Volume 11
`Number 2
`August
`1990
`
`12 Internationaljournal ofClinical, Experimental, and Developmental Investigations
`
`145
`
`147
`
`Editorials
`Breast Milk Jaundice Margit Hamosh
`
`Toward an Appreciation of Ophthalmology
`1n Pediatric Gastroenterology Gary Diamond
`
`205 A Study of the Relationship between Bile
`Salts, Bile Salt-Stimulated Lipase, and Free
`Fatty Acids in Breast Milk: Normal Infants
`and Those with Breast Milk Jaundice
`
`‘
`‘.
`‘
`
`J. S. Forsyth, L. Donnet, and P. E. Ross
`
`astroenterology
`and Nutntlon
`
`(Complete Contents Inside)
`
`Progress Report
`
`The Pathophysiological Basis for Viral
`Diarrhea: A Progress Report
`J. Richard Hamilton
`
`Reviews
`
`Pathophysiology and Dietary Treatment of
`the Glycogen Storage Diseases
`Shimon W. Moses
`
`Food, Mucosal Immunity, and IgA
`Nephropathy S. Kolacek, I. W. Booth, and
`C. M. Taylor
`
`Original Articles
`
`Visceral Neuropathies Responsible for
`Chronic Intestinal Pseudo-Obstruction
`Syndrome in Pediatric Practice: Analysis of
`26 Cases J. Navarro, E. Sonsino, N. Boige,
`B. Nabarra, L. Ferkadji,
`L. M. N. Mashako, and J. P. CezardR—
`
`Intestinal Giardiasis Associated with
`Ophthalmologic Changes
`M. Pettoello Mantovani, I. Giardino,
`A- Magli, L. di Martino, and S. GuandaliniR‘—
`
`Immunogenicity of Haemophilus influenzae
`Type B Vaccines in Children with
`Hf’l’flt0portoenterostomies Philip Rosenthal,
`Victor Wong, Lawrence A. Ross, and
`[Wang Sik Kim
`
`Measurement of Gastrointestinal pH and
`Regional Transit Times in Normal Children
`Jan Fallingborg, Lisbet A. Christensen,
`Margrethe Ingeman—Nielsen,
`Bent A. Jacobsen. Kirsten Abildgaard,
`Henrik H. Rasmussen, and
`Sten Narbv Rasmussen
`
`Serum Antibodies to Dietary Antigens: A
`Prospective Study of the Diagnostic
`Usefulness in Celiac Disease of Children
`
`Helge Scott, Johan Ek, Jacob Havnen,
`Helge Michalsen, Leif Brunvand,
`Hans Howlid, and Per Brandtzaeg
`
`Acetylcholinesterase-Stained Suction Rectal
`Biopsies in the Diagnosis of Hirschsprung’s
`Disease Deborah E. Schofleld,
`William Devine, and Eduardo J. Yum’s
`
`Variation in Macronutrients in Human Bank
`
`Milk: Influencing Factors and Implications
`for Human Milk Banking
`Kim Fleischer Michaelsen, Lisbeth Skafte,
`Jens Henrik Badsberg, and
`Merete Jorgensen
`
`Acceptability, Tolerance, and Nutritional
`Value of a Rice-Based Infant Formula
`Arturo Gastafiaduy, Angel Cordano, and
`George G. Graham
`
`KVK-TECH EXHIBIT 1040
`
`

`

`Journal of Pediatric Gastrocmerology and Nuiriiion
`11:211—214 ’6 1990 Raven Press, Ltd. New York
`
`Measurement of Gastrointestinal pH and Regional Transit
`Times in Normal Children
`
`Jan Fallingborg, Lisbet A. Christensen, *Margrethe Ingeman—Nielsen,
`Bent A. Jacobsen, Kirsten Abildgaard, Henrik H. Rasmussen, and
`Sten N¢rby Rasmussen
`
`Department of Medical Gastromzreroiogy and *Deparrmem ol'Diagnostic Radiology, Aalborg Hospital North.
`Aalborg. Denmark
`
`
`
`intestinal
`Summary: Gastrointestinal pH and regional
`transit
`times of a capsule were measured in twelve
`healthy Children aged 8—14 years using a radiotransmitting
`pH-sensitive capsule. The location of the capsule was
`determined by fluoroscopy. pH in the stomach was 1.5.
`but rose to 6.4 in the duodenum (mean values). pH grad-
`ually rose in the small intestine and reached an alkaline
`peak value of 7.4 in the distal part. pH dropped to 5.9 in
`the cecum but rose to 6.5 in the rectum. Median gastric
`residence time of the capsule was 1.1 h. Small intestinal
`
`
`transit time was 7.5 h. and colonic transit time was 17.2 h.
`pH profile and intestinal transit times found in the present
`study are almost identical to values found in studies on
`healthy adults. It is therefore concluded that the release
`pattern of pH-dependent sustained-release tablets in chil-
`dren is likely to be equal to that of adults. Key Words:
`Gastrointestinal pH—Gastrointestinal
`transit
`time—
`Small
`intestinal
`transit
`time—Colonic transit time—
`Children.
`
`Several new tablets developed for the treatment
`of chronic inflammatory bowel diseases and other
`diseased conditions are constructed in order to re—
`
`lease their active contents at a rate determined by
`gastrointestinal pH (1—5). Thus. the activity ofthese
`tablets is influenced by gastrointestinal pH and the
`transit times of the tablet through the different seg-
`ments of the gut. Although these factors have been
`investigated in adults (6—9). information concerning
`children is scarce. and important differences may
`exist.
`
`The development of small. radiotransmitting. pH—
`sensitive capsules (10—12) has provided a method
`that enables determination of intestinal pH under
`almost physiological conditions. The transit times
`of the capsule through the gut can be measured by
`repeated determinations of the location of the cap-
`sule by fluoroscopy.
`
`The purpose of this study was to determine the
`pH profile of the gut and to measure the regional
`intestinal transit times of a capsule in normal chil—
`dren.
`
`MATERIAL AND METHODS
`
`Subjects
`
`We studied 12 healthy children. 5 boys and 7
`girls. aged 8-14 years (median 12 years). All were
`without symptoms of gastrointestinal disease. and
`none received any medical treatment.
`Informed consent from the children and their par-
`ents was obtained. and the study protocol. contain-
`ing an estimate of the amount of radiation expected
`to be used. was approved by the local ethics com-
`mittee.
`
`.1. Fall-
`Address correspondence and reprint requests to Dr.
`ingborg at Department of Medical Gastroenterology. Aalborg
`Hospital North. DK-9000 Aalborg. Denmark.
`
`The pH-sensitive. radiotransmitting capsule used
`(Remote Control Systems. Ltd. London) measured
`
`pH Measurements
`
`211
`
`

`

`212
`
`J. FALLINGBORG ETAL.
`
`24 mm in length and 7 mm in diameter (Fig. I). The
`frequency of transmission changes with the pH of
`the capsule‘s environment. Before use the capsule
`was allowed to stabilize at 37°C for [0—14 h and then
`
`calibrated using pH 1 and pH 9 buffer solutions at
`37°C. Signals from the capsule were detected by an
`antenna and passed to the receiver. Determinations
`were made with the person standing. holding the
`antenna in place for ~15 s.
`
`Localization of the Capsule
`
`The location of the capsule was determined by
`fluoroscopy. An average of 10 s of exposure time
`was used for each determination. The median num-
`
`ber of determinations was 25 (range of [7—32: esti—
`mated maximal surface exposure of I30 mSv).
`When the capsule was located in the small intes—
`tine. a location in the upper left abdominal quadrant
`was designated “proximal." and a location in the
`right
`lower abdominal quadrant was designated
`“distal." The localization of the capsule in the co-
`lon relied upon the identification of bony landmarks
`and gaseous outlines (13).
`
`Study Design
`
`Studies began at 8 am on the first test day after a
`minimum fasting period of 8 h. After swallowing an
`untethered capsule. pH was measured every 10—15
`min until the capsule emptied into the duodenum.
`an event marked by an elevation of pH to a value
`above 5. The study subjects continued to fast until
`this had occurred. pH and the location of the cap—
`sule was determined every half hour. until the cap—
`
`llllllllllllllilllilllllllllll
`
`
`
`FIG. 1. The pH capsule.
`
`J Pt'diulr (iuxlrm'nlcml Nulr. Vol. II. No. 2. 1990
`
`sule entered the cecum. The intervals between de-
`
`terminations were then increased to 2 h. If the cap-
`sule had not been passed by ll pm.
`the study
`continued at 8 am on day 2. If the capsule still had
`not been passed by 11 pm on day 2. no further de-
`terminations were performed. All stools were ex-
`amined until the capsule was recovered. Recalibra-
`tion of the capsule was done after recovery, and
`corrections in pH calculations were made for fre-
`quency drift. which may have occurred during the
`study.
`
`The children were not restricted to any dietary
`control either before or during the study.
`
`Data Analysis
`
`Individual median pH values for each segment of
`the gut were calculated. and the Wilcoxon rank test
`for paired data was used to test for differences in
`
`pH between different segments. Significance was
`considered at the 5% level.
`
`RESULTS
`
`All children completed the study. and none com-
`plained of any discomfort that could be related to
`the capsule.
`The pH profile ofthe gut in the children studied is
`shown in Fig. 2. In all subjects. median pH values
`below 3 were found in the stomach. pH rose to a
`mean value of 6.4 in the duodenum and hereafter
`
`
`
`0‘00!9‘00! 9'005
`
`
`
`0'
`St
`
`.
`Du
`
`.
`Pr
`
`.
`MI
`
`.
`DI
`
`.
`Ce
`
`.
`As
`
`...
`Tr
`
`
`
`.
`
`S/R
`
`. D
`Fa
`
`.,
`De
`
`FIG. 2. Gastrointestinal pH profiles (mean : SEM) of the 12
`children studied. Statistical significant differences in pH be-
`tween segments of the gut are shown. St. stomach; Du, du-
`odenum; Pr. proximal small intestine; Mi. mid-small intestine;
`Di. distal small intestine; Ce, cecum; As. ascending colon; Tr.
`transverse colon; De. descending colon; S/Ft, sigmoid colon
`and rectum; Fa. feces.
`
`

`

`GASTROINTESTINAL [211 AND TRANSIT TIMES
`
`213
`
`gradually increased, reaching a peak alkaline value
`of 7.4 in the distal part of the small intestine. pH
`dropped to 5.9 in the cecum, but a significant ten-
`dency towards neutral pH in the left colon was ob-
`served. pH in the sigmoid colon and rectum was
`measured to be 6.5 Fecal pH was 6.4.
`The median gastric residence time ofthe capsule
`was 1.1 h (range of 0.2—2.3 h). Median small intes-
`tinal transit time was 7.5 h (range of 5.1—9.2 h).
`Judged by the number of observations in each seg-
`ment of the small intestine, the capsule was located
`in the duodenum for 8%,
`in the proximal part for
`5%, in the mid part for 12%, and in the distal part for
`75% of the time. Median colonic transit time was
`17.5 h (range of 6.2—54.7 h). For 43% of this time,
`the capsule was located in the cecum.
`
`DISCUSSION
`
`Very few studies on gastrointestinal pH in chil-
`dren have been published. Barbero et al. (14) inves-
`tigated pH in stools and intestinal fluids obtained by
`aspiration technique in infants up to 3 months of
`age. They found median pH levels between pH 6
`and 7 in the small intestine, which corresponds well
`to the levels found in our study. However, Barbero
`et al. found that pH reached an alkaline peak be—
`tween pH 7 and 8 in the cecum before it tended to
`fall in the distal part of the colon. In our study. the
`lowest pH levels were found in the cecum and in the
`right part of the colon. and the levels were ~2 pH
`units lower than the values reported by Barbero et
`al. (14). The diverging results almost certainly are
`due to differences in food consumption and colonic
`bacterial composition between the two different age
`groups of children studied. The gastrointestinal pH
`profile found in the present study corresponds well
`with results obtained in studies on adults (6.7.15).
`In our study, mean fecal pH was 6.4, which is in
`agreement with the results reported by Walker et al.
`(16). They also found that the acidity of feces in
`children could be increased by raising the crude fi—
`ber content in the diet. This effect has also been
`
`demonstrated in adults (17). Supplementation ofthe
`diet with protein, fat. and sugar foods did not sig-
`nificantly change the fecal pH level (16). This indi-
`cates that the acidity of colonic contents and feces
`is caused by bacterial fermentation of nonabsorbed
`carbohydrates such as cellulose. To our knowledge,
`the gastrointestinal transit of a single unit such as a
`tablet or a capsule has not been studied in children.
`In adults,
`it has been shown that one of the most
`
`important factors affecting the gastric residence
`time ofa particle >2 mm is the presence or absence
`of food in the stomach (18). A particle >2 mm taken
`with a meal most often will be retained in the stom-
`
`ach until it is empty of food. In the present study,
`the capsules were taken during a fasting state. and
`the gastric residence time found is almost identical
`to values measured in adults (19). The small intes—
`tinal transit time of7.5 h is considerably longer than
`values reported from other studies using different
`methods (20,21). The value, however, is in accor-
`dance with values in adults. measured with the
`
`same method as used in the present study (6,7). The
`capsule was located in the distal part of the small
`intestine for 75% of the small intestinal transit time,
`which demonstrates that
`the ileo-cecal transit is
`prolonged for larger particles.
`The results of the present study correlate well
`with results obtained from studies in adults. This
`
`indicates that the release pattern of pH-dependent
`sustained-release tablets in children is likely to be
`identical to that of adults.
`
`Acknowledgments: This study was supported by grants
`from the Danish Provincial Bank‘s research foundation,
`merchant L. F. Foght's foundation. and from the C. W.
`Obel family foundation.
`
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`