Accepted Manuscript

Effect of gum chewing on ameliorating ileus following colorectal surgery: A meta-

analysis of 18 randomized controlled trials

Qing Liu, Honglei Jiang, Dong Xu, Junzhe Jin

PII: S1743-9191(17)30665-9
DOI: 10.1016/j.ijsu.2017.07.107
Reference: IJSU 4066

To appear in: International Journal of Surgery

Received Date: 8 July 2017

Accepted Date: 31 July 2017

Please cite this article as: Liu Q, Jiang H, Xu D, Jin J, Effect of gum chewing on ameliorating ileus
following colorectal surgery: A meta-analysis of 18 randomized controlled trials, International Journal of
Surgery (2017), doi: 10.1016/j.ijsu.2017.07.107.

This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to
our customers we are providing this early version of the manuscript. The manuscript will undergo
copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please
note that during the production process errors may be discovered which could affect the content, and all
legal disclaimers that apply to the journal pertain.
 ACCEPTED MANUSCRIPT
Title page

Title: Effect of gum chewing on ameliorating ileus following colorectal surgery: a meta-
analysis of 18 randomized controlled trials

Running title: Role of chewing gum in ameliorating ileus following colorectal surgery

Authors: Qing Liu, Honglei Jiang, Dong Xu, Junzhe Jin

Corresponding author: Junzhe Jin, Email: jccccj@126.com

PT
Affiliation: Department of General surgery, The Fourth Affiliated Hospital of China Medical
University, No.4 Chongshan East Road, Huanggu District, Shenyang 110032, Liaoning
Province, China.

RI
U SC
AN
M
D
TE
C EP
AC
 ACCEPTED MANUSCRIPT
Effect of gum chewing on ameliorating ileus following colorectal surgery: a meta-analysis of
18 randomized controlled trials

Abstract

Background and Objective Chewing gum, as an alternative to sham feeding, had been shown
to hasten the recovery of gut function following abdominal surgery. However, conclusions
remained contradictory. We sought to conduct an updated meta-analysis to evaluate the efficacy of

PT
gum chewing in alleviating ileus following colorectal surgery.
Methods We searched PubMed, EMBASE, and Cochrane Library Databases through February
2017 to identify randomized controlled trials (RCTs) evaluating the efficacy of the additional use

RI
of chewing gum following colorectal surgery. After screening for inclusion, data extraction, and
quality assessment, meta-analysis was conducted by the Review Manager 5.3 software. The
outcomes of interest were the time to first flatus, time to first bowel movement, length of hospital

SC
stay, and some clinically relevant parameters. We also performed subgroup analyses according to
the type of surgical approaches or on trials that adopted enhanced recovery after surgery (ERAS)
protocol or sugared gum.

U
Results A total of 18 RCTs, involving 1736 patients, were included. Compared with
standardized postoperative care, Chewing gum resulted in a shorter passage to first flatus [WMD
AN
= -8.81, 95%CI: (-13.45, -4.17), P = 0.0002], earlier recovery of bowel movement[WMD = -16.43,
95%CI: (-22.68, -10.19), P < 0.00001], and a reduction in length of hospital stay [WMD = -0.89,
95%CI: (-1.72, -0.07), P = 0.03]. Chewing gum was also associated with a lower risk of
M

postoperative ileus [OR = 0.41, 95%CI: (0.23, 0.73), P = 0.003]. No evidence of significant
advantages in overall postoperative complication, nausea, vomiting, bloating, readmission and
reoperation towards the addition of chewing gum was observed. Subgroup analyses all favored
D

gum chewing. However, the findings are hampered by the significant heterogeneity between trials.
Conclusions Based on current evidence, chewing gum offers an inexpensive, well-tolerated,
TE

safe and effective method to ameliorate ileus following colorectal surgery. However, tightly
controlled, randomized and considerably larger multicenter trials are warranted to further validate
our findings.
EP

Key words gum chewing; ileus; colorectal surgery; meta-analysis

Introduction
C

Postoperative ileus, an important complication after colorectal surgery that usually results in
AC

nausea, vomiting and abdominal distension, is associated with delayed postoperative recovery,
extended hospitalization and increased healthcare costs [1, 2]. In the United States, the annual
economic consequences of postoperative ileus have been estimated to surpass one billion dollars
[3]. Accordingly, it is of great importance to acquire an effective, feasible, and safe solution to the
well-known problem. In clinical settings, investigators have tried various tactics to shorten
duration of ileus following gastrointestinal surgery. Enhanced recovery after surgery (ERAS), as
an integrated application of a series of evidence based interventions, is deemed to reduce the
incidence of postoperative ileus after colorectal surgery [4]. Contributors of the favorable result
have been shown to be multifactorial in the perioperative period and mainly include the following:
preoperative carbohydrate loading [5], rigorous management of intravenous fluid loading [6],
minimally invasive surgery (e.g. laparoscopy) [7], application of epidural anesthesia [8],
1
 ACCEPTED MANUSCRIPT
avoidance of nasogastric tube [9], early oral feeding [10] and early ambulation [11]. Besides
ERAS protocol and minimal trauma technique, gum chewing, a form of sham feeding, have been
demonstrated to be an alternative strategy to expedite recovery of bowel function following
colorectal surgery. Early oral feeding is an important factor promoting the return of gut function,
but it is not feasible due to postoperative nausea, vomiting and inability to tolerate oral feeding. In
contrast, chewing gum provides an inexpensive, well-tolerated and widely available solution to the
old problem.
Conclusions of the 4 recently published meta-analyses on the same topic are debatable. Ho et

PT
al. [12] and Song et al. [13] found that chewing gum significantly shortened the time to first flatus,
bowel movement and length of hospital stay. However, pooled estimates of subgroups evaluating
the potential of chewing gum on gut function after colectomy conducted by Yin et al. [14] and Li

RI
et al. [15] were controversial. Yin et al. revealed that chewing gum was associated with shorter
time to first flatus and bowel movement, but length of hospital stay was not reduced significantly;
Li et al. concluded that chewing gum significantly shortened the time to first bowel movement,

SC
but patients who were informed to consume gum did not experience shorter length of hospital stay
and time to first flatus. Previous meta-analyses paid little attention on several clinically important
parameters including postoperative complication, readmission and reoperation. To our knowledge,

U
only one study [12] included subgroup analysis on trials that applied ERAS protocol, two studies
AN
[13,16] performed subgroup analysis on trials involving laparoscopic surgery, all with limited
number of trials. No relevant study investigated pooed results of sugar-free or sugared gum on
recovery of gut function following colorectal surgery. Therefore, we performed the up-dated
meta-analysis to further evaluate the effect of chewing gum on ameliorating ileus following
M

colorectal surgery with several newly published eligible RCTs.

D

Materials and methods

Publication search strategy

TE

Studies published up to February 2017 were identified by searching the PubMed, Embase and
Cochrane Library databases. No regional and language restrictions were imposed. All search
EP

algorithms were structured by Mesh (Medical Subject Headings) and free text terms including as
follows: “chewing gum”, “gum chewing”, “sham feeding”, “colon”, “rectum”, “colorectal
surgery”, “resection”, “ileus”. The reference lists of identified articles and previous reviews or
C

meta-analyses were manually checked to identify additional relevant articles. To verify the search
results, two authors participated in the databases search.
AC

Inclusion and exclusion criteria

Studies were eligible for inclusion if they met the following criteria: (1) participants: adult patients
(＞18 years) undergoing colorectal surgery regardless of pathology and surgical approach (open,
laparoscopic or hybrid); (2) intervention: use of chewing gum in the postoperative period; (3)
comparison: standard postoperative care; (4) outcome measures: report at least one of the relevant
outcome data mentioned in table 1; (5) study design: randomized controlled trial (RCT).
Studies were excluded if they (1) were non-randomized, reviews, cohorts, case-controlled
trials, abstracts only, or animal research; (2) patients with contraindications to early gum chewing;
(3) consisted of no outcome measures of interest; (4) interventions other than chewing gum; (5)

2
 ACCEPTED MANUSCRIPT
were not involve in colorectal surgery.

Data extraction and outcome measures

Two authors independently checked all included studies and extracted all relevant data.
Disagreement was resolved through discussion between the reviewers. If they could not reach a
consensus, the third author participated in making the final decision. The demographic and surgery
details of the included studies (depicted in table 1) including: last name of the first author,
published year, country of study population, sample size, age, sex, pathology of disease, surgical

PT
approach and surgical cite, mean duration of operation and mean estimated blood loss.
Intervention details of the included studies (depicted in table 2) are as follows: type of chewing
gum, gum chewing duration, frequency, and ending time, application of ERAS protocol and bowel

RI
preparation, time of removal of NG tube, epidural use, and postoperative regimes of oral feeding
and ambulation.
Ten outcome measures (listed in table 1) were regarded suitable for evaluating the effect of

SC
gum chewing on alleviating ileus following colorectal surgery: time to first flatus, time to first
bowel movement, length of hospital stay, overall postoperative complication, postoperative ileus,
nausea, vomiting, bloating, readmission and reoperation. If the study provided medians, the first

U
and third quartiles or the minimum and maximum values, we imputed the means and standard
AN
deviations as described by Wan et al.[17].

Assessment of methodological quality

Two reviewers independently evaluated RCTs quality and risk of bias following the quality
M

checklist supplied in the Cochrane Handbook for Systematic Reviews of Interventions [18]. The
authors examined six domains: method of randomization, allocation concealment, blinding,
D

completeness of outcome data, selective reporting of outcomes, and other bias. The risk of bias in
each domain was categorized as low, high or unclear. “Unclear” indicated an insufficient
TE

information to evaluate risk of bias. We resolved discrepancy by consensus.

Statistical analysis
EP

All statistical analyses were performed using Review Manager 5.3 software from the Cochrane
Collaboration. Mean differences (MDs) with 95 % confidence intervals (CIs) were calculated to
analyze continuous variables. Weighted mean difference (WMD) was used when variables were
C

presented in the same scale, standard mean difference (SMD) indicated that variables were
presented in the different scale. Odds ratios (ORs) with 95% CIs were calculated for dichotomous
AC

variables. p of Q test > 0.1 and I2 < 50 % indicated a lack of heterogeneity, and in this case pooled
estimate was calculated by a fixed effects model. Otherwise, when p of Q test < 0.1 or I2 > 50 %, a
random effects model was adopted. The level of significance was defined as p < 0.05 (test for
heterogeneity was set at p < 0.1).

Results

Study characteristics

Figure 1 shows the flow chart for the search of articles. Of the 119 relevant articles identified in
the initial search, 18 RCTs [1,19-35] with a total of 1736 consecutive patients were included in the
3
 ACCEPTED MANUSCRIPT
meta-analysis. Details of demographic and characteristics are listed in table 1 and 2. These studies
were published between 2002 to 2017. Four studies were conducted in America, three in Japan,
two in UK, two in Mexico, two in China, one in Portland, one in Turkey, one in Italy, one in
Australia, and one in Netherlands. In individual studies, baseline materials regarding demographic
and surgery are comparable. As for regimes of gum chewing, patients in the gum chewing group
were given sugar-free or sugared gum, and they chewed for 5 to 60 minutes 3-4 times daily. Five
of the included studies [1,21,22,32,33], involving 793 patients, were conducted in conjunction
with ERAS protocol. Four studies [21-23,34], involving 378 patients, provided participants in

PT
chewing gum group with sugared gum (sorbitol-free or xybitol-free). Four studies [21,28,30,33],
involving 202 patients, incorporated subgroup of patients who received laparoscopic surgery.

RI
Methodological quality of included studies

The results of risk of bias for individual trials were shown in figure 2. All 18 RCTs showed low to
moderate overall risk of bias. All studies other than five [20,27-29,34] generated appropriately

SC
random sequence. Allocation concealment was conducted adequately in four studies [1,26,27,33].
Due to the nature of clinical intervention being compared, most studies were regarded as unclear
risk of bias for blinding.

Time to first flatus

U
AN
Sixteen studies included data on time to first flatus. High heterogeneity exists between the trials (P
＜0.00001, I2=91%), thus supporting the use of a random effects model. Pooled results indicated
that chewing gum significantly shortened the time to first flatus [WMD = -8.81, 95%CI: (-13.45,
M

-4.17), P = 0.0002]. (Fig. 3)

Time to first bowel movement

D

Sixteen of the 18 RCTs mentioned time to first bowel movement. The overall effect was calculated
TE

with random effects model owing to high heterogeneity (P＜0.00001, I2=82%). The pooled result
favored chewing gum, with a WMD of 16.4 hours reduction [95%CI: (-22.68, -10.19), P＜
0.00001]. (Fig. 4)
EP

Length of hospital stay

Sixteen of the included studies reported on length of hospital stay. There was statistical
C

heterogeneity between the trials (P＜0.00001, I2=90%). In random effects model, chewing gum
resulted in a reduction in length of hospital stay of 0.89 days [95%CI: (-1.72, -0.07), P = 0.03].
AC

(Fig. 5)

Several clinically relevant parameters

Six studies mentioned postoperative ileus. The overall effect was calculated with fixed effects
model owing to appropriate homogeneity (P = 0.94, I2 = 0). Pooled estimate indicated that
chewing gum was associated with lower risk of postoperative ileus [OR = 0.41, 95%CI: (0.23,
0.73), P = 0.003]. There are relatively limited number of trials mentioning nausea, vomiting,
bloating, readmission and reoperation. Pooled data revealed that chewing gum did not
significantly reduce risk of these indexes compared to standard postoperative care. (Table 3)

Subgroup analyses
4
 ACCEPTED MANUSCRIPT
We performed subgroup analyses for outcomes with significant heterogeneity and to assess the
robustness of our findings according to the type of surgical approach, gum and perioperative care
protocol. Pooled results indicated that chewing gum significantly shortened the time to first bowel
movement in patients chewing sugared gum (sorbitol-free or xylitol-free) or under ERAS protocol.
Under context of laparoscopic surgery, chewing gum was associated with shorter time to first
bowel movement and length of hospital stay. Pooled results for the subgroup of patients who
received open colorectal resection were similar to those observed across the entire study
population. The remaining outcomes (listed in table 4) showed only marginally reduction with the

PT
use of chewing gum compared to standard postoperative care.

Publication bias

RI
Fig. 6 shows the funnel plot of 16 trials included in the meta-analysis for length of hospital stay.
No asymmetric distribution was observed, indicating no significant publication bias.

SC
Discussion

The present meta-analysis revealed that, in patients who underwent colorectal resection, chewing
gum significantly reduced the time to first flatus, bowel movement, length of hospital stay and the

U
risk of postoperative ileus compared to standard care protocol. Although chewing gum reduced the
AN
risk of overall postoperative complication, nausea, vomiting, bloating, readmission and
reoperation, this did not reach a statistical significance. Significant reduction of the time to first
bowel movement with the addition of chewing gum was also seen in subgroups which adopted
ERAS protocol or sugared gum, moreover, showing a trend towards shorter passage to first flatus
M

and length of hospital stay (not significantly). In context of laparoscopic surgery, the use of
chewing gum significantly shortened the passage to first bowel movement and length of hospital
D

stay, and marginally reduced the time to first flatus. However, the subgroup of patients who
received open surgery demonstrated significantly reduction in all predefined outcomes with the
TE

addition of chewing gum.

Postoperative ileus (PI) occurs following almost all abdominal surgeries, and is regarded as
one of the limiting factors that delay early discharge. As self-limiting as it is defined, PI often
EP

recovery begins in the small intestine (about 8-12 hours), then the stomach (about 1-2 days), and
finally the colon (about 3-5 days) [16]. Chewing gum, as an alternative to sham feeding, elicits a
physiological intestinal stimulation without the complications associated with oral feeding. The
C

underlying mechanism is believed to be that sham feeding stimulates the cephalic vagal nervous
system, and hence acts in a prokinetic manner on the intestine [36]. Chewing mimics food intake
AC

and promote the motility of human duodenum [37], stomach [38] and rectum [39]. Furthermore,
sham feeding stimulates the secretion of the gastrointestinal hormones, saliva, and pancreatic
juices [38]. Gum also gives the patient a sense of well-being, and helps to maintain the user’s
mouth moist [32]. Sugar-free chewing gum contains sugar substitutes (e.g., sorbitol, xylitol), and
these substitutes are postulated to exert a non-stimulant laxative effect [40].
In addition, ERAS protocol is deemed to reduce the incidence of postoperative ileus after
colorectal surgery using a multimodal approach. The laparoscopic technique is also involve in
ameliorating postoperative ileus [41]. The mechanism may be that laparoscopic surgery minimizes
the extent of trauma and lessens the release of endogenous mediators of postoperative ileus [42].
Several systematic reviews have been conducted to determine the efficacy of chewing gum in

5
 ACCEPTED MANUSCRIPT
the patients undergoing colorectal resection, however, conclusions are inconsistent. Chan et al.
[43], included five RCTs involving 158 patients, found that chewing gum significantly shortened
the time to first flatus, bowel movement and length of hospital stay. Vasquez et al. [16], included
six RCTs involving 244 patients, suggested that chewing gum was associated with shorter passage
to first flatus and bowel movement, but patients who were assigned to chewing gum group did not
experience earlier discharge. Subgroup analyses demonstrated that chewing gum reduced the time
to first flatus in both open and laparoscopic surgery, but reached a significance only in open
resection subgroup. Small sample size as included in the above studies, conclusions drawn from

PT
these meta-analyses may not be regarded as definitive. Wang et al. [44] (include 13 RCTs), Ho et
al. [12] (include 10 RCTs), and Song et al. [13] (include 26 RCTs) recruited relatively more
patients, and found that chewing gum was associated with shorter passage to first flatus, bowel

RI
movement and length of hospital stay. Ho et al.’s subgroup analysis of patients within an ERAS
programme revealed no difference in postoperative gastrointestinal function. Song et al. also
conducted a subgroup analysis of patients undergoing laparoscopic surgery, and showed

SC
significant decrease in time to first flatus and bowel movement, but only marginal reduction in
length of hospital stay, however, elicited remarkable reduction in all prespecific outcomes within
the subgroup of open surgery. Since small sample size included in the subgroups, the conclusions

U
may be changed when more relevant trials are added.
AN
The updated meta-analysis differs as additional three RCTs were included with three abstract
only articles excluded due to absence of baseline materials. No language and region restrictions
were applied, thus more trials and patients were accrued in the current study. We also pooled data
of some clinically important indexes and firstly assessed the efficacy of sugared gum (sorbitol-free
M

or xylitol-free) in a subgroup compared to standard postoperative care, which provided a relatively

more comprehensive assess on chewing gum. Additionally, no publish bias was found in our
D

meta-analysis, indicating that the pooled results are reliable.

There were several shortcomings in the present meta-analysis. First, significant heterogeneity
TE

between trials was detected, which may be attributed to lack of blinding and allocation
concealment, differing pathology, surgical type, postoperative analgesia and regimes of chewing
gum and oral intake. Second, limited data were available on postoperative complications and
EP

subgroup analyses included relatively few trials, so the conclusions may be challenged if more
studies were analyzed. Third, stoma formation and range of colectomy may be confounding
factors which negate the benefits of chewing gum, thus more rigorously controlled randomized
C

trials are warranted for further research.

AC

Conclusions

The present meta-analysis suggests that chewing gum is an inexpensive, secure, well-tolerated and
widely available solution to ileus following colorectal resection. It is interesting to note that ERAS
programme and laparoscopic technique tend to negate the benefits of chewing gum. Furthermore,
sugared gum (sorbitol-free or xylitol-free) seems to be less effective in ameliorating ileus
following colorectal resection. However, outcomes of subgroup analyses all favored chewing gum.
The results should be interpreted with caution as there was significant heterogeneity. Conclusions
drawn from the subgroup analyses may not be regarded as definitive due to small sample size.
Accordingly, tightly controlled, randomized and considerably larger multicenter trials are
warranted to corroborate the role of gum chewing following elective colorectal resection.

6
 ACCEPTED MANUSCRIPT

References

[1] Atkinson C, Penfold CM, Ness AR, et al. Randomized clinical trial of postoperative chewing
gum versus standard care after colorectal resection. Br J Surg. 2016; 103:962-970.
[2] Boeckxstaens GE, de Jonge WJ. Neuroimmune mechanisms in postoperative ileus. Gut. 2009;
58: 1300-1311.

PT
[3] Delaney CP. Clinical perspective on postoperative ileus and the effect of opiates.
Neurogastroenterol Motil. 2004; 16:61-66.
[4] Holte K, Kehlet H. Postoperative ileus: a preventable event. Br J Surg. 2000; 87:1480-1493.

RI
[5] Soop M, Nygren J, Myrenfors P, et al. Preoperative oral carbohydrate treatment attenuates
immediate postoperative insulin resistance. Am J Physiol Endocrinol Metab. 2001; 280:576-583.
[6] Rahbari NN, Zimmermann JB, Schmidt T, et al. Meta-analysis of standard, restrictive and

SC
supplemental fluid administration in colorectal surgery. Br J Surg. 2009; 96:331-341.
[7] Siddiqui MR, Sajid MS, Qureshi S, et al. Elective laparoscopic sigmoid resection for
diverticular disease has fewer complications than conventional surgery: a meta-analysis. Am J

U
Surg. 2010; 200:144-161.
AN
[8] Jorgensen H, Wetterslev J, Moiniche S, et al. Epidural local anaesthetics versus opioid-based
analgesic regimens on postoperative gastrointestinal paralysis, PONV and pain after abdominal
surgery. Cochrane Database Syst Rev. 2000; 4:CD001893.
[9] Rao W, Zhang X, Zhang J, et al. The role of nasogastric tube in decompression after elective
M

colon and rectum surgery: a meta-analysis. Int J Colorectal Dis. 2011; 26:423-429.
[10] Dag A, Colak T, Turkmenoglu O, et al. A randomized controlled trial evaluating early versus
D

traditional oral feeding after colorectal surgery. Clinics (Sao Paulo). 2011; 66:2001-2005.
[11] Henriksen MG, Jensen MB, Hansen HV, et al. Enforced mobilization, early oral feeding, and
TE

balanced analgesia improve convalescence after colorectal surgery. Nutrition. 2002; 18:147-152.
[12] Ho YM, Smith SR, Pockney P, et al. A meta-analysis on the effect of sham feeding following
colectomy: should gum chewing be included in enhanced recovery after surgery protocols? Dis
EP

Colon Rectum. 2014; 57:115-126.

[13] Song GM, Deng YH, Jin YH, et al. Meta-analysis comparing chewing gum versus standard
postoperative care after colorectal resection. Oncotarget. 2016; 7:70066-70079.
C

[14] Yin Z, Sun J, Liu T, et al. Gum chewing: another simple potential method for more rapid
improvement of postoperative gastrointestinal function. Digestion. 2013; 87:67-74.
AC

[15] Li S, Liu Y, Peng Q, et al. Chewing gum reduces postoperative ileus following abdominal
surgery: a meta-analysis of 17 randomized controlled trials. J Gastroenterol Hepatol. 2013;
28:1122-1132.
[16] Vásquez W, Hernández AV, Garcia-Sabrido JL. Is gum chewing useful for ileus after elective
colorectal surgery? A systematic review and meta-analysis of randomized clinical trials. J
Gastrointest Surg. 2009; 13:649–656.
[17] Wan X, Wang WQ, Liu JM, et al. Estimating the sample mean and standard deviation from
the simple size, median, range and/or interquartile range. BMC Medical Research Methodology.
2014; 14:135.
[18] Higgins JPT, Green S (editors). Cochrane Handbook for systematic reviews of interventions

7
 ACCEPTED MANUSCRIPT
version 5.1.0 [updated March 2011]. The Cochrane Collaboration. Available from www.cochrane-
handbook.org.
[19] Matros E, Rocha F, Zinner M, et al. Does gum chewing ameliorate postoperative ileus?
Results of a prospective, randomized, placebo-controlled trial. J Am Coll Surg. 2006; 202: 773
-778.
[20] Topcu SY, Oztekin SD. Effect of gum chewing on reducing postoperative ileus and recovery
after colorectal surgery: A randomised controlled trial. Complement Ther Clin Pract. 2016; 23: 21-
25.

PT
[21] Lim P, Morris OJ, Nolan G, et al. Sham feeding with chewing gum after elective colorectal
resectional surgery: a randomized clinical trial. Ann Surg. 2013; 257:1016-1024.
[22] Zaghiyan K, Felder S, Ovsepyan G, et al. A prospective randomized controlled trial of

RI
sugared chewing gum on gastrointestinal recovery after major colorectal surgery in patients
managed with early enteral feeding. Dis Colon Rectum. 2013; 56: 328–335.
[23] Kobayashi T, Masaki T, Kogawa K, et al. Efficacy of gum chewing on bowel movement after

SC
open colectomy for left-sided colorectal cancer: A randomized clinical trial. Dis Colon Rectum.
2015; 58: 1058–1063.
[24] Bahena-Aponte JA, Cárdenas-Lailson E, Chávez-Tapia N, et al. Utilidad de la goma de

U
mascar para la resolución del íleo posoperatorio en resecciones de colon izquierdo. Rev
AN
Gastroenterol Mex. 2010; 75:369-373.
[25] Bonventre S, Inviati A, Di Paola V, et al. Evaluating the efficacy of current treatments for
reducing postoperative ileus: a randomized controlled trial in a single center. Minerva Chir. 2014;
69:47-55.
M

[26] Forrester DA, Doyle-Munoz J, McTigue T, et al. The efficacy of gum chewing in reducing
postoperative ileus: A multisite randomized controlled trial. J Wound Ostomy Continence Nurs.
D

2014; 41:227-232.
[27] Schuster R, Grewal N, Greaney GC, et al. Gum Chewing Reduces ileus after elective open
TE

sigmoid colectomy. Arch Surg. 2006; 141:174-176.

[28] 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.
EP

[29] Hirayama I, Suzuki M, Ide M, et al. Chewing gum stimulates bowel motility after surgery for
colorectal cancer. Hepatogastroenterology. 2006; 53:206-208.
[30] Crainic C, Erickson K, Gardner J, et al. Comparison of methods to facilitate postoperative
C

bowel function. Medsurg Nurs. 2009; 18: 235-238.

[31] van den Heijkant TC, Costes LM, van der Lee DG, et al. Randomized clinical trial of the
AC

effect of gum chewing on postoperative ileus and inflammation in colorectal surgery. Br J Surg.
2015; 102: 202–211.
[32] Quah HM, Samad A, Neathey AJ, et al. Does gum chewing reduce postoperative ileus
following open colectomy for left-sided colon and rectal cancer? A prospective randomized
controlled trial. Colorectal Dis. 2006; 8: 64–70.
[33] Shum NF, Choi HK, Mak JC, et al. Randomized clinical trial of chewing gum after
laparoscopic colorectal resection. Br J Surg. 2016; 103: 1447–1452.
[34] Vergara-Fernandez O, Gonzalez-Vargas AP, Castellanos-Juarez JC, et al. Usefulness of gum
chewing to decrease postoperative ileus in colorectal surgery with primary anastomosis: a
randomized controlled trial. Rev Invest Clin. 2016; 68:314-318.

8
 ACCEPTED MANUSCRIPT
[35] Yang Y, Zuo HQ, Li Z, et al. Comparison of efficacy of simo decoction and acupuncture or
chewing gum alone on postoperative ileus in colorectal cancer resection: a randomized trial. Sci
Rep. 2017; 7:37826.
[36] Lunding JA, Nordstrom LM, Haukelid AO, et al. Vagal activation by sham feeding improves
gastric motility in functional dyspepsia. Neurogastroenterol Motil. 2008; 20:618-624.
[37] Soffer EE, Adrian TE. Effect of meal composition and sham feeding on duodenojejumal
motility in humans. Dig Dis Sci. 1992; 37:1009-1014.
[38] Stern RM, Crawford HE, Stewart WR, et al. Sham feeding. Cephalic-vagal influences on

PT
gastric myoelectric activity. Dig Dis Sci. 1989; 34:521-527.
[39] Jepsen JM, Skoubo-Kristensen E, Elsborg L. Rectosigmoid motility response to sham feeding
in irritable bowel syndrome. Evidence of a cephalic phase. Scand J Gastroenterol. 1989; 24:53-

RI
56.
[40] Parnaby CN, MacDonald AJ, Jenkins JT. Sham feed or sham? A meta-analysis of randomized
clinical trials assessing effect of gum chewing on gut function after elective colorectal surgery. Int

SC
J Colorectal Dis. 2009; 24:585-592.
[41] Schwenk W, Bohm B, Haase O, et al. Laparoscopic versus conventional colorectal resection:
a prospective randomized study of postoperative ileus and early postoperative feeding.

U
Langenbecks Arch Surg. 1998; 383:49-55.
AN
[42] Koninger J, Gutt CN, Wente MN, et al. Postoperative ileus. Pathophysiology and prevention
(in German). Chirurg. 2006;77:904-912.
[43] Chan MK, Law WL. Use of chewing gum in reducing postoperative ileus after elective
colorectal resection: a systematic review. Dis Colon Rectum. 2007; 50:2149-2157.
M

[44] Wang XJ, Chi P. Effect of chewing gum on the promotion of intestinal function recovery after
colorectal surgery: a meta-analysis. Chin J Gastrointest Surg. 2013; 16: 1078-1083.
D
TE
C EP
AC

9
 ACCEPTED MANUSCRIPT

Table 1 The demographic and surgery details of the included studies

Sample size Male gender (%) Mean age (Years) Mean duration of surgery (min) Mean estimated blood loss (ml)
Studies Country Pathology Surgical approach Surgical site Outcome measures
Gum Control Gum Control Gum Control Gum Control Gum Control
Matros 2006 America 22 21 36 57 62 58 Cancer/benign Open Colon 158 174 230 200 1, 2, 3, 4, 9, 10
Topcu 2016 Turkey 30 30 55 63.97 NR Open Colon and rectum 175.5 188.5 NR 1, 2, 3
Lim 2013 Australia 77 80 61 60 63 62 Cancer/benign Laparoscopic/open Colon and rectum 169 171 NR 1, 2, 3, 4, 6, 7, 8, 9, 10
Lim 2013 O Australia 38 41 NR NR Cancer/benign Open Colon and rectum NR NR 1, 2, 3

PT
Lim 2013 L Australia 39 39 NR NR Cancer/benign Laparoscopic Colon and rectum NR NR 1, 2, 3
Zaghiyan 2013 America 54 60 61 56.7 42.1 48.8 NR Laparoscopic/openColorectum and small bowel 191.1 162.2 132.1 133.8 1, 2, 3, 4, 7, 9
Kobayashi 2015 Japan 21 22 47.6 72.7 66.4 68 Cancer Open Colon and rectum 221.3 232.1 240 241.3 1, 2, 3, 4

RI
Bahena-Aponte 2010 Mexico 16 16 68.8 56.3 56 56 Cancer/benign Open Colon NR NR 1, 2, 3, 4
Bonventre 2014 Italy 25 25 NR NR NR Open Colon and rectum 145.3 140.6 NR 1, 2, 3
Forrester 2014 America 13 18 NR NR Cancer/benign Laparoscopic/open Sigmoid colon NR NR 1, 2, 3

SC
Schuster 2006 America 17 17 64.7 70.6 60 63 Cancer/benign Open Sigmoid colon 108 115 119 110 1, 2, 3, 4
Asao 2002 Japan 10 9 70 66.7 58.6 60.6 Cancer Laparoscopic Colon 166.4 153.6 96.4 95.7 1, 2, 3, 4, 5, 9
Hirayama 2006 Japan 10 14 50 57.1 55.6 60.6 Cancer Open Colon and rectum 4.18 3.21 565.7 384.1 1, 2, 4, 6

U
Crainic 2009 Portland 20 24 NR NR NR Laparoscopic/open Colon NR NR 1, 2
Crainic 2009 O Portland 9 8 NR NR NR Open Colon NR NR 1, 2

AN
Crainic 2009 L Portland 8 15 NR NR NR Laparoscopic Colon NR NR 1
Atkinson 2016 UK 199 203 55.8 58.6 65.5 66.9 Cancer/benign Laparoscopic/open Colon and rectum NR NR 1, 2, 3, 4
Heijkant 2015 Netherlands 58 62 65.5 74.2 66 67 NR Open Colon and rectum 135 142 300 300 3, 4, 5, 10
Quah 2006 UK 19 19 68.4 63.2 67 68 Cancer Open Colon and rectum 155 150 NR 1, 2, 3, 4, 9, 10

M
Shum 2016 China 41 41 56.1 58.5 68 69 Cancer Laparoscopic Colon and rectum 196 206 86.7 48.3 1, 2, 3, 4
Fernandez 2016 Mexico 32 32 59.3 56 50 Cancer/benign NR Colon NR 162 223 3, 4, 5, 6, 7, 8
Yang 2017 China 190 189 55.8 54 53.3 54.1 Cancer Laparoscopic/openColorectum and small bowel 155.25 154.25 NR 1, 2, 3, 4

D
Yang 2017 O China 54 51 NR NR Cancer Open Colorectum and small bowel NR NR 1, 2, 3
Note: 1 = Time to first flatus; 2 = Time to first bowel movement; 3 = Length of hospital stay; 4 = Overall complication rate; 5 = Postoperative ileus; 6 = Nausea; 7 = Vomiting; 8 = Bloating; 9 = Readmission rate;

TE
10 = Reoperation rate; Lim 2013 O, Yang 2017 O and Crainic 2009 O: a subgroup of open surgery; Lim 2013 L and Crainic 2009 L: a subgroup of laparoscopic surgery; NR: not report
EP
4改为3；5改为4；16改为5；余不变
C
AC
 ACCEPTED MANUSCRIPT

Table 2 Intervention details of the included trials

Studies Type of chewing gumGum chewing duration Gum chewing frequency Gum chewing till ERAS protocol Bowel preparation Removal of NG tube Epidural use Oral feeding initiation Ambulation
Matros 2006 Sugar-free 45 min 3 times/day NR no NR POD 1 yes NR early
Topcu 2016 NR 15 min 3 times/day Discharge no NR POD 1 no NR 8 h post-surgery
lim 2013 Sorbitol-free 15 min 4 times/day NR yes no Avoid no early early
Zaghiyan 2013 Sugared 45 min 3 times/day POD 7 yes NR Avoid no POD 1 POD 1

PT
Kobayashi 2015 Xylitol-free ≥5 min 3 times/day Oral intake no NR POD 1 yes average 3 days NR
Bahena-Aponte 2010 Sugar-free 30 min 3 times/day Oral intake no NR NR NR NR NR
Bonventre 2014 Sugar-free 30 min 3 times/day NR no NR POD 1 no POD 3 POD 1

RI
Forrester 2014 Sugar-free at least 60 min at least 3 times/day NR no NR Not routine NR until first flatus early
Schuster 2006 Sugar-free 60 min 3 times/day Discharge no NR NR partial NR POD 1
Asao 2002 Sugar-free NR 3 times/day Oral intake no NR POD 1 yes until first flatus NR

SC
Hirayama 2006 Sugar-free 30 min 3 times/day NR no NR NR yes NR NR
Crainic 2009 Sugar-free 30 min 3 times/day Bowel movement no NR NR NR Varied NR
Atkinson 2016 Sugar-free at least 10 min 4 times/day 5 consecutive days yes NR NR NR NR NR
Heijkant 2015 Sugar-free not standardized not standardized Oral intake no NR NR yes NR NR

U
Quah 2006 Sugar-free at least 5 min 3 times/day Solid diet initiation yes yes NR yes POD 1 as soon as possible
Shum 2016 Sugar-free 30 min 3 times/day Discharge yes NR NR no 6 h after operation POD 1

AN
Fernandez 2016 Sorbitol-free 15 min about 4 times/day Discharge no NR NR no until first flatus NR
Yang 2017 Sugar-free at least 10 min 3 times/day 5 consecutive days no NR POD 1 no NR NR
Note: ERAS: enhanced recovry after surgery; NG: nasogastric; NR: not report; POD: postoperative day

M
D
TE
C EP
AC
 ACCEPTED MANUSCRIPT

Table 3 Overall results of meta-analysis for some clinically relevant indexes

No. of Patients Heterogeneity Effect model
Outcome No. of Studies OR (95% CI) Value of P 2
Gum Control I (%) P Fixed Random
Overall postoperative complication 14 766 785 0.7 (0.43, 1.13) 0.14 60 0.002 √
Postoperative ileus 6 187 199 0.41 (0.23, 0.73) 0.003 0 0.94 √

PT
Nausea 3 119 126 0.9 (0.48, 1.67) 0.74 42 0.18 √
Vomiting 3 163 172 0.62 (0.23, 1.67) 0.34 53 0.12 √

RI
Bloating 2 109 112 0.79 (0.43, 1.46) 0.45 0 0.47 √
Readmission 5 182 189 0.62 (0.26, 1.51) 0.3 0 0.8 √
√

SC
Reoperation 4 176 182 0.5 (0.2, 1.27) 0.15 33 0.21
Note: OR: odds ratio; CI: confidence interval

U
AN
M
D
TE
C EP
AC
 ACCEPTED MANUSCRIPT

Table 4 Subgroup analysis results of gum chewing following colorectal surgery

No. of Patients Heterogeneity Effect model
Outcome No. of Studies WMD (95% CI) Value of P 2
Gum Control I (%) P Fixed Random
Type of chewing gum : sorbitol-free or xylitol-free
Time to first flatus 3 152 162 -2.42 (-11.27, 6.43) 0.59 72 0.03 √

PT
Time to first bowel movement 3 152 162 -8.96 （-10.97， -6.95） ＜ 0.00001 0 0.83 √
Length of hospital stay 4 184 194 -0.9 （-2.79， 0.99） 0.35 95 ＜ 0.00001 √

RI
Studies of ERAS protocol
Time to first flatus 5 321 338 -5.06 (-14.24, 4.12) 0.28 86 ＜ 0.00001 √
Time to first bowel movement 5 350 351 -15.2 （-23.9， -6.5） 0.0006 72 0.007 √

SC
Length of hospital stay 5 390 403 -0.82 （-2.26， 0.63） 0.27 94 ＜ 0.00001 √
Studies of laparoscopic surgery

U
Time to first flatus 4 98 104 -9.66 (-20.01, 0.68) 0.07 86 0.0001 √
Time to first bowel movement 3 90 89 -28.39 （-52.82， -3.96） 0.02 90 ＜ 0.0001 √

AN
Length of hospital stay 3 90 89 -2.07 （-2.75， -1.39） ＜ 0.00001 0 0.56 √
Studies of open surgery

M
Time to first flatus 11 261 264 -11.24 （-17.03， -5.45） 0.0001 85 ＜ 0.00001 √
Time to first bowel movement 11 261 264 -17.4 （-27.93， -6.87） 0.001 85 ＜ 0.00001 √
Length of hospital stay 12 294 302 -1.26 （-2.18， -0.33） 0.008 83 ＜ 0.00001 √

D
Note: ERAS: enhanced recovery after surgery; WMD: weighted mean difference; CI: confidence interval

TE
C EP
AC
 ACCEPTED MANUSCRIPT

PT
RI
SC
Fig 1 Study flow diagram

U
AN
M
D
TE
C EP
AC

Fig 2 Assessment of risk of bias of the included studies

 ACCEPTED MANUSCRIPT

PT
RI
U SC
AN
Fig 3 Forest plot of gum chewing versus postoperative standard care for time to first flatus
M
D
TE
C EP
AC

Fig 4 Forest plot of gum chewing versus postoperative standard care for time to first bowel
movement
 ACCEPTED MANUSCRIPT

PT
RI
U SC
AN
Fig 5 Forest plot of gum chewing versus postoperative standard care for length of hospital stay
M
D
TE
C EP
AC

Fig 6 Funnel plot for publication bias

 ACCEPTED MANUSCRIPT
Highlights

1. A meta-analysis of RCTs about gum chewing helps to ameliorate ileus following colorectal
surgery was conducted.

2. Chewing gum shewed to be an inexpensive, secure, well-tolerated and widely available

solution to ileus following colorectal resection.

3. ERAS programme and laparoscopic technique tended to negate the benefits of chewing

PT
gum.

4. Sugared gum (sorbitol-free or xylitol-free) seemed to be less effective in ameliorating ileus

following colorectal resection.

RI
U SC
AN
M
D
TE
C EP
AC