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Ultrasound measurement of gastric emptying time in patients with cystic fibrosis and effect of ranitidine on delayed gastric emptying
Ultrasound measurement of gastric emptying time in patients with cystic fibrosis and effect of ranitidine o n delayed gastric emptying S. Cucchiara, MD, V. Raia, MD, R. Minella, MD, T. Frezza, MD, B. De Vizia, MD, and G. D e Ritis, MD From the Department of Pediatrics, University of Naples "Federico I1,'" Naples, Italy
Intestinal dysmotility is commonly reported in patients with cystic fibrosis (CF); however, gastric motor activity has rarely been investigated. We measured with real-time ultrasonography the antral distention and gastric emptying time of a solid-liquid meal in 29 patients with CF (age range, 5 to 17 years). A significantly prolonged gastric emptying time was present in 26 patients compared with 13 healthy control subjects (age range, 5 to 16 years); an exaggerated antral distention in the fed period was also detected. The patients with CF and delayed gastric emptying were randomly allocated to receive cisapride or ranitidine for 4 weeks. Twelve patients treated with ranitidine and 11 with cisapride completed the trial. There was a marked decrease in gastric emptying time, antral distention, and dyspeptic symptomatic score in patients receiving ranitidine but not in patients treated with cisapride. We conclude that gastric dysmotility is commonly detected in patients with CF and that H2 receptor blockers are more effective than prokinetics in improving dyspeptic symptoms and gastric emptying and distention. (J PEDIATR1996; 128:485-8) Symptoms and signs of intestinal dysmotility have occasionally been reported in patients with cystic fibrosis; these range from gastroesophageal reflux to intestinal pseudoobstructive events. 16 The latter are included in the so-called distal intestinal obstructive syndrome, characterized by a history of abdominal pain with fecal impacUon, subocclusive episodes, or both. 7 The successful use of cisapride, a prokinetic agent that enhances intestinal motor activity, in subjects with CF suggests that gastrointestinal motility can be deranged in these patients. 5-9
In this study we measured gastric distention and gastric emptying time of a mixed sofid-fiquid meal in a patient population with CF; patients with documented gastric emptying delay underwent a therapeuUc trial by comparing the prokinetic drug cisapride with ranitidine, an antagonist of the H2 receptors.
Presented in abstract form at the Fourth Joint Meeting of the North Arnerican Society for Pediatric Gastroenterology and Nutrition and the European Society for Paedialfic Gastroenterology and Nutriuon, Houston, Tex., Oct. 10-12, 1994. Submitted for publication Aug. 9, 1995; accepted Dec. 27, 1995. Reprint requests: Salvatore Cucchiara, MD, Department of Pediatrics, Gastrointestinal Motility and Endoscopy Unit, University of Naples "Federico II," Via S.Pansini 5, 80131 Napoli, Italy. Copyright © 1996 by Mosby-Year Book, Inc. 0022-3476/96/$5.00 + 0 9/20/71607
[
METHODS
In 29 patients with CF (16 gids; median age, 10.2 years; range, 5 to 17 years), gastric emptying time of a solid-liquid CF
Cysticfibrosis
[
mixed meal was measured by ultrasonography of the stomach. In all patients, the diagnosis of CF had been established through a previous positive sweat test result (sweat chloride determination, >70 rnmot/L) and the presence of typical clinical symptoms and signs. Patients entering into the study had not exhibited severe clinical features of intestinal dysmotility, such as obstruction or distention; however, dys-
485
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Cucchiara et al.
The Journal of Pediatrics April 1996
Table I. Gastric emptying time and antral area distention
Table II. Symptomatic score and gastric motility
in patients with cystic fibrosis and in control subjects
variables in cystic fibrosis patients treated with ranitidine or cisapride
Gastric emptying time* (min) Distention of antral areat At 60 min after feeding* At 90 min after feeding*
Patients with CF
Control subjects
240 (180-295)
140 (110-180)
222 (135-660) 197 (120-380)
I00 (40-150) 60 (35-130)
Values are expressedas median values (ranges). *p <0.01 betweenpatientsand controlsubjects. tPercentage of increasein comparisonwith baseline. peptic symptoms were recorded in most. Drugs affecting gastrointestinal motility and gastric acid secretion had not been administered for at least 3 weeks before the study. Most patients had pancreatic insufficiency as documented by steatocrit,10 and all were receiving oral pancreatic enzyme supplement with meals. Steatocrit, determined through microcentrifugation of fecal homogenate before patients were enrolled into the study ranged from 1.9% to 19%. 1° No significant episodes of pulmonary infections were detected, and patients with severe pulmonary dysfunction were excluded (maximal mid-expiratory flow rate, <40% of the predicted value). After an ovemight fast, all patients underwent measurement of gastric emptying time with real-time ultrasonography according to a technique previously described. TM12 U1trasonography of the gastric antrum was carried out both in the fasting state and every 15 minutes after a solid-liquid meal was ingested (bread, butter, ham, fruit juice). Distention of the antral area was also calculated 60 and 90 minutes after feeding and was measured as a percentage increase compared with the baseline value. Gastric emptying time and antral area distention were compared with those detected in 13 age-matched healthy control subjects (age range, 5 to 16 years; median age, 10.0 years) who had never exhibited clinieal features of intestinal dysmotility. Patients with delayed gastric emptying were randomly allocated to receive cisapride, 0.6 mg/kg per day three times a day 15 minutes before meals, or ranitidine, 10 mg/kg per day twice a for 4 weeks. Severity of dyspeptic symptoms (vomiting or regurgitation, or both, epigastric or mesogastric pain, fullness, early satiety) was,scored (0 to 6) on a weekly basis. Parents were instructed to fill in a weekly diary listing symptoms during the 2 weeks preceding the study and during drug treatment. Gastric ultrasonography was performed at baseline and at the end of the trial, during the last day of drug administration. Statistical comparisons were performed with nonparametric tests (signed rank test), with p less than 0.05 considered significant. Values were given as the median and ranges.
Ranitidine group Clinical score Pretrial 17.0 (14-22) Posttrial 8.0 (6-16)* Gastric emptying time (min) Pretrial 240 (195-285) Posttrial 172 (135-210)* Distention of antral area-~ At 60 min after feeding Pretrial 255 (135-600) Posttrial 157 (120-450)* At 90 min after feeding Pretrial 262 (120-300) Posttrial 155 (80-220)*
Cisapride group 18.0 (16-22) 13.0 (6-20)t 240 (195-270) 210 (165-255)t
225 (190-660) 200 (110-450)? 200 (170-380) 190 (130-260)t
Values are expressedas medianvalues (ranges). *p <0.01 versus pretrialvalues. tNot significantversus pretrialvalues. SPercentageof increasein compafisonwith baseline.
Coefficients of correlation between gastfic ultrasound variables (emptying time, distention) and clinical dyspeptic score were also calculated. Written informed consent was obtained from patents, and the protocol was approved by the ethical committee of our department.
RESULTS Gastric emptying time was significantly delayed in patients with CF in comparison with control subjects; distention of the antral area (percentage of increase compared with baseline value) was markedly higher in patients with CF both 60 and 90 minutes after feeding, in comparison with control subjects (Table I). Twenty-six patients with CF had a gastric emptying time beyond the range of values measured in the control subjects; these patients were randomly allocated to receive either cisapride or ranitidine for 4 weeks. Of the three patients with CF and normal gastric emptying time, two had a low steatocrit value (1.7%, 2.6%); steatocrit value in the third paüent suggested pancreatic insufficiency (11.5%). Only two patients with delayed gastric emptying had a low steatocrit value. The trial was completed with 23 patients, 12 receiving ranitidine and 11 receiving cisapride. The two groups were comparable in age (ranitidine group: 9.5 years; range, 7 to 16; cisapride group: 10.8 years; range, 8 to 16), as well as in steatocrit values (ranitidine group: 8.0%; range, 2.3% to 18%; cisapride group: 7.4%; range, 1.9% to 19%) and enzyme supplementation. Posttreatment results are reported in Table II. Gastric emptying time significantly decreased only in the ranitidine
The Journal of Pediatrics Volume 128, Number 4
group. Distention of the antral area 60 and 90 minutes after feeding was markedly reduced in the patients receiving ranitidine but not in the cisapride group. The symptomatic dyspeptic score showed a significant decrease only in patients receiving ranitidine. In the two groups of patients the basal symptomatic score correlated significantly with antral distention (coefficient of correlation: at 60 minutes in the ranitidine group, 0.66, and in the cisapride group, 0.65 [p <0.01 ]; at 90 minutes in the ranitidine group, 0.71 Ip <0.01], and the cisapride group, 0.57 Ip <0.05]); there was no significant correlation between symptomatic score and gastric emptying time (coefficient of correlation: ranitidine group, 0.17; cisapride group, 0.30 [not significant]). DISCUSSION
This study shows that gastric motor abnormalities such as delayed gastric emptying and exaggerated postfeeding antral distention can be found in a high proportion of patients with CF. Gastric motility was assessed through real-time ultrasonography, a recently introduced and validated tool for studying the gastric motor profile. TM13, 14 Previous reports on patients with CF had shown a normal gastric emptying time of liquid meals. 15, 16 Gastric emptying time is commónly believed to be accelerated in patients with exocrine pancreatic insufficiency, 17, 18In these studies, however, only emptying of liquids had been assessed, and gastric emptying was measured with the double sampling method, an invasive technique requiring nasogastric intubation. 19 This might explain the different results shown in out study, that is, the presence of gastroparesis in the majority of the CF patients investigated. Previous reports, mainly based on therapeutic observations, tend to support the view that intestinal motility can be deranged at various levels in patients with CF. 3 Administration of cisapride, a prokinetic agent capable of accelerating gastric emptying, has been shown to be associatedwith an increased caloric intake and weight gain in patients with CF. 9 Hyman 5 described postprandial antroduodenal hypomotility in a child with CF, documented by manometry and responsive to cisapride, 5 The author speculated that in CF an exaggerated feedback inhibition of gastric motility and emptying might be due to the high concentration of undigested fat in the duodenum because of impaired luminal digestion. The latter results both from low duodenal pH caused by reduced pancreatic secrefion of bicarbonate and from exocrine pancreatic insufficiency. 2° Various types of chemoreceptors in the duodenojejunal tract play a role in the feedback inhibition of gastric motility: lipid receptors, 21 osmoreceptors, 22 receptors for amino acids, 21 glucoreceptors, 23 and pH receptors. 24 Experimental evidence indicates that when a fatty solution is infused into the duodenojejunal lumen, the gastric fundus relaxes, antral motility is suppressed, and an in-
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creased pyloric activity occurs; these phenomenon result in slowing of the flow from the stomach to the duodenum. 25, 26 It is also possible that malabsorbed rat reaches the distal jejunum and the ileum, causing a marked inhibition of upper gut motility and gastric emptying through a reflex event known as ileal brake. This mechaism regulates gastric transit and gastroduodenal motility by the distal jejunum and the ileum perfused with a fat solution. 27,28 Changes in upper gut motility because of the presence of lttminal nutrients in the distal ileum seem to be mediated by increased plasma levels of neuropeptides known to affect gastrointestinal motor activity:28, 29 These observations coincide with the results of our study: detection of gastroparesis and abnormal distention in the majority of patients with CF and the superiority of ranitidine in comparison with cisapfide in reversing abnormal gastric motility. It is conceivable that ranitidine, by improving fat digestion through an increased duodenal pH, might counteract feedback inhibifion of gastric emptying caused by undigested lipid. Historically, treatment aimed at inhibiting gastric acid secretion has been used in patients with CF to improve fat absorption.30, 31 Excessive gastric acid secretion occurring in CF and inadequate secretion of bicarbonate can reduce the intraluminal duodenal pH. 32 If the latter drops to a value of less than 5.0, pancreatic lipase, trypsin, and amylase activity is decreased. Furthermore, at a low intraduodenal pH, glycine-conjugated bile salts will precipitate spontaneously; this reduces their availability for rat solubilization and micelle formation, which contributes to fat malabsorption. 33 Successful use of enzyme replacement therapy in pancreatic insufficiency depends considerably on intraluminal pH.34 Once ingested, irreversible acid inactivation of lipase occurs if the intraluminal pH of the stomach or upper small bowel is less than 4.0; furthermore, enteric-coated enzyme microspheres, even if protected against inactivation at low gastric and duodenal pH, require an alkaline pH for their dissolution. 35 Out study indicates that H2 receptor blockers can normalize gastric emptying time in patients with CF. This effect is of benefit in these patients because gastroparesis can worsen malnutfition by leading to gastric retention and dyspepsia. In this regard, improved gastric motility in patients receiving ranitidine was associated with a significant decrease in the dyspeptic symptomatic score. In our patients the symptomatic score significantly correlated with antral distention but not with gastric emptying time. This finding is not surprising, because previous observations in dyspeptic adults have shown a strong correlation between dyspeptic symptoms and antral distention. 36 Other studies indicate that patients with dyspepsia exhibit sensitivity of the upper gut to intraluminal stimuli such as distention. 37 We conclude that in a high proportion of patients with CF,
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delayed gastric emptying and excessive antral distention occur, accompanied by dyspeptic symptoms. Therapy with H2 receptor antagonists is more effective than promotility agents in achieving normal gastric motility and in improving related symptoms. It is suggested that in patients with CF, disturbed intraluminal digestion is the most likely mechanism of gastric dysmotility, rather than a primary motor disorder. REFERENCES
1. Park RW, Grand PO. Gastrointestinal manifestation of cystic flbrosis: a review. Gastroenterology 1981;81;1143-61. 2. Cucchiara S, Santamafta F, Andreotti MR, et al. Mechanisms of gastroesophageal reflux in children with dystic fibrosis. Arch Dis Child 1991;66:617-22. 3. Durie PR. Gastrointestinal motility disorders in cystic fibrosis. In: Milla PJ, ed. Disorders of gastrointestinal motility in childhgod. Sussex, England: John Wiley & Sons, 1988:91-9. 4. Ball A, Stableforth DE, Asquith P. Prolonged small-intestinal transit time in patients with cystic fibrosis. BMJ 1983; 287:1011-3. 5. Hyman PE. Absent postprandial duodenal motility in a child with cystic fibrosis: correlation of the symptoms and manometric abnormalities with cisapride. Gastroenterology 1986; 90:1274-9. 6. Koletzko S, Corey M, Ellis L, Spino M, Stringer DA, Dufte PR. Effects of cisapftde in patients with cystic fibrosis and dis: tal intestinal obstmction syndrome. J PêDtATR 1990; 117:81522. 7. Khoshoo V, Udall JN. Meconium ileus equivalent in children and adults. Am J Gastroenterol 1994;89:153-7. 8. Edwards CA, Holden S, Brown C, Read NW. Effect of cisapride on the gastrointesünal transit of a solid meal in a normal human subject. Gut 1987;28:13-6. 9. Prinsen JE, Thomas M. Cisapride in cystic fibrosis. Lancet 1985;1:512-3. 10. Colombo C, Maiavacca R, Ronchi M, Consalvo E, Amoretti M, Giunta A. The steatocrit: a simple method for monitoring fat malabsorption in patients with cystic fibrosis. J Peeatr Gastroenterol Nutr 1987;6:926-30. 11. Bolondi L, Bortolotti M, Santi V, Calletti T, Gaiani S, Labò G. Measurement of gastric emptying time by real-time ultrasonography. Gastroenterology 1985;89:752-9. 12. Cucchiara S, Riezzo G, Minella R, Pezzolla F, Giorgio I, Auricchio S. Electrogastrography in non-ulcer dyspepsia. Arch Dis Child 1992;67:613-7. 13. Bateman DN, Whittingham TA. Measurement of gastric emptying by real-time ultrasound. Gut 1982;23:524-7. 14. Ricci R, Bontempo I, Corazziari E, La Bella A, Torsoli A. Real-time ultrasonography of the gastric antrum. Gut 1993; 34:173-6. 15. Roulet M, Weber AM, Paradis Y, et al. Gastric emptying and lingual lipase activity in cystic flbrosis. Pediatr Res 1980; 14:1360-2. 16. Cavell B. Gastric emptying in infants with cystic fibrosis. Acta Pediatr Scand 1981;70:635-8. 17. Moberg S, Carlsberg G. Gastric emptying in healthy subjects and in patients with various malabsorptive states. Scand J Gastroenterol 1974;9:17-21.
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18. Long WB, Weiss JB. Rapid gastric emptying of fatty meals in pancreatic insufficiency. Gastroenterology 1974;67:920-5. 19. Heading RC. Methods based on gastric intubation: x-ray and ultrasound imaging methods--indirect techniques. In: Akkermans LMA, Johnson AG, Read NW, eds. Gastric and gastroduodenal motility. Eastboume, United Kingdom: Praeger Special Studies, 1984: 131-47. 20. Kopelman H, Corey M, Gaskin K, Dufte P, Weizman Z. Impalred chloride secretion, as well as bicarbonate secretion, underlies the fluid secretory defect in the cystic fibrosis pancreas. Gastroenterology 1988;95:349-55. 21. Cooke AR. Control of gastric emptying and motility. Gastroenterology 1975;68:804-16. 22. Thompson DG, Wingate DL. Effects of osmoreceptor stimulation on human duodenal motor activity. Gut 1988;29:173-80. 23. Lin HC, Doty JE, Ready TJ. Inhibition of gastric emptying by glucose depends on length ofintestine exposed to nutrients. Am J Physiol 1989;256:404-11. 24. Hunt JN, Knox MT. The slowing of gastric emptying by nine acids. J Physiol 1969;201:161-79. 25. Dooley CP, Reznick JB, Valenzuela JE. Variations in gastric and duodenal motility during gastric emptying of liquid meals in humans. Gastroenterology 1984;87:1114-9. 26. Azpiroz F, Malagelada JR. Intestine control of gastric tone. Am J Physiol 1985;249:501-9. 27. Keinke O, Ehrlein HJ. Effect of oleic acid on canine gastroduodenal motility, pyloric diameter and gastric emptying. Q J Exp Physiol 1983;68:675-86. 28. Spiller RC, Trotman IF, Higgins BE, et al. The ileal-brake inhibition of jejunal motility after ileal fat perfusion in man. Gut 1984;25:365-74. 29. Spiller RC, Trotman IF, Adrian TE, Bloom SR, Misiewicz JJ, Silk DBA. Further characterization of the "ileal brake" reflex in man: effect of ileal infusion of partial digests of fat, protein, and starch on jejunal motility and release of nenrotensin, enteroglucagon, and PYY. Gut 1988;29:1042-51. 30. Dufte PR, Bell L, Linton W, et al. Effect of cimetidine and sodium bicarbonate on pancreatic replacement therapy in cystic flbrosis. Gut 1980;21:778-86. 31. Heijerman HG. Omeprazole enhances the efficacy of pancreatin in cystic fibrosis. Ann Intern Med 1991;114:200-1. 32. Cox KL, Isenberg JN, Ament ME. Gastric acid hypersecretion in cystic fibrosis. J Pediatr Gastroenterol Nutr 1982;16:554-7. 33. Zentler-Murtro PL, Fine DR, Batten JC, Northfield TC. Effect of cimetidine on enzyme inactivation, bile acid precipitation and lipid solnbilisation in pancreatic steatorrhea due to cystic fibrosis. Gut 1985;26:892-901. 34. Bruno MJ, Rauws EAJ, Hoek FJ, Tytgat GNJ. Comparative effects of adjuvant cimetidine and omeprazole during pancreatic enzyme replacement therapy. Dig Dis Sci 1994;39:988-92. 35. Dutta SK, Hubbard VS, Appler M. Critical examination of therapeutic efflcacy of pH-sensitive enteric-coated pancreatic enzyme preparation in treatment of exocrine pancreatic insufficiency secondary to cystic flbrosis. Dig Dis Sci 1988;33:123744. 36. Ricci R, Buontempo I, Labella A, de Tschudy A, Corazziari E. Dyspeptic symptoms and gastftc antrum distribution: an ultrasonographic study. Ital J Gastroenterol 1987;19:215-7. 37. Troncon LEA, Bennett RJM, Ahluwalia NK, Thompson DJ. Abnormal intragastftc distributio of food during gastric emptying in functional dyspepsia patients. Gut 1994;35:327-32.
Intestinal dysmotility is commonly reported in patients with cystic fibrosis (CF); however, gastric motor activity has rarely been investigated. We measured with real-time ultrasonography the antral distention and gastric emptying time of a solid-liquid meal in 29 patients with CF (age range, 5 to 17 years). A significantly prolonged gastric emptying time was present in 26 patients compared with 13 healthy control subjects (age range, 5 to 16 years); an exaggerated antral distention in the fed period was also detected. The patients with CF and delayed gastric emptying were randomly allocated to receive cisapride or ranitidine for 4 weeks. Twelve patients treated with ranitidine and 11 with cisapride completed the trial. There was a marked decrease in gastric emptying time, antral distention, and dyspeptic symptomatic score in patients receiving ranitidine but not in patients treated with cisapride. We conclude that gastric dysmotility is commonly detected in patients with CF and that H2 receptor blockers are more effective than prokinetics in improving dyspeptic symptoms and gastric emptying and distention. (J PEDIATR1996; 128:485-8) Symptoms and signs of intestinal dysmotility have occasionally been reported in patients with cystic fibrosis; these range from gastroesophageal reflux to intestinal pseudoobstructive events. 16 The latter are included in the so-called distal intestinal obstructive syndrome, characterized by a history of abdominal pain with fecal impacUon, subocclusive episodes, or both. 7 The successful use of cisapride, a prokinetic agent that enhances intestinal motor activity, in subjects with CF suggests that gastrointestinal motility can be deranged in these patients. 5-9
In this study we measured gastric distention and gastric emptying time of a mixed sofid-fiquid meal in a patient population with CF; patients with documented gastric emptying delay underwent a therapeuUc trial by comparing the prokinetic drug cisapride with ranitidine, an antagonist of the H2 receptors.
Presented in abstract form at the Fourth Joint Meeting of the North Arnerican Society for Pediatric Gastroenterology and Nutrition and the European Society for Paedialfic Gastroenterology and Nutriuon, Houston, Tex., Oct. 10-12, 1994. Submitted for publication Aug. 9, 1995; accepted Dec. 27, 1995. Reprint requests: Salvatore Cucchiara, MD, Department of Pediatrics, Gastrointestinal Motility and Endoscopy Unit, University of Naples "Federico II," Via S.Pansini 5, 80131 Napoli, Italy. Copyright © 1996 by Mosby-Year Book, Inc. 0022-3476/96/$5.00 + 0 9/20/71607
[
METHODS
In 29 patients with CF (16 gids; median age, 10.2 years; range, 5 to 17 years), gastric emptying time of a solid-liquid CF
Cysticfibrosis
[
mixed meal was measured by ultrasonography of the stomach. In all patients, the diagnosis of CF had been established through a previous positive sweat test result (sweat chloride determination, >70 rnmot/L) and the presence of typical clinical symptoms and signs. Patients entering into the study had not exhibited severe clinical features of intestinal dysmotility, such as obstruction or distention; however, dys-
485
486
Cucchiara et al.
The Journal of Pediatrics April 1996
Table I. Gastric emptying time and antral area distention
Table II. Symptomatic score and gastric motility
in patients with cystic fibrosis and in control subjects
variables in cystic fibrosis patients treated with ranitidine or cisapride
Gastric emptying time* (min) Distention of antral areat At 60 min after feeding* At 90 min after feeding*
Patients with CF
Control subjects
240 (180-295)
140 (110-180)
222 (135-660) 197 (120-380)
I00 (40-150) 60 (35-130)
Values are expressedas median values (ranges). *p <0.01 betweenpatientsand controlsubjects. tPercentage of increasein comparisonwith baseline. peptic symptoms were recorded in most. Drugs affecting gastrointestinal motility and gastric acid secretion had not been administered for at least 3 weeks before the study. Most patients had pancreatic insufficiency as documented by steatocrit,10 and all were receiving oral pancreatic enzyme supplement with meals. Steatocrit, determined through microcentrifugation of fecal homogenate before patients were enrolled into the study ranged from 1.9% to 19%. 1° No significant episodes of pulmonary infections were detected, and patients with severe pulmonary dysfunction were excluded (maximal mid-expiratory flow rate, <40% of the predicted value). After an ovemight fast, all patients underwent measurement of gastric emptying time with real-time ultrasonography according to a technique previously described. TM12 U1trasonography of the gastric antrum was carried out both in the fasting state and every 15 minutes after a solid-liquid meal was ingested (bread, butter, ham, fruit juice). Distention of the antral area was also calculated 60 and 90 minutes after feeding and was measured as a percentage increase compared with the baseline value. Gastric emptying time and antral area distention were compared with those detected in 13 age-matched healthy control subjects (age range, 5 to 16 years; median age, 10.0 years) who had never exhibited clinieal features of intestinal dysmotility. Patients with delayed gastric emptying were randomly allocated to receive cisapride, 0.6 mg/kg per day three times a day 15 minutes before meals, or ranitidine, 10 mg/kg per day twice a for 4 weeks. Severity of dyspeptic symptoms (vomiting or regurgitation, or both, epigastric or mesogastric pain, fullness, early satiety) was,scored (0 to 6) on a weekly basis. Parents were instructed to fill in a weekly diary listing symptoms during the 2 weeks preceding the study and during drug treatment. Gastric ultrasonography was performed at baseline and at the end of the trial, during the last day of drug administration. Statistical comparisons were performed with nonparametric tests (signed rank test), with p less than 0.05 considered significant. Values were given as the median and ranges.
Ranitidine group Clinical score Pretrial 17.0 (14-22) Posttrial 8.0 (6-16)* Gastric emptying time (min) Pretrial 240 (195-285) Posttrial 172 (135-210)* Distention of antral area-~ At 60 min after feeding Pretrial 255 (135-600) Posttrial 157 (120-450)* At 90 min after feeding Pretrial 262 (120-300) Posttrial 155 (80-220)*
Cisapride group 18.0 (16-22) 13.0 (6-20)t 240 (195-270) 210 (165-255)t
225 (190-660) 200 (110-450)? 200 (170-380) 190 (130-260)t
Values are expressedas medianvalues (ranges). *p <0.01 versus pretrialvalues. tNot significantversus pretrialvalues. SPercentageof increasein compafisonwith baseline.
Coefficients of correlation between gastfic ultrasound variables (emptying time, distention) and clinical dyspeptic score were also calculated. Written informed consent was obtained from patents, and the protocol was approved by the ethical committee of our department.
RESULTS Gastric emptying time was significantly delayed in patients with CF in comparison with control subjects; distention of the antral area (percentage of increase compared with baseline value) was markedly higher in patients with CF both 60 and 90 minutes after feeding, in comparison with control subjects (Table I). Twenty-six patients with CF had a gastric emptying time beyond the range of values measured in the control subjects; these patients were randomly allocated to receive either cisapride or ranitidine for 4 weeks. Of the three patients with CF and normal gastric emptying time, two had a low steatocrit value (1.7%, 2.6%); steatocrit value in the third paüent suggested pancreatic insufficiency (11.5%). Only two patients with delayed gastric emptying had a low steatocrit value. The trial was completed with 23 patients, 12 receiving ranitidine and 11 receiving cisapride. The two groups were comparable in age (ranitidine group: 9.5 years; range, 7 to 16; cisapride group: 10.8 years; range, 8 to 16), as well as in steatocrit values (ranitidine group: 8.0%; range, 2.3% to 18%; cisapride group: 7.4%; range, 1.9% to 19%) and enzyme supplementation. Posttreatment results are reported in Table II. Gastric emptying time significantly decreased only in the ranitidine
The Journal of Pediatrics Volume 128, Number 4
group. Distention of the antral area 60 and 90 minutes after feeding was markedly reduced in the patients receiving ranitidine but not in the cisapride group. The symptomatic dyspeptic score showed a significant decrease only in patients receiving ranitidine. In the two groups of patients the basal symptomatic score correlated significantly with antral distention (coefficient of correlation: at 60 minutes in the ranitidine group, 0.66, and in the cisapride group, 0.65 [p <0.01 ]; at 90 minutes in the ranitidine group, 0.71 Ip <0.01], and the cisapride group, 0.57 Ip <0.05]); there was no significant correlation between symptomatic score and gastric emptying time (coefficient of correlation: ranitidine group, 0.17; cisapride group, 0.30 [not significant]). DISCUSSION
This study shows that gastric motor abnormalities such as delayed gastric emptying and exaggerated postfeeding antral distention can be found in a high proportion of patients with CF. Gastric motility was assessed through real-time ultrasonography, a recently introduced and validated tool for studying the gastric motor profile. TM13, 14 Previous reports on patients with CF had shown a normal gastric emptying time of liquid meals. 15, 16 Gastric emptying time is commónly believed to be accelerated in patients with exocrine pancreatic insufficiency, 17, 18In these studies, however, only emptying of liquids had been assessed, and gastric emptying was measured with the double sampling method, an invasive technique requiring nasogastric intubation. 19 This might explain the different results shown in out study, that is, the presence of gastroparesis in the majority of the CF patients investigated. Previous reports, mainly based on therapeutic observations, tend to support the view that intestinal motility can be deranged at various levels in patients with CF. 3 Administration of cisapride, a prokinetic agent capable of accelerating gastric emptying, has been shown to be associatedwith an increased caloric intake and weight gain in patients with CF. 9 Hyman 5 described postprandial antroduodenal hypomotility in a child with CF, documented by manometry and responsive to cisapride, 5 The author speculated that in CF an exaggerated feedback inhibition of gastric motility and emptying might be due to the high concentration of undigested fat in the duodenum because of impaired luminal digestion. The latter results both from low duodenal pH caused by reduced pancreatic secrefion of bicarbonate and from exocrine pancreatic insufficiency. 2° Various types of chemoreceptors in the duodenojejunal tract play a role in the feedback inhibition of gastric motility: lipid receptors, 21 osmoreceptors, 22 receptors for amino acids, 21 glucoreceptors, 23 and pH receptors. 24 Experimental evidence indicates that when a fatty solution is infused into the duodenojejunal lumen, the gastric fundus relaxes, antral motility is suppressed, and an in-
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creased pyloric activity occurs; these phenomenon result in slowing of the flow from the stomach to the duodenum. 25, 26 It is also possible that malabsorbed rat reaches the distal jejunum and the ileum, causing a marked inhibition of upper gut motility and gastric emptying through a reflex event known as ileal brake. This mechaism regulates gastric transit and gastroduodenal motility by the distal jejunum and the ileum perfused with a fat solution. 27,28 Changes in upper gut motility because of the presence of lttminal nutrients in the distal ileum seem to be mediated by increased plasma levels of neuropeptides known to affect gastrointestinal motor activity:28, 29 These observations coincide with the results of our study: detection of gastroparesis and abnormal distention in the majority of patients with CF and the superiority of ranitidine in comparison with cisapfide in reversing abnormal gastric motility. It is conceivable that ranitidine, by improving fat digestion through an increased duodenal pH, might counteract feedback inhibifion of gastric emptying caused by undigested lipid. Historically, treatment aimed at inhibiting gastric acid secretion has been used in patients with CF to improve fat absorption.30, 31 Excessive gastric acid secretion occurring in CF and inadequate secretion of bicarbonate can reduce the intraluminal duodenal pH. 32 If the latter drops to a value of less than 5.0, pancreatic lipase, trypsin, and amylase activity is decreased. Furthermore, at a low intraduodenal pH, glycine-conjugated bile salts will precipitate spontaneously; this reduces their availability for rat solubilization and micelle formation, which contributes to fat malabsorption. 33 Successful use of enzyme replacement therapy in pancreatic insufficiency depends considerably on intraluminal pH.34 Once ingested, irreversible acid inactivation of lipase occurs if the intraluminal pH of the stomach or upper small bowel is less than 4.0; furthermore, enteric-coated enzyme microspheres, even if protected against inactivation at low gastric and duodenal pH, require an alkaline pH for their dissolution. 35 Out study indicates that H2 receptor blockers can normalize gastric emptying time in patients with CF. This effect is of benefit in these patients because gastroparesis can worsen malnutfition by leading to gastric retention and dyspepsia. In this regard, improved gastric motility in patients receiving ranitidine was associated with a significant decrease in the dyspeptic symptomatic score. In our patients the symptomatic score significantly correlated with antral distention but not with gastric emptying time. This finding is not surprising, because previous observations in dyspeptic adults have shown a strong correlation between dyspeptic symptoms and antral distention. 36 Other studies indicate that patients with dyspepsia exhibit sensitivity of the upper gut to intraluminal stimuli such as distention. 37 We conclude that in a high proportion of patients with CF,
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delayed gastric emptying and excessive antral distention occur, accompanied by dyspeptic symptoms. Therapy with H2 receptor antagonists is more effective than promotility agents in achieving normal gastric motility and in improving related symptoms. It is suggested that in patients with CF, disturbed intraluminal digestion is the most likely mechanism of gastric dysmotility, rather than a primary motor disorder. REFERENCES
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