Randomized clinical trial of the effect of

gum chewing on postoperative ileus and

inflammation in colorectal surgery

Journal Reading
Ryan Arifin
I 11110011

Introduction (1)

Abdominal surgery is inevitably followed by an episode of

gastrointestinal hypomotility. A delayed return of gastrointestinal
function, as postoperative ileus (POI), has a great impact on patient
comfort, morbidity and recovery. POI often results in a prolonged
hospital stay and contributes significantly to healthcare costs.
The aetiology of POI involves an inflammatory response to bowel
manipulation.
Opening the peritoneal cavity and subsequent handling of the intestine
during abdominal surgery triggers a neurogenic response, leading to
local inflammation of the intestinal muscular layer and influx of
leucocytes.
This, together with a systemic inflammatory response to surgery, are
pivotal in the pathophysiology of POI following abdominal surgery

Introduction (2)

Experimental studies have shown that inhibition of the

inflammatory response is effective in reducing POI. Stimulation
of the vagus nerve just before and directly after surgery, by
means of electrical or pharmacological triggers or by
supplementation of lipid-enriched nutrition, attenuates the
inflammatory response and reduces POI
Gum chewing may exert an effect on POI via reduction of
postoperative inflammation through cephalic vagal activation.
However, the underlying mechanism remains elusive and the results
of clinical trials are ambiguous. This has hampered implementation
of gum chewing to reduce POI in clinical practice.
The present study investigated the effect of gum chewing before
and after colorectal surgery on POI, surgical complications,
length of hospital stay and inflammatory parameters.

Methods (1)

The protocol for this randomized clinical

trial was approved by the Medical Ethics
Committee of AtriumOrbis-Zuid and the
Medical Ethics Committee of Catharina
Hospital, and was designed in accordance
with the Declaration of Helsinki and Good
Clinical Practice.

Methods (2) (Patients)

Patients aged more than 18 years undergoing

elective, open colorectal surgery (right colectomy,
left colectomy (including sigmoid resection) and
rectal resection) at the Orbis Medical Centre in
Sittard and Catharina Hospital in Eindhoven, The
Netherlands, were eligible to participate in the
study.
Patients
with
peritoneal
carcinomatosis,
inflammatory bowel disease, a history of gastric or
oesophageal surgery, pre-existing ileostoma, allergy
to mint, or who used agents influencing gut motility
(including opioids) were excluded.
Patients
with
disturbance
of
acetylcholine
metabolism
owing
to
neurological
disease,
depression or use of medication (such as

Methods (3) (Interventions)

Patients were informed that gum chewing
and application of a dermal patch may
both be effective ways to stimulate the
autonomic
nerve
system
and
attenuate POI.
However, the dermal patch was a
placebo that did not contain active
ingredients.
Patients were not informed that the
dermal patch had been used as a placebo
until completion of the trial.

Methods (4) (Intervention

Group/Chewing Gum Group)
Patients started

chewing gum, each

chewing gum 3 h
including 12 pieces,
before the start of the
of commercially
operation. They were
available sugarless
encouraged by nursing
chewing gum
staff to take a new piece
(Stimorol ice; Kraft
at least three times
Foods, Northfield,
per hour, but were
Illinois, USA).
Patients were
The frequency
allowed to chew gum to
kept nil-byand duration oftheir own liking.
At 3 h after
mouth to
gum chewing
surgery they
solids for at
was not
were
least
standardized
encouraged to
6 h before
and all analyses
restart gum
surgery and
were performed
chewing as
to fluids for
based on
soon as
at least 2 h.

Methods (5) (Control Group/Dermal

Patch Group)
Patients assigned to
the control group
received a dermal
patch (72 5-cm
Hansapor Steril
dressings; Smith &
Nephew Medical,
London, UK) 3 h
before surgery.
Patients in this group
were
instructed not to chew
gum.

The dermal patch was

positioned in the
lumbar region on the
back until postoperative
enteral nutrition (fluid or
solid) was started.
The patch was
inspected daily and
replaced
when it did not adhere
to the skin (because of
transpiration or
loosening during
nursing).

Methods (6)

Only surgeons who were trained and

experienced
in
colorectal
surgery
participated in the trial. For each type of
operation, the anaesthetic and postoperative
care paths were standardized.

Randomization (1)

All patients provided written informed

consent before surgery and were assigned
randomly to the intervention or control
group
by
central
computerized
randomization on the day before
surgery

Outcomes (1)

The primary endpoints were POI and length

of hospital stay.
POI was defined as lack of passage of flatus or
stool and intolerance to oral intake for at
least 24 h.
Although all patients experience a temporary
decrease in gastrointestinal passage after surgery,
in this trial patients were classified as having POI
when the above criteria were met on day 5
after operation
Patients with POI received treatment for
symptoms (such as nasogastric tube and
intravenous fluids).
The start of oral intake (both fluids and solid

Outcomes (2)

Length of hospital stay was defined as

number of days of admission including the
day of surgery and day of discharge.
Patients were discharged when they tolerated
nutrition,
had
passed
flatus
or
defaecated, their postoperative pain was
controlled, and they were able to function
at home on their own or with the home
care provided.

Outcomes (3)

Secondary endpoints were local and

systemic
inflammation,
postoperative
complications and gastric emptying.
Markers of the systemic inflammatory
response were measured in blood samples
collected 4 h after the start of surgery. EDTAtreated plasma was separated by centrifugation,
and stored at 80C within 30 min until further
analysis.
Levels of soluble tumour necrosis factor
receptor 1 (TNFRSF1A) and interleukin (IL)
8 were determined in plasma samples by
enzyme
linked
immunosorbent
assay
(Hycult Biotech, Uden, The Netherlands).

Outcomes (4)

All complications were registered and

graded according to the ClavienDindo
classification.
Abdominal wall dehiscence was defined as
fascial
dehiscence
that
required
surgery.
Anastomotic leakage was defined as clinical
suspicion of leakage of the anastomosis,
confirmed by CT showing free abdominal air
and
fluids
in
the
proximity
of
the
anastomosis
or
a
visibly
dehiscent
anastomosis at the time of reoperation.
The chief investigator and the surgeons
performing
the
procedures were unaware of the allocated

Measurement of local inflammation

by transcriptional analyses

Tissue was removed from the resection

specimen according to a standard procedure
at the end of the operation.
A ring of colonic tissue was removed and
a smaller biopsy (approximately 50 mg)
including all intestinal layers was taken,
immediately snap-frozen in liquid nitrogen and
stored on dry ice in the operating room.
Directly after surgery, the samples were
transferred to the laboratory and stored at
80C until analysis.
RNA was isolated in TRIPure (Sigma, St
Louis,

Gastric Emptying (1)

Gastric emptying was measured by standardized

realtime ultrasonography
At a predefined time point (17.00 hours) on the
second postoperative day, the patient received
a standard meal consisting of 150 ml liquid
and one slice of round toast with a topping
of choice.
The
ultrasound
examinations
were
performed 15 and 90 min after the meal.
During each examination the longitudinal (D1)
and anteroposterior (D2) diameters of the gastric
antrum were measured three times. Mean
diameters (D1mean, D2mean) were noted in an
electronic database.

Gastric Emptying (2)

Antral area (A) was calculated fom the mean

diameters using the following formula :
A = D1mean D2mean/4.

The decrease in gastric antral area, the gastric

emptying rate (GER), was calculated as follows:
GER = [(A15min - A90min)/A15min] 100 per cent.

Statistical Analysis

The hypothesis of this study was that gum

chewing reduces the inflammatory response
by vagal activation, and thereby reduces POI
and enhances recovery.

RESULTS

Patient demographics, co-morbidity

and operative details

RESULT Length Of Hospital Stay

The
mean
(s.d.)
length of stay was
95(49) (median 9)
days
in
the
intervention group
and
140(145)
(median
9)
days
among controls. The
variability
within
groups
was
larger
than
expected.
Kaplan
Meier
analysis
revealed
that the difference
between
groups

RESULT Post-Operative Ileus (POI)

(Intervention
Group)
14 patient (27
percents) of 52
patients
43 patient
(38,4%) of the
112 patients met
the criteria of POI

P = 0,020

(Control Group)
29 patient (48
percents) of 60
patients

Time to first defaecation in chewing gum

(52 patients) and control (60) groups. P =
0006
More patients in
the intervention
group defaecated
within 4 days of
surgery: 44 (85
per cent) of 52
versus 34 (57 per
cent) of 60 (P =
0006)

Time to first flatus in chewing gum (52

patients) and control (60) groups. P =
0044

Some 34 patients
(65 percent) in
the chewing gum
group had passed
flatus within 2 days
of surgery compared
with 30 (50 per
cent) of controls
(P = 0044)
Time to first flatus
was more than 3
days in five patients
in the intervention

Gastric Emptying

Five patients in the

chewing gum group
and
ten
in
the
control group refused
to participate because
they felt unable to
eat
the
standard
meal (P = 0163).
There was a larger
decrease in antral
area
following
a
standard meal in the
chewing gum group
than
in
controls:
median 25 (range 36
to 54) versus 10 (
152 to 54) per cent

Inflammatory
markers
soluble
tumour necrosis factor receptor 1
(TNFRSF1A)
Plasma levels of
TNFRSF1A
were
significantly lower
at 4 h after the start
of surgery in the
intervention
group
compared with the
control
group:
0,74 (027298)
versus
0,92 (029219)

Inflamatory Markers interleukin 8

at 4 h after the onset of surgery
Plasma IL-8 levels
were also significantly
lower 4 h after surgery
in patients receiving
chewing gum: 133
(0774)
versus
control group 288
(0992) pg/ml

Complication
Sixty
of
120
patients
were
discharged without
complications.
In
total,
12
complications
that
needed
reintervention under
general. anaesthesia
were registered. Two
patients
in
the
chewing gum group
had an anastomotic
leak, whereas eight
control patients had
an anastomotic leak

Discussion Systemic Inflamation

Gum
Chewing

Reduction in Systemic
Inflamation
TNFRSF1A & IL-8 4 hours
after surgery

TNFRSF1A is a transmembrane receptor

through which TNF- exerts its effects,
and gives a good representation of TNF
levels in plasma
IL-8 is a chemoattractant that causes
migration and activation of neutrophils to
inflammatory regions
Level TNFRSF1A & IL-8 in patients treated with
chewing gum reflects a lowered inflammatory

Discussion Local Inflamation

reduced IL-6 levels were found in colonic tissue
from the chewing gum group this may play
a role.
when chewing gum exerts its effects by vagal
activation, such effects may also have an
anatomical origin. Vagal innervation is more
pronounced in the right colon and the small
bowel.
these data were acquired following
stratification of the data and further research is
needed to
substantiate the results.

Discussions
Complication
The reduced
incidence of surgical
complications (acute
abdominal wall dehiscence and anastomotic
leakage) was
surprising and could be explained in several
ways.
POI increases intra-abdominal pressure risk factor
for acute abdominal wall dehiscence
ileus potential risk factor for anastomotic leakage
TNF- and IL-10 expressed locally at the
anastomotic
site increasing the risk of anastomotic leakage
IL-8 and
TNFRSF1A
levels was
decreased in
the intervention

gum chewing
had a significant
effect on the
rate of grade IIIb
complications

further
studies are
needed to
address
these

Conclusion
Gum chewing is a safe and simple treatment
to reduce POI, and is associated with
a reduction in systemic inflammatory
markers and complications.

THANK YOU
DANKE
XIE XIE

Statistical Analysis (2)

To compare continuous data between
groups,
the
data were tested for normal distribution
(with skewness and kurtosis) and an
unpaired t test was performed when
appropriate; otherwise the MannWhitney
U test was used. Categorical data were
analysed by means of 2 test or Fishers
exact test, as appropriate.
Length of stay was calculated by Kaplan
Meier analysis, with comparison of groups
by MantelCox log rank test. P 0050 was

Abstract

Randomization (2)

As patient recruitment was slow early in the

inclusion
period,
patients
undergoing
colorectal surgery were also deemed eligible
to participate after the inclusion of 11
patients.
From
this
point
onwards
the
block
randomization was abandoned and patients
were included at an allocation ratio of 1 : 1.
Catharina Hospital started including patients
after 51 individuals had been recruited.

Discussion
POI is an important clinical problem that is
associated with increased healthcare costs
Several strategies have been developed
over the years to reduce the incidence of
POI, such as early oral feeding, minimally
invasive surgery and epidural anaesthesia
In the present study, gum chewing before
and
after surgery reduced POI, but did not
affect length of hospital stay. There is still
no consensus regarding the effects of gum
chewing on POI after colorectal surgery.

Discussion (2)

the previous randomized clinical trial reported

no beneficial effect on POI after laparoscopic
or open elective colorectal surgery, although
chewing gum was given only after surgery.
Time to first flatus and first defaecation were
significantly reduced by gum chewing in the
present study, as reported previously
Although both outcomes are often used as
surrogate endpoints for POI, these are
subjective, depend on patient reporting and
may not reflect whole-gut transit.

Dicussions (3)

Therefore, gastric emptying was assessed by

ultrasonographic antral measurement, a validated
method for estimating gastric emptying rate
The finding that gum chewing accelerated gastric
emptying indicates enhancement not only of
colonic transit, but also of motility of the proximal
intestinal tract.