Official Publication of the American Gastroe1lterological Association

Transcription

1 Official Publication of the American Gastroe1lterological Association COPYRIGHT 1977 THE WILLIAMS & WILKINS Co. Vol. 72 March 1977 Number 3 ALIMENTARY TRACT EVIDENCE THAT ABNORMAL MYOELECTRICAL ACTIVITY PRODUCES COLONIC MOTOR DYSFUNCTION IN THE IRRITABLE BOWEL SYNDROME WILLIAM J. SNAPE, JR., M.D., GERALD M. CARLSON, PH.D., STEPHEN A. MATARAZZO, M.D., AND SIDNEY COHEN, M.D. Gastrointestinal Section, Department of Medicine, University of Pennsylvania at the Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania Although the irritable bowel syndrome is characterized as an abnormality in colonic motor activity occurring in response to certain stimuli, the etiology of this disorder is unclear. The purpose of this study is to determine the relationship of altered slow wave activity and the abnormal motility of the distal colon seen in patients with the irritable bowel syndrome. Myoelectrical activity was recorded using a bipolar electrode clipped to the distal colonic mucosa and motor activity was measured by perfused catheters. Colonic slow waves and contractions were present at two frequencies, 6 and 3 cycles per min. The slow wave frequency seemed to determine the frequency of colonic motor activity. Patients with the irritable bowel syndrome had increased 3-cycle per min slow wave activity in the basal state (P < 0.001). However, no difference in basal3-cycle per min motor activity was present between the two groups (P > 0.05). When colonic motor activity was increased with cholecystokinin or pentagastrin, patients with irritable bowel syndrome showed a marked increase in 3-cycle per min contractile activity, occurring simultaneously with 3-cycle per min slow wave activity. These studies suggest that increased colonic 3-cycle per min slow wave activity in patients with the irritable bowel syndrome may be the basic abnormality that leads to colonic motor dysfunction in response to various physiological stimuli. The irritable bowel syndrome is a disorder that is manifested by the clinical features of an altered bowel habit and abdominal pain. 1 The characteristic radiographic changes in patients with irritable bowel syn- Received June 30, Accepted August 27, This paper was presented in part before the plenary session of the American Gastroenterological Association, Miami Beach, Florida, May 24, Address requests for reprints to: William J. Snape, Jr., M.D., 570 Maloney Building, Hospital of the University of Pennsylvania, 3400 Spruce Street, Philadelphia, Pennsylvania This work was supported by Research Grant 5 R01 AM from the National Institutes of Health. Dr. Cohen's work is supported by Research Career Development Award 5 K04 AM from the National Institutes of Health. The authors wish to thank Drs. E. Raffensperger and R. Soloway for allowing us to study their patients. The authors also thank Ms. Susan Kocmund and Mrs. Fe Green for expert technical assistance, and Ms. Wendy Owen and Ms. Mary Carroll for secretarial assistance. 383 drome are a diminution in distal colonic diameter and an increase in colonic haustrations. 2 An abnormality in colonic motor function has been demonstrated in patients with this clinical disorder. 3,4 Intraluminal pressure measurements have shown abnormal patterns of motor activity in response to emotional stress, feeding, cholinergic drugs, gastrointestinal hormones, or rectal distention.4-9 Most recently, we have demonstrated a basic difference in the myoelectrical activity of the distal colon in patients with the irritable bowel syndrome.!o Patients with the irritable bowel syndrome had an increased amount of slow wave activity occurring at a frequency of 3 cycles per min as compared to normal subjects. The purpose of this study is to determine a possible relationship between altered slow wave activity and colonic motor dysfunction in patients with the irritable bowel syndrome. These studies suggest that an abnormal pattern of colonic slow wave rhythm in patients with the irritable bowel syndrome may predispose to the altered colonic motor activity in this disease.

2 384 SNAPE ETAL. Vol. 72, No.3 Methods The diagnosis of the irritable bowel syndrome was made in 13 women and 7 men (ages 23 to 69) using the following criteria: (1) diarrhea, constipation, or a combination of both, lasting more than 3 months; (2) unexplained abdominal pain either related or unrelated to meals; (3) normal sigmoidoscopic examination, barium enema, and upper gastrointestinal radiographic study; (4) absence of ova or parasites and pathogenic bacteria on stool examination and culture; and (5) a negative history for lactose intolerance. All patients were symptomatic at the time of the study. Nine male and 3 female subjects (ages 21 to 47) served as controls. The controls had no history of gastrointestinal disease or previous abdominal surgery. Informed consent was obtained from each patient and subject. Studies were approved by the Committee on Studies Involving Human Beings of the University of Pennsylvania. All patients and subjects underwent sigmoidoscopy without air insufflation. Two or three bipolar silver-silver chloride wire electrodes were attached to the colonic mucosa 5 to 22 cm from the anus under direct vision through the sigmoidoscope. The type of electrode used in these studies has been previously described. 10 Two silver wires were implanted in an acrylic disc with the tips of the wires protruding 1 mm from the surface of the disc. The distance between the two electrode tips was 2 mm. Each silver wire electrode was soldered to a Tefloninsulated copper wire. The solder joint was covered with waterproof epoxy resin. Each bipolar electrode was connected to a junction box containing a-1iis amp fuse. The junction box was in tum connected to a rectilinear recorder (Beckman R411, Beckman Instruments, Inc., Fullerton, Calif.) through an A-C coupler (9806A) with a time constant of 1.0 sec and a 22-Hz filter. All subjects were grounded through an ECG surface electrode attached to the right leg. Intraluminal pressure was measured at the same level as each recording electrode. Pressure was measured using waterfilled polyvinyl catheters (1.4 mm-inner diameter) with side orifices of 1.2-mm diameter. Each catheter was continously perfused with distilled water at 4.0 ml per hr using an infusion pump (Harvard 2215, Harvard Apparatus Company, Millis, Mass.). Pressure was transmitted to transducers (Statham P231A, Statham Instruments, Oxnard, Calif.) and recorded simultaneously with the myoelectrical activity. Respirations were monitored by a pneumograph belt placed around the chest and connected to a transducer. Myoelectrical and intraluminal pressure recordings were begun 30 min after removal of the sigmoidoscope. During a 30- to 60-min control period, normal saline (0.9% NaCl solution) was infused intravenously, with the subject in the left lateral decubitus position. After the control period, pentagastrin (Ayerst Laboratories, New York, N.Y.), 0.5 flg per kg or cholecystokinin (GIH Research Unit, Karolinska Institute, Stockholm, Sweden), 1.0 U per kg were infused intravenously over a I-min period. The myoelectrical activity and intraluminal pressure were recorded for 30 min after injection. The gastrointestinal hormones were injected intravenously in a random order, with at least 45 min elapsing between injections. Each myoelectrical recording was evaluated for slow waves and spike potential bursts by two investigators. Slow waves appeared as regular, cyclical changes in electrical potential. Colonic slow waves were differentiated from respirations by differences in frequency. Spike potentials appeared as rapid fluctuations in electrical potential. Movement artifacts gave changes that occurred simultaneously in the myoelectrical, pressure, and respiratory recordings. These artifacts were easily differentiated from slow waves and spike potentials. The recordings were analyzed for the percentage of total recording time during which slow wave activity was present. Slow wave frequency was determined from continuous runs of slow waves lasting at least 90 sec. Spike potentials were counted over each 15-min period. Only one spike potential was counted per slow wave cycle. Pressure was evaluated by: (1) determining the number of contractions during each 15-min period; and (2) calculating a motility index (i.e., product of the mean amplitude of the pressure waves multiplied by the sum of duration of each pressure wave) for each 15-min period. ll The contraction frequency was determined from each series of contractions present continuously for at least 90 sec. Statistical analysis was made using the paired and unpaired Student t-test and X2 test. Results Myoelectrical activity consisting of both slow waves and spike potentials were recorded in all subjects. In figure 1 is shown representative myoelectrical and pressure tracings demonstrating the two basic types of slow wave activity recorded in normal persons and in patients with the irritable bowel syndrome. Figure 1A illustrates slow waves at a frequency of 6 cycles per min, and figure 1B illustrates slow waves at a frequency of 3 cycles per min. The 3-cycle per min slow wave activity comprised significantly more (39.6 ± 4.2%) of the total slow wave activity in patients with irritable bowel syndrome as compared to normal subjects (9.9 ± 2.2%) (P < 0.001). In figure 2 is shown the relationship of the frequency of contractions and the simultaneously recorded frequency of slow waves in all patients and subjects. Colonic contractions occurred at two frequencies, approximately 3 and 6 cycles per min. Continuous colonic contractions at 2.7 ± 0.1 cycles per min were associated with slow waves at 3.2 ± 0.1 cycles per min for 75.9% of the time. The remainder of the 3-cycle per min contractions were accompanied either by 6-cycle per min slow waves (16.1%) or isoelectric periods (8.0%). Likewise, B Myoelectric (8 cm from onus) mmh9 20 Pressure (13 em from onus) 1 0 l - ~ ~ A o ~ I m i n u t e ~ FIG. 1. Simultaneous recordings of myoelectrical activity, intraluminal pressure and respiration. A, record obtained in a normal subject; the slow wave frequency is 6.2 cycles per min. B, record obtained in a patient with irritable bowel syndrome; the slow wave frequency is 3.1 cycles per min. Neither record showed spike activity nor colonic contractions.

3 March 1976 MYOELECTRICAL AND MOTOR ACTIVITY IN IRRITABLE BOWEL 385 '" ~ ""- ~ " ~ Controctions - Contractions - subjects and in patients with the irritable bowel syndrome. There was no change in the total slow wave 3 Cycle / Minute 6 Cycle / Minute activity after cholecystokinin or pentagastrin administration in either group. After cholecystokinin or pentagastrin administration, the percentage of 3-cycle per min slow wave activity remained significantly higher in patients with the irritable bowel syndrome (P < 0.001). Spike potentials were increased equally in both groups by cholecystokinin or pentagastrin (P < 0.005). The motility index was also increased equally in both groups by cholecystokinin or pentagastrin (P < 0.01). Thus, both normal subjects and patients with the irritable bowel syndrome had quantitatively similar responses to the administration of either cholecystokinin or pentagastrin. A correlation coefficient between spike potentials and motor activity was not determined because intraluminal pressure is an insensitive measure of smooth muscle contractility. Although there was no difference in the motility index for the two groups, patients with the irritable bowel syndrome had more 3-cycle per min motor activity in response to both cholecystokinin and pentagastrin. In o ~ ~ ~ ~ ~ - - figure ~ 5 ~ is shown ~ a ~ recording - of -myoelectrical activity FIG. 2. Relationship of the frequency of colonic slow waves and contractions in all patients and subjects. The percentage of total time during which either 3- or 6-cycle per min colonic contractions were recorded was related to the simultaneous slow wave frequency. continuous colonic contractions at 6.0 ± 0.2 cycles per min were associated with slow waves at 6.2 ± 0.2 cycles per min for 89.0% of the time. The remainder of the 6- cycle per min contractions were accompanied by 3-cycle per min slow waves (5.5%) or isoelectric periods (5.5%). The relationship between contractions and slow wave frequency was similar both in the patients and in the normal subjects. Thus, the frequency of colonic contractions seemed to be closely associated with the underlying slow wave frequency (X 2 = 33.6, P < 0.001). In addition, contractions were more likely to be present during periods of slow wave activity and were rare during isoelectric periods. Because patients with the irritable bowel syndrome had increased 3-cycle per min slow wave activity, the percentage of total time occupied by 3-cycle per min colonic motor activity was compared in normal persons and in patients with the irritable bowel syndrome. In figure 3 is the basal 3-cycle per min motor activity both in the patients and in the normal subjects. The percentage of recording time during which continuous 3-cycle per min motor activity was present was plotted for each individual. Although a wide range of values was seen, the mean percentage of time occupied by 3-cycle per min motor activity was similar in both groups (P > 0.05). Thus, in the basal state, the significant increase in slow waves at a frequency of 3 cycles per min was not reflected in a significant increase in 3-cycle per min motor activity in patients with the irritable bowel syndrome. After the basal recording period, cholecystokinin or pentagastrin was given intravenously. In figure 4 is shown the myoelectrical and intraluminal pressure response to cholecystokinin or pentagastrin in normal and intraluminal pressure in a patient with the irritable bowel syndrome. The onset of 3-cycle per min motor Basal Normal 3 Cycle / Min Contractile Activity % I -10- B ffi "" a.. FIG. 3. Percentage of total basal recording time occupied by 3- cycle per min colonic contractions in normal subjects and in patients with the irritable bowel syndrome. Each point represents the value obtained during a single 30-min recording period. The mean ± SE is represented by the box.

4 386 SNAPE ETAL. Vol. 72, No.3 activity occurred 7 min after administration of cholecystokinin during a period of 3-cycle per min slow wave activity. In contrast to the basal period in which only a few slow waves had simultaneous accompanying con- 60 Normals Percent Slow Wave Activity Percent 3 Cycle / Min. Slow Waves tractions, all 3-cycle per min slow waves were now associated with 3-cycle per min motor activity after cholecystokinin administration. Figure 6 shows the percentage of time occupied by 3- cycle per min motor activity after the administration of cholecystokinin or pentagastrin. A greater percentage of 3-cycle per min motor activity was seen in patients with the irritable bowel syndrome after cholecystokinin (P < 0.01) or pentagastrin (P < 0.05). The increase in motor activity in normal subjects was composed of isolated contractions or 6-cycle per min contractions. Therefore, it seemed that the observed difference in the prevalence of the two slow wave frequencies was manifested in different frequencies of colonic motor activity only during periods of increased motor activity. The 3 Cycle / Minute Contractile Activity CCK - Cholecystokinin PG - Pentagaltrin 35 Normal Spike Potentials 1 5 ~ I ~ t ~ Motility Index., ~ CCK - Chole.,atoklnln PG - Pentooaalrln Basol CCK PG Basol CCK PG FIG. 4. Parameters of myoelectrical and motor activity in normal subjects and in patients with the irritable bowel syndrome under basal conditions and in response to cholecystokinin (CCK) or pentagastrin (PC). Slow wave activity as a percentage of total recording time was similar in both groups and did not change after hormone administration. Slow wave (3 cycles per min) activity as a percentage of total slow wave activity was increased in patients with the irritable bowel syndrome but did not change with the hormones. Spike potentials and motility were increased equally by cholecystokinin or pentagastrin; the change was similar in both patients and in normal subjects o L - ~ ~ ~ ~ ~ L - Basal CCK PG Basal CCK PG FIG. 6. Percentage of total recording time occupied by 3 cycles per min of colonic contractions for the lo-min period after cholecystokinin (CCK) or pentagastrin (PC) administration in normal subjects and in patients with the irritable bowel syndrome. Mean + SE are shown. Pressure (17em from Anus) Pressure (15 em from Anus) Respirations minute----l FIG. 5. Simultaneous recordings of colonic myoelectrical activity and intraluminal pressure obtained in the distal colon of a patient with the irritable bowel syndrome after cholecystokinin administration. The frequency of slow waves and the colonic contractions are both 2.9 cycles per min. Respirations are shown below.

5 March 1976 MYOELECTRICAL AND MOTOR ACTIVITY IN IRRITABLE BOWEL 387 quantification of spike-burst activity or motility index did not distinguish between these qualitative differences in types of colonic motor activity in normal persons and in patients with the irritable bowel syndrome. Discussion Studies in patients with the irritable bowel syndrome have demonstrated abnormalities in both colonic motor activity and colonic myoelectrical activity.4-io Colonic contractions at a frequency of approximately 2 to 3 cycles per min have been previously recorded in the pelvic colon, and are considered characteristic in patients with the irritable bowel syndrome, or idiopathic constipation These contractions are nonpropulsive and are thought to be manifestations of segmental contractions or haustrations that impede aborad fecal movement. 4, 14 These contractions may correspond to the increased haustrations present on barium enema in patients with the irritable bowel syndrome. 2 The present study suggests that altered colonic myoelectrical activity may be the underlying mechanism for the abnormal colonic motor activity reported in this disease. In patients with the irritable bowel syndrome, a prominent increase in the recorded 3-cycle per min slow wave activity was noted. During periods of 3-cycle per min motor activity, the predominant slow wave frequency was also approximately 3 cycles per min. Thus, it seems that slow wave frequency was closely associated with the frequency of colonic contractions and probably determines the frequency of these contractions. This observation is consistent with the demonstrated relationship of the frequency of slow waves and motor activity in the stomach, small intestine, and possibly colon Despite an over-all close relationship between slow waves and colonic contractions and an increased basal 3- cycle per min slow wave activity in patients with irritable bowel syndrome, there was no significant increase in the occurrence of basal 3-cycle per min contractions in these patients as compared to normal subjects. However, a striking difference in the frequency of colonic contractions was seen when the distal colon was stimulated by either pentagastrin or cholecystokinin. Mter gastrointestinal hormone infusion, patients with the irritable bowel syndrome showed a marked increase in 3-cycle per min contractions. After pentagastrin or cholecystokinin adminstration, spike potentials and the motility index were increased similarly in both groups. A comparison of the motility index alone would have masked the observed difference in the frequency of the colonic contractions in the two groups. Patients with the irritable bowel syndrome have been shown to have increased symptoms after eating or the administration of cholecystokinin. 4, 8 We hypothesize that the abnormality in colonic slow wave activity in irritable bowel syndrome predisposes to an abnormal pattern of colonic motor activity. Colonic stimulation by neural, hormonal, environmental, or local factors may act secondarily to produce characteristic symptoms. Under basal conditions, an abnormal colonic myoelectrical rhythm may be the only detectable disorder in these patients. With appropriate colonic stimulation an altered pattern of colonic motor response became manifest. In this study, patients with either diarrhea or constipation had similar myoelectrical and motor activity. Previous studies also have shown similar abnormalities in barium enema and colonic motor activity in patients with the irritable bowel syndrome with either diarrhea or constipation. 2, 19 Thus, abnormal colonic myoelectric and motor activity seem to correlate best with the overall clinical syndrome but not with specific types of symptoms. REFERENCES 1. Chaudhary NA, Truelove SC: The irritable colon syndrome. Q J Med 31: , Lumsden K, Chaudhary NA, Truelove SC: The irritable colon syndrome. Clin Radiol 14:54-63, Posey EL, Bargen JA: Observations of normal and abnormal human intestinal motor function. Am J Med Sci 221:10-20, Connell AM, Jones FA, Rowlands EN: Motility of the pelvic colon. Abdominal pain associated with colonic hypermotility after meals. 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