Randomized Clinical Trial of the Effect of Gum (Ryan Arifin)

Randomized clinical trial of the effect of gum chewing on postoperative ileus and inflammation in colorectal surgery

Ryan ArifinI 11110011

Journal Reading

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 parasympatheticomimetics, atropine) were also excluded.

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)chewing gum, each

including 12 pieces, of commercially

available sugarless chewing gum

(Stimorol® ice; Kraft Foods, Northfield,

Illinois, USA).

Patients started chewing gum 3 h

before the start of the operation. They were encouraged by nursing

staff to take a new piece at least three times per hour, but were

allowed to chew gum to their own liking. At 3 h after

surgery they were

encouraged to restart gum chewing as

soon as possible.

The frequency and duration of gum chewing

was not standardized

and all analyses were performed

based on intention to

treat.

Patients were kept nil-by-mouth to

solids for at least

6 h before surgery and to fluids for at least 2 h.

Methods (5) (Control Group/Dermal Patch Group)Patients assigned to the control group received a dermal patch (7⋅2 × 5-cm Hansapor® Steril

dressings; Smith & Nephew Medical, London, UK) 3 h

before surgery.

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).

Patients in this group were

instructed not to chew gum.

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 solidfood) was noted. Time to first flatus and defaecation wasregistered each day by the nursing staff

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. EDTA-treated plasma was separated by centrifugation, and stored at –80∘C 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).

Local inflammation was measured in colonic tissue by PCR.

Outcomes (4) All complications were registered and

graded according to the Clavien–Dindo 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 theprocedures were unaware of the allocated group. As thedifference between treatment modalities was evident, thecare providers on the surgical ward and the patients could not be blinded.

Measurement of local inflammationby 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 –80∘C until analysis.

RNA was isolated in TRIPure® (Sigma, St Louis,Missouri, USA) following the manufacturer’s instructions after the tissue had been thawed and homogenized.

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 = π × 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 9⋅5(4⋅9) (median 9) days in the intervention group and 14⋅0(14⋅5) (median 9) days among controls. The variability within groups was larger than expected. Kaplan Meier analysis revealed that the difference between groups was not statistically significant (P = 0⋅067)

RESULT Post-Operative Ileus (POI)

43 patient (38,4%) of the

112 patients met the criteria of POI

(Intervention Group)

14 patient (27 percents) of 52

patients

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

patients

P = 0,020

Time to first defaecation in chewing gum (52 patients) and control (60)

groups. P = 0⋅006

More patients in the intervention group defaecated within 4 days of surgery: 44 (85 per cent) of 52 versus 34 (57 percent) of 60 (P = 0⋅006)

Time to first flatus in chewing gum (52 patients) and control (60)

groups. P = 0⋅044 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 = 0⋅044)

Time to first flatus was more than 3 days in five patients in the intervention group and 17 in the control group.

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 = 0⋅163).

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 respectively (P = 0⋅004)

Inflammatory markers soluble tumour necrosis factor receptor 1 (TNFRSF1A)

Plasma levels of TNFRSF1A were significantly lowerat 4 h after the start of surgery in the intervention groupcompared with the control group: 0,74 (0⋅27–2⋅98) versus0,92 (0⋅29–2⋅19) ng/ml (P = 0⋅043)

Inflamatory Markers interleukin 8at 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 (0–774) versus control group 288 (0–992) pg/ml

ComplicationSixty 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 and two had dehiscence of the abdominal wall (P = 0,031).

Discussion Systemic InflamationGum

ChewingReduction in Systemic

Inflamation

↓ TNFRSF1A & IL-8 4 hours after surgery

TNFRSF1A is a transmembrane receptor through which TNF-α exerts its effects, and gives a good representation of TNF

levels in plasmaIL-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

response.

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 ComplicationThe 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-α and IL-10 expressed locally at the

anastomoticsite increasing the risk of anastomotic leakageIL-8 and

TNFRSF1A levels was

decreased in the intervention

group

gum chewing had a significant

effect on the rate of grade IIIb

complications

further studies are needed to address theseissues.

Conclusion

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

THANK YOUDANKEXIE –XIE

Statistical Analysis (2)

To compare continuous data between groups, thedata were tested for normal distribution (with skewness and kurtosis) and an unpaired t test was performed when appropriate; otherwise the Mann–Whitney U test was used. Categorical data were analysed by means of χ2 test or Fisher’s exact test, as appropriate.

Length of stay was calculated by Kaplan–Meier analysis, with comparison of groups by Mantel–Cox log rank test. P ≤ 0⋅050 was considered statistically significant.

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 andafter 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.