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Small Bowel Motility in Ulcerative Colitics Undergoing Ileal Pouch-Anal Anastomosis

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Small Bowel Motility in Ulcerative Colitics Undergoing Ileal Pouch-Anal Anastomosis SMALL BOWEL MOTILITY IN ULCERATIVE COLITICS UNDERGOING ILEAL POUCH-ANAL ANASTOMOSIS A thesis presented for the degree of Doctor of Medicine in the University of Glasgow by James S McCourtney BSc (Hons); MB,ChB; FRCS (Glasg) University Department of Surgery Glasgow Royal Infirmary University NHS Trust March, 1998 ProQuest Number: 13818663 All rights reserved INFORMATION TO ALL USERS The quality of this reproduction is dependent upon the quality of the copy submitted. In the unlikely event that the author did not send a com plete manuscript and there are missing pages, these will be noted. Also, if material had to be removed, a note will indicate the deletion. uest ProQuest 13818663 Published by ProQuest LLC(2018). Copyright of the Dissertation is held by the Author. All rights reserved. This work is protected against unauthorized copying under Title 17, United States C ode Microform Edition © ProQuest LLC. ProQuest LLC. 789 East Eisenhower Parkway P.O. Box 1346 Ann Arbor, Ml 48106- 1346 GMSGOro/WSiSIfy umt 11&44 (top^ "Those early weeks, when Campbell had spent hours waiting about in what Hadden had called the kebab squad, hanging about ghoulishly for operations that rarely delivered the goods, were not to be repeated. " Colin Douglas, "Ethics Made Easy" SUMMARY 1. Although much clinical research has been carried out in the last 14 years to examine the postoperative function of patients undergoing ileal pouch-anal anastomosis (IPAA), little is known about the small bowel which is used to create the reservoir in this procedure. This thesis has therefore examined the preoperative small bowel motility characteristics of patients with ulcerative colitis (UC) undergoing EPAA using in vivo and in vitro techniques. The in vitro studies were compared against control subjects of whom most were undergoing elective right hemicolectomy for non-obstructing neoplasms. During part of the research project access to ileal tissue from patients with idiopathic slow transit constipation (ISTC) undergoing subtotal colectomy and ileorectal anastomosis (SC+IRA) enabled a study of this interesting subgroup of patients to be made. A review of the IPAA operation performed at Glasgow Royal Infirmary between 1988 and 1995 i.e. totally stapled restorative proctocolectomy (TSRP), was also carried out. 2. An ambulatory manometry catheter assembly with 6 solid-state transducers, straddling the small bowel from duodenojejunal flexure to ileocaecal junction, was used to assess fasting patterns of small bowel motility in 9 UC patients and 2 patients with familial adenomatous polyposis (FAP) awaiting EPAA. In the 9 UC patients (7 intact; 2 staged i.e. previous subtotal colectomies) nocturnal recordings were possible in 8. In 1 staged UC patient, catheter advancement to terminal ileum was impossible and with hindsight, following IPAA, this was thought to have been caused by previous postoperative adhesions. The second staged UC patient had catheter migration into the stoma bag following insertion and recordings were therefore invalid. The 7 intact UC patients and 1 FAP patient were studied for a total of 81 hours in the nocturnal period. The 7 UC patients (6 males) had trace recordings analysed for migrating motor complex (MMC) characteristics including total number, cycle length, mean duration and mean velocity. Non-propagating MMCs, discrete clustered contractions (DCCs) and prolonged propagating contractions (PPCs) were also noted. The median recording period was 8.7hours (h), (range 6.5-9.5h) and the nocturnal stool frequency 2 (range 0-7). Other propagating contractions per subject included 1 PPC (0.9-2) and 2.1 DCCs (0-6). Calculation of Spearman's rank correlation coefficient failed to show any statistically significant associations between these motility parameters and nocturnal stool frequency. In particular the MMC pattern failed to show any relationship to nocturnal stool frequency. Recordings made in 5 UC patients during the diumal period were considered "too noisy" to show any meaningful relationship between stool frequency and motility parameters because of intense postprandial motor activity. On the basis of this pilot study, ambulatory small bowel manometry was considered to be uncomfortable for the patient, the data obtained time- consuming to analyse, unsuitable for assessment of patients who had previously undergone subtotal colectomy and limited by expensive equipment which was too easily damaged. While possible, the technique did not seem to be a practical way of assessing small bowel motility routinely in prospective EPAA patients. Albeit on the basis of 7 nocturnal recordings, the technique also failed to show any relationship between gross patterns of small bowel motility and stool frequency in intact UC patients. 3. When isolated mucosal-free strips of human ileum were suspended in conventional jacketed organ baths, bursts of rhythmic oscillations in tone (spontaneous activity) were noted in 59 control strips (60%) and 73 UC strips (49%). Analysis of this activity, in horizontally orientated strips, in a Golenhofen apparatus to enable synchronous measurement of both extracellular electrical and mechanical activity showed marked differences in the results from the 2 techniques. In 3 groups of patients i.e. control subjects, UC and ISTC patients, the Golenhofen measurements showed that spontaneous mechanical contractions were faster, stronger and of shorter duration than those measured in conventional organ baths. These differences reached statistical significance in 6 of the 9 comparative measurements among the recording techniques in the 3 patient categories. When the electrical and mechanical characteristics of UC (n=7) and ISTC (n=7) patients were compared with controls (n=10), significant differences were noted in terms of the number of electrical spike bursts and the duration of electrical spike bursts between ISTC patients and controls: 3.86+0.14 versus 9.71+1.78 electrical spikes per spike burst, P=0.03; 0.66+0.12 versus 2.18+0.62s duration of electrical spike bursts, P=0.04. Although trends emerged in the results from UC strips, suggesting the opposite in terms of greater numbers of electrical spikes per spike burst and longer duration of electrical spike bursts these differences did not reach statistical significance. These results suggest that, although the intestinal pacemaker is functional in the small bowel of ISTC patients, it generates spontaneous mechanical activity as a result of less intense, shorter duration electrical activity than controls. This supports the concept of ISTC being a panenteric disorder which is not solely confined to the colon. In UC patients undergoing EPAA no statistically significant differences were observed in spontaneous electrical and mechanical parameters when compared with control subjects. 4. The effects of cooling/ rewarming and certain drugs (potassium chloride, carbachol, atropine, diltiazem, sodium nitroprusside and metronidazole) were iv examined using the Golenhofen apparatus in control, UC and ISTC samples of ileum (3 patients, 3 muscle strips per category). Stepwise cooling from 37.5°C to 27.5°C reduced the frequency and amplitude of slow wave activity and the preceding spike bursts of electrical activity. Neither the resting tone nor the maximum amplitude of isometric contraction was affected by these temperature changes in the 3 patient groups. Rewarming produced reversal of these effects with visible recovery of electrical activity. 5. The presence of voltage-operated and receptor-operated channels were demonstrated in ileal tissue from the 3 patient groups using potassium chloride, carbachol, atropine, diltiazem and sodium nitroprusside (SNP). No differences were observed amongst the 3 patient groups in terms of the pattern of tissue reponse to each of these spasmogens and relaxants. Metronidazole, an antibiotic commonly used to treat pouchitis, an idiopathic inflammatory condition which can affect up to 31% of EPAA patients with UC, had no effect on extracellular electrical or mechanical activity. 6. In carbachol-induced tone, both control and UC samples of ileum responded to electrical field stimulation (EFS, l-64Hz, 0.05ms, supramaximal voltage) with a relaxation response followed by a rebound contraction. There were no statistically significant differences between control and UC tissues in terms of frequency/ response curves. The nitric oxide synthase (NOS) antagonist N^-nitro- L-arginine methyl ester (L-NAME, 10'^M) inhibited nerve-mediated relaxations in control tissues (10 patients, 17 muscle strips) by 60-90%. A more heterogeneous group of responses were noted in 18 UC patients (58 muscle strips, 11 synchronous EPAA procedures, 7 staged IPAA procedures). Thus, only 5 (10 muscle strips) v behaved in a similar fashion to control ileum i.e. L-NAME effectively inhibited nerve-mediated relaxations by 60-90%. L-NAME was only weakly effective in a further 3 patients (11 muscle strips) and ineffective in 5 patients (12 muscle strips). A further 5 UC patients (25 muscle strips) undergoing IPAA showed no evidence of functioning enteric neurons with EFS failing to elicit relaxation responses. NO would therefore seem to be the main inhibitory transmitter in control ileum but, in patients with UC, whilst some may behave in a comparable fashion to control tissue others have relaxation responses which suggest a possible alteration in the relative potencies of other inhibitory neurotransmitters. This may be due to the systemic effects of UC, to the medications used to treat this condition
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