Clinical Trial Details
— Status: Completed
Administrative data
| NCT number |
NCT02559635 |
| Other study ID # |
JGH-06-2015 |
| Secondary ID |
|
| Status |
Completed |
| Phase |
N/A
|
| First received |
|
| Last updated |
|
| Start date |
December 1, 2016 |
| Est. completion date |
July 18, 2022 |
Study information
| Verified date |
August 2022 |
| Source |
Jewish General Hospital |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
Postoperative ileus is the most commonly observed morbidity following ileostomy closure.
Studies have previously demonstrated that the defunctionalized bowel of a loop ileostomy
undergoes a series of functional and structural changes. It has been hypothesized that these
changes may contribute to the development of postoperative ileus, and that stimulating the
distal limb of a loop ileostomy prior to closure may functionally prepare the excluded bowel
for intestinal transit.
The purpose of the multicenter, randomized controlled trial is to determine the impact of
preoperative stimulation of the distal limb of a loop ileostomy on postoperative ileus.
Description:
Low anterior resection with total mesorectal excision is the standard operative treatment for
mid and some low rectal cancers.The most dreaded and morbid complication of this procedure is
anastomotic leak,with a varied incidence of 3-32%,and which can result in pelvic abscess and
sepsis,re-operation,and death.The creation of a loop ileostomy is the only measure proven to
reduce the morbidity and septic complications of anastomotic leakage. With the current trend
towards sphincter-preserving surgery and the performance of ultra-low anastomoses for low
rectal cancers, anastomotic dehiscence is increasingly being observed.That, in addition to
the frequent use of neoadjuvant radiotherapy has contributed to a greater use of diverting
ostomies. Furthermore, the use of a protective loop ileostomy is not limited to oncologic
surgeries, and is often performed during colonic resection for complicated diverticular
disease.
However, the formation of a loop ileostomy comes at a price as it requires a second surgery
typically 12 weeks after the initial operation to restore intestinal continuity. The
incidence of complications following ileostomy closure is certainly not negligible, at a
highly variable range of 11-45%. A systematic review of 48 studies including 6,107 cases
reported a 17.3% morbidity rate and a 3.7% re-operation rate. Of all complications,
postoperative ileus (POI) is the most commonly observed morbidity following ileostomy
closure, with rates typically reported between 15-32 %. POI can lead to increased patient
discomfort, postoperative morbidity, prolonged hospital stay, increased risk for nosocomial
infections,and ultimately higher health care costs.
Transient gut dysmotility can be expected after abdominal surgery. However, in the case of an
ileostomy, the defunctionalized segment of bowel undergoes a series of structural and
functional changes that may increase the time it takes for motility to resume after closure.
Studies performed in animals have shown that defunctionalization of the ileum leads to
atrophy of its villi and muscular layers.This was confirmed in humans by Williams et al.,who
demonstrated a significant loss of muscular contractility and atrophy of intestinal villi
following the creation of a diverting ileostomy.Oh et al. also revealed lower concentrations
of peptide YY secreted in the mucosa of the ileum and colon distal to a loop ileostomy,the
function of which is to inhibit gastric motility and promote water and electrolyte absorption
in the colon.Thus, the absorptive capacity of the colon is reduced following reconstruction
of the bowel.
It would appear that changes in the defunctionalized segment of bowel might leave it
functionally unprepared for intestinal transit, contributing to the development of POI. A
group in Spain proposed that preoperative stimulation of the excluded intestine might reverse
those changes and improve its absorptive and motor function prior to restoring intestinal
continuity, thus reducing the incidence of POI.They published a randomized controlled trial
of 70 patients, of which 35 patients underwent daily stimulation with a thickened
saline-based solution via the efferent limb of the ileostomy for two weeks. Following
ileostomy closure, they observed reduced rates of POI, earlier return to oral intake and
passage of flatus or stool, and shorter hospital stays in the group of patients that
underwent stimulation. While their results are promising, t was a single-institution study in
a European patient population, perhaps limiting its generalizability to our practice.
Furthermore, while randomization should allow for equal distribution of confounders amongst
the two groups, they did not report on electrolyte imbalances, narcotic use, and other
variables known to influence the development of POI. Miedema and colleagues were the only
other group to apply a similar technique of bowel stimulation before ileostomy closure, and
found no benefits in intestinal absorptive function or postoperative bowel function. However,
they only had six patients in their stimulated group, and all had undergone a restorative
proctocolectomy with ileoanal J pouch, thus only a short segment of distal ileum was
stimulated.
The idea of stimulating defunctionalized bowel to reduce POI is theoretically plausible, but
is lacking in evidence. To our knowledge, this study would be the first of its kind in North
America, and would complement the work done in Europe.The potential benefits of this
intervention are numerous, including the patient's overall postoperative outcome, a
postoperative course with a potential two-day reduction in length of stay and its associated
health care costs. If such findings are observed, the use of preoperative bowel stimulation
could be incorporated in Enhanced Recovery After Surgery (ERAS®) pathways for patients
undergoing ileostomy closure.
The aim of this study is to evaluate the impact of preoperative stimulation of the
defunctionalized intestine of a loop ileostomy on postoperative outcomes following ileostomy
closure. Investigators hypothesize that preoperative stimulation of the defunctionalized
intestine via the efferent limb will reduce the rates of postoperative ileus following
ileostomy closure.
This is a multicenter randomized controlled trial involving patients from 4 university
hospitals. Patients will be recruited by their individual surgeon, who will explain the
objectives of this study and obtain informed consent when obtaining consent for ileostomy
closure.
All patients who have undergone an anterior or low-anterior resection for neoplastic (benign
and malignant) or diverticular disease with a protective loop ileostomy by a fully trained
colorectal/general surgeon or surgical oncologist at one of the involved sites will be
offered to enter the study.
Patients with underlying Crohn's disease, with known metastases at the time of ileostomy
closure and patients from whom clear and informed consent cannot be obtained will be
excluded.
The current overall rate of POI following ileostomy closure at the involved institutions is
16%. Based on the previously published study and the clinical experience, investigators
estimate an absolute risk reduction in POI of 13%. With an alpha of 0.05, a power of 0.80 and
an estimated 5% loss to follow-up, 83 patients are required in each arm for a total of 166
patients. At each participating institution, at least 35 ileostomy closures eligible for this
study are performed per year. Assuming a 70% participation rate, investigators anticipate
being able to recruit 122 patients per year for all 5 institutions involved, thus requiring
1.4 years to complete the study. In order to mitigate losses to follow-up, patients will
receive a phone call, instructions and equipment for home stimulation if they are unable to
come to a stimulation session.
Block randomization will be performed using a computer-generator sequence, to ensure that the
initial surgical approach for colorectal resection (open vs. laparoscopic) is equally
distributed in the two groups. Group allocation will be concealed from the treating surgeons
and researchers involved in the study (except the research assistant doing the stimulation
sessions).
All patients enrolled in the study will follow the same preoperative protocol. Upon agreeing
to participate in the study, patients will be randomized to either the stimulation group or
the non-stimulation (control) group.The protocol for stimulation will be identical for all
patients. Stimulation will be performed daily on an outpatient basis for the two weeks (ten
business days) prior to ileostomy closure.The efferent limb of the ileostomy loop will be
canalized with an 18 Fr Foley catheter and infused with a solution comprising of 500mL of
normal saline mixed with 30g of a thickening-agent (Nestle Resource). It will be prepared in
five 100mL syringes and administered slowly over 20 minutes.
All surgeries will be performed by an attending colorectal surgeon with the assistance of one
or more General Surgery residents. Perioperative antibiotics will include one dose each of
cefazolin 1g intravenously and metronidazole 500mg intravenously just prior to surgery.
Procedures will be performed under general anesthesia, and a similar operative technique will
be used for each case. A parastomal incision will be made and carried out sharply into the
peritoneal cavity. Adhesiolysis will be conducted and intestinal continuity will be restored
with a side-to-side functional end-to-end enteroenteral stapled anastomosis.The intestine
will then be returned to the abdominal cavity. Fascia will be closed with interrupted or
running sutures.The fascia will then be infiltrated with 20mL of 0.25% bupivacaine,and the
skin will be closed with a purse-string suture and covered by dry dressings.Patients will be
given patient-controlled analgesia in the post-anaesthesia care unit for postoperative
analgesia. Epidurals will not be used.
Any operation necessitating conversion to a laparotomy incision due to technical difficulties
or intraoperative complications will be excluded from analysis.
All patients will follow the perioperative Enhanced Recovery After Surgery (ERAS®) protocol
for elective colorectal surgery already implemented at the involved sites. Specifically, this
protocol allows for a clear fluid diet on postoperative day 0, and a low-residue diet on the
morning of postoperative day 1. If this is well tolerated, the patient is further progressed
to a regular diet later in the day. Patients are also encouraged to chew gum and ambulate.
Criteria for granting discharge home from hospital will include the following:
1. tolerating oral diet;
2. no overt abdominal distension;
3. adequate pain control;
4. absence of fever or signs of surgical site infection;
5. ambulating at baseline; and
6. passage of flatus or stool.
Blood work, including CBC and electrolytes (and extended electrolytes), will be drawn daily
on postoperative days 1,2, and 3, and then as clinically indicated. All electrolyte
abnormalities will be corrected. Nurses will record all narcotic use in patient charts, and
this will be converted to morphine equivalents using an equianalgesic table at the time of
data collection. A trained, blinded assessor (a physician researcher or colorectal research
fellow) will prospectively collect postoperative clinical data by history, physical
examination, and chart review. This assessor will be blinded to the stimulation vs. control
group assignment and to any preoperative information.
Data regarding patient demographics and specifics of the primary surgery will be collected
prospectively, including the indication and approach used for colorectal resection, the
length of time between ileostomy creation and closure, and the use of any neoadjuvant or
adjuvant treatments in the case of colorectal cancer. All postoperative data will be
collected prospectively by the research assistant.
The primary outcome will be postoperative ileus, defined as an intolerance to oral food in
the absence of clinical or radiological signs of obstruction, that either a)lasts more than
72 hours; b)requires nasogastric tube insertion; or c)is associated with 2 of the following:
nausea/vomiting, abdominal distension, and the absence of flatus. Secondary outcomes will
include length of stay, time to tolerating a regular diet, time to first passage of flatus or
stool, and overall morbidity. Lastly, an analysis of additional risk factors for
postoperative ileus will be performed.
All statistical analyses will be performed using JMP® 11 statistical discovery software (SAS
Institute Inc.,Cary,NC,1989-2007). Patient characteristics, clinical variables, POI and other
postoperative outcomes will be compared between the two groups using Chi-square, student's t
and Wilcoxon rank sum tests for categorical, normally distributed continuous and non-normally
distributed continuous variables, respectively. Statistical significance will be considered
when p < 0.05.
