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The effect of simethicone on postoperative ileus in patients undergoing colorectal surgery (SPOT), a randomized controlled trial
Accepted Manuscript The Effect of Simethicone on Postoperative Ileus in Patients Undergoing Colorectal Surgery (SPOT), A Randomized Controlled Trial Jeremy E. Springer, Shiraz Elkheir, Cagla Eskicioglu, Aristithes G. Doumouras, Stephen Kelly, Ilun Yang, Shawn Forbes PII:
S1743-9191(18)31503-6
DOI:
10.1016/j.ijsu.2018.06.011
Reference:
IJSU 4689
To appear in:
International Journal of Surgery
Received Date: 25 April 2018 Accepted Date: 4 June 2018
Please cite this article as: Springer JE, Elkheir S, Eskicioglu C, Doumouras AG, Kelly S, Yang I, Forbes S, The Effect of Simethicone on Postoperative Ileus in Patients Undergoing Colorectal Surgery (SPOT), A Randomized Controlled Trial, International Journal of Surgery (2018), doi: 10.1016/j.ijsu.2018.06.011. 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.
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The Effect of Simethicone on Postoperative Ileus in Patients Undergoing Colorectal Surgery (SPOT), A Randomized Controlled Trial
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Running Head: Simethicone’s effect on ileus Jeremy E. Springer MD MSc1, Shiraz Elkheir MD MBBS MSc CMD2, Cagla Eskicioglu MD MSc FRCSC1†, Aristithes G. Doumouras MD MPH1, Stephen Kelly MD FRCS1*, Ilun Yang MD
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FRCSC1†, Shawn Forbes MD MSc FRCSC1† 1
Department of Surgery, Division of General Surgery, McMaster University, Hamilton, ON Department of Surgery, Riverside Healthcare, Fort Frances, ON † Assistant Professor, McMaster University, Dept. of Surgery, Hamilton, Ontario * Associate Professor, McMaster University, Dept. of Surgery, Hamilton, Ontario, Canada
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Correspondence: Shawn Forbes MD MSc FRCSC. Division of General Surgery. Juravinski
72875,
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Hospital, 711 Concession St. Hamilton, Ontario, L8V 1C3, Canada. Tel: (905) 521-2100 ext.
Fax: (905) 528-9388, email: [email protected]
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Disclosures: None
Trial Support: This trial was supported by the McMaster Surgical Associates Grant.
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Prior Presentations: This manuscript was presented as a poster presentation at the annual ASCRS Annual Scientific Meeting in Los Angeles, California (April 30th to May 4th, 2016). Contributions: Authors’ contributions: Dr. Cagla Eskicioglu and Dr. Shawn Forbes were responsible for the conception, design, data analysis, and editing of this manuscript. Dr. Jeremy Springer, Dr. Shiraz Elkheir, Dr. Aristithes Doumouras, Dr. Stephen Kelly and Dr. Ilun Yang contributed to the design and conduct of the trial, interpretation of the data, and revisions for the final approval of this manuscript. All authors provided substantial contributions to this manuscript.
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ABSTRACT Background: Postoperative ileus is a poorly understood multifactorial outcome following
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colorectal surgery that presents significant clinical challenges and contributes to increased morbidity, length of stay, and healthcare cost. To date, there are few pharmacological interventions that shorten the duration of postoperative ileus.
ileus symptoms in patients undergoing colorectal surgery.
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Objective: This study is the first to evaluate the efficacy of simethicone in treating postoperative
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Design: A multicenter, double-blinded, placebo controlled randomized controlled trial. Settings: This trial was conducted at two academic tertiary care centres in Ontario, Canada. Participants: 118 patients undergoing colorectal surgery.
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Interventions: Patients were randomized to receive either a five-day course of oral simethicone (n=58) or a placebo (n=60).
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Main Outcome Measures: The primary outcome was time to first passage of flatus. Secondary outcomes included time to first bowel movement, postoperative length of stay, and postoperative
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pain. Statistical analyses were performed on an intention-to-treat basis. Statistical significance set at p=0.05.
Results: The median time to first passage of flatus in simethicone arm was 25.2 hours and 26.7 hours in controls (P=0.98). There were no significant differences in the median time to first bowel movement (simethicone=41.1 hours vs. control=42.9 hours, P=0.91) or median length of hospital stay (simethicone=4.5 days vs. control=4.0 days, P=0.63).
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Conclusions: This study failed to show a difference in return of gastrointestinal motility in patients receiving simethicone following colorectal surgery. Postoperative ileus remains a
to identify a reliable and effective method of treatment. Key Words: post operative ileus, simethicone, colorectal surgery
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significant clinical and economic burden to the healthcare system and further research is needed
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Trial Registration: This study was registered with Clinicaltrials.gov.
INTRODUCTION
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Prolonged postoperative ileus is a poorly understood multifactorial outcome following major abdominal surgery that contributes to significant morbidity, increased length of stay, and healthcare cost.[1-3] The characteristic features of ileus are bowel dysfunction and reduced
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motility, resulting in ineffective transit of intestinal contents.[4,5] The multifactorial
pathogenesis of ileus is poorly understood, however it is thought to include complex interactions between surgical stress and inflammatory mediators, physical manipulation of bowel, use of
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anesthetics and analgesics and peri-operative fluid and electrolyte imbalances.[6,7] The
incidence rates of ileus varies amongst different studies and surgical specialities, however is
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reported to range between 10-30% following major abdominal surgery [6,8-11] with an economic impact estimated at $750 million per year in the US.[12] Furthermore, ileus is responsible for significant number of hospital readmissions.[13] Following four North American and one European phase 3 multicenter trials, Alvimopan, an oral peripherally acting mu-opioid
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receptor antagonist was approved by the FDA in May 2008 to reduce ileus following bowel resection.[14-18] The cost of the average 15 dose therapeutic course of Alvimopan is approximately $930.00 USD.[18] In publicly funded resource limited health care systems, there
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is increasing focus on cost reduction strategies and therefore the use of other pharmacological options to reduce ileus should be considered.
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Numerous studies have evaluated other pharmacological strategies to reduce ileus. The
focus of these medications is to target the pathophysiologic causes of ileus by either; minimizing sympathetic inhibition, inhibiting acetylcholinesterases, stimulating enteric motility, or decreasing inflammatory cascades. These agents are not routinely used as they have either not been adequately studied, or have not shown efficacy.[19] Alternative medications such as laxatives or anti-flatulence agents have been proposed as low risk interventions for ileus
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prevention. Simethicone is an inexpensive, readily available, orally administered anti-foaming agent compromised of polydimethylsiloxane and hydrated silica gel. It causes coalescence of gas bubbles in the intestinal tract, facilitating emission. Simethicone is not absorbed by the
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gastrointestinal tract and is known to have an excellent safety profile. The side effects of
simethicone include nausea, vomiting, diarrhea, and headache, however are only reported in 25% of patients.
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To date, only two older randomized controlled trials have evaluated the effect of
simethicone on ileus following gynecological surgery with results demonstrating earlier passage
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of flatus, reduced gas pain and decreased rates of ileus.[20,21] There are currently no studies that have evaluated the effects of simethicone on ileus in non-gynecological surgery, and therefore the present study was performed to evaluate the effect of simethicone on the reduction of ileus in
METHODS Design and Setting
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patients undergoing elective colorectal surgery.
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This was a multicenter, double-blinded, randomized controlled trial that compared simethicone versus placebo in patients undergoing colorectal surgery at two high volume
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colorectal surgery academic hospitals in Ontario, Canada. Both hospitals have a clear enhanced recovery after colorectal surgery protocol that has been followed for several years. A Clinical Trial Application was approved by Health Canada. This trial was also approved by the **** Research Ethics Board. This study was registered with Clinicaltrials.gov under the ID: NCT0216***.
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Population Participants were recruited into the study between October 2014 and April 2015 based on
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the following inclusion/exclusion criteria.
Inclusion Criteria: ≥ 18 years of age
(2)
Undergoing elective colorectal surgery involving bowel resection with or without
re-
anastomosis
(3)
Abdominal approach including either open or laparoscopic surgery
(4)
Surgery performed at one of the two participating academic tertiary care centres
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(1)
Exclusion Criteria:
Documented allergy to simethicone; and/or
(2)
Undergoing emergency surgery; and/or
(3)
Non-abdominal approach (i.e. perineal procedure); and/or
(4)
Individuals unable to provide informed consent (non-English speaking patients
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those with cognitive impairment).
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and
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(1)
Randomization and Blinding Study participants were engaged by research staff at the time of surgery booking.
Following consent, participants were randomized into one of the two study arms: simethicone or placebo. The randomization process was independently organized by the pharmacy team at both study sites. A random number generator was utilized to assign numbers to individual
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experimental and control drug regimens. The numbers were written on cards which were sealed in opaque envelopes. As patients were enrolled, an envelope was opened by a pharmacy team representative. Patients were then assigned to the corresponding drug regimen; either
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simethicone or placebo. No further strategies for randomization were employed (i.e. stratification and/or block randomization) due to the small number of participants enrolled in the study.
Due to the double-blinded study design, all participants, investigators, reviewers, nurses
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and research staff were not aware of which study arm the patient belonged to. Study participants were assigned a unique identifying code that was only revealed to the data safety monitoring
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committee and to the data analysts during the final analysis of study results.
Study Protocol
Participants randomized to Arm A were treated with a syrup form of simethicone (160
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mg) while participants randomized to Arm B were treated with a similarly prepared placebo that matched the study drug based on all its physical properties. The study dose was 160 mg of study drug or placebo four times a day. All participating patients received their initial dose of study
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drug or placebo at 22:00 after their surgery. Subsequent doses were administered at 8:00, 12:00, 16:00 and 22:00 starting postoperative day 1 through postoperative day 5. Treatment was
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continued until either, they completed the full 5 full day course or they were discharged from hospital (whichever occurred first). Subjective patient data including, time of first passage of flatus and bowel movements,
daily average pain score, food tolerance and abdominal distension was collected using a patientreported bedside diary (Figure 1).
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During the participants hospital stay, daily patient visits were performed by trained research staff. Research staff assessed the following: passage of flatus, passage of bowel movements, and postoperative pain. Relevant data pertaining to the participant’s postoperative
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course (i.e. use of other medications, laboratory and radiological findings, etc.) were collected from the participant’s medical records (paper and electronic). Patients were contacted by
telephone to assess outcomes at two-weeks and 30-days post-discharge. All study participants'
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charts were reviewed on postoperative day 30 to ensure no outcomes were missed. Outcomes
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The primary endpoint of the study was time-to-first passage of flatus (hours) or time to discharge if this occurred before first flatus. Participants were followed for the first 5 days postoperatively for these outcomes. This study was designed to assess a 40% reduction in time to the primary outcomes, with p <0.05 and 80% power (assuming a time-to-first flatus in the
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control arm of 84 hours based on previous literature).[22]
The secondary endpoints were time-to-first passage of bowel movement which was assessed in the same manner as the primary endpoint; early discharge (within 3 days), any
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emesis, any nasogastric output or any abdominal distension/bloating/cramping symptoms within the first 5 days. Additionally, hospital length of stay and the incidence of postoperative
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complications including but not limited to wound and anastomotic occurrences, bleeding, postoperative infections, readmission to hospital and death. Lastly, postoperative pain measured using the Visual Analogue Pain Scale (Figure 1).
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Statistical Analysis Descriptive statistics (means, medians, standard deviations) were used to characterize the patient population where applicable. Chi square was used to analyze dichotomous patient
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variables such as adverse events while continuous variables were analysed using T-tests. Our primary outcome was evaluated using a time-to-event analysis. Kaplan-Meier curves were
created for both groups and compared in a univariable manner using the log rank test. Two Cox
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models were then created to assess the hazard ratio between the treatment and control groups. The first was a univariable model using treatment as the only variable. A second, multivariable
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was created to ascertain the effect of the treatment after adjustment for important variables. Specifically, the variables adjusted for were age, sex, chronic opioid use, ASA class 3 or less, cancer diagnosis (vs. benign), rectal procedure, laparoscopic, stoma creation (colostomy or ileostomy) and epidural insertion. Time to first passage of bowel movement/discharge was
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assessed similarly. The binary secondary outcomes of early discharge, any emesis, any nasogastric output and any abdominal symptoms were assessed using a log transformed generalized linear model with robust confidence intervals. This provides the risk ratios for the
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effects. Similar to the primary outcomes, univariable and multivariable models were created using the same covariates as the primary analysis. Length of stay and post-operative pain scores
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were evaluated using the Wilcoxon rank-sum test. Statistical significance was set at P<0.05. Analysis was completed on an intention-to-treat basis. The 95% confidence intervals were provided where applicable. Data were analyzed using SPSS statistical software (IBM Corp. Released 2013. IBM SPSS Statistics for Windows, Version 22.0. Armonk, NY: IBM Corp).
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RESULTS A total of 120 patients were recruited from the two academic tertiary care centres. Of the 120 patients consented, 118 completed the study protocol due to 2 patients withdrawing consent
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during the study. Of the 58 total patients recruited from Hospital A, 30 patients were randomized to receive the simethicone treatment (Arm A) and 28 were randomized to receive the placebo (Arm B). Of the 60 total patients recruited from Hospital B, 28 patients were randomized to the
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simethicone treatment arm (Arm A) and 32 were randomized to the control arm (Arm B) (Figure 2).
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Table 1 presents the baseline patient characteristics for all patients who underwent randomization to simethicone or placebo. The average age of the cohort was 65 years, and 58% were male. The majority of the colorectal resections were performed for malignancy (77%). Seventy-four percent of the resections were performed laparoscopically and 73% were isolated
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colon resections. The majority of patients had an ASA score greater than 2. There was no statistically significant difference in patient characteristics amongst study groups. Additionally, there were no statistically significant differences in the use of intra-operative or post-operative
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analgesics.
Table 2 and Figures 3 & 4 present the primary outcome results. There was no significant
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difference in the median number of doses between the treatment and placebo group (13[0-21], 10[0-21], P=0.1335 respectively). In total, 51 (88%) of patients reached the primary endpoint in the treatment group and 56 (93%) in the control group (p=0.313). Figure 3 and 4 presents the Kaplan-Meier event curve for the primary outcomes. Overall, the hazard ratio between the treatment and control groups was 0.92 and the log rank test comparing each curve was not significant (95% CI, 0.66 - 1.88, P=0.664). The adjusted multivariable hazard for the treatment
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compared to the control group was 0.92 (95% CI, 0.62 - 1.38, P=0.69). Table 2 also presents the results for the secondary time-to-event analysis. There was no difference in this outcome occurring overall (78% in treatment vs 88% in control, P=0.12) and both the univariable (HR
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0.74 95%CI 0.49-1.10, P=0.119) and multivariable (HR 0.72 95%CI 0.47-1.10, P=0.123) were not significant.
Table 3 presents the results of the binary secondary outcomes. Univariable and
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multivariable risk ratios were calculated for each of these outcomes. After multivariable
adjustment, the risk ratios for early discharge (HR 0.87, 95%CI 0.64-1.18, P=0.367), emesis
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within 5 days (HR 0.97, 95%CI 0.52-1.78, P=0.915), nasogastric output within 5 days (HR 0.74, 95%CI 0.18-3.01, P=0.67) and any abdominal symptoms within 5 days (HR 0.95, 95%CI 0.721.26, P=0.762), were not significant.
Table 4 presents the analysis of patient reported postoperative pain scores categorized
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based on postoperative day as well as the 30-day follow-up analysis. There was no significant difference in the postoperative pain scores between the simethicone and placebo groups during the time period of POD1 to POD5. In addition, there was no significant difference in the median
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length of stay between the treatment and control group (4.5 days vs 4 days, P=0.6383, respectively). Adverse events included events in-hospital and within 30 days post-discharge.
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Thirty-five participants (30%) reported an adverse event within 30 days of operation. Adverse events were reported in 31% of the participants in the simethicone group and 28% in the participants from the placebo group (P=0.7481). There was no significant difference between groups in the 3 participants (33% from simethicone group, 66% from placebo group) who required an abdominal reoperation (P=1). Postoperative ileus occurred in 7 participants and there
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was no difference between the simethicone and placebo group (3 vs. 4, RR 0.86; CI 0.36-2.08, respectively, P=1). There were no postoperative mortalities during the 30-day follow-up period.
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DISCUSSION
The present study analyzed the effect of simethicone in a multicenter double-blinded randomized control trial on postoperative ileus following elective colorectal surgery. The major
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finding of this trial is that simethicone has no significant effect, when compared to placebo on time to first flatulence (HR 0.92, 95% CI, 0.66 - 1.88, P=0.664) or return of bowel function (HR
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0.72 95%CI 0.47-1.10, P=0.123) following elective colorectal surgery. Additionally, this study found that both the adverse events and post-operative pain was comparable in those patients randomized to the simethicone group or to the placebo group.
There are currently no recent trials investigating the effect of simethicone on ileus,
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however earlier trials in the gynecological literature did show benefit. A previous randomizedcontrolled trial in 50 women undergoing gynecological surgery demonstrated that patients who received 40mg simethicone postoperatively experienced earlier spontaneous passage of gas, less
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abdominal pain/distensions and fewer enema requirements.[20] They found no difference in the time to first bowel movement and length of hospital stay was not recorded.[20] In a larger
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double-blinded study, Gibstein et al. assessed the effect of simethicone on 200 non-randomized women undergoing abdominal hysterectomy or caesarean section. Patients received simethicone (80 mg every four hours starting on the night of surgery for a total of 14 doses) and analysis demonstrated a significant reduction in abdominal distension, severity of gas pains, and increased rates of spontaneous passage of flatus and stool.[21] Furthermore, they found a reduction in the number of rectal treatments (suppositories and enemas) and narcotic use with no
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documented toxicity or adverse events.[21] Though these studies demonstrated a benefit, gynecologic surgery is likely less intensive on bowel manipulation and the use of laparoscopy, as well as ERAS principles, were not utilized during the timeframe of the previous studies. The
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present study assessed only patients undergoing colorectal resection where the gastrointestinal tract was breached and manipulated with a resection, anastomosis, and possible stoma formation. These factors are likely responsible for the development of an ileus, as opposed to gynecological
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surgery where the gastrointestinal tract is left unaltered. In addition, the more robust design of the present study makes the results more reliable and generalizable to the general surgical
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audience.
There have been recent advancements in other pharmacologic agents for the treatment of ileus. Notably, Alvimopan is a peripheral mu opioid receptor antagonist and has been shown to reduce rates of ileus following colorectal, gynecological and urological surgery in several recent
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trials.[15-17, 23] It counteracts bowel inhibition caused by narcotics without affecting their analgesic effects. Wolff et al. assessed 510 patients following laparotomy in a multicenter double-blind placebo controlled randomized trial, and demonstrated that Alvimopan accelerated
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time to recovery of gastrointestinal function and time to discharge.[17] Similarly, Viscusi et al. assessed the effects of Alvimopan on 418 patients undergoing either bowel resection or
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hysterectomy in a randomized double-blind controlled study and demonstrated that with adjustment for significant covariates, the drug significantly accelerated gastrointestinal recovery time.[16] Finally, Delaney et al. showed in a similar randomized fashion that when Alvimopan is administered prior to and after colorectal resection and hysterectomy, that gastrointestinal function and time to hospital discharge is increased when compared to placebo.[15] Unfortunately, the above trials assessed both benign and malignant disease processes and pooled
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analysis demonstrates a relative lack of colorectal cancer patients. Further, a 2012 meta-analysis confirmed that Alvimopan is effective at reducing ileus, however these effects have not yet been confirmed for laparoscopic surgery.[24] In an economic cost analysis of the four Alvimopan
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North American trials, Bell et al. found that the mean cost based on the average dosing was approximately $930.00 USD per patient, however this cost was offset by the reduction in
hospital admission. The cost prohibitive nature of Alvimopan was additional motivation to
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evaluate a more commonly used inexpensive drug, however this trial failed to find efficacy. Postoperative ileus remains a significant complication following major abdominal
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surgery and contributes to significant postoperative morbidity, increased length of stay, and healthcare cost.[1-3] There have been numerous attempts over the past 2-3 decades to ameliorate or decrease the occurrence of postoperative ileus following gastrointestinal surgery, however it remains a largely unsolved problem. Despite our advancements in peri/postoperative
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management, as well as the use of laparoscopy, ileus continues to challenge gastrointestinal surgeons. It is well known that ileus increases duration of hospitalization, cost of care, and postoperative morbidity.[6] This multicenter, double-blinded, placebo controlled randomized
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trial failed to show a difference in return of gastrointestinal motility in patients receiving simethicone following colorectal surgery. It provides an update to the current body of literature
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and should inform further trials investigating potential pharmacologic options to reduce ileus which remains a significant clinical and economic burden to the healthcare system. This study has several limitations. The major limitation is the relatively small sample
size. While this trial was initially designed to be a pilot study, it was appropriately powered for our primary outcome and therefore the present study has adequate statistical power to detect the clinically relevant difference of ileus following either simethicone or placebo treatment.[25] An
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additional limitation is the variability in administered doses. Unfortunately, a number of missed doses occurred for various reasons; including participant refusal, nausea and vomiting, and oral intake restrictions. The variability in doses may have been offset by our decision to administer
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higher than average single doses compared to prior studies (160mg four times daily compared to 40mg four times daily). The study results may have also been influenced by recall bias because participants who were previously asked to complete a daily patient beside diary occasionally
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CONCLUSION
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submitted either incomplete and/or late entries.
This was the first randomized-trial assessing the role of simethicone as a treatment for return of bowel function after colorectal surgery. This multicenter, double-blinded, placebo controlled randomized trial failed to show a difference in return of gastrointestinal motility in
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Figure Legends
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patients receiving simethicone following colorectal surgery.
Figure 1: Patient Bedside Diary Card
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Figure 2: CONSORT diagram of patients recruited into the SPOT Study Figure 3: Survival analysis comparing the proportion of patients passing flatus to time, for the treatment group (Arm A) and control group (Arm B). Figure 4: Survival analysis comparing the proportion of patients having a bowel movement to time, for the treatment group (Arm A) and control group (Arm B).
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Table 1: Analysis of population characteristics, peri/intra-operative factors and postoperative medications ^ Placebo (n=60) 35 (58) 65 (16) 28.4 (5)
P Value 0.975 0.706 0.713
112 (95) 7/116 (6) 11/ 117 (9)
57 (98) 3 (5) 5 (9)
55 (92) 4 (7) 6 (10)
0.965 0.978 0.207
91 (77) 14 (12) 3 (3) 9 (8) 1 (1)
46 (79) 4 (7) 3 (5) 5 (9) 0
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Simethicone (n = 58) 34 (59) 66 (13) 28.8 (6)
0 6 (5) 91 (77) 16 (14) 0 6 (5)
45 (75) 10 (17) 0 4 (7) 1 (2)
0.143
0.774
4 (7) 47 (78) 7 (12)
3 (5)
2 (3)
87 (74) 11 (9) 20 (17)
43 (74) 4 (7) 11 (19)
44 (73) 7 (12) 9 (15)
0.650
86 (73) 29 (25) 3 (4)
40 (69) 16 (28) 2 (3)
46 (77) 13 (22) 1 (2)
0.588
113/114 (99) 112/114 (98) 10/117 (9) 118 (100)
54 (98) 53 (96) 6 (11) 58 (100)
59 (98) 59 (98) 4 (7) 60 (100)
0.483 0.231 0.522 1.00
20 (17) 82 (69)
8 (14) 38 (66)
12 (20) 44 (73)
0.369 0.357
59 (50) 73 (62)
25 (43) 36 (62)
34 (57) 37 (62)
0.141 0.964
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2 (3) 44 (76) 9 (16)
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Male Age (years, mean±SD) BMI (mean±SD) Preoperative Factors Comorbidities History of PONV Chronic opioid use Perioperative Factors Primary Diagnosis CRC/polyp/neoplasm IBD RP/Constipation/MD Diverticular disease Other ASA Grade 1 Grade 2 Grade 3 Grade 4 Grade 5 Grade 6 Intraoperative Factors Surgery Type Laparoscopic assisted Laparoscopic CtoO Open Procedure Type Colon Rectal Both Medication Gabapentin/Pregabalin Acetaminophen NSAIDs Opioids Anaesthesia Epidural Lidocaine Postoperative Medication PCA IV medications
Total (n=118) 69 (58) 65 (14) 28.6 (6)
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Opioids NSAIDS Tylenol Gabapentin Antiemetic
109 (92) 13(11) 111 (94) 54 (46) 76/117 (65)
52 (90) 5(9) 52 (90) 29 (50) 37 (65)
57 (95) 8(13) 59 (98) 25 (42) 39 (65)
0.318 0.414 0.059 0.364 0.992
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^ values: n (%) unless otherwise stated SD: standard deviation
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PONV: postoperative nausea and vomiting, CRC: colorectal cancer, IBD: inflammatory bowel disease, RP: rectal prolapse, MD: motility disorder, ASA: American Society of Anesthesiologists, CtoO: converted to open, PCA: patient-controlled analgesia, IV: intravenous, NSAIDS: non-steroidal antiinflammatories
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Table 2: Primary outcome measures for treatment group (Arm A) and control group (Arm B) ^
11 (0-21)
13 (0-21)
10 (0-21)
107 (91) 98 (83)
51 (88) 45 (78)
56 (93) 53 (88)
37.7, 25.2
37.6, 26.7
37.9, 23.9
42.1, 25.2
41.1, 28.2
42.9, 22.5
SD: standard deviation, CI: confidence interval
Univariable HR (95% CI)
Multivariable HR (95% CI)*
P value
0.664
0.92 (0.62, 1.38)
0.69
0.119
0.72 (0.47, 1.09)
0.123
P value^
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Placebo (n=60)
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Simethicone (n=58)
0.92 (0.63, 1.35)
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Number of Doses (median, range) Flatus/discharge n (%) BM/discharge n (%) Time to flatus/discharge (mean hrs±SD) Time to BM/discharge (mean hrs±SD)
Total (n=118)
0.74 (0.49, 1.10)
0.313 0.120
BM: bowel movement, POD: postoperative day, NG: nasogastric tube, PO: per os.
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^ P Value represents chi-square test for binary outcomes and log rank test for time-to-event outcomes
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* Adjusted for age, sex, chronic opiod use, ASA class 3 or less, cancer diagnosis, rectal procedure, laparoscopic, stoma and epidural
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Table 3: Secondary outcome measures for treatment group (Arm A) and control group (Arm B)^ Placebo (n=60) 35 (58) 16 (27) 5 (8) 37 (62)
^ values: n (%) unless otherwise stated
Univariable RR (95% CI)* 0.85 (0.63, 1.20) 0.97 (0.64, 1.49) 0.83 (0.23, 2.95) 0.98 (0.73, 1.31)
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Simethicone (n=58) 29 (50) 15 (26) 4 (7) 35 (60)
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Early discharge (<4 days) Emesis within 5 days NG output within 5 days Symptoms† within 5 days
Total (n=118) 64 (54) 31 (26) 9 (8) 72 (61)
P value 0.369 0.921 0.77 0.884
Multivariable RR (95% CI)** 0.87 (0.64, 1.18) 0.97 (0.52, 1.78) 0.74 (0.18, 3.01) 0.95 (0.72, 1.26)
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* Univariable analysis was a poisson log transformed regression with robust confidence intervals ** Same analysis as univariable with adjustments for age, sex, chronic opiod use, asa class 3 or less, cancer diagnosis, rectal procedure, laparoscopic, stoma and epidural
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Symptoms included; abdominal distension/bloating/cramping
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†
P value 0.367 0.915 0.67 0.762
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Table 4: Analysis of pain scores and events during 30 day follow-up period Simethicone (n=58)
POD-1 (n=113)
4, 2.5
4, 2.5
POD-2 (n=112)
3, 2.2
3, 2.3
POD-3 (n=101)
3, 2.4
3, 2.8
POD-4 (n=71)
3, 2.3
3, 2.6
3, 2.0
0.461
POD-5 (n=43)
3, 4.7
4, 2.8
3, 1.8
0.515
0.464
3, 2.1
0.590
3, 2.0
0.252
4,4
4.5, 4
4, 3
0.638
Any adverse event
35, 30
18, 31
17, 28
0.748
Postoperative ileus
7, 6
3, 5
4, 7
0.967
Abdominal reoperation
3, 3
1, 2
2, 3
0.986
11, 9
4, 7
7, 12
0.372
Readmission * values (median±SD)
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Length of Stay (median, IQR)
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30-day follow-up results^
P value
4, 2.5
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Pain Scores*
Placebo (n=60)
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Total (n=118)
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^ values (n, %) unless otherwise stated
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IQR: interquartile range
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Figure 1: Patient Bedside Diary Card
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120 pts consented
Hospital A 58 patients randomized
Arm B: 28
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Hospital B 60 patients randomized
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Arm A: 30
2 withdrew consent
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118 pts completed the study period
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Figure 2: CONSORT diagram of patients recruited into the SPOT Study
Arm A: 28
Arm B: 32
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Figure 3: Survival analysis comparing the proportion of patients passing flatus to time, for the treatment group (Arm A) and control group (Arm B).
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Figure 4: Survival analysis comparing the proportion of patients having a bowel movement to time, for the treatment group (Arm A) and control group (Arm B).
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The Effect of Simethicone on Postoperative Ileus in Patients Undergoing Colorectal Surgery (SPOT), A Randomized Controlled Trial
•
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Highlights: Post operative ileus presents significant clinical challenges and contributes to increased morbidity, length of stay, and healthcare cost following colorectal surgery.
Various pharmacological interventions have been developed and have been shown to
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reduce the rates of post operative ileus, however these generally carry negative side
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effects and increased cost.
Simethicone is a readily available, safe and easily tolerated oral anti-flatulence medication that has been shown to reduce post operative ileus following gynecological surgery.
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This multicenter randomized controlled trial demonstrated that simethicone has no effect on the resolution of post operative ileus or reduction in abdominal pain following
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colorectal surgery.
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International Journal of Surgery Author Disclosure Form The following additional information is required for submission. Please note that failure to respond to these questions/statements will mean your submission will be returned. If you have nothing to declare in any of these categories then this should be stated.
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Please state any conflicts of interest
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None to declare
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Please state any sources of funding for your research
McMaster Surgical Associates Grant
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Please state whether Ethical Approval was given, by whom and the relevant Judgement’s reference number
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This trial was approved by the McMaster Research Ethics Board. P9324
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Research Registration Unique Identifying Number (UIN) Please enter the name of the registry and the unique identifying number of the study. You can register your research at http://www.researchregistry.com to obtain your UIN if you have not already registered your study. This is mandatory for human studies only.
This study was registered with Clinicaltrials.gov under the ID: NCT02161367.
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Author contribution Please specify the contribution of each author to the paper, e.g. study design, data collections, data analysis, writing. Others, who have contributed in other ways should be listed as contributors.
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Dr. Cagla Eskicioglu and Dr. Shawn Forbes were responsible for the conception, design, data analysis, and editing of this manuscript. Dr. Jeremy Springer, Dr. Shiraz Elkheir, Dr. Aristithes Doumouras, Dr. Stephen Kelly and Dr. Ilun Yang contributed to the design and conduct of the trial, interpretation of the data, and revisions for the final approval of this manuscript. All authors provided substantial contributions to this manuscript.
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Dr. Shawn Forbes Dr. Cagla Eskicioglu
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Guarantor The Guarantor is the one or more people who accept full responsibility for the work and/or the conduct of the study, had access to the data, and controlled the decision to publish.
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S1743-9191(18)31503-6
DOI:
10.1016/j.ijsu.2018.06.011
Reference:
IJSU 4689
To appear in:
International Journal of Surgery
Received Date: 25 April 2018 Accepted Date: 4 June 2018
Please cite this article as: Springer JE, Elkheir S, Eskicioglu C, Doumouras AG, Kelly S, Yang I, Forbes S, The Effect of Simethicone on Postoperative Ileus in Patients Undergoing Colorectal Surgery (SPOT), A Randomized Controlled Trial, International Journal of Surgery (2018), doi: 10.1016/j.ijsu.2018.06.011. 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.
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The Effect of Simethicone on Postoperative Ileus in Patients Undergoing Colorectal Surgery (SPOT), A Randomized Controlled Trial
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Running Head: Simethicone’s effect on ileus Jeremy E. Springer MD MSc1, Shiraz Elkheir MD MBBS MSc CMD2, Cagla Eskicioglu MD MSc FRCSC1†, Aristithes G. Doumouras MD MPH1, Stephen Kelly MD FRCS1*, Ilun Yang MD
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FRCSC1†, Shawn Forbes MD MSc FRCSC1† 1
Department of Surgery, Division of General Surgery, McMaster University, Hamilton, ON Department of Surgery, Riverside Healthcare, Fort Frances, ON † Assistant Professor, McMaster University, Dept. of Surgery, Hamilton, Ontario * Associate Professor, McMaster University, Dept. of Surgery, Hamilton, Ontario, Canada
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Correspondence: Shawn Forbes MD MSc FRCSC. Division of General Surgery. Juravinski
72875,
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Hospital, 711 Concession St. Hamilton, Ontario, L8V 1C3, Canada. Tel: (905) 521-2100 ext.
Fax: (905) 528-9388, email: [email protected]
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Disclosures: None
Trial Support: This trial was supported by the McMaster Surgical Associates Grant.
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Prior Presentations: This manuscript was presented as a poster presentation at the annual ASCRS Annual Scientific Meeting in Los Angeles, California (April 30th to May 4th, 2016). Contributions: Authors’ contributions: Dr. Cagla Eskicioglu and Dr. Shawn Forbes were responsible for the conception, design, data analysis, and editing of this manuscript. Dr. Jeremy Springer, Dr. Shiraz Elkheir, Dr. Aristithes Doumouras, Dr. Stephen Kelly and Dr. Ilun Yang contributed to the design and conduct of the trial, interpretation of the data, and revisions for the final approval of this manuscript. All authors provided substantial contributions to this manuscript.
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ABSTRACT Background: Postoperative ileus is a poorly understood multifactorial outcome following
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colorectal surgery that presents significant clinical challenges and contributes to increased morbidity, length of stay, and healthcare cost. To date, there are few pharmacological interventions that shorten the duration of postoperative ileus.
ileus symptoms in patients undergoing colorectal surgery.
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Objective: This study is the first to evaluate the efficacy of simethicone in treating postoperative
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Design: A multicenter, double-blinded, placebo controlled randomized controlled trial. Settings: This trial was conducted at two academic tertiary care centres in Ontario, Canada. Participants: 118 patients undergoing colorectal surgery.
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Interventions: Patients were randomized to receive either a five-day course of oral simethicone (n=58) or a placebo (n=60).
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Main Outcome Measures: The primary outcome was time to first passage of flatus. Secondary outcomes included time to first bowel movement, postoperative length of stay, and postoperative
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pain. Statistical analyses were performed on an intention-to-treat basis. Statistical significance set at p=0.05.
Results: The median time to first passage of flatus in simethicone arm was 25.2 hours and 26.7 hours in controls (P=0.98). There were no significant differences in the median time to first bowel movement (simethicone=41.1 hours vs. control=42.9 hours, P=0.91) or median length of hospital stay (simethicone=4.5 days vs. control=4.0 days, P=0.63).
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Conclusions: This study failed to show a difference in return of gastrointestinal motility in patients receiving simethicone following colorectal surgery. Postoperative ileus remains a
to identify a reliable and effective method of treatment. Key Words: post operative ileus, simethicone, colorectal surgery
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significant clinical and economic burden to the healthcare system and further research is needed
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Trial Registration: This study was registered with Clinicaltrials.gov.
INTRODUCTION
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Prolonged postoperative ileus is a poorly understood multifactorial outcome following major abdominal surgery that contributes to significant morbidity, increased length of stay, and healthcare cost.[1-3] The characteristic features of ileus are bowel dysfunction and reduced
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motility, resulting in ineffective transit of intestinal contents.[4,5] The multifactorial
pathogenesis of ileus is poorly understood, however it is thought to include complex interactions between surgical stress and inflammatory mediators, physical manipulation of bowel, use of
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anesthetics and analgesics and peri-operative fluid and electrolyte imbalances.[6,7] The
incidence rates of ileus varies amongst different studies and surgical specialities, however is
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reported to range between 10-30% following major abdominal surgery [6,8-11] with an economic impact estimated at $750 million per year in the US.[12] Furthermore, ileus is responsible for significant number of hospital readmissions.[13] Following four North American and one European phase 3 multicenter trials, Alvimopan, an oral peripherally acting mu-opioid
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receptor antagonist was approved by the FDA in May 2008 to reduce ileus following bowel resection.[14-18] The cost of the average 15 dose therapeutic course of Alvimopan is approximately $930.00 USD.[18] In publicly funded resource limited health care systems, there
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is increasing focus on cost reduction strategies and therefore the use of other pharmacological options to reduce ileus should be considered.
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Numerous studies have evaluated other pharmacological strategies to reduce ileus. The
focus of these medications is to target the pathophysiologic causes of ileus by either; minimizing sympathetic inhibition, inhibiting acetylcholinesterases, stimulating enteric motility, or decreasing inflammatory cascades. These agents are not routinely used as they have either not been adequately studied, or have not shown efficacy.[19] Alternative medications such as laxatives or anti-flatulence agents have been proposed as low risk interventions for ileus
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prevention. Simethicone is an inexpensive, readily available, orally administered anti-foaming agent compromised of polydimethylsiloxane and hydrated silica gel. It causes coalescence of gas bubbles in the intestinal tract, facilitating emission. Simethicone is not absorbed by the
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gastrointestinal tract and is known to have an excellent safety profile. The side effects of
simethicone include nausea, vomiting, diarrhea, and headache, however are only reported in 25% of patients.
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To date, only two older randomized controlled trials have evaluated the effect of
simethicone on ileus following gynecological surgery with results demonstrating earlier passage
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of flatus, reduced gas pain and decreased rates of ileus.[20,21] There are currently no studies that have evaluated the effects of simethicone on ileus in non-gynecological surgery, and therefore the present study was performed to evaluate the effect of simethicone on the reduction of ileus in
METHODS Design and Setting
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patients undergoing elective colorectal surgery.
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This was a multicenter, double-blinded, randomized controlled trial that compared simethicone versus placebo in patients undergoing colorectal surgery at two high volume
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colorectal surgery academic hospitals in Ontario, Canada. Both hospitals have a clear enhanced recovery after colorectal surgery protocol that has been followed for several years. A Clinical Trial Application was approved by Health Canada. This trial was also approved by the **** Research Ethics Board. This study was registered with Clinicaltrials.gov under the ID: NCT0216***.
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Population Participants were recruited into the study between October 2014 and April 2015 based on
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the following inclusion/exclusion criteria.
Inclusion Criteria: ≥ 18 years of age
(2)
Undergoing elective colorectal surgery involving bowel resection with or without
re-
anastomosis
(3)
Abdominal approach including either open or laparoscopic surgery
(4)
Surgery performed at one of the two participating academic tertiary care centres
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(1)
Exclusion Criteria:
Documented allergy to simethicone; and/or
(2)
Undergoing emergency surgery; and/or
(3)
Non-abdominal approach (i.e. perineal procedure); and/or
(4)
Individuals unable to provide informed consent (non-English speaking patients
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those with cognitive impairment).
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and
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(1)
Randomization and Blinding Study participants were engaged by research staff at the time of surgery booking.
Following consent, participants were randomized into one of the two study arms: simethicone or placebo. The randomization process was independently organized by the pharmacy team at both study sites. A random number generator was utilized to assign numbers to individual
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experimental and control drug regimens. The numbers were written on cards which were sealed in opaque envelopes. As patients were enrolled, an envelope was opened by a pharmacy team representative. Patients were then assigned to the corresponding drug regimen; either
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simethicone or placebo. No further strategies for randomization were employed (i.e. stratification and/or block randomization) due to the small number of participants enrolled in the study.
Due to the double-blinded study design, all participants, investigators, reviewers, nurses
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and research staff were not aware of which study arm the patient belonged to. Study participants were assigned a unique identifying code that was only revealed to the data safety monitoring
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committee and to the data analysts during the final analysis of study results.
Study Protocol
Participants randomized to Arm A were treated with a syrup form of simethicone (160
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mg) while participants randomized to Arm B were treated with a similarly prepared placebo that matched the study drug based on all its physical properties. The study dose was 160 mg of study drug or placebo four times a day. All participating patients received their initial dose of study
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drug or placebo at 22:00 after their surgery. Subsequent doses were administered at 8:00, 12:00, 16:00 and 22:00 starting postoperative day 1 through postoperative day 5. Treatment was
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continued until either, they completed the full 5 full day course or they were discharged from hospital (whichever occurred first). Subjective patient data including, time of first passage of flatus and bowel movements,
daily average pain score, food tolerance and abdominal distension was collected using a patientreported bedside diary (Figure 1).
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During the participants hospital stay, daily patient visits were performed by trained research staff. Research staff assessed the following: passage of flatus, passage of bowel movements, and postoperative pain. Relevant data pertaining to the participant’s postoperative
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course (i.e. use of other medications, laboratory and radiological findings, etc.) were collected from the participant’s medical records (paper and electronic). Patients were contacted by
telephone to assess outcomes at two-weeks and 30-days post-discharge. All study participants'
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charts were reviewed on postoperative day 30 to ensure no outcomes were missed. Outcomes
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The primary endpoint of the study was time-to-first passage of flatus (hours) or time to discharge if this occurred before first flatus. Participants were followed for the first 5 days postoperatively for these outcomes. This study was designed to assess a 40% reduction in time to the primary outcomes, with p <0.05 and 80% power (assuming a time-to-first flatus in the
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control arm of 84 hours based on previous literature).[22]
The secondary endpoints were time-to-first passage of bowel movement which was assessed in the same manner as the primary endpoint; early discharge (within 3 days), any
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emesis, any nasogastric output or any abdominal distension/bloating/cramping symptoms within the first 5 days. Additionally, hospital length of stay and the incidence of postoperative
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complications including but not limited to wound and anastomotic occurrences, bleeding, postoperative infections, readmission to hospital and death. Lastly, postoperative pain measured using the Visual Analogue Pain Scale (Figure 1).
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Statistical Analysis Descriptive statistics (means, medians, standard deviations) were used to characterize the patient population where applicable. Chi square was used to analyze dichotomous patient
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variables such as adverse events while continuous variables were analysed using T-tests. Our primary outcome was evaluated using a time-to-event analysis. Kaplan-Meier curves were
created for both groups and compared in a univariable manner using the log rank test. Two Cox
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models were then created to assess the hazard ratio between the treatment and control groups. The first was a univariable model using treatment as the only variable. A second, multivariable
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was created to ascertain the effect of the treatment after adjustment for important variables. Specifically, the variables adjusted for were age, sex, chronic opioid use, ASA class 3 or less, cancer diagnosis (vs. benign), rectal procedure, laparoscopic, stoma creation (colostomy or ileostomy) and epidural insertion. Time to first passage of bowel movement/discharge was
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assessed similarly. The binary secondary outcomes of early discharge, any emesis, any nasogastric output and any abdominal symptoms were assessed using a log transformed generalized linear model with robust confidence intervals. This provides the risk ratios for the
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effects. Similar to the primary outcomes, univariable and multivariable models were created using the same covariates as the primary analysis. Length of stay and post-operative pain scores
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were evaluated using the Wilcoxon rank-sum test. Statistical significance was set at P<0.05. Analysis was completed on an intention-to-treat basis. The 95% confidence intervals were provided where applicable. Data were analyzed using SPSS statistical software (IBM Corp. Released 2013. IBM SPSS Statistics for Windows, Version 22.0. Armonk, NY: IBM Corp).
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RESULTS A total of 120 patients were recruited from the two academic tertiary care centres. Of the 120 patients consented, 118 completed the study protocol due to 2 patients withdrawing consent
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during the study. Of the 58 total patients recruited from Hospital A, 30 patients were randomized to receive the simethicone treatment (Arm A) and 28 were randomized to receive the placebo (Arm B). Of the 60 total patients recruited from Hospital B, 28 patients were randomized to the
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simethicone treatment arm (Arm A) and 32 were randomized to the control arm (Arm B) (Figure 2).
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Table 1 presents the baseline patient characteristics for all patients who underwent randomization to simethicone or placebo. The average age of the cohort was 65 years, and 58% were male. The majority of the colorectal resections were performed for malignancy (77%). Seventy-four percent of the resections were performed laparoscopically and 73% were isolated
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colon resections. The majority of patients had an ASA score greater than 2. There was no statistically significant difference in patient characteristics amongst study groups. Additionally, there were no statistically significant differences in the use of intra-operative or post-operative
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analgesics.
Table 2 and Figures 3 & 4 present the primary outcome results. There was no significant
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difference in the median number of doses between the treatment and placebo group (13[0-21], 10[0-21], P=0.1335 respectively). In total, 51 (88%) of patients reached the primary endpoint in the treatment group and 56 (93%) in the control group (p=0.313). Figure 3 and 4 presents the Kaplan-Meier event curve for the primary outcomes. Overall, the hazard ratio between the treatment and control groups was 0.92 and the log rank test comparing each curve was not significant (95% CI, 0.66 - 1.88, P=0.664). The adjusted multivariable hazard for the treatment
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compared to the control group was 0.92 (95% CI, 0.62 - 1.38, P=0.69). Table 2 also presents the results for the secondary time-to-event analysis. There was no difference in this outcome occurring overall (78% in treatment vs 88% in control, P=0.12) and both the univariable (HR
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0.74 95%CI 0.49-1.10, P=0.119) and multivariable (HR 0.72 95%CI 0.47-1.10, P=0.123) were not significant.
Table 3 presents the results of the binary secondary outcomes. Univariable and
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multivariable risk ratios were calculated for each of these outcomes. After multivariable
adjustment, the risk ratios for early discharge (HR 0.87, 95%CI 0.64-1.18, P=0.367), emesis
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within 5 days (HR 0.97, 95%CI 0.52-1.78, P=0.915), nasogastric output within 5 days (HR 0.74, 95%CI 0.18-3.01, P=0.67) and any abdominal symptoms within 5 days (HR 0.95, 95%CI 0.721.26, P=0.762), were not significant.
Table 4 presents the analysis of patient reported postoperative pain scores categorized
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based on postoperative day as well as the 30-day follow-up analysis. There was no significant difference in the postoperative pain scores between the simethicone and placebo groups during the time period of POD1 to POD5. In addition, there was no significant difference in the median
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length of stay between the treatment and control group (4.5 days vs 4 days, P=0.6383, respectively). Adverse events included events in-hospital and within 30 days post-discharge.
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Thirty-five participants (30%) reported an adverse event within 30 days of operation. Adverse events were reported in 31% of the participants in the simethicone group and 28% in the participants from the placebo group (P=0.7481). There was no significant difference between groups in the 3 participants (33% from simethicone group, 66% from placebo group) who required an abdominal reoperation (P=1). Postoperative ileus occurred in 7 participants and there
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was no difference between the simethicone and placebo group (3 vs. 4, RR 0.86; CI 0.36-2.08, respectively, P=1). There were no postoperative mortalities during the 30-day follow-up period.
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DISCUSSION
The present study analyzed the effect of simethicone in a multicenter double-blinded randomized control trial on postoperative ileus following elective colorectal surgery. The major
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finding of this trial is that simethicone has no significant effect, when compared to placebo on time to first flatulence (HR 0.92, 95% CI, 0.66 - 1.88, P=0.664) or return of bowel function (HR
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0.72 95%CI 0.47-1.10, P=0.123) following elective colorectal surgery. Additionally, this study found that both the adverse events and post-operative pain was comparable in those patients randomized to the simethicone group or to the placebo group.
There are currently no recent trials investigating the effect of simethicone on ileus,
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however earlier trials in the gynecological literature did show benefit. A previous randomizedcontrolled trial in 50 women undergoing gynecological surgery demonstrated that patients who received 40mg simethicone postoperatively experienced earlier spontaneous passage of gas, less
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abdominal pain/distensions and fewer enema requirements.[20] They found no difference in the time to first bowel movement and length of hospital stay was not recorded.[20] In a larger
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double-blinded study, Gibstein et al. assessed the effect of simethicone on 200 non-randomized women undergoing abdominal hysterectomy or caesarean section. Patients received simethicone (80 mg every four hours starting on the night of surgery for a total of 14 doses) and analysis demonstrated a significant reduction in abdominal distension, severity of gas pains, and increased rates of spontaneous passage of flatus and stool.[21] Furthermore, they found a reduction in the number of rectal treatments (suppositories and enemas) and narcotic use with no
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documented toxicity or adverse events.[21] Though these studies demonstrated a benefit, gynecologic surgery is likely less intensive on bowel manipulation and the use of laparoscopy, as well as ERAS principles, were not utilized during the timeframe of the previous studies. The
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present study assessed only patients undergoing colorectal resection where the gastrointestinal tract was breached and manipulated with a resection, anastomosis, and possible stoma formation. These factors are likely responsible for the development of an ileus, as opposed to gynecological
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surgery where the gastrointestinal tract is left unaltered. In addition, the more robust design of the present study makes the results more reliable and generalizable to the general surgical
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audience.
There have been recent advancements in other pharmacologic agents for the treatment of ileus. Notably, Alvimopan is a peripheral mu opioid receptor antagonist and has been shown to reduce rates of ileus following colorectal, gynecological and urological surgery in several recent
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trials.[15-17, 23] It counteracts bowel inhibition caused by narcotics without affecting their analgesic effects. Wolff et al. assessed 510 patients following laparotomy in a multicenter double-blind placebo controlled randomized trial, and demonstrated that Alvimopan accelerated
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time to recovery of gastrointestinal function and time to discharge.[17] Similarly, Viscusi et al. assessed the effects of Alvimopan on 418 patients undergoing either bowel resection or
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hysterectomy in a randomized double-blind controlled study and demonstrated that with adjustment for significant covariates, the drug significantly accelerated gastrointestinal recovery time.[16] Finally, Delaney et al. showed in a similar randomized fashion that when Alvimopan is administered prior to and after colorectal resection and hysterectomy, that gastrointestinal function and time to hospital discharge is increased when compared to placebo.[15] Unfortunately, the above trials assessed both benign and malignant disease processes and pooled
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analysis demonstrates a relative lack of colorectal cancer patients. Further, a 2012 meta-analysis confirmed that Alvimopan is effective at reducing ileus, however these effects have not yet been confirmed for laparoscopic surgery.[24] In an economic cost analysis of the four Alvimopan
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North American trials, Bell et al. found that the mean cost based on the average dosing was approximately $930.00 USD per patient, however this cost was offset by the reduction in
hospital admission. The cost prohibitive nature of Alvimopan was additional motivation to
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evaluate a more commonly used inexpensive drug, however this trial failed to find efficacy. Postoperative ileus remains a significant complication following major abdominal
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surgery and contributes to significant postoperative morbidity, increased length of stay, and healthcare cost.[1-3] There have been numerous attempts over the past 2-3 decades to ameliorate or decrease the occurrence of postoperative ileus following gastrointestinal surgery, however it remains a largely unsolved problem. Despite our advancements in peri/postoperative
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management, as well as the use of laparoscopy, ileus continues to challenge gastrointestinal surgeons. It is well known that ileus increases duration of hospitalization, cost of care, and postoperative morbidity.[6] This multicenter, double-blinded, placebo controlled randomized
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trial failed to show a difference in return of gastrointestinal motility in patients receiving simethicone following colorectal surgery. It provides an update to the current body of literature
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and should inform further trials investigating potential pharmacologic options to reduce ileus which remains a significant clinical and economic burden to the healthcare system. This study has several limitations. The major limitation is the relatively small sample
size. While this trial was initially designed to be a pilot study, it was appropriately powered for our primary outcome and therefore the present study has adequate statistical power to detect the clinically relevant difference of ileus following either simethicone or placebo treatment.[25] An
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additional limitation is the variability in administered doses. Unfortunately, a number of missed doses occurred for various reasons; including participant refusal, nausea and vomiting, and oral intake restrictions. The variability in doses may have been offset by our decision to administer
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higher than average single doses compared to prior studies (160mg four times daily compared to 40mg four times daily). The study results may have also been influenced by recall bias because participants who were previously asked to complete a daily patient beside diary occasionally
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CONCLUSION
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submitted either incomplete and/or late entries.
This was the first randomized-trial assessing the role of simethicone as a treatment for return of bowel function after colorectal surgery. This multicenter, double-blinded, placebo controlled randomized trial failed to show a difference in return of gastrointestinal motility in
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Figure Legends
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patients receiving simethicone following colorectal surgery.
Figure 1: Patient Bedside Diary Card
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Figure 2: CONSORT diagram of patients recruited into the SPOT Study Figure 3: Survival analysis comparing the proportion of patients passing flatus to time, for the treatment group (Arm A) and control group (Arm B). Figure 4: Survival analysis comparing the proportion of patients having a bowel movement to time, for the treatment group (Arm A) and control group (Arm B).
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Pharm. 2009;66(14):1267-1277. doi:10.2146/ajhp080445. Delaney CP, Weese JL, Hyman NH, et al. Phase III trial of alvimopan, a novel, peripherally acting, Mu opioid antagonist, for postoperative ileus after major abdominal surgery. Dis Colon Rectum. 2005;48(6):1114-1129. doi:10.1007/s10350-005-0035-7. 16.
Viscusi ER, Goldstein S, Witkowski T, et al. Alvimopan, a peripherally acting mu-opioid receptor antagonist, compared with placebo in postoperative ileus after major abdominal 16
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surgery: results of a randomized, double-blind, controlled study. Surg Endosc. 2006;20(1):64-70. doi:10.1007/s00464-005-0104-y. Wolff BG, Michelassi F, Gerkin TM, et al. Alvimopan, a novel, peripherally acting mu
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Gynecol. 1974;44(1):148-154.
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colorectal resection: A systematic review. Dis Colon Rectum. 2007;50(12):2149-2157.
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Lee CT, Chang SS, Kamat AM, et al. Alvimopan accelerates gastrointestinal recovery
after radical cystectomy: a multicenter randomized placebo-controlled trial. Eur Urol. 2014;66(2):265-272. doi:10.1016/j.eururo.2014.02.036. 24.
Vaughan-shaw PG, Fecher IC, Harris S, Knight JS. A Meta-analysis of the Effectiveness 17
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of the Opioid Receptor Antagonist Alvimopan in Reducing Hospital Length of Stay and Time to Gi Recovery in Patients Enrolled in a Standardized Accelerated Recovery Program After Abdominal Surgery. Dis Colon &. 2012;55(5):611-620.
Dimick JB, Diener-West M, Lipsett PA. Negative Results of Randomized Clinical Trials
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Published in the Surgical Literature. Arch Surg. 2001;136(7):796.
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doi:10.1001/archsurg.136.7.796.
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25.
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doi:10.1097/dcr.0b013e318249fc78.
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Table 1: Analysis of population characteristics, peri/intra-operative factors and postoperative medications ^ Placebo (n=60) 35 (58) 65 (16) 28.4 (5)
P Value 0.975 0.706 0.713
112 (95) 7/116 (6) 11/ 117 (9)
57 (98) 3 (5) 5 (9)
55 (92) 4 (7) 6 (10)
0.965 0.978 0.207
91 (77) 14 (12) 3 (3) 9 (8) 1 (1)
46 (79) 4 (7) 3 (5) 5 (9) 0
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Simethicone (n = 58) 34 (59) 66 (13) 28.8 (6)
0 6 (5) 91 (77) 16 (14) 0 6 (5)
45 (75) 10 (17) 0 4 (7) 1 (2)
0.143
0.774
4 (7) 47 (78) 7 (12)
3 (5)
2 (3)
87 (74) 11 (9) 20 (17)
43 (74) 4 (7) 11 (19)
44 (73) 7 (12) 9 (15)
0.650
86 (73) 29 (25) 3 (4)
40 (69) 16 (28) 2 (3)
46 (77) 13 (22) 1 (2)
0.588
113/114 (99) 112/114 (98) 10/117 (9) 118 (100)
54 (98) 53 (96) 6 (11) 58 (100)
59 (98) 59 (98) 4 (7) 60 (100)
0.483 0.231 0.522 1.00
20 (17) 82 (69)
8 (14) 38 (66)
12 (20) 44 (73)
0.369 0.357
59 (50) 73 (62)
25 (43) 36 (62)
34 (57) 37 (62)
0.141 0.964
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2 (3) 44 (76) 9 (16)
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Male Age (years, mean±SD) BMI (mean±SD) Preoperative Factors Comorbidities History of PONV Chronic opioid use Perioperative Factors Primary Diagnosis CRC/polyp/neoplasm IBD RP/Constipation/MD Diverticular disease Other ASA Grade 1 Grade 2 Grade 3 Grade 4 Grade 5 Grade 6 Intraoperative Factors Surgery Type Laparoscopic assisted Laparoscopic CtoO Open Procedure Type Colon Rectal Both Medication Gabapentin/Pregabalin Acetaminophen NSAIDs Opioids Anaesthesia Epidural Lidocaine Postoperative Medication PCA IV medications
Total (n=118) 69 (58) 65 (14) 28.6 (6)
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Opioids NSAIDS Tylenol Gabapentin Antiemetic
109 (92) 13(11) 111 (94) 54 (46) 76/117 (65)
52 (90) 5(9) 52 (90) 29 (50) 37 (65)
57 (95) 8(13) 59 (98) 25 (42) 39 (65)
0.318 0.414 0.059 0.364 0.992
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^ values: n (%) unless otherwise stated SD: standard deviation
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PONV: postoperative nausea and vomiting, CRC: colorectal cancer, IBD: inflammatory bowel disease, RP: rectal prolapse, MD: motility disorder, ASA: American Society of Anesthesiologists, CtoO: converted to open, PCA: patient-controlled analgesia, IV: intravenous, NSAIDS: non-steroidal antiinflammatories
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Table 2: Primary outcome measures for treatment group (Arm A) and control group (Arm B) ^
11 (0-21)
13 (0-21)
10 (0-21)
107 (91) 98 (83)
51 (88) 45 (78)
56 (93) 53 (88)
37.7, 25.2
37.6, 26.7
37.9, 23.9
42.1, 25.2
41.1, 28.2
42.9, 22.5
SD: standard deviation, CI: confidence interval
Univariable HR (95% CI)
Multivariable HR (95% CI)*
P value
0.664
0.92 (0.62, 1.38)
0.69
0.119
0.72 (0.47, 1.09)
0.123
P value^
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Placebo (n=60)
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Simethicone (n=58)
0.92 (0.63, 1.35)
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Number of Doses (median, range) Flatus/discharge n (%) BM/discharge n (%) Time to flatus/discharge (mean hrs±SD) Time to BM/discharge (mean hrs±SD)
Total (n=118)
0.74 (0.49, 1.10)
0.313 0.120
BM: bowel movement, POD: postoperative day, NG: nasogastric tube, PO: per os.
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^ P Value represents chi-square test for binary outcomes and log rank test for time-to-event outcomes
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* Adjusted for age, sex, chronic opiod use, ASA class 3 or less, cancer diagnosis, rectal procedure, laparoscopic, stoma and epidural
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Table 3: Secondary outcome measures for treatment group (Arm A) and control group (Arm B)^ Placebo (n=60) 35 (58) 16 (27) 5 (8) 37 (62)
^ values: n (%) unless otherwise stated
Univariable RR (95% CI)* 0.85 (0.63, 1.20) 0.97 (0.64, 1.49) 0.83 (0.23, 2.95) 0.98 (0.73, 1.31)
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Simethicone (n=58) 29 (50) 15 (26) 4 (7) 35 (60)
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Early discharge (<4 days) Emesis within 5 days NG output within 5 days Symptoms† within 5 days
Total (n=118) 64 (54) 31 (26) 9 (8) 72 (61)
P value 0.369 0.921 0.77 0.884
Multivariable RR (95% CI)** 0.87 (0.64, 1.18) 0.97 (0.52, 1.78) 0.74 (0.18, 3.01) 0.95 (0.72, 1.26)
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* Univariable analysis was a poisson log transformed regression with robust confidence intervals ** Same analysis as univariable with adjustments for age, sex, chronic opiod use, asa class 3 or less, cancer diagnosis, rectal procedure, laparoscopic, stoma and epidural
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Symptoms included; abdominal distension/bloating/cramping
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†
P value 0.367 0.915 0.67 0.762
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Table 4: Analysis of pain scores and events during 30 day follow-up period Simethicone (n=58)
POD-1 (n=113)
4, 2.5
4, 2.5
POD-2 (n=112)
3, 2.2
3, 2.3
POD-3 (n=101)
3, 2.4
3, 2.8
POD-4 (n=71)
3, 2.3
3, 2.6
3, 2.0
0.461
POD-5 (n=43)
3, 4.7
4, 2.8
3, 1.8
0.515
0.464
3, 2.1
0.590
3, 2.0
0.252
4,4
4.5, 4
4, 3
0.638
Any adverse event
35, 30
18, 31
17, 28
0.748
Postoperative ileus
7, 6
3, 5
4, 7
0.967
Abdominal reoperation
3, 3
1, 2
2, 3
0.986
11, 9
4, 7
7, 12
0.372
Readmission * values (median±SD)
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Length of Stay (median, IQR)
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30-day follow-up results^
P value
4, 2.5
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Pain Scores*
Placebo (n=60)
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Total (n=118)
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^ values (n, %) unless otherwise stated
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IQR: interquartile range
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Figure 1: Patient Bedside Diary Card
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120 pts consented
Hospital A 58 patients randomized
Arm B: 28
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Hospital B 60 patients randomized
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Arm A: 30
2 withdrew consent
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118 pts completed the study period
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Figure 2: CONSORT diagram of patients recruited into the SPOT Study
Arm A: 28
Arm B: 32
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Figure 3: Survival analysis comparing the proportion of patients passing flatus to time, for the treatment group (Arm A) and control group (Arm B).
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Figure 4: Survival analysis comparing the proportion of patients having a bowel movement to time, for the treatment group (Arm A) and control group (Arm B).
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The Effect of Simethicone on Postoperative Ileus in Patients Undergoing Colorectal Surgery (SPOT), A Randomized Controlled Trial
•
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Highlights: Post operative ileus presents significant clinical challenges and contributes to increased morbidity, length of stay, and healthcare cost following colorectal surgery.
Various pharmacological interventions have been developed and have been shown to
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reduce the rates of post operative ileus, however these generally carry negative side
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effects and increased cost.
Simethicone is a readily available, safe and easily tolerated oral anti-flatulence medication that has been shown to reduce post operative ileus following gynecological surgery.
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This multicenter randomized controlled trial demonstrated that simethicone has no effect on the resolution of post operative ileus or reduction in abdominal pain following
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colorectal surgery.
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International Journal of Surgery Author Disclosure Form The following additional information is required for submission. Please note that failure to respond to these questions/statements will mean your submission will be returned. If you have nothing to declare in any of these categories then this should be stated.
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Please state any conflicts of interest
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None to declare
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Please state any sources of funding for your research
McMaster Surgical Associates Grant
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Please state whether Ethical Approval was given, by whom and the relevant Judgement’s reference number
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This trial was approved by the McMaster Research Ethics Board. P9324
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Research Registration Unique Identifying Number (UIN) Please enter the name of the registry and the unique identifying number of the study. You can register your research at http://www.researchregistry.com to obtain your UIN if you have not already registered your study. This is mandatory for human studies only.
This study was registered with Clinicaltrials.gov under the ID: NCT02161367.
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Author contribution Please specify the contribution of each author to the paper, e.g. study design, data collections, data analysis, writing. Others, who have contributed in other ways should be listed as contributors.
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Dr. Cagla Eskicioglu and Dr. Shawn Forbes were responsible for the conception, design, data analysis, and editing of this manuscript. Dr. Jeremy Springer, Dr. Shiraz Elkheir, Dr. Aristithes Doumouras, Dr. Stephen Kelly and Dr. Ilun Yang contributed to the design and conduct of the trial, interpretation of the data, and revisions for the final approval of this manuscript. All authors provided substantial contributions to this manuscript.
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Dr. Shawn Forbes Dr. Cagla Eskicioglu
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Guarantor The Guarantor is the one or more people who accept full responsibility for the work and/or the conduct of the study, had access to the data, and controlled the decision to publish.
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