- Email: [email protected]
Does Gum Chewing Ameliorate Postoperative Ileus? Results of a Prospective, Randomized, Placebo-Controlled Trial
Does Gum Chewing Ameliorate Postoperative Ileus? Results of a Prospective, Randomized, Placebo-Controlled Trial Evan Matros, MD, Flavio Rocha, MD, Michael Zinner, MD, FACS, John Wang, MD, Stanley Ashley, MD, FACS, Elizabeth Breen, MD, FACS, David Soybel, MD, FACS, Brent Shoji, MD, FACS, Anne Burgess, RN, Ronald Bleday, MD, FACS, Richard Kuntz, MD, Edward Whang, MD, FACS A preliminary report has been interpreted to suggest that gum chewing reduces duration of postcolectomy ileus. STUDY DESIGN: We rigorously tested this hypothesis in a prospective, randomized, placebo-controlled study. Patients undergoing open colectomy (n ⫽ 66) were randomized to receive 1 of 3 postoperative regimens beginning on postoperative day 1: sips (control, n ⫽ 21); sips and accupressure wrist bracelet (placebo, n ⫽ 23); and sips and gum chewing (treatment, n ⫽ 22). Patients were unaware of which regimen constituted placebo or treatment; end points were assessed by blinded investigators. Power was set a priori at 85% to detect a 0.75-day difference in time to first postoperative passage of flatus between placebo and treatment groups. Groups were compared using the log-rank test. RESULTS: Groups were equivalent with respect to demographic and surgical characteristics. Median times to first postoperative passage of flatus were as follows: sips, 67 hours; bracelet and sips, 72 hours; gum and sips, 60 hours (p ⫽ 0.384). There were no significant differences in time to passage of first bowel movement, time until patients were ready for discharge, or time until actual discharge among the three groups. Inpatient and 30-day followup demonstrated no difference in frequency or distribution of postoperative complications. CONCLUSIONS: In contrast to findings of a preliminary study, our clinical trial suggests that gum chewing, although safe, does not reduce duration of postcolectomy ileus. (J Am Coll Surg 2006;202: 773–778. © 2006 by the American College of Surgeons) BACKGROUND:
Postoperative ileus remains a source of morbidity and the major determinant of length of stay after abdominal operation. Its economic burden in the United States health-care system is estimated to surpass $1 billion.1 For these reasons, strategies to reduce duration of postoperative ileus are of great importance. Therapies such as motility agents, early postoperative refeeding regimens, and physical therapy have been tested in clinical trials, but are not routinely used because of their limited clin-
ical efficacy.2-10 So far, surgeons have little to offer patients other than reassurance that bowel function will return. Recently, Asao and colleagues11 reported that gum chewing has efficacy in accelerating resolution of ileus after colon operation. They observed that subjects who chewed gum after laparoscopic colectomy passed gas and bowel movements at a mean of approximately 1 day sooner than patients who did not chew gum during the postoperative period. The findings were intriguing but the study had methodologic limitations, including the absence of either blinding or a placebo arm. To more rigorously evaluate the efficacy of gum chewing in accelerating resolution of postoperative ileus, we tested the hypothesis that gum chewing is more effective than a placebo in hastening bowel recovery and shortening hospitalization after open colectomy.
Competing Interests Declared: None. Received December 14, 2005; Revised January 31, 2006; Accepted February 6, 2006. From the Departments of Surgery (Matros, Rocha, Zinner, Ashley, Breen, Soybel, Shoji, Burgess, Bleday, Whang) and Medicine (Wang, Kuntz), Brigham and Women’s Hospital, Harvard Medical School, Boston, MA. Correspondence address: Edward Whang, MD, FACS, Department of Surgery, Brigham and Women’s Hospital, 75 Francis St, Boston, MA 02115. email: [email protected]
© 2006 by the American College of Surgeons Published by Elsevier Inc.
773
ISSN 1072-7515/06/$32.00 doi:10.1016/j.jamcollsurg.2006.02.009
774
Matros et al
Does Gum Chewing Ameliorate Postoperative Ileus?
METHODS From April 2003 to June 2004 all patients ages 18 to 85 years undergoing elective partial colectomy at the Brigham and Women’s Hospital for colorectal cancer or benign conditions were screened for participation in this trial. Patients were eligible for inclusion if they were scheduled to undergo these procedures: segmental colonic resection, low anterior resection, abdominoperineal resection, hemicolectomy, or end-colostomy reversal. Patients were excluded if they had metastatic disease, history of inflammatory bowel disease, earlier abdominal radiation, mint allergy, wore dentures, had concomitant resection of small intestine, had nasogastric tube drainage beyond the first postoperative morning, had a diverting ileostomy, or had more than one bowel anastomosis during their operation. A total of 88 subjects enrolled and consented for the study; 22 were not randomized for the following reasons: operation required ileal diversion, need for ongoing nasogastric drainage, declined participation after operation. Institutional Review Board approval was obtained for this study. Computer-generated randomization was performed by the Brigham and Women’s Hospital Pharmacy at 8 AM on the first postoperative morning. Subjects were stratified according to type of colectomy performed (low anterior resection, hemicolectomy, abdominoperineal resection, end colostomy reversal, segmental resection). Subjects were randomized to one of three postoperative regimens: standard of care; accupressure bracelet worn in a sham location on the dorsum of the wrist (placebo); or chewing gum (experimental therapy). Gum type was standardized with all subjects receiving sugar-free peppermint-flavored gum. Ingredients include sorbitol, gum base, glycerol, mannitol, natural and artificial flavors, maltitol, aspartame, softeners, acesulfame K. Subjects in the latter two groups were instructed to wear either the bracelet or chew gum for 45 minutes three times daily at 9 AM, 4 PM, and 8 PM. To ensure compliance, nurses were informed of the study and administered either the gum or bracelet to subjects as a medication at the prespecified times. Administration and receipt of the therapy was recorded by initialing a box on the medication administration record. All subjects received the same postoperative care regimen, including epidural analgesia when not contraindicated, removal of the nasogastric tube on the first postoperative morning, and early ambulation. Diet consisted of sips of water up
J Am Coll Surg
to 30 mL per hour for patients assigned to standard of care and the placebo and active therapy arms until first passage of flatus. After flatus, diet was advanced at the discretion of the surgical team. Subjects were discharged by the surgical team once they were passing flatus and tolerating a regular diet, in the absence of other complications. To assess perioperative complications, clinical activity was monitored throughout hospitalization and for the first 30 postoperative days for each subject. This monitoring was achieved by screening routine office visits, hospital encounters through the hospital computer information system, and by a single phone call conducted by the study staff. To maintain patient blinding, subjects were unaware the accupressure bracelet was being used as a placebo in an inert location. Accupressure bracelets are normally worn on the ventral surface of the wrist and apply pressure to a defined pressure point P6.12 To ensure blinding of the study investigators and surgical team, subjects were instructed during enrollment not to inform the surgeon, surgical team, or research nurse to which group they were randomized. In addition, the primary surgical team and study investigators did not make clinical rounds during the specified treatment times of 9 AM, 4 PM, and 8 PM. To conceal the bracelet or gum, subjects stored these items inside the bedside drawer when not in use. To accurately monitor recovery of bowel function, patients were instructed to notify nurses or study investigators immediately after they passed either gas or a bowel movement. Outcomes were tallied daily by either a study nurse or investigator in a blinded fashion and rounded to the nearest whole hour. The primary end point in the study was time to first postoperative passage of flatus. Secondary end points include time to first postoperative bowel movement, time until patients were ready for discharge (defined as passing gas and tolerating two regular meals in the absence of complications), time until actual discharge, and complications at 30 days. Power calculation for the study was based on the primary end point of time to first passage of flatus. The null hypothesis for the first comparison was that gum chewing would be equivalent to the placebo (ie, accupressure bracelet) therapy, and the alternative hypothesis is that they would not be equivalent. The null hypothesis for the second comparison is that gum chewing is equivalent to standard of care therapy, although the alternative states that these two therapies are not equal. The sample
Vol. 202, No. 5, May 2006
Matros et al
Does Gum Chewing Ameliorate Postoperative Ileus?
775
Table 1. Demographic and Surgical Characteristics Characteristics
Age* (y) Female gender (%) Non-Caucasian race (%) Operative length* (h:min) Type of operation Abdominoperineal resection Colostomy reversal Low anterior resection Hemicolectomy Segmental resection No. of prior abdominal operations* Estimated blood loss* (mL) Patients with epidural analgesia (%) ASA class 1 2 3
Standard (n ⴝ 21)
Bracelet (n ⴝ 23)
Gum (n ⴝ 22)
58 (⫾15) 43 10 2:54 (⫾56)
54 (⫾11) 61 22 3:04 (⫾43)
62 (⫾14) 64 5 2:38 (⫾57)
4 2 5 6 4 .7 (⫾1.1) 200 (⫾140) 95
5 2 6 6 4 0.9 (⫾1.2) 335 (⫾420) 96
4 2 5 6 5 0.6 (⫾0.6) 230 (⫾190) 86
2 17 2
1 20 2
1 15 6
None of the differences was statistically significant. *Values are mean ⫾ SD. ASA, American Society of Anesthesiologists.
size calculation was adjusted for the two primary comparisons using Bonferroni correction and a corresponding Z-value for a two-sided ␣ of 0.025. Preliminary data indicated that enrollment of 22 patients in each of 3 arms was necessary to detect a 0.75-day difference in time to flatus with a power of 85% using a two-sided p value of 0.025. Median time to events was compared among the three groups using the log-rank test. Kaplan-Meier curves graphically depict the time-to-event data. All analyses were based on the principle of intention to treat. In Table 1 between-group comparisons for continuous variables were made using either ANOVA or Kruskal-Wallis tests, as appropriate, based on the distribution of the data. For categorical variables, chi-square test for heterogeneity was used. Statistical analyses were performed using STATA, version 7 (Stata Corp). RESULTS Between April 2003 and June 2004, a total of 66 subjects met inclusion criteria, provided consent, and underwent randomization. Twenty-one were assigned to standard of care, 22 were assigned the active therapy (gum chewing), and 23 were assigned to the placebo group (accupressure bracelet). All three groups were statistically equivalent with respect to demographic and surgical characteristics (Table 1).
Recovery of gastrointestinal function was determined by the first passage of flatus and bowel movement postoperatively. Median time to first flatus was 72 hours and 76 hours postoperatively for subjects who received standard of care and placebo bracelet, respectively. Median time to flatus was most rapid in the gum-chewing group (66 hours postoperatively); this parameter was not significantly different from corresponding values associated with either of the other two groups (p ⫽ 0.384) (Table 2). Similarly, no significant differences with respect to time to first bowel movement were observed among the groups. Subjects in the gum-chewing group had a median time to first bowel movement of 86 hours postoperatively, patients in the standard of care and placebo bracelet groups passed stool at 93 and 87 hours postoperatively (p ⫽ 0.913). These findings are shown graphically in the Kaplan-Meier curves in Figures 1A and 1B. Because postoperative ileus is a major determinant of length of stay, this end point was captured as part of the secondary analysis. As shown in Table 2, there was no significant difference in either overall length of stay or time until patients were ready for discharge among the three groups. The distribution and nature of postoperative and perioperative complications is shown in Table 3. Because of the low frequency of these events, meaningful statis-
776
Matros et al
Does Gum Chewing Ameliorate Postoperative Ileus?
J Am Coll Surg
Table 2. Time to Event for Primary and Secondary Outcomes Median time*
To flatus To bowel movement (n ⫽ 49)‡ Until ready for discharge To actual discharge
Standard
Bracelet
Gum
Overall
p Value†
67 (57–85)
72 (46–97)
60 (53–76)
67 (52–84)
0.384
88 (69–108)
74 (58–111)
80 (69–103)
78 (68–105)
0.913
102 (94–118) 117 (97–123)
98 (90–165) 116 (95–168)
105 (93–123) 119 (99–138)
103 (93–123) 118 (98–138)
0.354 0.787
*Interquartile range. † p value determined by log-rank test. ‡ Patients were not required to have a bowel movement before discharge.
tical analyses cannot be performed; gum chewing does not appear to be associated with an increased number of adverse postoperative events. DISCUSSION Postoperative ileus is defined as the transient cessation of luminal transit after laparotomy or laparoscopy because of inhibition of intestinal motility.13 This process is usually self-limiting, with resolution of bowel activity occurring first in the small bowel, then stomach, and finally colon.14 This common phenomenon is clinically important as it contributes to patient discomfort, prolonged hospitalization, and increased health-care cost. In the study by Asao and colleagues,11 patients who underwent laparoscopic colectomy for colon cancer were randomly assigned to either gum chewing three times a day from the first postoperative day until first flatus or standard postoperative management. Patients in the gum-chewing group passed gas at a mean of 1 day sooner and had their first bowel movement at a mean of 2.7 days before those in the control group. There were
no differences in length of stay among groups observed. The authors concluded that gum chewing is a simple and cost-effective way to reduce postoperative ileus. Several factors limit the interpretation of this study. First, patient selection and accrual were not described, and neither the type of operation nor epidural use was mentioned. Second, the effect of bias from lack of blinding might account for many of the measured differences. Finally, the trial did not incorporate a study arm to measure a placebo effect, if present. From a mechanistic and physiologic standpoint it is plausible that gum chewing could have beneficial effects on bowel recovery. The proposed mechanism is through a sham feeding pathway in which activation of the cephalic phase of digestion leads to upregulation of gastrointestinal hormones and motility.15 These responses increase as the duration of sham feeding lengthens. In addition, it is well described that chewing stimulates secretion from salivary glands, stomach, pancreas, and liver through neural and hormonal pathways.15 Evidence suggests this pathway can be vagally mediated because
Figure 1. Kaplan-Meier representations of (A) time to first passage of flatus postoperatively and (B) time to first postoperative bowel movement.
Vol. 202, No. 5, May 2006
Matros et al
Does Gum Chewing Ameliorate Postoperative Ileus?
777
Table 3. Complications Standard (n ⴝ 21)
In hospital Myocardial infarction Wound infection Pneumonia Reoperation for fascial dehiscence Transfer to ICU Within 30 days Pneumonia Intraabdominal abcess Wound infection Ileus requiring readmission
Bracelet (n ⴝ 23)
Gum (n ⴝ 22)
1*
1†
1 1 1 1
1 1 2 2
1 1 1
*ICU required for management of stroke. † ICU required for management of pulmonary edema.
vagotomized patients have a blunted sham feeding response.16,17 In conjunction with the recent findings by Asao and colleagues,11 this background data provided sufficient evidence to warrant additional investigation into effects of gum chewing on postoperative ileus. Despite rigorous methodology and adequate sample size, our results support that there is no benefit with either gum chewing or a placebo bracelet relative to the current standard of care at our institution. Our findings differ significantly from the only other published study evaluating the role of gum chewing in postoperative bowel recovery. Some explanations are worth mentioning. First, we studied open colectomies, not laparoscopic colectomies. In the current study, it should be easier to measure an effect with gum chewing because the magnitude of ileus might be greater after laparotomy.18 It is difficult to postulate that there is a fundamental difference in ileus after laparoscopic operation than in open operation to explain the positive findings after laparoscopy. Second, the effect of blinding might account for many of the measured differences.19 Here, outcomes were assessed in a blinded manner by the study team and patients were unaware which was the intended active therapy (gum or bracelet). This is particularly important when soft end points, such as passage of flatus and discharge time, are being measured. Our study was adequately powered to answer the question of whether gum chewing has a substantial impact on postoperative bowel function recovery; our sample size calculation was based on reduction in time to first flatus by three-quarters of a day relative to the placebo group. Our study does not exclude the possibility that gum chewing might be associated with smaller mag-
nitude reductions in duration of ileus. We do not believe such small magnitude changes would be clinically important. This study also highlights the need for conducting rigorous prospective, randomized, blinded studies to evaluate potential therapies for surgical disease.20,21 Currently, most surgical clinical research involves either retrospective reviews or analyses of prospectively maintained databases of clinical outcomes. Device trials are limited because they often lack blinding, objective end points, or both.22 Whenever feasible, we should strive to attain level-one evidence to justify the therapies we impose on patients. In conclusion, our study suggests that gum chewing does not induce a clinically relevant reduction in duration of ileus after open colectomy. Gum chewing is safe and can be consumed without deleterious effects in those patients who desire to chew gum while awaiting resolution of postoperative ileus.
Author Contributions Study conception and design: Matros, Wang, Bleday, Kuntz, Whang Acquisition of data: Matros, Rocha, Burgess Analysis and interpretation of data: Matros, Rocha, Kuntz, Whang Drafting of manuscript: Matros, Rocha Critical revision: Zinner, Ashley, Breen, Soybel, Shoji, Bleday, Kuntz, Whang Supervision: Whang
778
Matros et al
Does Gum Chewing Ameliorate Postoperative Ileus?
REFERENCES 1. Delaney CP. Clinical perspective on postoperative ileus and the effect of opiates. Neurogastroenterol Motil 2004;16[Suppl 2]:61–66. 2. Holte K, Kehlet H. Postoperative ileus: a preventable event. Br J Surg 2000;87:1480–1493. 3. Carli F, Trudel JL, Belliveu P. The effect of intraoperative thoracic epidural anesthesia and postoperative analgesia on bowel function after colorectal surgery. Dis Colon Rectum 2001;44: 1083–1089. 4. Taguchi A, Sharma N, Saleem RM, et al. Selective postoperative inhibition of gastrointestinal opioid receptors. N Engl J Med 2001;345:935–940. 5. Cheape JD, Wexner SD, James K, Jagelman DG. Does metoclopramide reduce the length of ileus after colorectal surgery? A prospective randomized trial. Dis Colon Rectum 1991;34:437– 441. 6. Jepsen S, Klaerke A, Nielsen PH, Simonsen O. Negative effect of metoclopramide in postoperative adynamic ileus: a prospective, randomized, double blind study. Br J Surg 1986;73:290–291. 7. Peeters T, Matthijs G, Depoortere I, et al. Erythromycin as a motilin receptor agonist. Am J Physiol 1989;257:G470–G74. 8. Basse L, Hjort Jakobsen D, Billesbolle P, et al. A clinical pathway to accelerate recovery after colonic resection. Ann Surg 2000; 232:51–57. 9. Carr CS, Ling KD, Boulos P, Singer M. Randomised trial of safety and efficacy of immediate postoperative enteral feeding in patients undergoing gastrointestinal resection. Br Med J 1996; 312:869–871. 10. Stewart BT, Woods RJ, Collopy BT, et al. Early feeding after elective open colorectal resections: a prospective randomized trial. Aust N Z J Surg 1998;68:125–128.
J Am Coll Surg
11. Asao T, Kuwano H, Nakamura J, et al. Gum chewing enhances early recovery from postoperative ileus after laparoscopic colectomy. J Am Coll Surg 2002;195:30–32. 12. Tokumaru O, Chen JD. Effects of acupressure on gastric myoelectrical activity in healthy humans. Scand J Gastroenterol 2005;40:319–325. 13. Luckey A, Livingston E, Tache Y. Mechanisms and treatment of postoperative ileus. Arch Surg 2003;138:206–214. 14. Waldhausen JH, Shaffrey ME, Skenderis BS II, et al. Gastrointestinal myoelectric and clinical patterns of recovery after laparotomy. Ann Surg 1990;211:777–784. 15. Chang EB, Sitrin MD, Black DD. Gastrointestinal, hepatobiliary, and nutritional physiology. Philadelphia: Lippincott-Raven; 1996. 16. Bradshaw BG, Thirlby RC. The value of sham-feeding tests in patients with postgastrectomy syndromes. Arch Surg 1993;128: 982–986; discussion 986–987. 17. Stenquist B, Forssell H, Olbe L, et al. Role of acid secretory response to sham feeding in predicting recurrent ulceration after proximal gastric vagotomy. Br J Surg 1994;81:1002–1006. 18. Chen HH, Wexner SD, Iroatulam AJ, et al. Laparoscopic colectomy compares favorably with colectomy by laparotomy for reduction of postoperative ileus. Dis Colon Rectum 2000;32: 61–65. 19. Johnson AG, Dixon JM. Removing bias in surgical trials. BMJ 1997;314:916–917. 20. Hall JC, Mills B, Nguyen H, et al. Methodologic standards in surgical trials. Surgery 1996;119:466–472. 21. Horton R. Surgical research or comic opera: questions, but few answers. Lancet 1996;347:984–985. 22. Wittes J. Clinical trials of the effectiveness of devices: an analogy with drugs. Surgery 2001;129:517–523.
Postoperative ileus remains a source of morbidity and the major determinant of length of stay after abdominal operation. Its economic burden in the United States health-care system is estimated to surpass $1 billion.1 For these reasons, strategies to reduce duration of postoperative ileus are of great importance. Therapies such as motility agents, early postoperative refeeding regimens, and physical therapy have been tested in clinical trials, but are not routinely used because of their limited clin-
ical efficacy.2-10 So far, surgeons have little to offer patients other than reassurance that bowel function will return. Recently, Asao and colleagues11 reported that gum chewing has efficacy in accelerating resolution of ileus after colon operation. They observed that subjects who chewed gum after laparoscopic colectomy passed gas and bowel movements at a mean of approximately 1 day sooner than patients who did not chew gum during the postoperative period. The findings were intriguing but the study had methodologic limitations, including the absence of either blinding or a placebo arm. To more rigorously evaluate the efficacy of gum chewing in accelerating resolution of postoperative ileus, we tested the hypothesis that gum chewing is more effective than a placebo in hastening bowel recovery and shortening hospitalization after open colectomy.
Competing Interests Declared: None. Received December 14, 2005; Revised January 31, 2006; Accepted February 6, 2006. From the Departments of Surgery (Matros, Rocha, Zinner, Ashley, Breen, Soybel, Shoji, Burgess, Bleday, Whang) and Medicine (Wang, Kuntz), Brigham and Women’s Hospital, Harvard Medical School, Boston, MA. Correspondence address: Edward Whang, MD, FACS, Department of Surgery, Brigham and Women’s Hospital, 75 Francis St, Boston, MA 02115. email: [email protected]
© 2006 by the American College of Surgeons Published by Elsevier Inc.
773
ISSN 1072-7515/06/$32.00 doi:10.1016/j.jamcollsurg.2006.02.009
774
Matros et al
Does Gum Chewing Ameliorate Postoperative Ileus?
METHODS From April 2003 to June 2004 all patients ages 18 to 85 years undergoing elective partial colectomy at the Brigham and Women’s Hospital for colorectal cancer or benign conditions were screened for participation in this trial. Patients were eligible for inclusion if they were scheduled to undergo these procedures: segmental colonic resection, low anterior resection, abdominoperineal resection, hemicolectomy, or end-colostomy reversal. Patients were excluded if they had metastatic disease, history of inflammatory bowel disease, earlier abdominal radiation, mint allergy, wore dentures, had concomitant resection of small intestine, had nasogastric tube drainage beyond the first postoperative morning, had a diverting ileostomy, or had more than one bowel anastomosis during their operation. A total of 88 subjects enrolled and consented for the study; 22 were not randomized for the following reasons: operation required ileal diversion, need for ongoing nasogastric drainage, declined participation after operation. Institutional Review Board approval was obtained for this study. Computer-generated randomization was performed by the Brigham and Women’s Hospital Pharmacy at 8 AM on the first postoperative morning. Subjects were stratified according to type of colectomy performed (low anterior resection, hemicolectomy, abdominoperineal resection, end colostomy reversal, segmental resection). Subjects were randomized to one of three postoperative regimens: standard of care; accupressure bracelet worn in a sham location on the dorsum of the wrist (placebo); or chewing gum (experimental therapy). Gum type was standardized with all subjects receiving sugar-free peppermint-flavored gum. Ingredients include sorbitol, gum base, glycerol, mannitol, natural and artificial flavors, maltitol, aspartame, softeners, acesulfame K. Subjects in the latter two groups were instructed to wear either the bracelet or chew gum for 45 minutes three times daily at 9 AM, 4 PM, and 8 PM. To ensure compliance, nurses were informed of the study and administered either the gum or bracelet to subjects as a medication at the prespecified times. Administration and receipt of the therapy was recorded by initialing a box on the medication administration record. All subjects received the same postoperative care regimen, including epidural analgesia when not contraindicated, removal of the nasogastric tube on the first postoperative morning, and early ambulation. Diet consisted of sips of water up
J Am Coll Surg
to 30 mL per hour for patients assigned to standard of care and the placebo and active therapy arms until first passage of flatus. After flatus, diet was advanced at the discretion of the surgical team. Subjects were discharged by the surgical team once they were passing flatus and tolerating a regular diet, in the absence of other complications. To assess perioperative complications, clinical activity was monitored throughout hospitalization and for the first 30 postoperative days for each subject. This monitoring was achieved by screening routine office visits, hospital encounters through the hospital computer information system, and by a single phone call conducted by the study staff. To maintain patient blinding, subjects were unaware the accupressure bracelet was being used as a placebo in an inert location. Accupressure bracelets are normally worn on the ventral surface of the wrist and apply pressure to a defined pressure point P6.12 To ensure blinding of the study investigators and surgical team, subjects were instructed during enrollment not to inform the surgeon, surgical team, or research nurse to which group they were randomized. In addition, the primary surgical team and study investigators did not make clinical rounds during the specified treatment times of 9 AM, 4 PM, and 8 PM. To conceal the bracelet or gum, subjects stored these items inside the bedside drawer when not in use. To accurately monitor recovery of bowel function, patients were instructed to notify nurses or study investigators immediately after they passed either gas or a bowel movement. Outcomes were tallied daily by either a study nurse or investigator in a blinded fashion and rounded to the nearest whole hour. The primary end point in the study was time to first postoperative passage of flatus. Secondary end points include time to first postoperative bowel movement, time until patients were ready for discharge (defined as passing gas and tolerating two regular meals in the absence of complications), time until actual discharge, and complications at 30 days. Power calculation for the study was based on the primary end point of time to first passage of flatus. The null hypothesis for the first comparison was that gum chewing would be equivalent to the placebo (ie, accupressure bracelet) therapy, and the alternative hypothesis is that they would not be equivalent. The null hypothesis for the second comparison is that gum chewing is equivalent to standard of care therapy, although the alternative states that these two therapies are not equal. The sample
Vol. 202, No. 5, May 2006
Matros et al
Does Gum Chewing Ameliorate Postoperative Ileus?
775
Table 1. Demographic and Surgical Characteristics Characteristics
Age* (y) Female gender (%) Non-Caucasian race (%) Operative length* (h:min) Type of operation Abdominoperineal resection Colostomy reversal Low anterior resection Hemicolectomy Segmental resection No. of prior abdominal operations* Estimated blood loss* (mL) Patients with epidural analgesia (%) ASA class 1 2 3
Standard (n ⴝ 21)
Bracelet (n ⴝ 23)
Gum (n ⴝ 22)
58 (⫾15) 43 10 2:54 (⫾56)
54 (⫾11) 61 22 3:04 (⫾43)
62 (⫾14) 64 5 2:38 (⫾57)
4 2 5 6 4 .7 (⫾1.1) 200 (⫾140) 95
5 2 6 6 4 0.9 (⫾1.2) 335 (⫾420) 96
4 2 5 6 5 0.6 (⫾0.6) 230 (⫾190) 86
2 17 2
1 20 2
1 15 6
None of the differences was statistically significant. *Values are mean ⫾ SD. ASA, American Society of Anesthesiologists.
size calculation was adjusted for the two primary comparisons using Bonferroni correction and a corresponding Z-value for a two-sided ␣ of 0.025. Preliminary data indicated that enrollment of 22 patients in each of 3 arms was necessary to detect a 0.75-day difference in time to flatus with a power of 85% using a two-sided p value of 0.025. Median time to events was compared among the three groups using the log-rank test. Kaplan-Meier curves graphically depict the time-to-event data. All analyses were based on the principle of intention to treat. In Table 1 between-group comparisons for continuous variables were made using either ANOVA or Kruskal-Wallis tests, as appropriate, based on the distribution of the data. For categorical variables, chi-square test for heterogeneity was used. Statistical analyses were performed using STATA, version 7 (Stata Corp). RESULTS Between April 2003 and June 2004, a total of 66 subjects met inclusion criteria, provided consent, and underwent randomization. Twenty-one were assigned to standard of care, 22 were assigned the active therapy (gum chewing), and 23 were assigned to the placebo group (accupressure bracelet). All three groups were statistically equivalent with respect to demographic and surgical characteristics (Table 1).
Recovery of gastrointestinal function was determined by the first passage of flatus and bowel movement postoperatively. Median time to first flatus was 72 hours and 76 hours postoperatively for subjects who received standard of care and placebo bracelet, respectively. Median time to flatus was most rapid in the gum-chewing group (66 hours postoperatively); this parameter was not significantly different from corresponding values associated with either of the other two groups (p ⫽ 0.384) (Table 2). Similarly, no significant differences with respect to time to first bowel movement were observed among the groups. Subjects in the gum-chewing group had a median time to first bowel movement of 86 hours postoperatively, patients in the standard of care and placebo bracelet groups passed stool at 93 and 87 hours postoperatively (p ⫽ 0.913). These findings are shown graphically in the Kaplan-Meier curves in Figures 1A and 1B. Because postoperative ileus is a major determinant of length of stay, this end point was captured as part of the secondary analysis. As shown in Table 2, there was no significant difference in either overall length of stay or time until patients were ready for discharge among the three groups. The distribution and nature of postoperative and perioperative complications is shown in Table 3. Because of the low frequency of these events, meaningful statis-
776
Matros et al
Does Gum Chewing Ameliorate Postoperative Ileus?
J Am Coll Surg
Table 2. Time to Event for Primary and Secondary Outcomes Median time*
To flatus To bowel movement (n ⫽ 49)‡ Until ready for discharge To actual discharge
Standard
Bracelet
Gum
Overall
p Value†
67 (57–85)
72 (46–97)
60 (53–76)
67 (52–84)
0.384
88 (69–108)
74 (58–111)
80 (69–103)
78 (68–105)
0.913
102 (94–118) 117 (97–123)
98 (90–165) 116 (95–168)
105 (93–123) 119 (99–138)
103 (93–123) 118 (98–138)
0.354 0.787
*Interquartile range. † p value determined by log-rank test. ‡ Patients were not required to have a bowel movement before discharge.
tical analyses cannot be performed; gum chewing does not appear to be associated with an increased number of adverse postoperative events. DISCUSSION Postoperative ileus is defined as the transient cessation of luminal transit after laparotomy or laparoscopy because of inhibition of intestinal motility.13 This process is usually self-limiting, with resolution of bowel activity occurring first in the small bowel, then stomach, and finally colon.14 This common phenomenon is clinically important as it contributes to patient discomfort, prolonged hospitalization, and increased health-care cost. In the study by Asao and colleagues,11 patients who underwent laparoscopic colectomy for colon cancer were randomly assigned to either gum chewing three times a day from the first postoperative day until first flatus or standard postoperative management. Patients in the gum-chewing group passed gas at a mean of 1 day sooner and had their first bowel movement at a mean of 2.7 days before those in the control group. There were
no differences in length of stay among groups observed. The authors concluded that gum chewing is a simple and cost-effective way to reduce postoperative ileus. Several factors limit the interpretation of this study. First, patient selection and accrual were not described, and neither the type of operation nor epidural use was mentioned. Second, the effect of bias from lack of blinding might account for many of the measured differences. Finally, the trial did not incorporate a study arm to measure a placebo effect, if present. From a mechanistic and physiologic standpoint it is plausible that gum chewing could have beneficial effects on bowel recovery. The proposed mechanism is through a sham feeding pathway in which activation of the cephalic phase of digestion leads to upregulation of gastrointestinal hormones and motility.15 These responses increase as the duration of sham feeding lengthens. In addition, it is well described that chewing stimulates secretion from salivary glands, stomach, pancreas, and liver through neural and hormonal pathways.15 Evidence suggests this pathway can be vagally mediated because
Figure 1. Kaplan-Meier representations of (A) time to first passage of flatus postoperatively and (B) time to first postoperative bowel movement.
Vol. 202, No. 5, May 2006
Matros et al
Does Gum Chewing Ameliorate Postoperative Ileus?
777
Table 3. Complications Standard (n ⴝ 21)
In hospital Myocardial infarction Wound infection Pneumonia Reoperation for fascial dehiscence Transfer to ICU Within 30 days Pneumonia Intraabdominal abcess Wound infection Ileus requiring readmission
Bracelet (n ⴝ 23)
Gum (n ⴝ 22)
1*
1†
1 1 1 1
1 1 2 2
1 1 1
*ICU required for management of stroke. † ICU required for management of pulmonary edema.
vagotomized patients have a blunted sham feeding response.16,17 In conjunction with the recent findings by Asao and colleagues,11 this background data provided sufficient evidence to warrant additional investigation into effects of gum chewing on postoperative ileus. Despite rigorous methodology and adequate sample size, our results support that there is no benefit with either gum chewing or a placebo bracelet relative to the current standard of care at our institution. Our findings differ significantly from the only other published study evaluating the role of gum chewing in postoperative bowel recovery. Some explanations are worth mentioning. First, we studied open colectomies, not laparoscopic colectomies. In the current study, it should be easier to measure an effect with gum chewing because the magnitude of ileus might be greater after laparotomy.18 It is difficult to postulate that there is a fundamental difference in ileus after laparoscopic operation than in open operation to explain the positive findings after laparoscopy. Second, the effect of blinding might account for many of the measured differences.19 Here, outcomes were assessed in a blinded manner by the study team and patients were unaware which was the intended active therapy (gum or bracelet). This is particularly important when soft end points, such as passage of flatus and discharge time, are being measured. Our study was adequately powered to answer the question of whether gum chewing has a substantial impact on postoperative bowel function recovery; our sample size calculation was based on reduction in time to first flatus by three-quarters of a day relative to the placebo group. Our study does not exclude the possibility that gum chewing might be associated with smaller mag-
nitude reductions in duration of ileus. We do not believe such small magnitude changes would be clinically important. This study also highlights the need for conducting rigorous prospective, randomized, blinded studies to evaluate potential therapies for surgical disease.20,21 Currently, most surgical clinical research involves either retrospective reviews or analyses of prospectively maintained databases of clinical outcomes. Device trials are limited because they often lack blinding, objective end points, or both.22 Whenever feasible, we should strive to attain level-one evidence to justify the therapies we impose on patients. In conclusion, our study suggests that gum chewing does not induce a clinically relevant reduction in duration of ileus after open colectomy. Gum chewing is safe and can be consumed without deleterious effects in those patients who desire to chew gum while awaiting resolution of postoperative ileus.
Author Contributions Study conception and design: Matros, Wang, Bleday, Kuntz, Whang Acquisition of data: Matros, Rocha, Burgess Analysis and interpretation of data: Matros, Rocha, Kuntz, Whang Drafting of manuscript: Matros, Rocha Critical revision: Zinner, Ashley, Breen, Soybel, Shoji, Bleday, Kuntz, Whang Supervision: Whang
778
Matros et al
Does Gum Chewing Ameliorate Postoperative Ileus?
REFERENCES 1. Delaney CP. Clinical perspective on postoperative ileus and the effect of opiates. Neurogastroenterol Motil 2004;16[Suppl 2]:61–66. 2. Holte K, Kehlet H. Postoperative ileus: a preventable event. Br J Surg 2000;87:1480–1493. 3. Carli F, Trudel JL, Belliveu P. The effect of intraoperative thoracic epidural anesthesia and postoperative analgesia on bowel function after colorectal surgery. Dis Colon Rectum 2001;44: 1083–1089. 4. Taguchi A, Sharma N, Saleem RM, et al. Selective postoperative inhibition of gastrointestinal opioid receptors. N Engl J Med 2001;345:935–940. 5. Cheape JD, Wexner SD, James K, Jagelman DG. Does metoclopramide reduce the length of ileus after colorectal surgery? A prospective randomized trial. Dis Colon Rectum 1991;34:437– 441. 6. Jepsen S, Klaerke A, Nielsen PH, Simonsen O. Negative effect of metoclopramide in postoperative adynamic ileus: a prospective, randomized, double blind study. Br J Surg 1986;73:290–291. 7. Peeters T, Matthijs G, Depoortere I, et al. Erythromycin as a motilin receptor agonist. Am J Physiol 1989;257:G470–G74. 8. Basse L, Hjort Jakobsen D, Billesbolle P, et al. A clinical pathway to accelerate recovery after colonic resection. Ann Surg 2000; 232:51–57. 9. Carr CS, Ling KD, Boulos P, Singer M. Randomised trial of safety and efficacy of immediate postoperative enteral feeding in patients undergoing gastrointestinal resection. Br Med J 1996; 312:869–871. 10. Stewart BT, Woods RJ, Collopy BT, et al. Early feeding after elective open colorectal resections: a prospective randomized trial. Aust N Z J Surg 1998;68:125–128.
J Am Coll Surg
11. Asao T, Kuwano H, Nakamura J, et al. Gum chewing enhances early recovery from postoperative ileus after laparoscopic colectomy. J Am Coll Surg 2002;195:30–32. 12. Tokumaru O, Chen JD. Effects of acupressure on gastric myoelectrical activity in healthy humans. Scand J Gastroenterol 2005;40:319–325. 13. Luckey A, Livingston E, Tache Y. Mechanisms and treatment of postoperative ileus. Arch Surg 2003;138:206–214. 14. Waldhausen JH, Shaffrey ME, Skenderis BS II, et al. Gastrointestinal myoelectric and clinical patterns of recovery after laparotomy. Ann Surg 1990;211:777–784. 15. Chang EB, Sitrin MD, Black DD. Gastrointestinal, hepatobiliary, and nutritional physiology. Philadelphia: Lippincott-Raven; 1996. 16. Bradshaw BG, Thirlby RC. The value of sham-feeding tests in patients with postgastrectomy syndromes. Arch Surg 1993;128: 982–986; discussion 986–987. 17. Stenquist B, Forssell H, Olbe L, et al. Role of acid secretory response to sham feeding in predicting recurrent ulceration after proximal gastric vagotomy. Br J Surg 1994;81:1002–1006. 18. Chen HH, Wexner SD, Iroatulam AJ, et al. Laparoscopic colectomy compares favorably with colectomy by laparotomy for reduction of postoperative ileus. Dis Colon Rectum 2000;32: 61–65. 19. Johnson AG, Dixon JM. Removing bias in surgical trials. BMJ 1997;314:916–917. 20. Hall JC, Mills B, Nguyen H, et al. Methodologic standards in surgical trials. Surgery 1996;119:466–472. 21. Horton R. Surgical research or comic opera: questions, but few answers. Lancet 1996;347:984–985. 22. Wittes J. Clinical trials of the effectiveness of devices: an analogy with drugs. Surgery 2001;129:517–523.