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Variability of motility of the ileum and jejunum in healthy humans
GASTROENTEROLOGY
1982;82:694-700
Variability of Motility of the Ileum and Jejunum in Healthy Humans PAUL KERLIN and SIDNEY PHILLIPS Gastroenterology
Unit, Mayo Clinic
and Mayo Foundation,
Motor patterns of the distal small bowel were defined in healthy humans, using a multilumen polyvinyl tube, passed by mouth in 11 healthy subjects. Five recording sites, spanning 100 cm of tube and featuring a nitrogen hydraulic infusion system, were used to obtain records during 6 h offasting and 6 or more hours after ingestion of a 600-kcal liquid test meal. The loci of recordings were designated as jejunal, ileal, or terminal ileal, as judged by the length of tube within the intestine and by fluoroscopy. During fasting, the migrating motor complex was present in all subjects and at all levels of the small intestine, but it could not be traced into the colon. Interdigestive cycles were defined primarily by the presence of an “activity front” (phase 3 of the migrating motor complex). Ninety-six migrating motor complexes occurred each 97 min (grand mean for all loci), but intervals between individual activity fronts varied markedly (15-195 min), in contrast to what is reported in other species. The velocity of aboral migration was 4.7 t 1.8, 1.3 it 0.4, and 0.9 + 0.2 cm - min-l (mean 2 SD) in jejunal, ileal, and terminal ileal, respectively. Rates of continuous, rhythmic contractions during activity fronts declined distally: 12.5 to 10.5 (jejunal), 10.9 to 9.3 (ileaf), and 10.0 to 8.6 cycle/min [terminal ileal], respectively. In individual subjects, maximum rates of contraction and velocities of migration always declined distally, but the duration of activity fronts was unrelated to the level of recording. Food interrupted the fasting cycles of motility for periods Received August 3, 1981. Accepted November 12, 1981. Address requests for reprints to: SF. Phillips, M.D., Gastroenterology Unit, Mayo Clinic, Rochester, Minnesota 55901. This work was supported in part by the Mayo Foundation and Research Grant RR 00585, Public Health Service, Bethesda, Maryland. Dr. Kerlin was Rappaport Fellow of the Mayo Foundation; his present address is Department of Gastroenterology, Princess Alexandra Hospital, Brisbane, Australia. The authors thank Mrs. Anne Haddad and Mr. Richard Tucker for expert technical assistance and Mrs. Mary Hanenberger for her secretarial assistance. 0 1982 by the American Gastroenterological Association 0016-5085/82/040694-07$2.50
Rochester,
Minnesota
ranging from 2.75 to >lO h. The transition from the fasting to the fed pattern was prompt and the postprandial motility was that of irregular bursts of contractions interspersed with transient quiescence. These studies demonstrate that the migrating motor complex occurs throughout the human small intestine, and that inter- and intraindividual variations are marked; food disrupts the complex for variable periods. These variations must be considered when abnormalities are being sought in disease states. Unlike the upper intestine proximal to the ligament of Treitz and the hindgut distal to the sigmoid colon, the motility of the human ileum and proximal colon is largely unexplored. Reasons why these segments have received little attention include their relative inaccessibility in humans and the lack of reliable techniques of recording. For example, descriptions of human ileal motor patterns still rely on results of balloon-kymograph recordings from retrograde intubation of ileostomies (1). However, the ileum has several special absorptive functions, including the active transport of electrolytes, vitamin B12, and bile acids, as well as the capacity to compensate dramatically for the loss of reabsorptive surface following resection of the proximal bowel (2). Further, the ileocecal junction has characteristics of a sphincter which probably prevents reflux of bacteria into the small intestine (3,~). Less well established, but of considerable potential importance, are the storage of thyme and its controlled entry into the colon (5). Thus, the motility of the ileum could be an important determinant of a variety of absorptive events. Recent concepts of fasting motility in the stomach, duodenum, and proximal jejunum (6-11) have emphasized the interdigestive migrating motor complex (MMC). This is the motor equivalent of the interdigestive migrating myoelectric complex (IDMEC), first described in the canine small intestine by Szurszewski in 1969 (6). Although Fleckenstein (7) has recorded an IDMEC in the human ileum of 2 subjects, its motor equivalent has received little atten-
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MOTILITY
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tion. However, an understanding of motor activity and transit in ileum and jejunum may be relevant to huinan disease, since Vantrappen et al. (8) have reported disturbances of MMCs in the proximal intestine of patients with bacterial overgrowth. The aims of this study were to utilize recent developments in manometric techniques to record fasting motor activity at all levels of the intact human small intestine, and to examine the effect of a meal on these motor patterns.
Materials and Methods Volunteers Eleven healthy volunteers (8 men and 3 women, aged 19-67 yr, mean 36 yr) participated in these studies after giving informed, written consent. The protocol was approved by the Mayo Clinic Human Studies Committee in December 1979. Intestinal
Tube
A multilumen polyvinyl (PV) tube of 450 cm was constructed by bonding separate catheters (ID 0.9 mm) with tetrahydrofuran; a small mercury weight led the tube, to facilitate transit. One catheter was radiopaque to facilitate its location fluoroscopically. The perfusion sites were located at side holes, cut proximal to occluding steel plugs at 0, 20, 60, 80, and 100 cm from the distal end. The maximal outer diameter of the catheter bundle was 4.5 mm. Recording
System
The technique was based on the hydraulic capillary infusion system described by Arndorfer et al. for esophageal manometry (12). A head of nitrogen pressure (10 psi) was applied to a plexiglass chamber that was connected by stainless steel capillary tubing to Konigsberg pressure transducers (model P3535; Konigsberg Inc., Pasadena, Calif.). The flow rate was 0.1 ml * min-’ (60 cm, 30 gauge steel capillary tubing) in four capillaries and 0.5 ml * min-* (40 cm, 27 gauge) in the other. The proximal ends of the intestinal tubes connected to the transducers. The i&sate (100 mM NaCl, 10 mM KCl, 45 mM NaHC03) simulated the composition of fasting contents of the distal small intestine (13). A belt pneumograph recorded respiration simultaneously via a sixth transducer. The output from all transducers was displayed on a Honeywell or M.F.E. 1600 recorder, using a paper speed of 0.25 mm - s-‘.
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Amplitude of recording response to transient pressures. A syringe driven by ar eccentric cam (Harvard Respirator) was used to apply sine waves of pressure at two frequencies to a chamber. Within the chamber, a Millar M&o-Tip Transducer (Millar Instruments, Inc., Houston, Tex.) acted as a pressure reference. The ends of two PV catheters (450 cm, flow rate 0.1 ml * min-’ and 390 cm, flow rate 0.5 ml * min-‘) were placed within the chamber and an airtight seal ensured. Pressure transients were applied at 12 cycle/min, to stimulate the duodenal slow-wave frequency (14) and at 60 cyclelmin, a frequency that exceeds any anticipated in the small intestine. Amplitudes of responses for the PV catheters were expressed as the percentage of the amplitude recorded simultaneously by the reference (Millar) transducer. Protocol Subjects were intubated by mouth after an over night fast. During distal passage of the tube, subjects were fed a low residue diet in the Clinical Research Center. Before each recording session the tube locus was classified as jejunal (J), ileal (I), or terminal ileal (TI) on the basis of fluoroscopy and length of tube from the teeth to the distal end, after “slack” had been removed from the stomach. In general, for jejunal studies the tube was sited fluoroscopitally on the left side of the abdomen and up to 200 cm had passed beyond the teeth. For ileal studies the tube had progressed to the lower abdomen and its tip was beyond 200 cm from the teeth. For the tube to be located in the terminal ileum required the simultaneous recording of motor activity in the cecum from the terminal locus. Fasting motility of the small bowel was recorded for approximately 6 h in all subjects and in 9 subjects recording was continued for about 6 h after a test meal. Studies were begun in the early morning, after the position of the tube was noted. Fluoroscopy was repeated after each recording session to confirm the location of the tube. Composition
of Meal
The liquid test meal contained 30 g of VIP (a mixture of amino acids, from Synergy Plus, 2530 Polk St., Union, N.J.), 60 g of Polycose (glucose polymers derived from corn starch, Ross Laboratories, Columbus, Ohio), and 26 g of emulsified corn oil. These nutrient proportions (protein 20%, carbohydrate 40%, fat 40%) resemble those in the average American diet (15). Water (260 ml) was added to provide a final volume of 400 cm3. The emulsified meal provided 600 cal and had a measured osmolality of 450 mosmol (5100 B Vapor Pressure Osmometer, Wescar, Inc., Logan, Utah). Definitions
Characteristics
of the Manometric
System
Response of catheters to end occlusion. Occlusion of catheters was used to determine the performance of the infusion system and transducers at both rates of flow. A 390-cm length of catheter (perfused at 0.5 ml . min-‘) was occluded and a 450-cm catheter (flow rate 0.1 ml - min-‘) was occluded at 50-cm intervals from the distal end.
Migrating motor complexes were defined by the presence, and aboral migration, of “activity fronts” (AF: phase 3 of the MMC). Phase 3 was defined as 3 min or more of uninterrupted rhythmic contractions, followed by quiescence. Migration required the recording of phase-3 activity from at least three sequential recording points. The period between MMCs was the mean interval between
696
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KERLIN AND PHILLIPS
successive activity fronts from each study. The rate of rhythmic contractions was measured at each recording site as the number of contractions per minute during 3 or more minutes of continuous contractions in phase 3. The duration of phase 3, from the onset of regular contractions to quiescence, was calculated for each study. The velocity of migration (cm * min-‘) of the MMC was assessed by dividing the distance transversed by the migrating phase 3 by the time taken to cross three to five recording sites. Recordings of motility between periods of phase-3 activity were divided arbitrarily into phase 1 [quiescence) and phase 2 (intermittent activity). The contribution of phases 1, 2, and 3 to the length of each complete cycle was calculated. To determine how often a MMC originated beyond the ligament of Treitz, the frequency of “distal starts” was assessed. A distal start required the absence of phase 3 at higher levels, within the anticipated time interval. To compensate for the adequacy of our recording system, the number of incomplete jejunal MMCs was also assessed, i.e., (a) the number of MMCs in which phase 3 “skipped” a recording site and (b) the number of MMCs showing incomplete distal migration. The motility index of the proximal colon was calculated by the product of the total duration of activity and the mean amplitude of the pressure waves (16). The colonic motor response to the meal was assessed by comparing the motility index in the hour before the test meal to the first postprandial hour. Statistical
Analyses
Analyses were performed using the paired t-test and results were considered significant if p < 0.05.
Results Characteristics
of the Manometric
System
end occlusion. At 0.1 Response to ml - min-l, occlusion of outflow at the level of the transducer elicited a pressure rise rate of 42 mmHg - SC’. When the pressure response to occlu-
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sion of different lengths of tubing was measured, the rise was 24 mmHg - s-l with 450 cm of tubing, 27.5 mmHg - s-l with 350 cm, and 36 mniHg * s-l with 50 cm. With the faster infusion rate, 0.5 ml * min-I, occlusion at the level of the transducer elicited a rise of 310 mmHg * s-l; adding 390 cm of PV tube gave a postocclusion rise of 134 mmHg - s-l. Amplitude response. At a frequency of 12 cycle/min the infused catheters registered all waves and the mean amplitude was 96% of that recorded simultaneously by the Millar transducer. At 60 cycle/min there was also less than 5% damping compared to the reference transducer. Fasting
Studies
Migrating motor complexes were recognized in all subjects and at all levels of the small intestine (Figure i). At the jejunal level, 7 subjects contributed 13 separate days of study. Fifty-nine MMCs were identified in 86.5 h of recording. At the ileal locus, 5 subjects provided 8 days of study. Twenty MMCs were noted in 47.75 h of recording. In the terminal ileum, 5 subjects were studied, 1 person on two occasions. Seventeen MMCs occurred in 37 h of recording. The periods between MMCs, characteristics of the activity front, and the velocities of its migration are shown in Table 1. The mean period between MMCs was approximately 90 min, but the range was wide, from 15 min to >3 h. This variability in periodicity is demonstrated in Figure 2, which shows the range of intervals in individuals having three or more MMCs in any recording session. The duration of phase 3 was also variable, both between and within subjects. In general, phase-3 activity lasted from 7 to 12 min and was unrelated to the level of recording. In every study the velocity of migration of the MMC decreased with distal progression along the small
o
520 540 J80 Jloo Reapkatbn
Figure
I. Migrating motor complex adjacent to each tracing.
in the human jejunum.
The distance
of the recording
orifices from the ligament
of Treitz is shown
MOTILITY OF HUMAN SMALL BOWEL
April 1982
Table 1.
Characteristics of the Activity Front (Phase 3 Migrating Motor Complex) and Migration in Healthy
697
Humans Terminal ileum
Jejunum
Ileum
Period between MMCs (min) (Mean -t SD) Range
100 2 42
94 k 45 41-188
37-195
Rate of contractions during phase 3
12.5-10.5
10.9-9.3
10.0-8.6
Duration of phase 3 (min) (Mean ‘- SD) Range
7.3 k 1.8
11.6 f 3.4
11.1 IT 4.1
3-11
3-23
3-42
Velocity of migration (cm/min)
4.7 t 1.8
1.3 2 0.4
0.9 + 0.2
15-184
(No./min)
of MMC
84 2 17
Values are mean ? SD and/or range.
intestine. Five subjects had recordings at two or more intestinal loci on separate days. In these subjects the maximum rate of contraction and the velocity of migration always declined distally. The rate of rhythmic contractions decreased in an orderly sequence from the duodenum to the distal ileum (Figure 3). This aboral decline in frequency of contractions could be noted also over the total recording distance of 100 cm, for any individual study (p < 0.05). One subject, illustrated in Figure 3, had a rhythmic rate of contractions that was faster than the other 10 subjects, and this was seen at all loci. The duration of each phase of the MMC was
established at the three recording loci; the results are shown in Figure 4. At the more distal sites (ileum and terminal ileum) the active phases (2 and 3) were more prominent and the quiescent phase (1)was shorter. However, inter- and intraindividual variability was prominent. In several subjects, phase 2 shortened markedly when the patient was asleep. Thus, motility in these persons consisted mainly of quiescence interrupted periodically by phase-3 periods. Migrating motor complexes with a distal start could be identified confidently only in the jejunal studies. In these, 10 (17%) of the 59 MMCs originat-
240 .
Je junum . . . . . . . . . . . . Ileum . -----Terminal ileum 160 Maximum and minimum period between MMC’s (min)
120 -
80 -
1
40
80
I
,
120
,
1
140
Mean period between MMC’s (min) Figure
2. The mean period between successive activity fronts (phase 3 of MMC) for individuals with three or more MMCs in a single recording session is shown on the abscissa. The range for each individual for the same recording period is plotted on the ordinate. Numbers refer to individual subjects, some of whom contributed more than one recording session.
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Figure
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KERLIN AND PHILLIPS
3. The frequency gradient of regular, rhythmic contractions in the human small intestine. The solid line represents the mean rate of contractions determined during activity fronts. The hatched area depicts the range of values encountered at any distance from the teeth. The go-cm mark is the approximate location of the ligament of Treitz. Plotted separately are the values of a subject with a considerably faster rate of contraction at all loci.
Contractions per minute
10
-
8
-
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7lI
1
I
70
00
I
I
110
I
130
I
I
I 150
I
I 170
I 190
I
I 210
I
I
I 230
I
J
250+
Distance from incisor teeth (centimeters)
ed beyond the ligament of Treitz at 110-150 cm (median 135 cm) beyond the incisor teeth. In contrast, a MMC was seen to “skip” a single recording site in two of 59 complexes and three MMCs well established proximally were not detected distally. Recordings of cecal motility were obtained in 5 subjects. Motor activity was variable and not clearly related to the arrival of MMCs in the terminal ileum. The motility index in the first hour after the meal was not enhanced when compared with the hour before eating (0.5 < p < 0.1). When contracting regularly, the predominant frequency was 6 cycle/ min, although both faster and slower rhythms were noted infrequently. Postprandial
Studies
After fasting recordings, 9 subjects ingested the liquid test meal. Eating disrupted the cycle of interdigestive motor activity at all levels of the small intestine. Migrating motor complexes were recorded at the start of the meal in six instances (jejunal 3, ileal 2, terminal ileal 1). In each case, progression of the MMC was interrupted and a postcibal pattern of motility was established. This consisted of short random contractions, interbursts of irregular, spersed with transient periods of quiescence. The maximum rate of contraction, assessed during activity lasting more than 60 s, was identical to that occurring in the same subject during fasting. An MMC returned at variable times after the meal (Table 2). This variability was present between and within subjects.
system offers the opportunity of recording motility throughout the human small intestine and proximal colon. Shorter, stiffer tubing (such as polyethylene) and faster rates of infusion provide theoretical advantages (12,171 but we chose 450 cm of polyvinyl tubing and lower flow rates so that our subjects could sleep without restraint. In addition, although polyethylene is less compliant (and better theoretically) than PV tubing, it cannot be bonded easily and the tube assembly may be less well tolerated. Of practical importance, the performance of our recording system during tests in vitro gave us confidence in employing the assembly of long polyvinyl tubes. Our major finding is that the MMC could be identified in all subjects and at all levels of the small intestine. Further, inter- and intraindividual variations were prominent, in contrast to previous studies in the canine small intestine (6,18). Thus, the interval between MMCs was highly variable and the recording of a MMC within 15 min of an earlier sequence challenges the relevance to humans of suggestions that a MMC begins in the upper gut only
43 intervals 7 aubjecta JEJUNUM 11 intervals 4 aubjecla
15 intervala 6 subjects
Phase
Discussion This study demonstrates that motility of the human distal small bowel can be recorded faithfully, using long polyvinyl tubes and low rates of flow. Our
Figure
4.
I
Phase
II
Phase
Ill
The percent duration of individual phases of the MMC at various levels of the human small intestine during fasting. The values are mean -t SD, and the length of each MMC has been normalized to a value of lOOa&
April
1982
Table
2.
MOTILITY
Duration Humans”
of Fed
Pattern
of Motility
in Healthy
Postprandial recording time (h) Site of Recordinab
Subject No.
Total
i
1 1
t
3 2
6 6 6.75
I I I I I I TI TI TI TI TI
4 4 5 6 7 8 9 9 5 6 3
5.5 5.5 6.5 6.75 6.5 7.5 6.25 18.5 17.75 18 18.25
MMC returned bv
a After a meal of 600 kcal (40% fat, 40% carbohydrate, protein). b J = jejunal; I = ileal; TI = terminal ileal.
5
2.75 4.25 6.75
5.75 4.25
4.5 10.5 6 8.75 20%
when the preceding sequence reaches the terminal ileum (6,18). As suggested by others (8) phase-3 activity was the most readily defined facet of fasting motility. It is possible that the activity front (phase 3) increases in duration distally, as noted during recordings of the IDMEC. For instance, Fleckenstein recorded a phase 3 lasting 36 min in the ileum (7). However, sleeving of the intestine on the tube cannot be quantified and yet may contribute to any apparent increase in duration of the activity front. In our subjects, there was no consistent increase when individuals were studied at more than one level. The velocity of migration of the MMC slowed with aboral progression of the recording site. This is in keeping with Fleckenstein’s finding (7) and with results in the canine model (6,18). The relative contribution of phases 1, 2, and 3 to length of MMC cycle was also variable. This variability was noted from one MMC cycle to the next in most subjects and within a single cycle recorded simultaneously at several recording sites. Phase-2 activity became brief or absent in some subjects during sleep, although we did not monitor the stage of sleep by electroencephalography. This depression of general motor activity (19,20) and specifically of phase-2 activity has been noted by others (21). Fleckenstein (7) reported that phase 1 may at times be quite brief or even absent, supporting the concept of variability. The maximum rate of intestinal contraction was most readily assessed during the regular uninter-
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rupted contractions that characterized phase 3. A gradient was observed from proximal jejunum to terminal ileum, equivalent to the “Alvarez gradient” (22); it was readily apparent and consistent. This finding is in keeping with the slow-wave gradient reported by Christensen et al. (14) in the intact bowel and with results from isolated studies featuring intubation of ileostomies (23). One subject demonstrated a jejunal rate of contraction that was above our normal range consistently, and also more rapid than the slow-wave frequency of Christensen. Thyroid function (14) was tested, found to be normal, and no other explanation was found. Ten of the 59 jejunal MMCs originated beyond the ligament of Treitz. This figure agrees well with the 21% incidence of distal starts reported by Vantrappen et al. (8). Recent studies in the dog suggest that activity fronts which begin beyond the duodenum may be controlled separately from those fronts that begin in the distal stomach (24). Thus, “ectopic” fronts are independent of the cyclic fluctuations in plasma motilin which are concomitant with the gastroduodenal onset of MMCs in the dog (24,25). Further, 100 g of meat interrupts proximal activity fronts, but ectopic fronts persist after the meal (24). In our studies, the appearance of MMCs in the distal bowel postprandially was always delayed, and this finding argues against the persistence of cyclic activity in the human distal bowel after a meal. Our liquid test meal produced a prompt change in motor activity. We never recognized a progression of phase-3 activity to more distal recording sites after a meal was commenced, suggesting that phase-3 activity is stopped “in its tracks.” The postprandial activity consisted of noncyclical, intermittent, irregular contractions. The MMC returned at a variable interval, ranging from 2.75 h in the jejunum to over 10 h in the terminal ileum. Our test meal was designed to be palatable and to simulate the mixed composition of the average U.S. diet. DeWeever et al. (26) investigated the disruptive effect of equicaloric nutrients in the dog and determined that oil, sucrose, and milk protein was associated with progressively shorter fed patterns of motility. Failure to demonstrate augmentation of motility in the proximal colon following the test meal may be due to the nature of the meal. Recordings of the motor response of the distal colon to a meal (27,28) suggest that amino acids may inhibit the excitatory effect of other meal components on the postprandial response. These studies were designed to document the feasibility of recording faithfully the motor patterns of the human distal small bowel. We believe our system offers an acceptable approach and that these data provide a basis for further studies of factors that modify ileal motility in health and disease. The
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KERLIN AND PHILLIPS
variations noted here in health must be considered when perturbations are sought in later studies.
15
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NC. Motor action of the small bowel. In: Code CF, ed. Handbook of physiology, Section 6, Alimentary canal, Vol IV, Motility. Washington, DC.: American Physiological Society, 1968:2001-24. Weser E. The management of patients after small bowel resection. Gastroenterology 1976;71:146-50. Cohen S, Harris LD, Levitan R. Manometric characteristics of the human ileocecal junctional zone. Gastroenterology 1968;54:72-5. Kelley ML Jr, DeWeese JA. Effects of eating and intraluminal filling on ileocolonic junctional zone pressures. Am J Physiol 1969;216:1491-5. Gazet JC, Kopp J. Surgical significance of the ileocecal junction. Surgery 1964;56:565-73. Szurszewski JH. A migrating electric complex of the canine small intestine. Am J Physiol 1969;217:1757-63. Fleckenstein P. Migrating electrical spike activity in the fasting human small intestine. Am J Dig Dis 1978;23:769-75. Vantrappen G, Janssens J, Hellemans J, Ghoos Y. The interdigestive motor complex of normal subjects and patients with bacterial overgrowth of the small intestine. J Clin Invest 1977;59:1158-66. Rees WDW, Go VLW, Malagelada JR. Simultaneous measurement of antroduodenal motility, gastric emptying and duodenogastric reflux in man. Gut 1979;20:963-70. Lewis TD, Collins SM, Fox JAE, Daniel EE. Initiation of duodenal acid-induced motor complexes. Gastroenterology 1979;77:1217-24. Thompson DG, Wingate DL, Archer L, et al. Normal patterns of human upper small bowel motor activity recorded by prolonged radiotelemetry. Gut 1980;21:500-6. Arndorfer RC, Stef JJ. Dodds WJ, et al. Improved infusion system for intraluminal esophageal manometry. Gastroenterology 1977;73:23-7. Phillips SF, Giller J. The contribution of the colon to electrolyte and water conservation in man. J Lab Clin Med 1973; 81:733-46. Christensen J, Schedl HP, Clifton JA. The small intestinal basic electrical rhythm (slow wave) frequency gradient in
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normal man and in patients with a variety of diseases. Gastroenterology 1966;50:309-15. Committee on Dietary Allowances, Food and Nutrition. Board, National Research Council: Recommended dietary allowances. Washington, D.C.: Washington National Academy of Sciences Publications, 1974:34. Connell AM. The motility of the pelvic colon. 1. Motility in normals and in patients with asymptomatic duodenal ulcer. Gut 1961:2:175-86. Dodds WJ, Stef JJ, Hogan WJ. Factors determining pressure measurement accuracy by intraluminal esophageal manometry. Gastroenterology 1976;70:117-23. Code CF, Marlett JA. The interdigestive myo-electric complex of the stomach and small bowel of dogs. J Physiol (Lond) 1975;246:289-309. Helm JD, Kramer P, MacDonald RM, Ingelfinger FJ. Changes in motility of the human small intestine during sleep. Gastroenterology 1948;40:135-7. Fink S. The intraluminal pressures in the intact human intestine. Gastroenterology 1959;36:661-71. Ritchie HD, Thompson DG, Wingate DL. Diurnal variation in human jejunal fasting motor activity. J Physiol (proceedings]: in press. Alvarez WC, Mahoney LJ. Action currents in stomach and intestine. Am J Physiol 1921;58:476-93. Daniel EE, Wachter BT, Honour AF, Bogoch A. The relationship between electrical and mechanical activity of the small intestine of dog and man. Can J Biochem Physiol 1960; 38:777-801. Poitras P, Steinbach JH, Van Deventer G, et al. Motilinindependent ectopic fronts of interdigestive myoelectric complex in dogs. Am J Physiol 1980;39:G215-20. Itoh Z, Takeuchi S, Aizawa I, et al. Changes in plasma motilin concentration and gastrointestinal contractile activity in conscious dogs. Am J Dig Dis 1978;23:929-35. DeWeever I, Eeckhout C, Vantrappen G, Hellemens J. Disruptive effect of test meals on interdigestive motor complex in dogs. Am J Physiol 1978;235:E661-5. Battle WM, Cohen S, Snape WJ Jr. Inhibition of postprandial colonic motility after ingestion of an amino acid mixture. Dig Dis Sci 1980;25:647-52. Wright SH, Snape WJ, Battle W, et al. Effect of dietary components on gastrocolonic response. Am J Physiol 1980; 238(3):G228-32.
1982;82:694-700
Variability of Motility of the Ileum and Jejunum in Healthy Humans PAUL KERLIN and SIDNEY PHILLIPS Gastroenterology
Unit, Mayo Clinic
and Mayo Foundation,
Motor patterns of the distal small bowel were defined in healthy humans, using a multilumen polyvinyl tube, passed by mouth in 11 healthy subjects. Five recording sites, spanning 100 cm of tube and featuring a nitrogen hydraulic infusion system, were used to obtain records during 6 h offasting and 6 or more hours after ingestion of a 600-kcal liquid test meal. The loci of recordings were designated as jejunal, ileal, or terminal ileal, as judged by the length of tube within the intestine and by fluoroscopy. During fasting, the migrating motor complex was present in all subjects and at all levels of the small intestine, but it could not be traced into the colon. Interdigestive cycles were defined primarily by the presence of an “activity front” (phase 3 of the migrating motor complex). Ninety-six migrating motor complexes occurred each 97 min (grand mean for all loci), but intervals between individual activity fronts varied markedly (15-195 min), in contrast to what is reported in other species. The velocity of aboral migration was 4.7 t 1.8, 1.3 it 0.4, and 0.9 + 0.2 cm - min-l (mean 2 SD) in jejunal, ileal, and terminal ileal, respectively. Rates of continuous, rhythmic contractions during activity fronts declined distally: 12.5 to 10.5 (jejunal), 10.9 to 9.3 (ileaf), and 10.0 to 8.6 cycle/min [terminal ileal], respectively. In individual subjects, maximum rates of contraction and velocities of migration always declined distally, but the duration of activity fronts was unrelated to the level of recording. Food interrupted the fasting cycles of motility for periods Received August 3, 1981. Accepted November 12, 1981. Address requests for reprints to: SF. Phillips, M.D., Gastroenterology Unit, Mayo Clinic, Rochester, Minnesota 55901. This work was supported in part by the Mayo Foundation and Research Grant RR 00585, Public Health Service, Bethesda, Maryland. Dr. Kerlin was Rappaport Fellow of the Mayo Foundation; his present address is Department of Gastroenterology, Princess Alexandra Hospital, Brisbane, Australia. The authors thank Mrs. Anne Haddad and Mr. Richard Tucker for expert technical assistance and Mrs. Mary Hanenberger for her secretarial assistance. 0 1982 by the American Gastroenterological Association 0016-5085/82/040694-07$2.50
Rochester,
Minnesota
ranging from 2.75 to >lO h. The transition from the fasting to the fed pattern was prompt and the postprandial motility was that of irregular bursts of contractions interspersed with transient quiescence. These studies demonstrate that the migrating motor complex occurs throughout the human small intestine, and that inter- and intraindividual variations are marked; food disrupts the complex for variable periods. These variations must be considered when abnormalities are being sought in disease states. Unlike the upper intestine proximal to the ligament of Treitz and the hindgut distal to the sigmoid colon, the motility of the human ileum and proximal colon is largely unexplored. Reasons why these segments have received little attention include their relative inaccessibility in humans and the lack of reliable techniques of recording. For example, descriptions of human ileal motor patterns still rely on results of balloon-kymograph recordings from retrograde intubation of ileostomies (1). However, the ileum has several special absorptive functions, including the active transport of electrolytes, vitamin B12, and bile acids, as well as the capacity to compensate dramatically for the loss of reabsorptive surface following resection of the proximal bowel (2). Further, the ileocecal junction has characteristics of a sphincter which probably prevents reflux of bacteria into the small intestine (3,~). Less well established, but of considerable potential importance, are the storage of thyme and its controlled entry into the colon (5). Thus, the motility of the ileum could be an important determinant of a variety of absorptive events. Recent concepts of fasting motility in the stomach, duodenum, and proximal jejunum (6-11) have emphasized the interdigestive migrating motor complex (MMC). This is the motor equivalent of the interdigestive migrating myoelectric complex (IDMEC), first described in the canine small intestine by Szurszewski in 1969 (6). Although Fleckenstein (7) has recorded an IDMEC in the human ileum of 2 subjects, its motor equivalent has received little atten-
April
MOTILITY
1982
tion. However, an understanding of motor activity and transit in ileum and jejunum may be relevant to huinan disease, since Vantrappen et al. (8) have reported disturbances of MMCs in the proximal intestine of patients with bacterial overgrowth. The aims of this study were to utilize recent developments in manometric techniques to record fasting motor activity at all levels of the intact human small intestine, and to examine the effect of a meal on these motor patterns.
Materials and Methods Volunteers Eleven healthy volunteers (8 men and 3 women, aged 19-67 yr, mean 36 yr) participated in these studies after giving informed, written consent. The protocol was approved by the Mayo Clinic Human Studies Committee in December 1979. Intestinal
Tube
A multilumen polyvinyl (PV) tube of 450 cm was constructed by bonding separate catheters (ID 0.9 mm) with tetrahydrofuran; a small mercury weight led the tube, to facilitate transit. One catheter was radiopaque to facilitate its location fluoroscopically. The perfusion sites were located at side holes, cut proximal to occluding steel plugs at 0, 20, 60, 80, and 100 cm from the distal end. The maximal outer diameter of the catheter bundle was 4.5 mm. Recording
System
The technique was based on the hydraulic capillary infusion system described by Arndorfer et al. for esophageal manometry (12). A head of nitrogen pressure (10 psi) was applied to a plexiglass chamber that was connected by stainless steel capillary tubing to Konigsberg pressure transducers (model P3535; Konigsberg Inc., Pasadena, Calif.). The flow rate was 0.1 ml * min-’ (60 cm, 30 gauge steel capillary tubing) in four capillaries and 0.5 ml * min-* (40 cm, 27 gauge) in the other. The proximal ends of the intestinal tubes connected to the transducers. The i&sate (100 mM NaCl, 10 mM KCl, 45 mM NaHC03) simulated the composition of fasting contents of the distal small intestine (13). A belt pneumograph recorded respiration simultaneously via a sixth transducer. The output from all transducers was displayed on a Honeywell or M.F.E. 1600 recorder, using a paper speed of 0.25 mm - s-‘.
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Amplitude of recording response to transient pressures. A syringe driven by ar eccentric cam (Harvard Respirator) was used to apply sine waves of pressure at two frequencies to a chamber. Within the chamber, a Millar M&o-Tip Transducer (Millar Instruments, Inc., Houston, Tex.) acted as a pressure reference. The ends of two PV catheters (450 cm, flow rate 0.1 ml * min-’ and 390 cm, flow rate 0.5 ml * min-‘) were placed within the chamber and an airtight seal ensured. Pressure transients were applied at 12 cycle/min, to stimulate the duodenal slow-wave frequency (14) and at 60 cyclelmin, a frequency that exceeds any anticipated in the small intestine. Amplitudes of responses for the PV catheters were expressed as the percentage of the amplitude recorded simultaneously by the reference (Millar) transducer. Protocol Subjects were intubated by mouth after an over night fast. During distal passage of the tube, subjects were fed a low residue diet in the Clinical Research Center. Before each recording session the tube locus was classified as jejunal (J), ileal (I), or terminal ileal (TI) on the basis of fluoroscopy and length of tube from the teeth to the distal end, after “slack” had been removed from the stomach. In general, for jejunal studies the tube was sited fluoroscopitally on the left side of the abdomen and up to 200 cm had passed beyond the teeth. For ileal studies the tube had progressed to the lower abdomen and its tip was beyond 200 cm from the teeth. For the tube to be located in the terminal ileum required the simultaneous recording of motor activity in the cecum from the terminal locus. Fasting motility of the small bowel was recorded for approximately 6 h in all subjects and in 9 subjects recording was continued for about 6 h after a test meal. Studies were begun in the early morning, after the position of the tube was noted. Fluoroscopy was repeated after each recording session to confirm the location of the tube. Composition
of Meal
The liquid test meal contained 30 g of VIP (a mixture of amino acids, from Synergy Plus, 2530 Polk St., Union, N.J.), 60 g of Polycose (glucose polymers derived from corn starch, Ross Laboratories, Columbus, Ohio), and 26 g of emulsified corn oil. These nutrient proportions (protein 20%, carbohydrate 40%, fat 40%) resemble those in the average American diet (15). Water (260 ml) was added to provide a final volume of 400 cm3. The emulsified meal provided 600 cal and had a measured osmolality of 450 mosmol (5100 B Vapor Pressure Osmometer, Wescar, Inc., Logan, Utah). Definitions
Characteristics
of the Manometric
System
Response of catheters to end occlusion. Occlusion of catheters was used to determine the performance of the infusion system and transducers at both rates of flow. A 390-cm length of catheter (perfused at 0.5 ml . min-‘) was occluded and a 450-cm catheter (flow rate 0.1 ml - min-‘) was occluded at 50-cm intervals from the distal end.
Migrating motor complexes were defined by the presence, and aboral migration, of “activity fronts” (AF: phase 3 of the MMC). Phase 3 was defined as 3 min or more of uninterrupted rhythmic contractions, followed by quiescence. Migration required the recording of phase-3 activity from at least three sequential recording points. The period between MMCs was the mean interval between
696
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KERLIN AND PHILLIPS
successive activity fronts from each study. The rate of rhythmic contractions was measured at each recording site as the number of contractions per minute during 3 or more minutes of continuous contractions in phase 3. The duration of phase 3, from the onset of regular contractions to quiescence, was calculated for each study. The velocity of migration (cm * min-‘) of the MMC was assessed by dividing the distance transversed by the migrating phase 3 by the time taken to cross three to five recording sites. Recordings of motility between periods of phase-3 activity were divided arbitrarily into phase 1 [quiescence) and phase 2 (intermittent activity). The contribution of phases 1, 2, and 3 to the length of each complete cycle was calculated. To determine how often a MMC originated beyond the ligament of Treitz, the frequency of “distal starts” was assessed. A distal start required the absence of phase 3 at higher levels, within the anticipated time interval. To compensate for the adequacy of our recording system, the number of incomplete jejunal MMCs was also assessed, i.e., (a) the number of MMCs in which phase 3 “skipped” a recording site and (b) the number of MMCs showing incomplete distal migration. The motility index of the proximal colon was calculated by the product of the total duration of activity and the mean amplitude of the pressure waves (16). The colonic motor response to the meal was assessed by comparing the motility index in the hour before the test meal to the first postprandial hour. Statistical
Analyses
Analyses were performed using the paired t-test and results were considered significant if p < 0.05.
Results Characteristics
of the Manometric
System
end occlusion. At 0.1 Response to ml - min-l, occlusion of outflow at the level of the transducer elicited a pressure rise rate of 42 mmHg - SC’. When the pressure response to occlu-
J
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sion of different lengths of tubing was measured, the rise was 24 mmHg - s-l with 450 cm of tubing, 27.5 mmHg - s-l with 350 cm, and 36 mniHg * s-l with 50 cm. With the faster infusion rate, 0.5 ml * min-I, occlusion at the level of the transducer elicited a rise of 310 mmHg * s-l; adding 390 cm of PV tube gave a postocclusion rise of 134 mmHg - s-l. Amplitude response. At a frequency of 12 cycle/min the infused catheters registered all waves and the mean amplitude was 96% of that recorded simultaneously by the Millar transducer. At 60 cycle/min there was also less than 5% damping compared to the reference transducer. Fasting
Studies
Migrating motor complexes were recognized in all subjects and at all levels of the small intestine (Figure i). At the jejunal level, 7 subjects contributed 13 separate days of study. Fifty-nine MMCs were identified in 86.5 h of recording. At the ileal locus, 5 subjects provided 8 days of study. Twenty MMCs were noted in 47.75 h of recording. In the terminal ileum, 5 subjects were studied, 1 person on two occasions. Seventeen MMCs occurred in 37 h of recording. The periods between MMCs, characteristics of the activity front, and the velocities of its migration are shown in Table 1. The mean period between MMCs was approximately 90 min, but the range was wide, from 15 min to >3 h. This variability in periodicity is demonstrated in Figure 2, which shows the range of intervals in individuals having three or more MMCs in any recording session. The duration of phase 3 was also variable, both between and within subjects. In general, phase-3 activity lasted from 7 to 12 min and was unrelated to the level of recording. In every study the velocity of migration of the MMC decreased with distal progression along the small
o
520 540 J80 Jloo Reapkatbn
Figure
I. Migrating motor complex adjacent to each tracing.
in the human jejunum.
The distance
of the recording
orifices from the ligament
of Treitz is shown
MOTILITY OF HUMAN SMALL BOWEL
April 1982
Table 1.
Characteristics of the Activity Front (Phase 3 Migrating Motor Complex) and Migration in Healthy
697
Humans Terminal ileum
Jejunum
Ileum
Period between MMCs (min) (Mean -t SD) Range
100 2 42
94 k 45 41-188
37-195
Rate of contractions during phase 3
12.5-10.5
10.9-9.3
10.0-8.6
Duration of phase 3 (min) (Mean ‘- SD) Range
7.3 k 1.8
11.6 f 3.4
11.1 IT 4.1
3-11
3-23
3-42
Velocity of migration (cm/min)
4.7 t 1.8
1.3 2 0.4
0.9 + 0.2
15-184
(No./min)
of MMC
84 2 17
Values are mean ? SD and/or range.
intestine. Five subjects had recordings at two or more intestinal loci on separate days. In these subjects the maximum rate of contraction and the velocity of migration always declined distally. The rate of rhythmic contractions decreased in an orderly sequence from the duodenum to the distal ileum (Figure 3). This aboral decline in frequency of contractions could be noted also over the total recording distance of 100 cm, for any individual study (p < 0.05). One subject, illustrated in Figure 3, had a rhythmic rate of contractions that was faster than the other 10 subjects, and this was seen at all loci. The duration of each phase of the MMC was
established at the three recording loci; the results are shown in Figure 4. At the more distal sites (ileum and terminal ileum) the active phases (2 and 3) were more prominent and the quiescent phase (1)was shorter. However, inter- and intraindividual variability was prominent. In several subjects, phase 2 shortened markedly when the patient was asleep. Thus, motility in these persons consisted mainly of quiescence interrupted periodically by phase-3 periods. Migrating motor complexes with a distal start could be identified confidently only in the jejunal studies. In these, 10 (17%) of the 59 MMCs originat-
240 .
Je junum . . . . . . . . . . . . Ileum . -----Terminal ileum 160 Maximum and minimum period between MMC’s (min)
120 -
80 -
1
40
80
I
,
120
,
1
140
Mean period between MMC’s (min) Figure
2. The mean period between successive activity fronts (phase 3 of MMC) for individuals with three or more MMCs in a single recording session is shown on the abscissa. The range for each individual for the same recording period is plotted on the ordinate. Numbers refer to individual subjects, some of whom contributed more than one recording session.
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Figure
GASTROENTEROLOGY
KERLIN AND PHILLIPS
3. The frequency gradient of regular, rhythmic contractions in the human small intestine. The solid line represents the mean rate of contractions determined during activity fronts. The hatched area depicts the range of values encountered at any distance from the teeth. The go-cm mark is the approximate location of the ligament of Treitz. Plotted separately are the values of a subject with a considerably faster rate of contraction at all loci.
Contractions per minute
10
-
8
-
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7lI
1
I
70
00
I
I
110
I
130
I
I
I 150
I
I 170
I 190
I
I 210
I
I
I 230
I
J
250+
Distance from incisor teeth (centimeters)
ed beyond the ligament of Treitz at 110-150 cm (median 135 cm) beyond the incisor teeth. In contrast, a MMC was seen to “skip” a single recording site in two of 59 complexes and three MMCs well established proximally were not detected distally. Recordings of cecal motility were obtained in 5 subjects. Motor activity was variable and not clearly related to the arrival of MMCs in the terminal ileum. The motility index in the first hour after the meal was not enhanced when compared with the hour before eating (0.5 < p < 0.1). When contracting regularly, the predominant frequency was 6 cycle/ min, although both faster and slower rhythms were noted infrequently. Postprandial
Studies
After fasting recordings, 9 subjects ingested the liquid test meal. Eating disrupted the cycle of interdigestive motor activity at all levels of the small intestine. Migrating motor complexes were recorded at the start of the meal in six instances (jejunal 3, ileal 2, terminal ileal 1). In each case, progression of the MMC was interrupted and a postcibal pattern of motility was established. This consisted of short random contractions, interbursts of irregular, spersed with transient periods of quiescence. The maximum rate of contraction, assessed during activity lasting more than 60 s, was identical to that occurring in the same subject during fasting. An MMC returned at variable times after the meal (Table 2). This variability was present between and within subjects.
system offers the opportunity of recording motility throughout the human small intestine and proximal colon. Shorter, stiffer tubing (such as polyethylene) and faster rates of infusion provide theoretical advantages (12,171 but we chose 450 cm of polyvinyl tubing and lower flow rates so that our subjects could sleep without restraint. In addition, although polyethylene is less compliant (and better theoretically) than PV tubing, it cannot be bonded easily and the tube assembly may be less well tolerated. Of practical importance, the performance of our recording system during tests in vitro gave us confidence in employing the assembly of long polyvinyl tubes. Our major finding is that the MMC could be identified in all subjects and at all levels of the small intestine. Further, inter- and intraindividual variations were prominent, in contrast to previous studies in the canine small intestine (6,18). Thus, the interval between MMCs was highly variable and the recording of a MMC within 15 min of an earlier sequence challenges the relevance to humans of suggestions that a MMC begins in the upper gut only
43 intervals 7 aubjecta JEJUNUM 11 intervals 4 aubjecla
15 intervala 6 subjects
Phase
Discussion This study demonstrates that motility of the human distal small bowel can be recorded faithfully, using long polyvinyl tubes and low rates of flow. Our
Figure
4.
I
Phase
II
Phase
Ill
The percent duration of individual phases of the MMC at various levels of the human small intestine during fasting. The values are mean -t SD, and the length of each MMC has been normalized to a value of lOOa&
April
1982
Table
2.
MOTILITY
Duration Humans”
of Fed
Pattern
of Motility
in Healthy
Postprandial recording time (h) Site of Recordinab
Subject No.
Total
i
1 1
t
3 2
6 6 6.75
I I I I I I TI TI TI TI TI
4 4 5 6 7 8 9 9 5 6 3
5.5 5.5 6.5 6.75 6.5 7.5 6.25 18.5 17.75 18 18.25
MMC returned bv
a After a meal of 600 kcal (40% fat, 40% carbohydrate, protein). b J = jejunal; I = ileal; TI = terminal ileal.
5
2.75 4.25 6.75
5.75 4.25
4.5 10.5 6 8.75 20%
when the preceding sequence reaches the terminal ileum (6,18). As suggested by others (8) phase-3 activity was the most readily defined facet of fasting motility. It is possible that the activity front (phase 3) increases in duration distally, as noted during recordings of the IDMEC. For instance, Fleckenstein recorded a phase 3 lasting 36 min in the ileum (7). However, sleeving of the intestine on the tube cannot be quantified and yet may contribute to any apparent increase in duration of the activity front. In our subjects, there was no consistent increase when individuals were studied at more than one level. The velocity of migration of the MMC slowed with aboral progression of the recording site. This is in keeping with Fleckenstein’s finding (7) and with results in the canine model (6,18). The relative contribution of phases 1, 2, and 3 to length of MMC cycle was also variable. This variability was noted from one MMC cycle to the next in most subjects and within a single cycle recorded simultaneously at several recording sites. Phase-2 activity became brief or absent in some subjects during sleep, although we did not monitor the stage of sleep by electroencephalography. This depression of general motor activity (19,20) and specifically of phase-2 activity has been noted by others (21). Fleckenstein (7) reported that phase 1 may at times be quite brief or even absent, supporting the concept of variability. The maximum rate of intestinal contraction was most readily assessed during the regular uninter-
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rupted contractions that characterized phase 3. A gradient was observed from proximal jejunum to terminal ileum, equivalent to the “Alvarez gradient” (22); it was readily apparent and consistent. This finding is in keeping with the slow-wave gradient reported by Christensen et al. (14) in the intact bowel and with results from isolated studies featuring intubation of ileostomies (23). One subject demonstrated a jejunal rate of contraction that was above our normal range consistently, and also more rapid than the slow-wave frequency of Christensen. Thyroid function (14) was tested, found to be normal, and no other explanation was found. Ten of the 59 jejunal MMCs originated beyond the ligament of Treitz. This figure agrees well with the 21% incidence of distal starts reported by Vantrappen et al. (8). Recent studies in the dog suggest that activity fronts which begin beyond the duodenum may be controlled separately from those fronts that begin in the distal stomach (24). Thus, “ectopic” fronts are independent of the cyclic fluctuations in plasma motilin which are concomitant with the gastroduodenal onset of MMCs in the dog (24,25). Further, 100 g of meat interrupts proximal activity fronts, but ectopic fronts persist after the meal (24). In our studies, the appearance of MMCs in the distal bowel postprandially was always delayed, and this finding argues against the persistence of cyclic activity in the human distal bowel after a meal. Our liquid test meal produced a prompt change in motor activity. We never recognized a progression of phase-3 activity to more distal recording sites after a meal was commenced, suggesting that phase-3 activity is stopped “in its tracks.” The postprandial activity consisted of noncyclical, intermittent, irregular contractions. The MMC returned at a variable interval, ranging from 2.75 h in the jejunum to over 10 h in the terminal ileum. Our test meal was designed to be palatable and to simulate the mixed composition of the average U.S. diet. DeWeever et al. (26) investigated the disruptive effect of equicaloric nutrients in the dog and determined that oil, sucrose, and milk protein was associated with progressively shorter fed patterns of motility. Failure to demonstrate augmentation of motility in the proximal colon following the test meal may be due to the nature of the meal. Recordings of the motor response of the distal colon to a meal (27,28) suggest that amino acids may inhibit the excitatory effect of other meal components on the postprandial response. These studies were designed to document the feasibility of recording faithfully the motor patterns of the human distal small bowel. We believe our system offers an acceptable approach and that these data provide a basis for further studies of factors that modify ileal motility in health and disease. The
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KERLIN AND PHILLIPS
variations noted here in health must be considered when perturbations are sought in later studies.
15
References 1. Hightower
2. 3.
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NC. Motor action of the small bowel. In: Code CF, ed. Handbook of physiology, Section 6, Alimentary canal, Vol IV, Motility. Washington, DC.: American Physiological Society, 1968:2001-24. Weser E. The management of patients after small bowel resection. Gastroenterology 1976;71:146-50. Cohen S, Harris LD, Levitan R. Manometric characteristics of the human ileocecal junctional zone. Gastroenterology 1968;54:72-5. Kelley ML Jr, DeWeese JA. Effects of eating and intraluminal filling on ileocolonic junctional zone pressures. Am J Physiol 1969;216:1491-5. Gazet JC, Kopp J. Surgical significance of the ileocecal junction. Surgery 1964;56:565-73. Szurszewski JH. A migrating electric complex of the canine small intestine. Am J Physiol 1969;217:1757-63. Fleckenstein P. Migrating electrical spike activity in the fasting human small intestine. Am J Dig Dis 1978;23:769-75. Vantrappen G, Janssens J, Hellemans J, Ghoos Y. The interdigestive motor complex of normal subjects and patients with bacterial overgrowth of the small intestine. J Clin Invest 1977;59:1158-66. Rees WDW, Go VLW, Malagelada JR. Simultaneous measurement of antroduodenal motility, gastric emptying and duodenogastric reflux in man. Gut 1979;20:963-70. Lewis TD, Collins SM, Fox JAE, Daniel EE. Initiation of duodenal acid-induced motor complexes. Gastroenterology 1979;77:1217-24. Thompson DG, Wingate DL, Archer L, et al. Normal patterns of human upper small bowel motor activity recorded by prolonged radiotelemetry. Gut 1980;21:500-6. Arndorfer RC, Stef JJ. Dodds WJ, et al. Improved infusion system for intraluminal esophageal manometry. Gastroenterology 1977;73:23-7. Phillips SF, Giller J. The contribution of the colon to electrolyte and water conservation in man. J Lab Clin Med 1973; 81:733-46. Christensen J, Schedl HP, Clifton JA. The small intestinal basic electrical rhythm (slow wave) frequency gradient in
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