GASTROENTEROIJOGY. Official Publication of the American Gastroenterological Association

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1 GASTROENTEROJOGY Official Publication of the American Gastroenterological Association COPYRGHT ly6g THE W,LL,AMS & W,LK,NS CO. VOLUME 50 1,1 arch 1966 NUMBER ::\ THE SMALL NTESTNAL BASC ELECTRCAL RHYTHM (SLOW WAVE) FREQUENCY GRADENT N NORMAL MEN AND N PATENTS WTH A VARETY OF DSEASES JAMES CHRSTENSEN, M.D., HAROLD P. SCHEDL, M.D., PH.D., AND JAMES A. CLF TON, M.D. Gastroenterology Research Laboratory, Department of Medicine, College of Medicine, Univers1:ty of owa, O'UJa City, owa Physiological gradients of many kinds have been described in the small intestine. One of these, a declining gradient in the frequency of the electrical slow waves in animals, was first reported by Alvarez. 1 Electrodes implanted in the muscular wall of the gut of 'various animals have heretofore served as the method of recording these slow waves. We have reported previously 2 the use of an intraluminal salt bridge electrode to record slow waves from the duodenum in normal subjects. We have extended this method to study Received June 17, Accepted November 10, Presented in part at the annual meeting of the Gastroenterologiral Resparch Forum, Dallas, Texas, April 23, Address requests for reprints to: Dr. James A. Clifton, Department of Medicine, University of owa, owa City, owa This investigation was supported in part by Training Grant 5-T-AM-5390 from the United States Public Health Service, and by Research Grants AM and AM from the National nstitute of Arthritis and Metabolic Diseases. Dr. Christensen is a Markle Scholar in Academic Medi cine. His present address is: Department of Pharmacology, University of Alberta, Edmonton, Alberta, Canada. Dr. Schedl's present address is: Churchill College, Cambridge University, Cambridge, England. 309 the frequency gradient of the slow wave or basic electrical rhythm (BER) in the entire small intestine in normal persons and in patients with diseases affecting the intestines. Materials and Methods Electrode. ntestinal electrical activity was recorded with a modification of the electrode previously described: A perforated nylon capsule containing a silver-silver chloride potassium chloride salt bridge was mounted on a 4-m length of pliable rubber-insulated electrical wire with an outside diameter of 5 mm. A ml water-filled latex balloon, attached to the capsule opposite its point of contact with the mucosa, communicated with a 4-m length of water-filled polyethylene tubing with an inside diameter of 1.7 mm. The tubing was tied at 6-inch intervals to the insulated wire. Subjects and patients. Twelve normal volunteers were studied. They ranged from 21 to 49 years in age. All were in good health, and none had a history of gastrointestinal disease. The 13 patients studied were in the University Hospitals. There were four patients with hyperthyroidism, none of whom had gastrointestinal symptoms. Two patients had myxedem a; one, adult cejiac disease; one, hyperparathyroidism with gastric hypersecretion and diarrhea; one, hypoparathyroidism with postgastrectomy diarrhea; two, chronic functional diarrhea; and one, chronic episodic abdominal pain of unknown cause. Method of study. All subjects and patients

2 310 CHRSTENSEX ET _-1L. Vol. 50, No.3 fasted at least 8 hr before beginning the study, but were allowed food ad libitum after the electrode began moving down the intestine. A 5'70 dyclonine hydrochluride spray was used to induce pharyngeal anesthesia. The electrode assembly, weighted with a latex bag containing 2 ml of mercury, was introduced in the distal duodenum with fluoroscopic guidance and allowed to progress freely through the small intestine. The BER was recorded at intervals of 2 to 6 hr. Each recording period lasted from 30 to 90 min. At the beginning of each recording period the distance of the electrode capsule below the incisor teeth was determined by measuring the length of the residual wire after withdrawing any slack wire looped in the stomach. The total period of observation was ended either when the electrode had stopped advancing or when severe discomfort attended the procedure. Each study lasted from 18 to 72 hr. At the end of each stud' the electrode was withdrawn over a period of 1 hr. The method of recording has been described in a previous publication: Respiration and intraluminal balloon pressure changes were recorded so that artifacts from breathing and gut motility in t.he record of electrical activity could be identified. Slow wave frequency was calculated from the time required to complete from five to 10 full cycles in continuity. During each recording period two to 15 such computations were possible. The data were analyzed bv standard statistical methods." " Results N ol'lnal subjects. n all subjects the BER frequency decreased a s the electrode progressed down the intestine. n "ome subjects the mean frequency declined sharply at about 100 to 120 em below the incisor teeth and again at about 200 cm. n others the gradient appeared to have only one of these sharp declines in rate and in some the gradient appeared to be linear (fig. 1). Figure 2 shows that the line connecting the segmental mean frequencies retains the general form of some of the gradients seen in individuals: a steep decline from 80 to 120 cm, a lesser decline from 120 to 190 em, and a steeper decline beyond this point. Although the distance of the ligament of Treitz from the incisor teeth varied from 75 to 80 em, that distance is arbitrarily shown as 75 cm. The data were combined by calculating the mean of all measured rates in each 15-cm gut segment. n the succeeding figures the range encompassed by 2 SD from the mean in these normal subjects is shown as a shaded area. Hyperthyroidism. We have described previously the direct relationship between the level of thyroid function and the BER frequency in the human duodenum. 2 n 12- '"" O 9 \!i DES , r t, '" f-' G 10 \ /-'-' )... FB. J.G DE F. GP.H 8 L--'----'---L...\r" - --'- 0 0, ij " r'-'.-.-.".-- -\-"' \y.' '-.-. r: , " t lr.- f'\- \ ; l so.-,, " u. m \ "L DSTANCE FROM NCSOR TEETH N CENTMETERS FG. 1. Gradients of mean BER frequency in 12 normal subjects. Each dot represents the mean of two to 15 computations of frequency at one level of the intestine.

3 March 1966 NTESTNAL SLOW WAVE FREQUENCY GRADENT T C( O.O, T 9.0 ) ;S 8.0 e: e; 7.5 ct:i L ---L L- -L L- L--L N W W W DSTANCE FROM NCSOR TEETH N CENTMETERS FG. 2. Mean BER frequency gradient from 12 normal sutjects. Each dot shows the mean of all frequencies in the 12 subjects for one i5-cm segment of intestine. The brackets above and below each dot indicate 2 SD from the mean. four patients with hyperthyroidism we found rates faster than normal at all levels of the intestine except at 225 cm in one patient. n a fifth patient who was euthyroid after treatment for hyperthyroidism, the rates were normal. These gradients are shown in figure 3. n three of the untreated patients the proximal rapid decline was small or absent so that the duodenal rate persisted to a depth of 160 cm. n the subjects in whom the electrode went the farthest the distal BER frequencies approached the range of rates seen in the normal subjects. Hypothyroidism. n two patients with hypothyroidism the frequencies were abnormally slow at all levels of the small intestine (fig. 3). Other diseases. n one patient with hypoparathyroidism and postgastrectomy diarrhea and in one patient with adult celiac disease the frequency gradients were normal. n a patient with hyperparathyroidism, gastric hypersecretion, and diarrhea, the frequencies in the proximal small intestine were slow while those in the distal intestine were in the range seen in normal subjects. These gradients are shown in figure 4. Functional bowel complaints. n three patients who had gastrointestinal complaints of functional origin the gradients fell within the range of normal subjects. Two patients had chronic diarrhea and the third, chronic episodic abdominal pain. n the two with chronic diarrhea the duodenal frequency persisted well into the jejunum. Discussion The early work of Alvarez demonstrated a gradient in the frequency of the rhythmic contractions of the rabbit intestine. This contraction gradient appeared to be linear when determined in vitro from excised segments of intestine. 4 A figure in a later paper5 shows gradients of

4 312 CHRSTENSEN ET AL. Vol. 50, No ij 11.0 ) G 10.0 ::) 9.5 e: Cj 8.0. "-.. " OO '70--' roo -2'-0 0--L DSTANCE FROM NCSOR TEETH N CENTMETERS FG. 3. BER frequency gradients in patients with thyroid disease. A, B, C, and D = gradients from four patients with untreated hyperthyroidism. E = gradient from another patient who was euthyroid 4 months after treatment with 1'31 for hyperthyroidism. The dashed arrows indicate his duodenal rate before and after treatment. F and G = gradients from two patients with hypothyroidism. n all gradients in this and subsequent figures the vertical lines show 2 SD from the mean at each recording period. The shaded area in this and the following figure encompasses the mean BER frequency gradient ± 2 SD found in 12 normal subjects (from fig. 2). rhythmic contraction rates in an intact and an excised rabbit intestine. These gradients of contractile activity have the same general form that we have found for electrical (slow wave) frequency in some human subjects: a steep decline from duodenum to proximal jejunum, a less steep decline through the remainder of the jejunum, and a steeper decline in the distal small intestine. Alvarez! later reported a gradient in the frequency of the intestinal slow waves in animals but did not determine the form of this gradient. Others have confirmed the existence of such a gradient. 6 Most reported studies were done in dogs where the frequency declines from 17 to 20 cycles per min in the duodenum to 12 to 14 cycles per min in the ileum. 6 The existence of a gradient of BER frequency in the human small intestine is apparent from our previous report that the normal mean duodenal frequency is cycles per min,2 and ileal rates of 7.25 ± 0.3 (SE) and 7.6 ± 0.3 (SE) found by Daniel and colleagues 7 in two patients

5 March 1966 NTESTNAL SLOW WAVE FREQUENCY GRADENT : LL--L L--L L--L FG. 4. BER frequency gradients in three patients with miscellaneous diseases. A = gradient in a patient with hypoparathyroidism and postgastrectomy steatorrhea; B = gradient in a patient with adult celiac disease. C = gradient in a patient with hyperparathyroidism, gastric hypersecretion, and diarrhea. with ileostomies. The possible effects of intestinal disease and ileal surgery on slow wave frequency in these two patients are unknown. There are no other published data of rates below the duodenum in man. Our previous studies 2 showed a mean duodenal BER frequency of cycles per min (SD ± 0.45) in 37 normal subjects. n the group of 12 subjects in this study the mean duodenal rate was ± When compared by the t-test, the means are not different (P > 0.6). We reported previously that the rate does not decline between proximal and distal duodenum in man.:! n most subjects in the present study, this duodenal rate was preserved for a short distance into the jejunum. n some subjects there were one or more zones of steep decline in frequency. f observations are not made sufficiently close together, these zones may be missed so that the gradient appears linear. For this reason, the data were pooled and a mean gradient constructed as shown in figure 2. The mean gradient tends to retain the stepwise configuration: two steep declines separated by a zone of 80 to 100 cm of gentler decline. The method has a major limitation which may cause the observed variability in form of the BER frequency gradient. t is probable that the electrode moves through the intestine with sleeving or bunching of the elastic bowel on the inelastic wire. There is no way to assess the degree of such sleeving, and it must vary from subject to subject. The degree of sleeving very likely increases with increasing depth of the electrode, and this may account for the wide scatter of data beyond 220 cm. t is impossible to state the anatomical correlates of the depths shown on the horizontal axes in the figures. The ligament of Treitz is easily identified by the configuration of the wire seen fluoroscopically. The depth of the ileocecal valve cannot be identified in this way. n some of the subjects we recorded rates at the deepest electrode position corresponding to those found in patients with ileostomies. 7 n others we may have stopped the

6 314 CHRSTENSEN ET AL. Vol. 50, No.3 study before the electrode reached the terminal ileum. Our subjects fasted to avoid difficulty in duodenal intubation but took liquids freely after the electrode had started to move through the intestine. The effects of eating on intestinal electrical activity have been studied in dogs. 8, 9 Fast activity occurred more frequently after feeding, indicating increased smooth muscle contractile activity, but changes in BER frequency were not reported. n the duodenum slow waves arise in a pacemaker located in the duodenum near the entrance of the bile ducpo and are propagated aborally. All levels of the intestine have the potential to be pacemakers, and since different levels have different BER frequencies, it appears that these areas are driven by separate pacemakers, and precise determinations of the BER frequency gradient should indicate their location. f the gradient is truly stepwise, as in some of the normal subjects, slower pacemakers may be in the areas where we observed steeper declines in rate. We have shown previously that the duodenal rates are altered in patients with thyroid disease. 2 The present studies confirm these observations and show a similar relationship between thyroid function and rates in the lower small intestine. The form of the gradient in patients with hyperthyroidism suggests that duodenal frequencies persist to levels of 160 cm or more, and this may indicate a shift of pacemaker location. A similar gradient form was found in the two patients with functional diarrhea. n the patient with hyperparathyroidism, gastric hypersecretion, and diarrhea (fig. 4C), the BER frequency gradient is abnormal. We have previously reported ll duodenal BER frequencies in patients with parathyroid disease whose serum calcium concentrations varied from 6.8 to 13.5 mg per 100 ml. There did not appear to be any correlation between serum calcium concentration and duodenal BER frequencies. n this hyperparathyroid patient the duodenal rate was more than 3 SD below the normal mean. t may be that this reduction in duodenal frequency is a nonspecific result of severe chronic illness. The BER frequency gradient may be an important factor in small intestinal transit time. The rate of the slow wave at any level of the intestine establishes the maximal frequency of rhythmic segmenting contractions or type waves at that level,6 and Code et alp have pointed out that declining gradients of frequency of these contractions may be responsible for the orderly progression of the fluid intestinal contents. Precise methods to determine small intestinal transit time could be used in conjunction with studies of the slow wave frequency gradient to investigate this relationship. Since such methods are not available, the role of the BER frequency gradient in governing the transit time of the small intestine remains unknown. Summary We used an intraluminal salt-bridge electrode to record the small intestinal slow wave or basic electrical rhythm (BER) at many levels of the intestine. We found a descending BER frequency gradient in 12 normal subjects and in 13 patients with a variety of diseases. The descending gradient was stepwise in some normal subjects but linear in others. The data from normal subjects have been pooled to establish a range of normal values. The mean frequency at the ligament of Treitz was cycles per min (SD 0.32) ; at 225 to 239 cm below the incisor teeth it was 9.39 cycles per min (SD 0.18). Abnormal gradients were found in patients with hyperthyroidism and hypothyroidism, and in a patient with hyperparathyroidism, gastric hypersecretion, and diarrhea. The form and magnitude of this gradient may be important determinants of small intestinal motor function. REFERENCES 1. Alvarez, W. C., and L. J. Mahoney Action currents in stomach and intestine. Amer. J. Physiol. 58: Christensen, J., H. P. Schedl, and J. A. Clifton The basic electrical rhythm

7 March 1966 NTESTNAL SLOW WAVE FREQUENCY GRADENT 315 of the duodenum in normal human subjects and in patients with thyroid disease. J. Clin. nvest. 43: Hill, A. B Principles of medical statistics. Oxford University Press, London. 252 p. 4. Alvarez, W. C Functional variations in contractions of different parts of the small intestine. Amer. J. Physiol. 35: Alvarez, W. C., and E. Starkweather X. The metabolic gradient underlying intestinal peristalsis. Amer. J. Physiol. 46: Daniel, E. E., and K. M. Chapman Electrical activity of the gastrointestinal tract as an indication of mechanical activity. Amer. J. Dig. Dis. 8: Daniel, E. E., B. T. Wachter, A. J. Honour, and A. Bogoch The relationship between electrical and mechanical activity of the small intestine of dog and man. Canad. J. Biochem. Physiol. 38: McCoy, E. J., and P. Bass Chronic electrical activity of gastroduodenal area: Effects of food and certain catecholamines. Amer. J. Physiol. 205: Allen, G. L., E. W. Poole, and C. F. Code Relationships between electrical activities of antrum and duodenum. Amer. J. Physiol. 207: Milton, G. W., and A. W. M. Smith The pacemaking area of the duodenum. J. Physiol. (London) 132: Christensen, J., H. P. Schedl, and J. A. Clifton The small intestinal basic electrical rhythm (BER) in man: ts frequency and gradient. Gastroenterology 46: Code, C. F., N. C. Hightower, Jr., and C. G. Morlock Motility of the alimentary canal in man. Review of recent studies. Amer. J. Med. 13: