Scandinavian Journal of Gastroenterology

ISSN: 0036-5521 (Print) 1502-7708 (Online) Journal homepage: http://www.tandfonline.com/loi/igas20

Treatment of Postoperative Paralytic Ileus with Cisapride P. O. Tollesson, J. Cassuto, G. Rimbäck, A. Faxén, L. Bergman & E. Mattsson To cite this article: P. O. Tollesson, J. Cassuto, G. Rimbäck, A. Faxén, L. Bergman & E. Mattsson (1991) Treatment of Postoperative Paralytic Ileus with Cisapride, Scandinavian Journal of Gastroenterology, 26:5, 477-482 To link to this article: http://dx.doi.org/10.3109/00365529108998569

Published online: 08 Jul 2009.

Submit your article to this journal

Article views: 20

View related articles

Citing articles: 2 View citing articles

Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=igas20 Download by: [University of Otago]

Date: 09 October 2015, At: 14:31

Treatment of Postoperative Paralytic Ileus with Cisapride P. 0. TOLLESSON, J. CASSUTO, G. RIMBACK, A. FAXEN, L. BERGMAN & E. MA'ITSSON Depts. of Radiology, Anesthesiology and Surgery, Central Hospital, Molndal, and Dept. of Surgery, Karlstad Hospital, Karlstad, Sweden

Downloaded by [University of Otago] at 14:31 09 October 2015

Tollesson PO, Cassuto J , Rimback G , FaxCn A, Bergman L, Mattsson E. Treatment of postoperative ileus with cisapride. Scand J Gastroenterol 1991, 26, 477432 The effect of cisapride on postoperative colonic motility was studied in 40 patients undergoing cholecystectomy under randomized, double-blind conditions. The patients received 10 mg of cisapride or placebo by intravenous injection starting on the day of surgery and repeated every 12 h until the 3rd postoperative day. The return of propagative motility in the colon was visualized by means of radiopaque markers and serial abdominal radiographs. Cisapride induced a significantly earlier return of propulsive motility in the right colon, as indicated by the propagation of markers from the ascending colon to the transverse colon ( p < 0.05). Radiopaque markers reached the descending colon ( p < 0.05) and the rectosigmoid colon ( p < 0.05) significantly earlier in the cisapride group than in controls. The first passage of feces occurred significantly earlier in cisapride-treated patients than in controls ( p < 0.05). The first passage of gas after surgery did not differ significantly between the groups. Our results suggest that cisapride can be used to induce earlier return of propagative motility in the colon after major abdominal surgery. Key words: Cisapride; colon; gastrointestinal motility; postoperative period; radiography; surgery, cholecystectomy

Per Olof Tollesson, M . D . , Dept. of Radiology, Sahlgren's Hospital, S-413 45 Goteborg, Sweden

Intra-abdominal surgery is known to induce a temporary gastrointestinal paralysis characterized by nausea, inability to feed orally, delayed defecation, and abdominal distention (1,2). Normal propagative motility in the gastrointestinal tract is first resumed in the small intestine (3,4) and stomach (4), whereas inhibition is most persistent in the colon (5-7). The pathophysiology of paralytic ileus is unclear, although several hypotheses have been proposed, mainly suggesting increased extrinsic sympathetic activity to the gut and inhibition of intrinsic cholinergic activity (1,2,8). However, treatment of postoperative adynamic ileus with adrenergic antagonists and cholinergic agonists has yielded conflicting results (9-12). Cisapride, a prokinetic agent, has been reported to stimulate

gastrointestinal motility (13-15), possibly by facilitating postganglionic release of acetylcholine in the myenteric plexus (16) or by direct excitatory effects on the smooth muscle (17,18). In the present study the effect of cisapride on postoperative paralytic ileus in cholecystectomized patients was investigated with radiopaque markers and serial abdominal radiographs. SUBJECTS AND METHODS

All subjects fasted for at least 12 h before the operation. Preanesthetic medication consisted of 0.05-0.075 mg fentanyl and 2.50-3.75 mg droperidol intramuscularly. Anesthesia was induced with thiopental (5 mglkg). After the administration of 1 mg pancuronium to prevent fas-

Downloaded by [University of Otago] at 14:31 09 October 2015

418

P. 0. Tollesson et al.

ciculations, tracheal intubation was done under succinylcholine relaxation (1mg/kg). After intubation 5mg pancuronium was given with additional doses of 1 mg as indicated during surgery. Anesthesia was maintained with N 2 0 and O2 and a bolus dose of 0.1-0.2 mg fentanyl at the induction of anesthesia, followed by a standardized dose of 0.003 mg.kg-'.h-'. At the conclusion of surgery 1 mg of atropine followed by 2.5 mg of neostigmine was administered to reverse neuromuscular blockade. Postoperative pain relief was achieved with intramuscular injections of morphine. Intravenous infusions during the first postoperative day were restricted to isotonic saline or Ringer's lactate solutions. Subjects Forty patients scheduled for elective cholecystectomy were studied. All patients gave informed consent, and the protocol was approved by the Regional Ethics Committee and the Radiation Safety Committee. Patients with hepatic, renal, cardiovascular, or hormonal diseases were excluded. Preoperative bowel habits were investigated, and patients with stool frequency between three stools daily and three stools weekly were included. Patients using laxatives or drugs known to affect gastrointestinal motility and patients with a history of gastrointestinal diseases or complications to surgery were excluded. All women capable of childbearing were asked about their menstrual cycle. When the possibility of pregnancy could not be minimized, the patient was excluded. Experimental design Patients were randomly allocated to receive double-blind intravenous injections of 10 mg cisapride (2 mi) ( n = 20) or a corresponding injection of isotonic saline (2 ml) (n = 20). Treatment was started at 2000 h on the day of surgery and was repeated at 0800 h and 2000 h on the first and second postoperative days, On the third day after surgery, a single injection was given at 0800 h, making a total of six injections. Measurement of colonic propulsive motility Four types of radiopaque markers were

prepared: 10 x 2 mm cylindrical tubes (type l), 17 x 2 mm cylindrical tubes (type 2 ) , 10 x 2 mm cylindrical tubes filled with barium sulfate powder and sealed at the ends (type 3), and 17 x 2mm barium-filled cylindrical tubes (type 4). All markers were cut from a radiopaque tube with a specific gravity (SG) of 1.4 (Tubing 2501, Meadox Surgimed, Denmark). Four markers, one of each type, were enclosed in two gelatin capsules. Patients swallowed the markers at 2000 h on the evening before surgery. The shape and size of each marker was such that they were easily distinguished from each other on the radiographs. Localization of radiopaque markers on abdominal films was determined by gaseous outlines of the colon. When colonic outlines were unclear, bony landmarks as described by Arhan et al. (19) were used for localization. Transit of the radiopaque markers was followed by means of plain abdominal radiographs. The first radiograph was taken immediately after the operation, with another taken at 0800 h on the second day after surgery. The subsequent films were taken every 12 h until the markers reached the rectosigmoid colon or until a maximum of eight radiographs had been taken. The radiographs were analyzed by a radiologist who was unaware of to which group the patient belonged. The colon was outlined on the radiographs and divided into four segments: segment 0 (cecum and ascending colon), segment 1 (transverse colon), segment 2 (descending colon), and segment 3 (rectosigmoid colon). Starting from the end of surgery, the time taken for the fastest marker to reach a certain segment of the colon was recorded. The choice of the fastest marker as indicator for propulsive motility was based on the propagative properties of the markers evaluated by comparison with water-soluble iodine contrast injected into the common bile duct (20,21). When markers were propelled across the border of more than one segment on two consecutive radiographs, the time for the passage through intermediary segment(s) was considered to be equal to the time for the markers to reach the distal segment. Record was kept of the first postoperative passage of gas and feces.

Cisapride and Postoperative Paralytic Ileus

479

Table I. Data in patients undergoing cholecystectomy and treated with cisapride or placebo. Data are mean 2 SEM

Age (year) Weight (kg) Duration of surgery (min) Sex (M/F) Postoperative morphine (mg) First postoperative passage of gas (h) First postoperative passage of feces (h)

Placebo

Cisapride

45 2 3 69 2 3 99 t 8 13:7 28 2 5

55 ? 3 74 2 106 t 8 10: 10 21 t 5

41

?

3

79 ? 9

*

38 2 4 52 ? 8*

Downloaded by [University of Otago] at 14:31 09 October 2015

' P < 0.05 versus placebo. All other differences were not significant.

Statistical methods Inter-group comparison of postoperative segmental colonic motility was done with the log rank test for censored observations (22), taking into consideration patients in whom markers had not reached segment 2 or 3 before the last radiograph. All other intergroup differences were analyzed with the Wilcoxon rank sum test.

RESULTS The two groups were comparable with regard to clinical and personal data (Table I). The dose of fentanyl given during surgery and the total amount of morphine required postoperatively was similar in the two groups ( p > 0.05) (Table I). Preoperative frequency of defecation was 1.3 2 0.9 defecations/day in the control group and 1.8 1.1 in the cisapride group ( p > 0.05). No adverse reactions to cisapride were reported.

*

Colonic motility In all patients, three or four markers were located in the cecum o r ascending colon on the first radiograph taken after surgery. In six control patients and five cisapride patients one marker was located in the small intestine o r outside the cecum/ascending colon on the first postoperative radiograph. In all these cases markers in the small intestine were propelled into the right colon on the radiograph taken on the morning of the second postoperative day. In no patient from any of the groups did propulsive motility in the right colon occur before this radiograph was taken.

The start of propulsive motility in the right colon after surgery, as indicated by the propagation of radiopaque markers from the ascending colon (segment 0) to the transverse colon (segment l), occurred significantly earlier in cisapride-treated patients than in placebo-treated controls ( p < 0.05) (Fig. 1). This difference remained in favor of cisapride with regard to propagation of markers from the transverse colon (segment 1) to the descending colon (segment 2 ) ( p < 0.05) and from the descending colon to the rectosigmoid colon (segment 3) ( p < 0.05) (Fig. 1). The first passage of feces after surgery occurred significantly earlier in cisapride-treated patients than in controls ( p < 0.05) (Table I). No significant differences were seen between the groups with regard to the first passage of gas ( p > 0.05). DISCUSSION Cisapride is a newly synthetized prokinetic agent that facilitates the release of acetylcholine in the myenteric plexus of the gut. In a study by Baeyens et al. (13), cisapride was shown t o accelerate mouth-to-cecum transit of a barium meal in patients with upper gastrointestinal symptoms. Similar results were obtained by other investigators (14,23) in normal volunteers showing decreased mouth-to-cecum transit using radiopaque markers or the breath hydrogen test. In accordance, Krevsky et al. (15) demonstrated a significantly shortened colonic half-emptying time, using a gamma camera in normal volunteers treated with cisapride. However, studies inves-

480

P. 0. Toiiesson et ai

* I

Downloaded by [University of Otago] at 14:31 09 October 2015

* I

Transverse colon

Descending colon

Rectosigmoid colon

Fig. 1. Time taken for the radiopaque markers in the cecum/ascending colon to reach other segments of the colon in patients receiving cisapride (hatched bars) or placebo (open bars). Propagation of markers was studied by serial abdominal radiographs. * P< 0.05 versus placebo. Data are expressed as mean 2 SEM.

tigating the effects of cisapride on postoperative colonic motility have shown conflicting results. Several authors were able to demonstrate reduced duration of colonic paralysis (24-28), whereas others failed to influence postoperative colonic motility (29). A possible explanation of these conflicting results could be that rather insensitive variables (30), such as bowel sounds and the first passage of gas, were used in most of these studies to indicate the restoration of colonic motility after surgery. In the present study we were unable to demonstrate any significant effect of cisapride on the first postoperative passage of gas. This may be explained by results failing to show a significant correlation between the first postoperative passage of gas and the first passage of feces or between the passage of gas and the propagation of radiopaque markers in the colon (5,20,21). These data suggest that the first passage of gas does not represent the reappearance of propulsive motility in the colon after surgery but rather increased postoperative segmental activity in the rectosigmoid colon. In the study by Pescatori (26). measuring the time for the first postoperative passage of stools, and in that of Van Rooy et al. (28), using the breath hydrogen test, cisapride was shown to shorten the duration

of colonic paralysis. These results were confirmed by our data showing significantly earlier passage of feces in patients treated with cisapride. In contrast, Von Ritter et al. (29) failed to influence stool passage after surgery with cisapride. To investigate further the effect of cisapride on the paralytic colon, the present study used a technique enabling a more objective recording of colonic propulsive motility in the postoperative period. In view of data suggesting that the start of propagative motility in the colon after surgery is elicited from the right colon (4,6,21), it is of great importance to visualize such activity when evaluating the effects of prokinetic drugs. The present technique takes advantage of the fact that markers given before surgery will be localized in the right colon until propulsive activity is resumed. The properties of the markers have previously been evaluated and shown to correlate well with the propagation of water-soluble iodine contrast (20,21). Our data based on marker propagation and postoperative time to defecation show cisapride to have a significant prokinetic effect on the return of propulsive motility in the colon after surgery. Influence of opiate administration on the outcome of this study can be ruled out, since the amount of peroperative fentanyl

Downloaded by [University of Otago] at 14:31 09 October 2015

Cisapride and Postoperative Paralytic lleus

and postoperative morphine did not differ significantly between the groups (Table I). In a previous study in human volunteers (15) cisapride was shown to accelerate emptying time of the cecum and ascending colon and transit through the transverse colon but not the descending colon. In the present study on postoperative patients cisapride was shown to accelerate transit through all colonic segments, possibly as a result of repeated administrations as opposed to the single dose in the study of Krevsky et al. (15). The mechanisms by which cisapride stimulates gastrointestinal motility are several. The drug acts in part by enhancing the release of acetylcholine from postganglionic nerve endings in the myenteric plexus (16). Unlike other prokinetic agents, such as metoclopramide, cisapride is without antidopaminergic or direct cholinomimetic effects (16). In the colon ascendens, cisapride has been shown to induce contractions only partly inhibited by tetrodotoxin (17, IS), suggesting also a direct stimulatory effect on colonic smooth muscle. These data may explain, at least in part, the mechanisms for the action of cisapride on the paralytic colon, particularly when considering that the colon ascendens has been proposed as the site for the pacemaker activity responsible for the return of propulsive motility in the colon after surgery (4,6,21). In conclusion, the present results show significantly earlier return of propulsive motility in the colon of cisapride-treated patients after abdominal surgery as visualized by the first passage of feces and the propagation of radiopaque markers on serial abdominal radiographs.

ACKNOWLEDGEMENTS Supported by grants from Bohuslandstinget, Janssen Pharma, the Medical Society of Gothenburg, Gothenburg University, and the Swedish Medical Research Council (grant 09072). Presented in part at the 22nd Meeting of the Scandinavian Society of Gastroenterologists, Umeb, Sweden, 1-3 June 1989.

481

REFERENCES 1. Furness JB, Costa M. Adynamic ileus, its pathogenesis and treatment. Med Biol 1974, 52, 82-89 2. Dubois A. Mechanical gastrointestinal obstruction and paralytic ileus. In: Kumar D , Gustavsson S, eds. An illustrated guide to gastrointestinal motility. Wiley & Sons, New York, 1988, 365-382 3. Noer T. Roentgenological transit time through the small intestine in the immediate postoperative period. Acta Chir Scand 1968, 134, 577-580 4. Graber JN, Schulte WJ, Condon RE, Cowles VE. Relationship of duration of postoperative ileus to extent and siteofoperative dissection. Surgery 1982, 92, 87-92 5. Wilson JP. Postoperative motility of the large intestine in man. Gut 1975, 16, 689-692 6. Woods JH, Erickson LW, Condon RE, Schulte WJ, Sillin LF. Postoperative ileus: A colonic problem? Surgery 1978, 84, 527-533 7. Condon RE, Cowles VE, Schulte WJ, Frantzides CT, Mahoney JL, Sarna SK. Resolution of postoperative ileus in humans. Ann Surg 1986,203,574581 8. Smith J, Kelly KA, Weinshilboum RM. Pathophysiology of postoperative ileus. Arch Surg 1977, 112, 20S209 9. Neely J, Catchpole B. Ileus: the restoration of alimentary-tract motility by pharmacological means. Br J Surg 1971, 58, 21-28 10. Heimbach DM, Crout JR. Treatment of paralytic ileus with adrenergic neuronal blocking drugs. Surgery 1971, 69, 582-587 11. Ruwart MJ, Klepper MS, Rush BD. Adrenergic and cholinergic contributions to decreased gastric emptying, small intestinal transit, and colonic transit in the postoperative ileus rat. J Surg Res 1980, 29, 126134 12. Hallerback B, Carlsen E, Carlsson K, et al. pAdrenoceptor blockade in the treatment of postoperative adynamic ileus. Scand J Gastroenterol 1987, 22, 149-155 13. Baeyens R, Reyntjens A, Verlinden M. Cisapride accelerates gastric emptying and mouth-to-caecum transit of a barium meal. Eur J Clin Pharmacoll984, 27, 315-318 14. Bigard MA, Durivaux B, Fraitag B . Action du cisapride sur le temps de transit oro-caecal d’un repas dyspeptogkne chez le sujet sain. Gastroenterol Clin Biol 1988, 12, 75-76 15. Krevsky B, Malmud LS, Maurer AH, Somers MB, Siege1 JA, Fisher RS. The effect of oral cisapride on colonic transit. Aliment Pharmacol Ther 1987, 1, 293-304 16. McCallum RW, Prakash C, Campoli-Richards DM, Goa KL. Cisapride. A preliminary review of its pharmacodynamic and pharmacokinetic properties, and therapeutic use as a prokinetic agent in gastrointestinal motility disorders. Drugs 1988,36,652681 17. Schuurkes JAJ, Van Nueten JM, Van Daele PGH, Reyntjens AJ, Janssen PAJ. Motor-stimulating properties of cisapride on isolated gastrointestinal

Downloaded by [University of Otago] at 14:31 09 October 2015

482

P. 0.Tollesson er al.

preparations of the guinea pig. J Pharmacol Exp Ther 1985, 234,775-783 18. Den Hertog A, Van Den Akker J. The effect of cisapride on smooth muscle cells of guinea-pig taenia caeci. Eur J Pharmacol 1986, 126, 31-35 19. Arhan P, Devroede G , Jehannin B, et al. Segmental colonic transit time. Dis Col Rect 1981,24,625-629 20. Tollesson PO, Cassuto J, Fax& A, Rimback G, Wallin G. Is the first passage of flatus and faeces a valid indicator of the return of propulsive colonic motility in the postoperative period? Gut 1984,25A, 1313-1314 21. Tollesson PO, Cassuto J, Rimback G, Faxtn A. Methods for the study of postoperative colonic motility. Scand J Gastroenteroll989,24(suppl159), 47 22. Cox DR, Oakes D. Analysis of survival data. Chapman-Hall, London, 1984 23. Edwards CA, Holden S, Read NW. The effect of cisapride on gastrointestinal transit in normal volunteers. Dig Dis Sci 1986, 31, 287 24. Boghaert A, Haesaert G , Mourisse P, Verlinden Received 21 September 1990 Accepted 26 November 1990

M. Placebo-controlled trial of cisapride in postoperative ileus. Acta Anaesth Belg 1987, 38, 195199 25. Verlinden M, Michiels G, Boghaert A, de Coster M, Dehertog P. Treatment of postoperative gastrointestinal atony. Br J Surg 1987, 74, 614-617 26. Pescatori M. Effect of cisapride on clinical parameters of postoperative ileus. Progr Med 1987,43, 111-1 14 27. De Coster M, Verlinden M. Cisapride shortens postoperative gastrointestinal atony. Progr Med 1987, 43, 105-110 28. Van Rooy F, Creve U, Verlinden M, Hubens A. Effect of cisapride on the post-cholecystectomy upper gastrointestinal transit time. Int J Clin Pharmacol Ther Tox 1988, 26, 265-268 29. Von Ritter C, Hunter S, Hinder RA. Cisapride does not reduce postoperative paralytic ileus. S Afr J Surg 1987, 25, 19-21 30. Connell AM. Tests of gastrointestinal motility. Clin Gastroenterol 1978, 7, 317-328

Treatment of postoperative paralytic ileus with cisapride.

The effect of cisapride on postoperative colonic motility was studied in 40 patients undergoing cholecystectomy under randomized, double-blind conditi...
653KB Sizes 0 Downloads 0 Views