_ anish
`Medical Bulletin
`
`JOURNAL OF THE HEALTH SCIENCES
`
`No. 3. June 1999. Vol. 46. Pages 183—290
`
`DOCTOR OF MEDICAL SCIENCE
`
`lntraluminal pH of the human gastrointestinal tract. Jan Fallingborg
`
`183
`
`On the pathophysiology oflate onset non-insulin dependent diabetes mellitus. Current
`controversies and new insights. Allan Vizag
`197
`
`Left ventricular systolic function after acute myocardial infarction: prognostic im-
`portance, relation to congestive heart failure and as a target for intervention. Lars
`Kaber
`235
`
`ORIGINAL ARTICLES
`
`Gastric mucosal interleukin-8 and lL-S antibody concentrations related to prevailing
`Helicobacter pylori
`infections. A Danish-Albanian study. Ole Huugen Nielsen.
`Thomas Horn, Skercli Prifti, Peter Peic/rl, Jens Henrik Sclreibel & Ivan James Dalton
`Lindley
`249
`
`Cardiovascular effects of ocsophageal dilation under general anaesthesia. Charlotte
`Ila/m Jakobsen. Vcrner Rasmussen & Jacob Rosenberg 252
`
`Risk factors in wound infections after laparotomy in obstetrics and gynaecology.
`Isabel de. In Fuente FUnnest, Bjm'ne Stigsby & Lars lleister‘berg
`254
`
`Risk indicators of disability pension. A 15 year follow-up study. Fin Biering Suren-
`sen, Jens Luncl, Ola J Haydn/52770, Erik M. Darre, Allan Deis, Peter Kryger &
`Cecilia Flarval] Miiller
`258
`
`The Danish National Hospital Register A valuable source of data for modern health
`sciences. Tuvs Folmer/Indersen, Metre Madsen, Jorge/7 Jnrgcnsen. Lene Mellemkjwr
`& Jargon H. Olsen
`263
`
`The Danish Prevention Register A comprehensive health and socio-economic, indi-
`vidual based register. Annette Snberg Rood, Claus Juli] & Finn Kamper-Jwgen-
`sen
`269
`
`ABSTRACTS OF PILD. DISSERTATIONS. See cover page 2
`
`MEDICAL Tl-IESES AND PHD. DISSERTATIONS.
`
`288
`
`SUMMARIES
`
`Bibliotek for nger. A journal devoted to medical history, ethics, philosophy and
`clinical theory, founded in 1809.
`289
`
`
`glam
`
`
`
`
`
`
`
`
`m“no.“ mmum m «um.
`
`Published by me
`Danish Medical Association and Danish Medical Society
`with support from the Faculties ofllealth Sciences
`ofthe Universities of Copenhagen,
`Aarlrus. and ()densc. and the Danish National Board ofllcalth
`This material was emptied
`atthe NLM and ”nay be
`Euzbjett Uzifioplvright‘ Laws
`
`PROPERTY OF THE
`NATIONAL
`LIBRARY OF
`MEDICINE
`
`KVK-TECH EXHIBIT 1039
`
`KVK-TECH EXHIBIT 1039
`
`

`

`DOCTOR OF MEDICAL SCIENCE
`
`Jan Fallinghorg
`
`tract -from the entire intestinal et al ( 16) studied nique, but Barbero
`
`
`
`
`
`
`
`the stomach to the rectum of infants (aged two weeks to three
`
`
`
`
`
`months) by an aspiration technique using an infant Miller-Abbott tube
`Intraluminal pH of the human
`
`
`
`
`
`with a balloon inflated with 5-8 ml air. The balloon was inflated when
`to
`
`
`
`the tube was placed in the duodenum. The tube then passed rapidly
`
`gastrointestinal tract
`
`
`
`
`
`
`
`the terminal ileum, and more slowly, within 24-36 hours, through the
`
`
`
`
`colon to the rectum. The ethical aspects ofperfo1111ing this potential­
`
`
`
`
`ly hazardous procedure in infants are mentioned in their article.
`·�·his review
`
`
`
`
`has been accepted as a thesis together with five previously pub­
`2. 1.2 Di(l/ysis bags
`
`
`
`
`
`
`lished papers, by the University of/\arhus, December 14, 1998, and defended
`A method introduced by Mamer ( 17), later described and utilized by
`
`
`
`on April 23, 1999.
`
`
`
`
`( 18) involved the use of a suitable membrane filled
`Rune and Koster
`Department of Medical Gastroenterology, /\alborg Sygchus.
`
`
`
`
`
`
`
`
`tube.via a connecting in the stomach with disti lied water and placed
`
`
`
`
`Correspondence: Jan Fallingborg. Ducbrndrevej 23, DK-9000 /\alborg.
`
`
`Alier a time the contents of the bag were withdrawn, and the hydro­
`
`
`
`
`Otlicial opponents: Per Brohech 1\.forlense11. MD, Peter Al. Func/1 Jrnsen.
`
`
`
`
`gen-ion content was determined. This method is useful in determin­
`
`
`MD, and S1ee11 Lindka:r Jensen. professor, MD.
`
`
`
`
`but does not reflect rapiding an average pll level in the stomach,
`
`
`changes in gastric pl-I.
`1. INTRODlJCTION
`
`
`
`
`The recent and increasing interest in the pl I of the contents of the
`2. /.3 Electrodes
`
`
`
`gastrointestinal tract is well founded. One reason is the development
`Intubated glass electrodes or antimony electrodes may be used to de­
`
`
`
`
`
`
`
`
`of several oral preparations which release the drug at a site and/or at
`tract.termine the intrnluminal pH or the upper gastrointestinal
`
`
`
`
`
`
`
`a rate determined by the pll orthc surrounding fluid (1-10). Precise
`
`
`
`Electrodes have the advantage over dialysis bags and aspiration tech­
`
`
`
`knowledge or the pl I profile or the gut, including the interindividual
`niques
`
`
`occurringthat they arc capable of reflecting pl I fluctuations
`
`
`
`
`
`
`variability, is a prerequisite for designing optimal delivery systems
`in the gut lumen. Furthermore,
`
`registrations can be made continu­
`
`based on this concept.
`
`
`is connected ously on ambulant patients when the electrode
`
`to an am­
`
`
`From a theoretical point of view the intraluminal pl I of the gut pri­
`bulatory
`
`
`
`
`recording system. Savarino et al ( 19) found an excellent cor­
`
`
`
`
`
`marily is determined by three factors: the absorption and secretion of
`
`
`
`
`
`relation between values obtained with an intragastric pH monitoring
`
`
`
`acid and base by the intestinal epithelium, the bacterial degradation
`equipment
`
`
`
`Sweden) and simultaneous(Digitrnppcr 6000, Synetics,
`
`
`
`contents of the intestinal or ingested food, and the rate of transpm1
`
`gastric aspiration.
`
`through the gut.
`2.2 TUBELESS TECI INIQUES
`
`
`
`Determinations of the intraluminal pll of the gastrointestinal tract
`2.2. l Cltemiml methods
`
`
`
`
`have been performed for several decades. Early studies were based
`Indirect methods of determining the presence or absence or gastric
`
`
`
`
`
`
`
`
`
`
`on aspiration of gastric or intestinal fluids, or measurements on fae­
`acidity
`
`
`have been suggested. One method involved the use of cationic
`
`
`
`ces. I lowever, the development of small pl !-sensitive, radiotrans­
`
`
`
`
`
`exchange resins to determine the absence or presence or free hydro­
`
`
`
`
`pl I-determina­a method which allows mitting capsules has provided
`
`
`
`
`chloric acid. The procedure depends on the dissociation of the resin
`
`tion under almost physiological conditions.
`
`
`
`by the hydrochloric acid in the stomach. The cation is absorbed
`and
`
`
`
`The aims of the investigations ( l l -15) presented in this review
`
`in the urine in the presence of free acid only (20).
`excreted
`a method of determining were as follows: to evaluate
`
`
`local intralu­
`
`
`
`containing Another technique involves the use of pills
`
`methylene
`
`
`
`and use ofpl I-capsules minal pH of the gut based upon the combined
`
`
`
`
`blue wrapped in an indigestible sac tied by a catgut suture. Free acid,
`
`the pl I-profile fluoroscopy; to use this method in studying
`
`orthe gas­
`
`
`
`
`
`if present in the stomach, dissolves the suture and allows the release
`
`human subjects and in children;
`trointest
`inal tract in healthy
`to study
`
`
`
`of the dye. The dye is then absorbed and excreted in the urine. Lack
`
`
`
`the effect of various factors on this pl I-profile.
`
`
`
`of free acid prevents the release orthe dye. This procedure (Dcsmoid
`
`
`
`of the intrnlu­current knowledge The present review discusses
`
`
`
`by Sahli in 1905 and reintroduced pill technique) was first devised
`
`reference to data generated
`
`mim1l intestinal pl I with special
`with pl!­
`
`by Levere and Palmer
`in 1960 (21 ).
`capsules.
`
`
`
`
`Obviously, these methods are indirect, nonspecific, time consum­
`
`
`ing, and consequently oflimitcd value.
`2.METHODS
`pH of the gut is a very sensitive
`parameter, inlluenecd by many kinds
`
`
`
`2.2.2 Rmliote/emetry capsule.�
`
`
`
`
`of outside impacts. A major problem in measuring gastrointestinal
`In 1957 the first radiotelemetry capsule for measuring pH was in­
`
`
`
`
`
`
`
`pl! is, therefore, that it involves the introduction of a tube or a trans­
`
`resin, which vented by Jacobsen and MacKay (22). A copolymer
`
`ducer into the gut or the subject
`
`studied, and the procedure in itself
`
`changed its dimensions with changes
`in pl!, was used as the trans­
`
`Various might induce changes in the pl I it measures.
`
`methods
`have
`
`was transferred to an iron core mov­
`
`ducer. The change in dimensions
`
`
`
`
`been developed with the intend to minimize the physical trauma to
`
`
`ing inside a coil, and this caused a shift in the frequency of the os­
`
`
`
`
`
`the subject, thereby minimizing the possible ellect of the procedure
`cillator
`
`
`in the capsule. The very slow response time of the transduc­
`
`on the recorded pl I.
`
`
`
`er decreased the clinical value of the capsule, and there are no reports
`
`
`
`
`of its use for clinical investigations. In 1959 a telemetry capsule using
`2.1 INTU8ATION TECI INIQUES
`
`
`
`
`an antimony electrode as transducer was developed (23).
`by Niiller
`n techniques arc easily performed,
`
`
`
`Naso-intestinal intubatio
`but pose
`
`
`and this pH-capsule was later referred to as the Heidelberg capsule.
`a number of limitations
`that can provide
`
`less than accurate results.
`
`
`
`The pll measuring cell in the Heidelberg capsule is made up or an
`
`For example, hypcrsalivati
`
`
`on caused by the intubation may dilute
`the
`
`
`
`
`
`
`annular external antimony electrode which is in contact with the sur­
`
`
`
`and thereby raise the gastric pl I due to the alkaline pH or
`aspirate
`
`
`
`
`
`rounding fluid, and an internal AgCI electrode separated by a semi­
`
`
`
`
`
`
`saliva. Reflux through the pyloric sphincter due to nausea caused by
`
`
`
`
`
`permeable membrane (24). pH changes the potential difference be­
`
`
`
`
`the procedure may also falsely raise the gastric pl I. Conversely, gast­
`
`
`
`tween the electrodes, which in turn control the frequency of the ra­
`
`
`
`ric fluid transported along the tube may falsely decrease the pH in
`with the early type of this
`
`dio transmitter. The main disadvantages
`the small intestine.
`
`capsule were the short life and serious drill problems
`, caused by ,111
`
`2. I. I Aspiration teclt11iq11e
`
`
`
`oxidation of the antimony
`
`
`
`fluids electrode in the presence of intestinal
`
`
`
`
`
`
`Aspiration of gastric fluids through catheters has been employed for
`(25, 26). The limitations
`
`made it suitable only for
`of this capsule
`decades, and it has the advantage
`
`
`of direct measurement on the fluid.
`
`studies or the stomach
`
`
`although Arnllani et al
`and small intestine,
`Only the proximal
`
`
`
`
`gastrointestinal tract is usually studied by this tech-
`(27)used it in a study orthe entire
`
`
`tinal tract in htmum vol-
`gastrointes
`
`Bull.:tin
`Danish Medical
`
`This material w.as'l:opied
`
`at th.e NLM and
`
`
`Su.l:J.ject. US Copyright Laws
`
`183
`
`

`

`unteers and patients. The study subjects initially passed a tube
`throughout the gastrointestinal canal and then the capsule was pulled
`through. Later improvement ofthe capsule has made it a more reli-
`able tool of pH measurement, but the accuracy ofthe capsule is still
`only about 0.5 pll units (28, 29), and the lifetime is only 22 h (2‘)).
`ln 1965-6 two pll capsules using glass electrodes were designed: a
`Japanese capsule (30), which, however, has never later been men-
`tioned in clinical studies, and a capsule manufactured by Remote
`Control Systems Ltd, London, England, referred to in the present pa-
`per as the RC8 capsule (31). The main problem with the p11 glass
`electrode is the high impedance. The electrode must also be sealed
`to prevent development of leakage paths, which shunt the potential
`produced by the transducer. The early RCS capsule depended on
`epoxy resins to form the seal, but moisture caused a gradual deteri-
`oration in the p11 response and a short lifetime for these capsules.
`Later a covering layer of glass was added which increased the life-
`time ofthe capsule to more than one month (32). The Japanese cap-
`sule and the RC3 capsules respond to alterations in pH by changing
`the transmission frequency ofthe transmitter in the capsule. The RCS
`capsule uses a PM oscillator with a transmission frequency of ap-
`proximately 400 kHz, whereas the transmission frequency of the
`Japanese capsule is 1.9 MHz. The electrical circuits ofthe two cap-
`sules share many aspects. A glass pl l—electrode is in contact with the
`surrounding fluid and an Ag/AgCl reference electrode is situated in
`the battery cap ofthe capsule. Variation in potential difference be-
`tween the pH-electrode and the reference electrode causes a change
`in the capacitance ofa reverse biased diode (varicap), with a corres-
`ponding change in output frequency (32, 33). The response in trans-
`mission frequency of the RC8 capsule is linear in the interval be-
`tween pll l and p11 9 (33, 34).
`A small number ofother types ofradiotelemetry pl'l-capsules have
`been developed but the Heidelberg capsule and the RCS capsule (Fig.
`1) are those most frequently used in published clinical studies.
`
`2.2.2.1 Methodological problems using the pll—capsule
`a. Localization of the capsule
`When an untethered capsule is ingested, it travels freely throughout
`the gastrointestinal canal, and a crucial point is how to determine the
`precise location ofthe capsule in the gut at the time ofpll measure-
`ment. The location which poses most problems is the ileo-caecal re-
`gion. By using a radio directional antenna to determine the position
`at which the maximum signal strength oftransmission is received,
`the regional localization ofthe capsule can be made with an accur-
`acy 015 cm (35, 36), but it is not possible to determine by this method
`whether it
`is located in the caecum or in the terminal
`ileum.
`
`Fluoroscopy enables a more precise localization, but if the gas con-
`tent ofthc colon is sparse, the distinction between the terminal ileum
`
`
`
`Fig. l. Thepll-sensi/ivc, rmliote/emetrycapsule (RCS capsule). Dimensions:
`diameter 7 mm. lung/1! 27 nun (a male/1 is shown/or comparison of'size).
`
`and the caecum may be diflicult. The use ofradiopaquc contrast (15)
`or gamma scintigraphy technique (35) to visualize the region may be
`an advantage. Repeated fluoroscopic investigations with short inter-
`vals in between can be ofgreat help, especially when sudden changes
`in pll occur. It is often observed that a capsule located in the ileocae-
`cal region has dropped 5 to 10 cm dowawards (i.e. into the caecum)
`between two fluoroscopic investigations, and usually this is associat-
`ed with a sharp decrease in pl 1. However, it must be recognized that
`even with the use of frequent fluoroscopic determinations ofthe loca—
`tion ofthe capsule, and even with the assistance ofa skilled radiolo-
`gist, a small number ofthe determinations may be incorrect. The ma-
`jor problem with repeated fluoroscopic investigations is the radiation
`exposure. The length of radiation must be kept as shott as possible,
`and this may best be achieved with the collaboration ofa radiologist.
`An improved method of localisation of the pl-l-capsule in the
`caecum was used by Sosa/ti et a] ( 37). A contrast colonogram was ob—
`tained before the investigation. The receiver was connected to a com-
`puter-assisted analysing system, and when pH sharply decreased by
`1 pH unit/min or more (i.e. when the capsule entered the caecum) the
`system generated a beeping sound. A plain abdominal x—ray was per—
`formed and superimposed on the previously performed contrast
`colonogram, and the presence ofthe capsule in the caecum could be
`verified. Thereafter, the position ofthe capsule in the colon was de—
`termined at 2-h intervals with a radio directional antenna. In two pa—
`tients a plain x-ray film was taken after a measurement of pH by the
`antenna, and the position ofthe capsulejudgcd by the antenna method
`was correct. The study demonstrates, that ifthe configuration of the
`colon is known, the localization ofthe capsule can be reasonably well
`determined by the use ofa radio directional antenna. The method is
`elegant and the computer-assisted analysing system could be ofgrcat
`help in monitoring pH in the colon of patients with chronic inflam-
`matory bowel disease, where very low pH values have been report—
`ed (14). However, a contrast colonogram may not be available in all
`patients, and the topographic position ofthe colon may be slightly
`influenced by the position (upright or succumb) ofthe patient.
`
`b. Gastrointestinal transit of the capsule
`When the capsule is ingested, it is freely mobile and its localization
`in the gut will be determined by the propulsion movements of the
`gastrointestinal myometrium. The gastric emptying oflarge (>1 mm)
`particles is dependent on the interdigestivc migrating myoelectric
`complex (lMMC) (38, 39). When solid food is present in the stem-
`ach it contracts 3-4 times per minute, and the pylorus is partially
`opened, allowing liquid and small particles to pass. When the stom—
`ach is empty of food, several phases of myoelectric activity occur,
`ending with the phase 111, the lMMC, which consists ofan opening
`ofthe pylorus and of3-4 peristaltic contractions from the stomach to
`the caecum, allowing emptying ofthe stomach of undigested mate—
`rial (“the housekeeper wave”) (40, 41). This cyclic pattern ofevents
`occurs on average every two hours in fasting humans, but it is inter—
`rupted when food is ingested. The gastric residence time (GRT) of
`the pH-capsule therefore depends on the dietary state ofthe subject.
`In a fasting subject the average GRT ofthe capsule is 1.1 to 1.9 hours
`(11-13, 29, 42). A small liquid meal prolongs the mean GRT to 2.6
`hours, and frequent intakes of food increases it to more than 14.5
`
`hours (42). This important aspect concerning the gastric emptying
`must be taken into account when sustained release tablets with coat—
`
`ings resistant to acid are prescribed. lfsuch tablets are taken together
`with meals, they will remain in the stomach until it is empty of food.
`and ifthe subject eats frequent meals during the day the stomach will
`not be empty before sometime during the night. Consequently, it is
`of no relevance to take such tablets two or more times daily, while
`all or most ofthe tablets will remain in the stomach the entire day
`and later all are emptied into the duodenum sometime during the fol-
`lowing night (43, 44).
`The small intestinal transit time (SITT) of the capsule in adults
`varies from 2.8 to more than 14 hours (1 1, 45) and average values of
`5.7 to 8 hours are reported (1 l, 35). The capsule travels rapidly from
`
`184
`
`This mate-rial wasteopiael
`atthe NLMand may be
`Subject UEEopy‘right Laws
`
`V0146 No. 3/Junc 1999
`
`1w
`
`

`

`the duodenum to the distal part ofthe small intestine, and about two-
`thirds ofthe SlTT is spent in the part ofthe small intestine that is lo-
`cated in the lower right abdominal quadrant (1 1). This slow transit
`through the distal small intestine is in accordance with the observa-
`tion of Ker/in & Phillips (46), who found that the lMMC travels
`through the small intestine with a velocity that decreases from 4.7
`cm/min in thejejunum to 0.9 cm/min in the terminal ileum. Ingestion
`offood also interrupts the lMMC ofthe small intestine (46). In child-
`ren, the median SlTT was almost identical
`to that of adults (7.5
`hours), and for three quarters ofthat time the capsule is located in the
`distal small
`intestine (13). The rapid transit through the jejunum
`makes it difficult to study the p11 ofthis part ofthe gut with a freely
`moving pl 1 capsule. In a study using capsules tethered with a 2 metres
`long nylon line it was possible to obtain pH measurements from the
`proximal part ofthejejunum (34). However, the line slowed the tran-
`sit ofthe capsule considerably, so it was not possible to measure pll
`in the more distal parts ofthe small intestine in that study.
`The colonic transit time ofthe capsule is about 17.5 hours (equal
`in adults and children), but it varies widely from less than 10 hours
`to l 12 hours, and the capsule is located in the caecum for about half
`ofthis time (1 1, 13). The colonic transit time tends to be longer in fe-
`males than in males (1 1).
`The day-to-day variation ofthe regional transit times is consider-
`able, and in a study ofthe day-to-day variation in 13 healthy subjects
`the variation coefiicients ofthe CRT and colonic transit time were
`about one (1 l). The SlTT was more consistent and the variation eo-
`elfteient was 0.40 (11).
`
`e. Linearity li'equency drift, precision and accuracy
`The response ofthe transmission frequency to alterations in p11 was
`tested by Me/a’rzmz er [I] (33) and by Fallingborg er a] (34) concern-
`ing the RC8 capsule, and was found to be linear within the interval
`between p11 1 and pH 9. The response ofthe Heidelberg capsule has
`also been found to be linear in the interval between pH 2 and 7, but
`above and below this interval the frequency response decreased (47).
`Calibrations ofthe capsules before and after a study will secure their
`accuracy at the calibration levels at the beginning and at the end of
`the study. As previously mentioned, the main problem with the ear-
`ly types of radiotelemetry capsules, and especially the Heidelberg
`capsule, was the frequency drift. This was mainly due to an oxida-
`tion ofthe antimony electrode in the presence ofintcstinal fluids. The
`problem was less with capsules using glass electrodes, and in the
`study of Fallingborg at a] (1 1), using the RC8 capsule, a maximal
`drift of 0.5 pH units was registered, with the exception ofone sub-
`ject in whom the increased drift was due to a defective reference cap.
`The frequency drift may affect both the accuracy (zero-point drift)
`and the precision (change ofthe slope ofthe response-curve) ofthe
`pll capsule, but, assuming that the drift develops with a constant rate
`during the study, a correction ofthe frequency drift can be performed
`after recalibration ofthe recovered capsule (14):
`
`
`
`
`0.1111('1‘(.)—0p119('ro)- ' en '10
`
`xtow 1 nan-0m 1 memo-Opt |9(To)‘op| [9(Te11d))
`
`
`
`
`
`o,,,,.,(,.,,,d,:
`
`Corrected pll value, measured at T)(
`le'x
`Time ofpre—calibration
`1;:
`Time of post-calibration
`Tend:
`Time of p11 measurement
`TX:
`Transmission frequency measured at time Tx
`61),:
`611111111113 Transmission frequency ofthe capsule at pH 1 , 37°C, measured
`at pro-calibration
`0mm 1WD: Transmission frequency ofthe capsule at pH], 37°C, measured
`at post-calibration
`Op] Wt 1b,: Transmission frequency ofthe capsule at p119, 37°C, measured
`at prc-calibration
`'l'ransmission frequency ofthe capsule at p119, 37°C, measured
`at post-calibration
`
`
`The accuracy ofthe RCS capsule has been evaluated by Meldrum et
`a] (33) and by Fullingbmg cf (11 (12) by comparing p11 in faeces and
`ileostomy output, measured by the RC8 capsules and with a pl l-meter
`(Radiometer, Copenhagen), respectively. The maximal difference be-
`tween pl 1 values measured with the two methods was 0.2 and 0.3 pH
`units, respectively, in the two studies.
`
`d. Frequency ofmeasurements
`In some studies pH was automatically registered 6 or 60 times per
`tninute and stored in a recording system, whereas in other studies in-
`cluding those made by the author of this thesis the measurements
`were performed manually with intervals of 10 minutes or more. The
`frequent, automatic recording method has several advantages: it can
`be used in outpatients, it is able to demonstrate pH-changes of short
`duration, and measurements can also be performed while the person
`sleep. The major disadvantages ofthis system are that only one sub-
`ject can be studied at a time for each recording system, and that meas-
`urements obtained during periods with low signal or signal loss may
`be incorrect. The importance ofa high signal quality was emphazised
`by Press e! a/ (48) who observed that artificial low pH values could
`be registered when the recorder indicated poor signal quality. The
`main advantage with manual recording is that an optimal signal qual-
`ity can be secured at each recording, and that more than one subject
`can be studied at the same time. The disadvantages are that p11-
`changes that occur between measurements will not be discovered,
`and that the method cannot be used in outpatients.
`
`3. GASTROINTESTINALpII IN NORMAL
`HUMAN SUBJECTS
`
`Since 1964 a number ofstudies on human gastrointestinal p11 using
`pll-sensitive capsules have been published. The majority ofthese
`studies deal with measurements of gastric residence time or meas-
`urements ofthe acid secretory capacity ofthe stomach, and, there-
`fore, only contain pH measurcments from the stomach and the duo-
`denum (Table 1). However, a numberofstudies also report pll meas-
`urements from tnore distal parts of the gut (Table 2). Many papers
`contain data obtained from normal human subjects, but in several of
`
`
`
`Fig. 2. Median (broken line) and interquarli/e range ofgastrointestinal pl!
`lileuszn‘ed in 33 lieu/[Int adult volunteers (11).
`
`Danish Medical Bulletin
`
`This material wast-{spied
`atthe NLM and may be
`Subject Ui{1e~py‘right Laws
`
`185
`
`

`

`
`
`‘ m I/
`'
`Published stud/es (
`'
`()ch’fillm.
`[/0]. ill [/16 ll“
`
`Table 1
`aclr (1)76
`
`1e
`
`.
`my (Jpll-scnsilivc. I'm/iali'cmsmfiling capsules. [/7 viti'o studies and human studies confined to nwasurenicms In the xlonr
`
`Subjects
`Type irfeapstrle
`
`itci‘crcnu:
`
`—
`—
`30 duodenal ulcer patients
`—
`30 normal subjects and patients
`50 normal subjects (+ antacids)
`—
`
`prototype, 400 k1 lz
`.......................
`M «Km 1957 (22) ........................ prototype, 1.9 M1 12
`JW’b‘O’Z 8:“ 3) ...............
`(l leidelbcrg)
`N51,” 1 )5
`H
`.................... Heidelberg
`-
`-
`-
`.
`.
`,
`1‘: ”liters, 1964 (25) .
`..................... Heidelberg
`CHEW/f 41/1 1965 (47) ......................... Heidelberg
`Stein/WALES
`.
`1 1965 (49) ........................... Heidelberg
`”WSW AV lat/0’ 9(5 (50) """"""""""
`rolot
`e 400 kl 12
`Ran/l & Nil/cl: l106’5 (3 1) ................................
`pRCS)yp .
`20 duodenal ulcer patients
`”mm” & (I).
`.................. Heidelberg
`l8 atients with d strophia rnyotonica
`)
`‘ 6 51) ............................ Heidelber’
`46 ilyspectic patiei/its (+ Spasrno-Nervogastrol®)
`Stu/WW); :i’llll'9lééfil5él
`................. Heidelber:
`-
`'
`'
`'
`'
`'
`'
`'
`I
`i
`I
`j
`i
`I
`i
`i
`12 patients (+ mctocloprainide)
`.
`11:11'1-[1/27-‘196763.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`-
`-
`-
`.................... Heidelberg
`(Eases
`.
`Stijl/lgé’: 1967 (54). .
`.5.
`.
`.
`.
`.
`i
`i
`j
`Z :1 ....................... Heidelberg
`'t' ‘ 1‘
`1* ..
`'l
`)
`77
`'
`Cases
`MUiWM ‘1’ “l' [967 (5 ) ............................... Heidelberg
`24 normal subjects, .2 duodena ti cet pa ten s
`Ki'lllcr, 1967 (5(7) »
`-
`-
`'
`' 1969(26) .......................... Heidelberg
`26 patients
`A‘vmici‘ycm & Bing/mm.”4
`........................... Heidelberg
`.1
`,
`2‘) patients
`.
`_
`‘
`.
`,
`)lirbml’gh a! (Il. 1969 (- ) ............................. Heidelberg
`45 patients with anaemia (21 With pernicious anaemia)
`Dev/ile er al, 1969 (57) ............................. Herdelbei‘g
`1 normal subject-and 29 patients
`.
`.
`iVil/iwiixwl L” "1' 1969 (58) ............................ Heidelberg
`23 dyspeptic patients (+ acetysalicylrc actd)
`Stuck, 1969 (59) ......... (1)1. ‘
`' ........................ Heidelberg
`13 normal subjects (+ antactds)
`Russell & Goldberg. 197? ( ) 61) ......................... Heidelberg
`27 dyspeptic patients
`Gall/3W” & I’M/"mm I )707(
`......................... Heidelberg
`Cases
`.
`Andres & Bil7glm’77- 1970 (6') ...........................
`Prototype, [-9 MHZ
`10 duodenal ulcer patients
`KIWI! C” "L '97] (63) ................................ Heidelberg
`.
`37 healthy children
`-/(3/7a”’7"3-"”" “1 ”l‘ 1973’ (64) ............................ Heidelberg
`16 normal subjects (+ antacids)
`Sfl‘ldlikom' 1973 (65) """(i
`i
`. (jo) ...................... Heidelberg
`23 normal subjects (transeranial electrothcrapy)
`Mill/Ge & Al’lllw'll/icllunl'
`l )75 (
`..................... Heidelberg
`1 18 normal subjects (7L antacids)
`Kuiiei' e! (Il, 1975 (67) .................................. Heidelberg
`10 normal subjects (+ antacids)
`”WC/"’1’" 6’ "l' 1975 (68) ............................. Heidelberg
`
`5 normal subjects (+ insulin :: bromazepam)
`EkWWC‘I‘Q ”mam 1975 (69) ......................... Heidelberg
`4 normal subjects + 19 peptic ulcer patients
`SIM/7"" & Starker. 1975 (70) ..............................
`2 prototypes
`12 normal subjects
`Misti/ii & meil, 1976 (71) ......................... Hcidclbcrg
`147 patients
`Rifle/16119 Erni, 1977 (72) ----~*""""”":: .......... Heidelberg
`11 normal subjects (+ sucralfatc / + antacids)
`[lei’lkel' 1980 (73) ................................ Heidelberg
`24 normal subjects, 31 duodenal ulcer patients.
`McGniw e! Ill. 198' (74)19é; (75) iiiiiiiiiiiiiiiiii Heidelberg
`10 normal subjects (+ antacids)
`U1’5i’"1" & Keyrilulncii.
`J
`iiiiiiiiiiiiiiiiiiiiiiiii
`llcidelber v
`16 normal subjects
`[MIC/1810,, 1984 (76) ....................................
`[Icidelbcrz
`1 patient with Crohn’s disease
`111(1jcivei‘i'ui7 er [I], 1985 (42) .............................
`[Icidclberg
`4 duodenal ulcer patients
`Faegcnbiirg er zil, 1985 (77) ,
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`. .... RCS
`8 normal men (+ procainamide)
`Reynolds 0! ul. 1986 (78) -
`'
`-
`'
`'
`‘
`'
`’
`‘
`'
`'
`i
`'
`I
`'
`i
`i
`i
`i
`i
`i
`I
`i
`i
`I
`j
`..... Heidelberg
`8 normal subjects (+ aspirin)
`Rocci cl (Il. 1987 (70) .................................
`Ileidelbcrg
`45 normal subjects
`lllly'uveriun 61 (II, 1987 (80) ............................
`[[eidclbcrg
`10 normal subjects
`Mnjtiverluii er Lil, 1988 (81) ..............................
`”ciddbcrg
`12 normal men (i ranitidine)
`Ewe ctul. 1989 (82) 'i'”H'HUHHHHHH-im.:: .... Heidelberg
`:liealtlryl/ mlcn (+ diclofenac sodium)
`IciiI/(yluwfiljflfijdljtlfgo (83)
`'
`i
`'
`I
`i
`i
`.......... Heidelberg
`norma Stnjects
`7cm 0 u.
`............... lleidclbei"
`6 normal males (+ ketoconazole :t ciinetidine 2t sucrall‘ate)
`Maiziveriun ci a], 1991 (29) -
`~
`'
`'
`‘
`'
`i
`j
`I
`..... Heidelberg
`'
`'
`'
`i
`'
`'
`l
`'
`i
`i
`i
`i
`i
`i
`6 normal subjects (+ glutamic acid i ranitidine)
`”SCI-’81“ 0’ "l' 1991 (85)'
`'
`i
`'
`'
`'
`'
`'
`j
`'
`I
`j
`i
`i
`j
`i
`j
`i
`i
`j
`j
`i
`j H ........ Heidelberg
`12 normal subjects (+ theophylline i: ranitidine)
`Kim/2p at al. 1991 (89) -
`-
`'
`’
`'
`'
`'
`'
`'
`'
`'
`'
`'
`'
`'
`I
`i
`j
`i
`j
`I
`i
`i
`......... Heidelberg
`12 normal subjects (+ enoxacin i ranitidinc/pentagastrin)
`Bel/ac]: et ul, 1991 (87) .................................. Heidelberg
`79 healthy elderly subjects
`Lehmch at a], 1:))2(88) .
`i
`i
`i
`j
`I
`i
`i
`I
`i
`j
`i
`i
`I
`i
`i
`i
`i
`i
`i
`i ............ Heidelberg
`8 normal subjects, 7 achlorhydric subjects. (+ theophylline)
`RUSH)” el ul, 1‘? )3 £8 )) .................................. Heidelberg
`18 normal subjects (+ diclofenac i ranitidine)
`New]. 61 “1' 1(1)} (()0) iiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiii Heidelberg
`24 normal subjects (+ l1uconazole or itraconazole)
`imam Li, “A I ))3/()119)9.4. 97 9;) I
`i
`i
`i
`i
`j
`I
`i
`j
`............. Heidelberg
`11 healthy subjects (> 64 years, + dipyridamole i famotidine)
`£1,752,221; [till/fl" 1869,4794)
`( A"
`i
`j
`I
`.................. Heidelberg
`12 normal subjects (+ l1ucona7o1e i omeprazole)
`,
`.
`""""""""""" Heidelberg
`10
`‘n' I Sub' ~cts (+ 2':
`~
`r
`t
`)
`'i
`)
`'1ni i.
`i" r
`.
`[Mmmnmm 0’ "l‘ 1994(95) """"""""""""""
`ii rd in
`"9” 1“ l
`'1‘- ‘
`' 1C 390 a ctr l “C ( X" b
`amo K1119)
`Henderson er til, 1995 (96) ...............................
`Ll
`‘- 7‘J‘l:
`5 norma’ sir 7kale .
`(Ironing & Bei‘iiigen. 1996 (97) ........................... Heidelberg
`
`'3Lewis & Neuron, 1997 (98) ............................... 13 normal subjects
`
`
`these articles the results from the healthy subjects and those obtained
`from patients are not separated. Therefore, only a limited number of
`these study results can be used to describe the pH-profile of normal
`humans (Table 3). On the basis of these selected studies, supple-
`mented with results from studies using other methods, a picture of
`the pH profile ofthe normal gastrointestinal tract can be made.
`However, it should be kept in mind that a normal colonic pH-proiilc
`may vary in different ethnic and cultural groups and in different parts
`ofthe world, because dietary habits may affect the intraluminal p11
`(see Chapter 7.1).
`tract, based on
`The pl l-profile of the normal gastrointestinal
`measurements obtained with the RC8 capsule, is shown in Fig. 2
`(11).
`
`3.1 STOMACH
`
`The acid environment in the lumen ofthe stomach is attained by pro~
`ton secretion from the parietal cells in the corporal mucosa. 1n a fast—
`ing subject, the p11 ofthe gastric fluid ranges from 1 to 3.5 (11, 27.
`30, 89), but ingestion of food, milk, or antacids may shortly increase
`p11 to about 7 (24, 33, 89, 110).
`
`3.2 DUODENUM
`
`Due to the rapid transit ofthe untcthered pl 1 capsule through the duo—
`denum, only a few recordings can be performed in this region using
`this method. Thus, results obtained with tubes", glass electrodes, or
`tethered capsules must be regarded as the most reliable. in the duo-
`denum, the p11 ofthc intestinal fluid is changed from acid to neutral
`
`186
`
`This mate-rial wastap
`i“
`at: the NLM arid may be
`Subjeet‘ LIE {iupyright‘ Laws
`
`Vol 46 No. 3/JuitL‘ 1900
`
`

`

`Table 2. Clinical .s‘lIlt/ies 0n lmmun grist/‘0intestinal [)1] [Measured with [III-sensitive. I‘m/iotrunsmfil