaving the stomach per minute (%/min)], gastric fluid output (milliliters per kilogram per hour), and gastric acid output (millimoles per

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ABNORMALITY

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kilogram per hour) were determined using a phenol red dye dilution technique previously described and validated (2,3). This technique was modified for studies of infants (4). The meal contained 5% glucose, 15 ml/kg. Antroduodenal motility studies were performed using a triple-lumen polyvinyl tube assembly with orifices 5 cm apart. The water perfusion system was identical to that described above for esophageal manometry. The tube was placed under fluoroscopic guidance so that the proximal port was in the gastric antrum, the middle port in the duodenal bulb, and the distal port in the middle duodenum. Recordings were initiated after a 4-h fast on 4 consecutive days. Fasting recordings were continued for 30-60 min on each day, or until one episode of a migrating activity front was recorded. On successive days the patient received (a) no drug; (b) metoclopramide (Reglan, A.H. Robins, Co., Inc., Richmond, Va.), 10 mg by slow intravenous injection; (c) bethanechol (Urecholine, Merck Sharpe Dohme, Inc., West Point, Pa.), 0.1 mg/kg subcutaneously; and (d) cisapride (Janssen Pharmaceutics, Piscataway, N.J.), 0.1 mg/kg by slow intravenous push. Before the use of cisapride, informed written consent was obtained from the parent, and approval from the Harbor-UCLA Human Subjects Committee and the Food and Drug Administration was granted. Drugs were injected during a period of phase II motor activity that followed phase 1 activity after the migrating activity front. Ensure (Ross Laboratories, Columbus, Ohio) (240 ml) was offered to the infant 10 min after drug injections, and voluntary intake was recorded. The remainder of the feeding was infused by gravity drip through a gastrostomy tube. In all instances, at the time of initiating the feeding, irregular contractile motor activity was present. Fasting motility data analysis included determination of the presence of the interdigestive motor complex, and the different phases comprising the complex (5). The duration of the complete complex was not assessed. The different periods of fasting motility were as follows: phase I, <3 waves >l2 mmHg during a lo-min period; phase II, 23 waves >12 mmHg in 10 min at less than the maximal rate (3imin in the antrum and llimin in the duodenum); and phase III, at least 3 consecutive waves within 1 min in the antrum, and 11 consecutive waves within 1 min in the duodenum. Migration of phase III (the activity front) was defined by the sequential onset of phase III with an interval of 230 s between the proximal and distal recording ports. After the meal a normal “fed pattern” was defined by the same criteria as for phase II. Records were analyzed visually for the recurring patterns of contractile activity that defined the various phases of the interdigestive motor complex.

Results Mean basal lower esophageal sphincter pressure was 14 mmHg; lower esophageal sphincter relaxation with swallows was complete. The amplitude and esophagus

duration of peristaltic were normal.

sequences

in the

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anlrum

proximal

duodenum

I

50mmHg

1

mid Figure

duodenum

1. Antroduodenal by the irregular

manometry contractions

during fasting. Phase III of the migrating myoelectric complex preceding phase III, and phase I by the absence of motility

The basal fractional gastric emptying rate was 12%/min. The fractional emptying rate of the glucose meal was 7%/min. Although there are no studies of fractional gastric emptying rate in normal infants available for comparison with the present study population, fasting fractional gastric emptying rates in studies of healthy adults were 9.5%/min (6), 10% + l%/min (7), and 12.2% ? 2.5%/min (B), with no postcibal delay after clear liquid meals of up to 15% glucose (8). Basal acid output was 0.014 mmolikglh and postmeal acid output was 0.054 mmol/kg/h. Basal secretion was 1.9 ml/kg/h and postmeal secretion was 4.2 ml/kg/h. The interdigestive motor complex, including all phases of activity, was present in the fasting patient (Figure 1). The duration of phase III averaged 3.0 min

-do

is present. Phase II is characterized that follows phase III.

[range 2.0-4.1 min). The rate of migration of phase III averaged 6 cm/min [range 4-17 cmimin). On the first day of the study, the patient received no medication and refused oral feeding. The feeding (240 ml of Ensure) was given via gastrostomy over 10 min beginning 29 min after a migrating activity front, and 6 min after the reappearance of contractile activity. Slowly over the next 30 min the patient became diaphoretic and irritable, and developed abdominal distention, The contractile activity disappeared and there was no evidence of further contractile activity for 1 h after the feeding (Figure 2). After 1 h, 210 ml of fluid was aspirated from the stomach. On the second day of the study, phase II activity had been present for 24 min before the injection of bethanechol. Irregular contractile activity persisted after the

1

I

_J-,.

proximal

.A

duodenum I

Smin

50 mmHg

mid duodenum Figure

2.

Antroduodenal

motility

after a complex

liquid

meal.

There

is no contractile

activity.

MOTILITY ABNORMALITY IN CYSTIC FIBROSIS

May 1986

proximal

duodenum

I

Smin

1277

50 mmHg

mid duodenum Figure

3. Antroduodenal

motility after cisapride

and a complex liquid meal. Postprandial

bethanechol injection and after the voluntary ingestion of 120 ml of the feeding. Four minutes after the oral feeding was complete, an additional 120 ml was added to the stomach. All contractile activity ceased within 2 min after the gastrostomy feeding. The patient developed gagging, diaphoresis, and then became irritable and lethargic 30 min after completion of the gastrostomy feeding. After 1 h, 225 ml of fluid was aspirated from the stomach and his symptoms resolved. On the third day the patient received metoclopramide during phase II, drank 90 ml of the feeding, and was given 150 ml via gastrostomy. There was no contractile activity after feeding. After 1 h, 200 ml of fluid was aspirated from the stomach. On the fourth day the patient received cisapride 38 min after a migrating activity front, during phase II. Irregular contractile activity persisted after cisapride during the fasting period. The patient voluntarily drank 90 ml of the feeding, and then an additional 150 ml of feeding was added to the stomach. Contractile activity occurred during the feeding, and persisted during the 1-h postprandial test period (Figure 3). The patient remained playful and alert. After 1 h, 90 ml of fluid was aspirated from the stomach. Clinical Course Several hours after cisapride infusion the patient developed a diarrhea1 episode characterized by four large watery stools over a 12-h period, but without evidence of fever or malaise. On the day after cisapride infusion the infant was permitted Ensure ad libitum; to assure that fluid requirements were met, oral intake was supplemented with an intravenous infusion. Total voluntary oral intake was 180 ml for five feedings offered over 24 h. On the next day the patient received 0.1

contractile

activity is present.

mg/kg of cisapride orally 30 min before each of the four scheduled feedings. Consecutive voluntary oral intakes were 120, 150, 240, and 240 ml. Intravenous fluids were discontinued and the patient remained asymptomatic, with adequate voluntary oral intake. Bowel movements became soft and regular (one to two times daily), but diarrhea did not recur. The patient was discharged taking 0.1 mg/kg of oral cisapride 30 min before each feeding, to a maximum daily dose of 0.5 mg/kg. During the next 6 mo the patient’s appetite, behavior, and stool patterns were normal for his age, except for three brief trial periods when cisapride was not given. Without cisapride, the patient’s voluntary oral intake decreased immediately, and the characteristic episodes of repeated retching, diaphoresis, dehydration, and somnolence occurred within 24 h. After 6 mo the parents observed the insidious onset of a decrease in voluntary oral intake and a decrease in general activity level. The amount of cisapride was increased to 0.2 mg/kg per dose to a maximum daily dose of 1.0 mgikg. There was an immediate improvement in the severity of symptoms. After 1 yr of treatment, the patient’s weight increased to 14.0 kg and his height increased to 90.8 cm. There has been no laboratory evidence of hepatic, renal, hematopoietic, or cardiovascular abnormality during treatment with cisapride. The patient had no side effects attributable to cisapride. Discussion The pathogenesis of the symptomatic episodes in our patient remained obscure, despite the description and correction of an associated manometric disorder. Several conditions sharing some of the features of our patient’s episodes were considered but ruled out. The vomiting crisis of familial

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HYMAN

dysautonomia includes episodes of repeated retching, diaphoresis, lethargy, and hypertension (9). Our patient was never hypertensive, had a normal response to intradermal histamine, and was not of Askenazai Jewish ancestry. A dumping syndrome following fundoplication in infants is associated with rapid gastric emptying and hyperglycemia (10). Our patient had delayed gastric emptying of the complex liquid meal, no evidence of hyperglycemia, and the symptoms of vomiting and constipation antedated fundoplication. Chronic intestinal pseudoobstruction was excluded based on normal contrast and noncontrast radiologic studies, normal esophageal motility, and normal lower esophageal sphincter relaxation (11,lZ). Antroduodenal manometry studies were initiated to continue the evaluation, although there are no studies of antroduodenal motility in normal, similarly aged children, or in children with cystic fibrosis for comparison. In studies of healthy term infants, all phases of the migrating motor complex were recorded (13,14). After feeding, the neonates had irregular motor activity typical of the adult postprandial pattern (13), as well as nonmigrating repetitive contractile activity (14). Based on these observations it would appear that antroduodenal motor activity in the term neonate is qualitatively similar to that of the adult both during fasting and after feeding. In our patient, all phases of the migrating motor complex were present during fasting. After finding absent postprandial motor activity, we unsuccessfully attempted to stimulate contractions with bethanechol and metoclopramide, two agents that stimulated motor activity in earlier studies (15). Cisapride, which has recently been shown to stimulate antroduodenal contractions in adults (16), both stimulated contractions and alleviated the symptomatic episodes in our patient. It is possible that the absence of postcibal contractions was the result of a maturational delay that improved coincidently with cisapride treatment. This possibility seems unlikely, however, because on three occasions in the past 8 mo, failure to provide continuous treatment with cisapride resulted in the return of symptoms. It is attractive to speculate a role for the patient’s primary disorder, cystic fibrosis, in the pathogenesis of the motility disorder. In normal adults the gastric emptying of liquids is determined by the pressure gradient between the stomach and duodenum, as the gastric fundus increases tonic contraction after a meal (17). Duodenal receptors sensitive to acid, osmolarity, and fatty acids appear to modulate the emptying of liquids by inhibiting the tonic contraction of the fundus (18,19). In cystic fibrosis, gastric acid secretion is normal (20) or high (21), but bicarbonate secretion from the pancreas is impaired (22),

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so that the duodenal pH may remain low as the meal empties. The luminal digestion of fats is impaired, secondary to the pancreatic insufficiency of cystic fibrosis (23), resulting in a high concentration of luminal fatty acids. Finally, the unstirred water layer thickness is significantly decreased in cystic fibrosis (24) so that diffusion barriers to the acid, osmolarity, and fatty acid-sensitive receptors are reduced. One possibility to explain the patient’s disorder is that the aforementioned features of cystic fibrosis resulted in an exaggerated feedback inhibition of gastric emptying. Earlier studies of asymptomatic infants (25) and children (26) with cystic fibrosis did not find abnormalities in the gastric emptying of complex liquid meals. The role of postprandial duodenal contractile activity in the emptying of liquids is not clear. In dogs, fundic distention resulted in the disappearance of intestinal cyclic motor activity and the appearance of continuous irregular activity (27). In adults, duodenal contractile activity increased only transiently after fat and acid liquid meals, and not after saline (28). In our patient, symptoms were associated with the absence of contractile activity, and abated when contractile activity was stimulated. It is possible that in adults, nonpropagated contractile activity may increase intraduodenal pressure, thus decreasing the gastroduodenal pressure gradient and slowing gastric emptying. In our patient, the contractions appeared to be propagated caudally. Peristaltic contractions might act to empty the duodenum, increase the pressure gradient, and thus speed gastric emptying. Cisapride facilitates acetylcholine release from myenteric neurons, without antidopaminergic or cholinomimetic effects. In adults cisapride increased antroduodenal motility (16) and improved gastric emptying (29). Similarly, in our patient cisapride stimulated antroduodenal contractile activity and eliminated the symptoms associated with absent postprandial contractions. Additionally, cisapride improved the chronic constipation that had been present since infancy. Cisapride appears to be safe and effective in this patient, and may prove to be a useful pharmacologic agent in the treatment of other patients with gastrointestinal motility disorders. It must be emphasized that no conclusion can be drawn concerning the pathogenesis of our patient’s symptoms. The observations that temporally link the symptoms to the absence of postprandial motor activity, and the absence of symptoms to the presence of a fed-state pattern, do not prove causality. Moreover, the findings in this single case may not be applicable to others. However, this study should stimulate further exploration of the potential usefulness of antroduodenal motility studies in children.

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