Postoperative Ileus: An Algorithm for Prevention and Management

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Postoperative
Ileus:
A
An Algorithm for Prevention
and Management
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MARSHA DANIEL, PHARMD, CPH
Clinical Research Fellow
Department of Colorectal Surgery
Cleveland Clinic Florida
Weston, Florida
Department of Pharmacy
Cleveland Clinic Florida
Weston, Florida
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BADMA BASHANKAEV, MD
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STEVEN D. WEXNER, MD
Department of Surgery and
Transplantation
Sheba Medical Center
Sackler School of Medicine
Tel-Aviv, Israel
Chief Academic Officer
Professor and Chairman
Department of Colorectal Surgery
Cleveland Clinic Florida
Weston, Florida
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MARAT KHAIKIN, MD
ince the mid-1970s, remarkable
advances have been made in
anesthesiology, perioperative care, and
surgical techniques that allow surgeons to
perform more extensive and radical procedures
using a patient-friendly approach. According to
data from the Healthcare Cost and Utilization
Project (HCUP) Nationwide Inpatient Sample
(NIS), more than 500,000 elective major
abdominal operations were performed in the
United States in 2006 (Table 1).1 The total cost
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of these procedures exceeded $10 billion.
Although new achievements have dramatically improved the quality of care and the spectrum of surgical options, many old problems,
such as infection, hemorrhage, and postoperative ileus (POI) still persist and pose challenges
to the medical community.2-5 Accordingly, as
minimally invasive techniques and minimal
access surgery have continued to improve, surgeons and other specialists have sharpened their
focus on these persistent obstacles to improved
patient outcomes.6
POI, or paralytic ileus, is defined as a transient, functional impairment of intestinal motility occurring after surgery.7 The most common
factors associated with the development of ileus
include several types of surgery (gynecologic,
urologic, thoracic, orthopedic, general surgical, or colorectal surgical procedures). Abdominal surgery, postoperative opioid analgesics,
prolonged sedentary recovery, and the use of
inhalant anesthetics all have been reported as
contributing to POI. Ileus is generally considered
virtually normal or “inevitable” after most major
surgical procedures. Laparotomy, which includes
colorectal surgery, is one of the most frequent
causes of POI; up to 40% of patients undergoing
laparotomy experience POI.8,9 Reconstructive
P H A R M AC Y P R AC T I C E N E WS S P E C I A L E D I T I O N • 2 0 0 9
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Table 1. Healthcare Cost and Utilization Project
Nationwide Inpatient Sample (NIS) 2006
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146: Rectal resection with CC
21,219
8.9
17,931
147: Rectal resection without CC
8,679
5.2
11,003
148: Major small and large bowel
procedures with CC
211,083
11.1
22,614
149: Major small and large bowel
procedures without CC
71,429
5.2
10,748
150: Peritoneal adhesiolysis with CC
56,072
9.2
17,745
151: Peritoneal adhesiolysis without CC 27,673
4.3
9,128
154: Stomach, esophageal, and duodenal procedures, age >17, with CC
42,431
12.2
27,146
22,477
3.5
9,719
155: Stomach, esophageal, and duodenal procedures, age >17, without CC
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Hospital
Length of Stay, Costs, $
(mean)
days (mean)
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303: Kidney, ureter, and major
bladder procedures for neoplasm
53,779
6.2
14,947
304: Kidney, ureter, and major bladder 38,747
procedures for non-neoplasia with CC
6.7
14,938
305: Kidney, ureter, and major
bladder procedures for
non-neoplasia without CC
26,964
2.7
9,225
353: Pelvic evisceration, radical
hysterectomy, and radical vulvectomy
11,362
5.0
11,753
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Physical, Psychological, and
Economic Impacts of POI
Diagnosis-Related Groups
Patients
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radical cystectomy also is associated with a high (up to 17%) rate
of ileus.10 Even surgery of the hip
or knee can lead to ileus, with as
many as 4% of patients developing intestinal motility impairments after total hip or knee
arthroplasty.11 Stany and Farley, in
their review of complications in
gynecologic surgery, noted that
approximately 3% of patients
who undergo total abdominal
hysterectomy also develop POI.12
Normal bowel function requires
coordination of motility, mucosal
transport, and evacuatory reflexes
in the gastrointestinal (GI) tract.
GI motility must be considered
an integrated process of electrophysiologic activity—which
includes smooth muscle function
with neural input from the intrinsic and autonomic nervous systems—accompanied by hormonal
interactions. Thus, the pathogenesis of POI is multifactorial and
includes activation of inhibitory
reflexes, inflammatory mediators,
and endogenous and exogenous
opioids.13
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Physiologic awakening of GI
Total
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tract function after abdominal
surgery is generally thought to
CC, complications and comorbidities
occur in sequence: first, in the
small intestine and the stomach,
and postoperative malnutrition.18-23 In turn, the physiand, ultimately, in the colon. Failure of the postoperacal and psychological side effects of POI lead to protive patient to tolerate a diet, have flatus, and experilonged hospital length of stay (LOS) and increased
ence a bowel movement within 5 days after laparotomy
health care costs.24 In 1999, Prasad, using calculations
or within 3 days after laparoscopic surgery, are indic14,15
Clinical presentation of
published by Moss et al in 1986, estimated that the ecoative of a prolonged POI.
POI is accompanied by abdominal distention, delayed
nomic impact of ileus and its complications on the US
or absent passage of gas, delayed or absent passage
health care system would exceed $1 billion in 2000.16,25
In 2000, Woods hypothesized that effective manageof stool, decreased, or the absence of, bowel sounds,
ment of POI—estimating that 750,000 patients could
and accumulation of gas and fluid in the bowel with
be discharged an average of 1 day earlier if effectively
attendant nausea and/or vomiting.16,17 Nausea caused
by ileus usually is described by patients as a very taxing
managed—could result in a potential savings of $1.1 bilpostoperative complication. Another important clinical
lion per year.26 More recent data from Goldstein et al
suggest that annual costs attributed to managing POI
manifestation of POI is recurrence of ileus, which can
is approximately $1.5 billion.27
happen even after the patient is discharged from the
hospital. Readmission occurs in approximately 10% of
Coding for POI
post-abdominal surgery patients, approximately half of
There are numerous problems in defining ileus. Unlike
whom are readmitted for GI failure or some measure of
the vast majority of diseases, there are no objective criterecurrent, or perhaps incompletely resolved, POI.14 POI
makes physical recovery more difficult, has a detrimenria by which ileus can be judged. There are no serologic,
tal psychological effect on patients, and increases the
concrete radiographic, or histopathologic examinapotential for wound infection, pulmonary complications,
tions that can conclusively diagnose POI and none that
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can grade its severity or predict and risk stratify ileus.
Because it is so elusive, it is even more difficult to measure any impact that therapy may have upon prevention or prompting the resolution of POI. Specifically, and
again using the analogy of most other diseases, we can
stratify patients by risk to allow prognostication, and,
therefore, optimally assign therapeutic terms. We can
then measure the impact of interventions using objective pre- and post-therapeutic scales. POI has no such
definable criteria and, therefore, assessing the impact of
any intervention on ileus is exceptionally difficult.
No specific code exists for POI within the various
coding systems (Diagnosis-Related Group, Clinical Classifications Software codes, and Major Diagnostic Categories MDC). The closest that one can come to labeling
patients as having ileus is with the use of a combination of codes from the International Classification of
Diseases, Ninth Revision, Clinical Modification (ICD9-CM):
• Code 997.4: Digestive system complications: Complications of intestinal (internal anastomosis and
bypass not elsewhere classified, except that involving the urinary tract);
• Code 560.1: Adynamic ileus; ileus (of intestine) (of
bowel) (of colon); paralysis of intestine or colon;
• Code 564.4: Other postoperative functional disorders (diarrhea following gastrointestinal surgery).
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Prophylaxis of POI is certainly preferred to therapy.
Every step of the preoperative, operative, and postoperative period should be directed toward decreasing
the risk for developing POI. Kehlet summarized that
the underlying rationale for multimodal rehabilitation
is the simultaneous application of several interventions to improve overall postoperative morbidity.29
The process should commence with preoperative
counseling. Counseling should include a thorough
discussion with the patient and the patient’s family,
if possible, about the importance of compliance with
the postoperative regimen. Early ambulation and diet
as tolerated should be emphasized.
The surgeon may have the opportunity to perform
the procedure in a laparoscopic manner, in which case
POI may be less severe than after laparotomy. Surgical manipulation should be based on meticulous tissue handling, with minimal or no tissue trauma, and
meticulous hemostasis. The following grades of evidence have been established for tissue handling:
• Gentle handling and minimal manipulation of the
intestines (grade 1C);
• Mid-thoracic epidurals with local anesthetics for
postoperative pain control (grade 2A);
• Minimally invasive surgery instead of laparotomy
(grade 2C);
• Limiting the length of laparotomy incisions (grade
2C); and
• Nonsteroidal anti-inflammatory drugs (NSAIDs)
instead of opioids for analgesia (grade 2C).30
Regimens for Minimizing and Reducing POI
“Fast-Track” Protocols
Implementation of an enhanced recovery strategy for
after surgery, or a “fast-track” protocol, has significantly
reduced the incidence of POI.31-34 The protocol is a set
of perioperative measures that includes both preoperative counseling (including the distribution and review
of printed educational materials) and postoperative care
pathways. The protocol calls for the absence of mechanical bowel preparation, standard general anesthesia
without premedication, limited intraoperative fluid resuscitation, high concentrations of perioperative oxygen, use
of epidural analgesia, standardized general anesthesia,
minimal or transverse incisions, abandonment of routine
use of NGTs, limited use of drains, enforced early postoperative mobilization, and opioid-sparing analgesia. Other
measures include early nutrition and early bladder catheter removal.35,36 Every step of the fast-track protocol is
evidence-based and oriented toward reducing surgeryrelated physical and psychological stressors.37
The Effects of Opioids and Fluid Management
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Opioid drugs, the historical drugs of choice for postoperative analgesia, are known to have negative effects
on various parts of GI system through presynaptic blockage of excitatory neurons, specific membrane receptors, and activation of μ2-receptors, leading to bowel
dysfunction. Some known effects of opioids on the GI
tract are listed in Table 2.38
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Attempts have been made to describe a unified clinical scenario after major abdominal surgery
by deriving pooled data from a homogenous placebo group of 3 randomized controlled trials (RCTs)
designed to represent “typical” postoperative recovery after major abdominal colorectal surgery.28 The
authors reviewed incidences of nausea, vomiting,
nasogastric tube (NGT) insertion, upper and lower
GI recovery, and hospital discharge, as well as readmission, in patients who underwent bowel resection
by laparotomy with multimodal postoperative care
designed to minimize POI. This regimen included
early postoperative removal of the orogastric tube or
NGT and the commencement of oral diet immediately
after surgery with increased ambulation and diet on
postoperative day 1 and an offer of solid food on postoperative day 2. The time to recovery of upper and
lower GI functions were measured by either toleration
of solid food or first bowel movement. Most of the
patients in these studies managed to achieve at least
one of these 2 criteria by postoperative day 4. However, 30% of patients still had not achieved GI recovery by day 6. Moreover, POI was a serious adverse
event (AE) reported in 9.2% of patients. The majority of patients were discharged from the hospital by
day 6; mean time until the hospital discharge order
written was 6.1 days. However, 25% of patients were
discharged from the hospital on or after postoperative day 7, and 12.2% of patients required insertion of
postoperative NGT during their hospital stay.
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Table 2. Effects of Opioids
On the Gastrointestinal Tract
Gallbladder
• Contraction with biliary pain
• Spasm in sphincter of Oddi, with delayed
digestion and decreased secretion
Gastroduodenum
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• Inhibition of gastric emptying causing anorexia
• Increased duodenal motility, followed by
quiescence with resulting nausea and emesis
• Increased pyloric tone
• Enhanced gastric acid secretion
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Small bowel
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Colon
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• Increased tone/segmentation with constipation
• Increased transit time, causing hard, dry stools
• Increased absorption, inducing bloating and
distension
• Decreased secretion, producing spasm, cramps,
and pain
Anorectum
• Decreased rectal sensitivity with feeling of
incomplete evacuation
• Increased internal sphincter tone, causing
straining and constipation
Based on reference 38.
Laparoscopy has been shown to significantly
decrease tissue trauma and postoperative pain, thereby
decreasing both the local inflammatory component of
ileus as well as the need for opioids with the attendant
AEs of the opioids. Added benefits of the laparoscopic
approach include improved pulmonary function, which
lowers the risk for developing pneumonia, atelectasis,
and other problems that predispose a patient to further bed rest.17 A Cochrane review of short-term benefits for laparoscopic colorectal resection that included
8 studies of 1,116 patients showed that flatus was
achieved 1 day earlier with laparoscopy than with laparotomy (P<0.0001). Also, data collected from 9 trials that included 1,130 patients showed that patients
who underwent laparoscopy reported their first bowel
movement 0.9 days earlier than patients in the laparotomy group (P<0.0001).41
Traditionally, rectal surgery has been associated with
a more prolonged ileus than colon surgery; however,
with the adaptation of laparoscopic techniques along
with the standard fast-track protocol, hospital LOS has
been decreased to a mean of 3 days, with 90% of the
patients discharged at or before postoperative day 5.42
The authors also reported a very respectable readmission rate of 8%, and noted that such impressive results
would not have been possible without an educated and
dedicated team working with patients from the time of
scheduling the surgery to the time of discharge.
With the combination of minimally invasive techniques and these clinical pathways, the instance of POI
and small bowel obstruction after gynecologic operative laparoscopy was reduced to 0.036%.12
Multiple nonpharmacologic modalities such as acupuncture, electrical stimulation, mechanical massage,
and psychological suggestion have been purported
to help prevent or treat POI.17 Chinese medicine has
a 6,000-year history that includes various modalities
used for surgery. Although some authors speculate
about the potential role of acupuncture and herbal enemas in the treatment of POI, very few data exist in English-language literature.43 All of these modalities require
further investigation.
One of the most recent trends in ileus treatment
is sham feeding, in which patients are given chewing
gum after surgery. The mechanism of action for reducing POI is unknown, although authors often cite the
cephalic-vagal stimulation of digestion, bowel motility, hormonal secretion, and mechanical stimulation of
the motility of the duodenum, stomach, and rectum,
through the secretion of saliva, and pancreatic juices.
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Nonpharmacologic Modalities for POI
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The use of postoperative opioid analgesics clearly
exacerbates ileus. Accordingly, both IV patient-controlled analgesia and epidural opioid administration
have been routinely used in an attempt to reduce dysmotility and POI inception and exacerbation.7 More
recently, the use of NSAIDs, such as ketorolac and ibuprofen, has been recommended to reduce the use of
opioids. Administration of NSAIDs in the early postoperative period not only produces opioid-steering
effects, but it also directly affects prostaglandin synthesis and decreases inflammation. Wider application
of thoracic epidural administration of local anesthetics combined with IV lidocaine has been reported to
effectively mitigate the postoperative effects of colon
surgery by reducing cytokine levels and pain, and facilitating bowel function.39
The management of excessive fluid during the early
postoperative phase leads to sequestration of fluid in
the intestinal wall, which can further hamper GI motility
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Laparoscopy and POI
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• Increased tone/segmentation with constipation
• Increased transit time, resulting in delayed
digestion
• Increased absorption, causing hard, dry stool
• Decreased secretion
and thereby prolong POI and its numerous adverse
sequelae.40 A meta-analysis performed by the Heidelberg group showed the benefits of restrictive rather
than standard fluid replacement after colorectal resection by reducing postoperative morbidity.37
Sorbitol and other hexitols, the main ingredients in
sugar-free chewing gums, are offered as hypothetical
ileus ameliorating agents.44 Although a single prospective, randomized placebo-controlled trial questioned
the effectiveness of chewing gum in postcolectomy
ileus,45 several meta-analyses have shown that chewing gum does enhance bowel recovery without shortening of hospital stay.46-51
Pharmacologic Management of POI
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To date there is no gold standard for the use of pharmacologic agents for treatment or prevention of ileus,
although there are numerous reports of a variety of
attempts.17
The Cochrane systematic review of 39 RCTs regarding systemic prokinetic pharmacologic treatment for
POI after abdominal surgery in adults was published in
2008.52 The review included 4,615 patients who underwent major abdominal surgery, or major abdominal-vascular surgery, major abdominal urologic or gynecologic
surgery. The review evaluated a variety of agents for
anti-ileus activity, including the following:
• cholinergic agonists (bethanechol, neostigmine)
• benzamides (cisapride, metoclopramide,
bromopride)
• dopamine antagonists (domperidone)
• peptide hormones (cholecystokinin, ceruletide,
vasopressin)
• adrenergic antagonists (propranolol)
• macrolide antibiotic (erythromycin)
• ergotamine derivates (dihydroergotamine)
• systemic application of local anesthetics
• prostaglandins
• vitamins (pantothenic acid, dexpanthenol)
• selective GI opioid antagonists
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Six RCTs from the Cochrane review support the effectiveness of alvimopan (Entereg, Adolor/GlaxoSmithKline), a novel peripheral µ-opioid receptor antagonist,
for POI.52
METHYLNALTREXONE
Erythromycin has shown homogenous and consistent absence of efficacy in numerous trials.52 Recent
results obtained from a randomized, double-blind,
placebo-controlled study from the University of Iowa
Carver College of Medicine showed no significant difference between erythromycin IV infusion and placebo.55
Data from 11 patients in each group who underwent cystectomy with urinary diversion secondary to primary
bladder cancer or interstitial cystitis found that erythromycin was not useful in improving POI as measured
by the time to onset of bowel sounds, passage of flatus, passage of the first bowel movement, or toleration
of a regular diet.
CHOLECYSTOKININ-LIKE AGENTS
The evidence in a Cochrane review was insufficient
to recommend the use of cholecystokinin-like drugs,
cisapride, dopamine antagonists, propranolol, or vasopressin. The effects of these medications were inconsistent across outcomes, the trials were quite small, and
the methodology of the trials was sometimes suboptimal.52 Moreover, cisapride was withdrawn from the
market in many countries in 2000 because of serious
cardiac toxicity.
However, the concept of preventing sympathetic
inhibition by the prevention of the release of acetylcholine from excitatory fibers and myenteric plexus is very
promising. In a recent study from Japan, mosapride, a
serotonin 5-hydroxytryptan-4 receptor agonist without the effect on the dopamine D2 receptor or other
receptors, was administered to patients who underwent
hand-assisted laparoscopic colectomy.56 Patients in the
mosapride group had a bowel movement 20.8 hours
earlier (P=0.02) and a hospital LOS of 1.7 fewer days
(P=0.04) compared with patients in the control group.
The authors concluded that treatment with mosapride
significantly improves postoperative GI motility and
shortens POI in patients having a laparoscopic colectomy, with no AEs.
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ALVIMOPAN
ERYTHROMYCIN
A Cochrane review has shown that systemic application of local anesthetics, such as IV lidocaine and
neostigmine, might have a potential effect on POI,
but more evidence on clinically relevant outcomes is
needed. A research group from Liège, Belgium randomly assigned 40 laparoscopic colectomy patients
into 2 groups—one group received perioperative 2%
lidocaine as a bolus injection of 1.5 mg/kg lidocaine
at the induction of anesthesia, followed by continuous infusion of 2 mg/kg per hour during surgery
and 1.3 mg/kg per hour for the first 24 hours after
surgery. The control group received placebo saline
in coded 50-mL syringes.57 All patients in the study
were enrolled in an acute rehabilitation program. The
patients who received lidocaine showed statistically
significant reduction in time to passage of first flatus
compared with control group patients (17 vs 28 hours,
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Methylnaltrexone (Relistor, Progenics Pharmaceuticals, Inc. and Wyeth Pharmaceuticals) is also a peripherally acting µ-opioid antagonist. Although it is a
quaternary derivative of the opioid antagonist naltrexone, it is unable to cross the blood–brain barrier, thus
it maintains the centrally mediated analgesic effects
of opioids. Methylnaltrexone is approved by the FDA
in the subcutaneous injection form for the treatment
of opioid-induced bowel dysfunction (constipation)
in palliative care due to an advanced illness such as
incurable cancer, end-stage heart and lung disease,
and AIDS, as well as in methadone users and patients
suffering from chronic pain.53,54 As of September 2009,
its application in surgical patients in the United States
was still under investigation.
LOCAL ANESTHETICS
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Table 3. Algorithm of Postoperative Rehabilitation
At Cleveland Clinic Florida After Major Abdominal Surgery
Postoperative Day
0
Activity
Comments
Oral/nasogastric tube removed at extubation
Enforced early postoperative mobilization
5 laps in the hallway (approximately 100 m)
A
Clear liquid diet, ice chips
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Incentive spirometry exercises
Prevention of respiratory problems
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5,000 units every 8 h
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Subcutaneous heparin; deep vein thrombosis
prophylaxis
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Awaiting flatus or bowel movement
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Removal of dressing
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Removal of bladder catheter
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If flatus or bowel movement has occurred, advance
diet to full liquid diet
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Oral pain medication
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Discontinue patient-controlled analgesia pump
Advance diet to low-residue diet, unless distended
4
Anticipate discharge home
Table 4. Definition of Diets
At Cleveland Clinic Florida
After Major Abdominal Surgery
Diet
Foods Allowed, Only:
Clear liquid
Broth, clear juices (apple, grape,
cranberry), coffee, tea, soda,
fruit ice, popsicle, sugar, salt
Clear liquid,
Give regular clear liquid
American Diabetes Association
(diabetic)
Full liquid
All items allowed on clear liquid diet, plus pudding, strained
cream soups, oatmeal, cream of
rice, ice cream, sherbet, milk
Low residue
Low fiber (avoid whole grains,
fresh fruits, and vegetables)
without any differences in either endocrine or metabolic profiles. The authors suggested that IV lidocaine
infusion had an inhibitory effect of N-methyl-D-aspartate receptors, which play a major role in postoperative hyperalgesia and polymorphonuclear leukocyte
priming. A meta-analysis on the effects of lidocaine
on POI was recently published in the British Journal of
Surgery.58 The meta-analysis, which included 8 RCTs
and 320 patients, concluded that the continuous IV
administration of lidocaine during and after abdominal surgery improves patient rehabilitation and shortens hospital LOS.
Cleveland Clinic Florida Practice
te
Our practice at Cleveland Clinic Florida includes a
fast-track protocol (Table 3), a component of which is
diet acceleration (Table 4). We do not employ epidural analgesia, but we do use patient-controlled analgesia. Patients are expected to ambulate commencing the
day of surgery and attempt to ingest clear fluids on the
day of surgery. The absence of progress at any step, or
the development of nausea and/or vomiting, may lead
to the acceleration of the protocol.
Ultimately, the biggest challenge in treating POI may
be distinguishing it from other postoperative intraabdominal problems, including an anastomotic leak,
sepsis, fluid collection, electrolyte imbalance, pneumonia, or bowel obstruction.15 When any collection exists
within the bowel, a water-soluble upper GI series with
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respectively; P<0.001), time to first bowel movement
(28 vs 51 hours, respectively; P=0.001), and had a
shorter hospital LOS (2 vs 3 days; P=0.001). Patients
who received lidocaine also required significantly less
analgesia with opioids (8 vs 22 mg; P=0.005), had
less postoperative pain, and experienced less fatigue,
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small bowel follow through and/or a computed tomography scan with oral contrast might be useful in diagnosing, and potentially treating, obstruction. In these
cases, Gastrografin (Bracco Diagnostics, Inc.) may be
prokinetic.59-65 Gastrografin has an osmolarity of 1,900
mOsm/L, which is approximately 6 times that of extracellular fluid. It has been hypothesized that Gastrografin
promotes shifting fluid into the bowel lumen, decreasing the pressure gradient across obstructive sites or
bowel lumen. After the Gastrografin is diluted it may
facilitate passage of contents within the intestinal track,
with decreased bowel wall edema. Unlike barium, Gastrografin is relatively safe even if intestinal perforation
and peritoneal spread occurs.63,66,67
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Conclusion
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Despite significant advances in surgical and perioperative care, one of the most basic problems encountered in the postoperative period remains one of the
most vexing. POI remains an Achilles’ heel of abdominal surgery. It has been ill-defined, has been difficult to
characterize, and even harder to treat. Hopefully, some
of the new pharmacologic modalities and fast-track
protocols may help diminish this very troubling postoperative problem.
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