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ASHP Chapter Meeting Content
The Evolving Multimodal Management
Plan for Postoperative Ileus:
Improving Time to Bowel Recovery
Educational Learning Objectives
• Describe the prevalence, pathophysiology, and
defining criteria for postoperative ileus (POI)
• Distinguish evidence-based therapeutic options
for the management of POI
• Describe how to implement a multimodal
management plan in your institution for patients
undergoing bowel resection procedures to
improve time to bowel recovery
Postoperative Ileus (POI)
A temporary impairment of GI motility
that occurs for a variable period after
abdominal surgery
Kehlet H, Holte K. Am J Surg. 2001;182 (5A Suppl):3S-10S.
Holte K, Kehlet H. Drugs. 2002;62:2603-2615.
Postoperative Ileus (POI)
• Results in a functional inhibition of propulsive bowel
activity, irrespective of pathogenetic mechanisms
– Primary POI: such cessation occurring in the absence of any
precipitating complication
– Secondary POI: that occurring in the presence of a precipitating
complication (infection, anastomotic leak, etc.)
• Paralytic ileus: form of POI lasting > 5 days after open
and > 3 days after laparoscopic colectomy
Livingston EH, Passaro EP Jr. Dig Dis Sci. 1990;35:121-132.
Delaney CP, et al. Clinical Consensus Update in General Surgery. 2006.
There Are Numerous Risk Factors for POI
Surgical
Site
Patient
Age,
Gender,
Race
Extent of
Bowel
Manipulation
POI Is Expected to
Affect Almost
Every Patient Who
Undergoes
Abdominal Surgery
Operation
Time
Patient
Health
Amount of
Opioids
Systemic
Infections
Resnick J, et al. Am J Gastroenterol. 1997;92:751-762.
Resnick J, et al. Am J Gastroenterol. 1997;92:934-940.
Senagore AJ. Am J Health-Syst Pharm. 2007;64(suppl 13):S3-S7.
Senagore AJ, et al. Surgery. 2007;142:478-486.
Woods MS. Perspect Colon Rectal Surg. 2000;12:57-76.
POI: Pathogenesis Is Multifactorial
Inhibitory Neural
Reflexes1,2
Stimulation of somatic
and visceral fibers
inhibits GI motility
Minimizing the effects
of 1 or more of these
factors could potentially
shorten the duration of
POI and reduce the
incidence of morbidity
Opioids1-3
Endogenous
and exogenous
opioids reduce
propulsive
activity in GI tract
Endogenous opioids = endorphins, enkephalins, and dynorphins.
1. Holte K, et al. Drugs. 2002;62:2603-2615.
2. Behm AJ, et al. Clin Gastroenterol Hepatol. 2003;1:71-80.
3. Bauer B, et al. Curr Opin Crit Care. 2002;8:152-157.
Inflammatory
Mediators1
Release of nitric
oxide, vasoactive
intestinal peptide,
calcitonin generelated peptide,
substance P, and
prostaglandins
contributes to POI
Origins of Postoperative Ileus
Neural regulation of the digestive tract
involves both intrinsic and extrinsic control
systems
Intrinsic control occurs via the enteric
nervous system
• Executes basic motility patterns
• Responds to local and extrinsic events
Extrinsic control occurs via the autonomic
nervous system
• Integrates gut function into homeostatic
balance of the organism
Alterations in the intrinsic or extrinsic control
systems of the gut contribute to the
pathogenesis of POI, as do several other
mechanisms, pathways, and mediators
Goyal RK, Hirano I. N Engl J Med. 1996;334:1106-1115.
Inflammatory Pathways of Postoperative Ileus
Anti-Inflammatory
HO-1 (CO/Biliverdin)
Macrophages
Intestinal
Surgery
α-adrenergic
iNOS
Muscularis Externa
Inflammatory cytokines
Adhesion molecules
Prostanoids
NO
PMN
Sympathetic Efferents
Primary Afferents
COX-2 (prostanoids)
Motility
NO (iNOS)
PGs (COX – 2)
Cytokines (IL – 6)
ROIs and Proteases
Macrophage
Monocytes
(inhibition)
iNOS
Vagal
acetylcholine
α-7 receptor
JAK / STAT
Moore B, et al. Sem Col Rect Surg. 2005;16(4):184-187.
Mast Cells
“Barrier Function Disruption”
Lumenal Colo-Lymphatic
Factors Activate Leukocytes
HO-1: heme oxygenase-1; NO: nitric oxide;
iNOS: inducible nitric oxide synthase; PGs: prostaglandins;
ROIs: reactive oxygen intermediates
GI Effects of Opioids
Pharmacologic
Clinical
Decreased gastric motility
Increased GI reflux
Inhibition of small intestinal propulsion
Delayed absorption of medications
Inhibition of large intestinal propulsion
Straining, incomplete evacuation,
bloating, abdominal distension
Increased amplitude of non-propulsive
segmental contractions
Spasm, abdominal cramps and pain
Constriction of sphincter of Oddi
Biliary colic, epigastric discomfort
Increased anal sphincter tone, impaired
reflex relaxation with rectal distension
Impaired ability to evacuate bowel
Diminished gastric, biliary, pancreatic and Hard, dry stool
intestinal secretions. Increased absorption
of water from bowel contents
Pappagallo M. Am J Surg. 2001;182 (suppl):11S-18S.
Vanegas G, et al. Cancer Nurs. 1998;21:289-297.
Kurz A, Sessler DI. Drugs. 2003;63:649-671.
Incidence of POI for
Common Abdominal Surgeries
Procedure Description
Procedures, N
POI Cases, %
Abdominal hysterectomy
456,292
4.1
Large bowel resection
257,336
14.9
Small bowel resection
48,824
19.2
Appendectomy
175,964
6.2
Cholecystectomy
81,013
8.5
Nephroureterectomy
44,808
8.9
Other procedures
597,492
9.0
1,661,729
8.5
Total
HCFA Data (Medicare, 1999-2000). Evaluating 161,000 major intestinal/colorectal resections from
150 US hospitals.
Delaney CP, et al. Clinical Consensus Update in General Surgery. 2006.
Consequences of Prolonged POI
•
•
•
•
Delayed passage of flatus and stool
Increased postoperative pain and cramping
Increased nausea and vomiting
Delay in resuming oral intake
– Possible need for parenteral nutrition
• Poor wound healing
• Delay in postoperative mobilization
• Increased risk of other postoperative
complications
– Deconditioning
– Pulmonary complications
– Other nosocomial infections
• Prolonged hospitalization
• Decreased patient satisfaction
• Increased health care costs
Delaney CP, et al. Clinical Consensus Update in General Surgery. 2006.
Hospital Discharge Associated
With Recovery of GI Function
GI-2 recovery
25
Hospital discharge
Patients (%)
20
15
10
5
0
0
1
2
3
4
5
6
Postoperative Day
GI-2 = Recovery of bowel movement and toleration of solid food
Delaney CP, et al. Am J Surg. 2006;191:315-319.
7
8
9
10
There Is an Overall Health Care Burden
Associated With POI
POI
Prolonged hospitalization
Beds
occupied for
more time
Increased
resource
utilization
Schuster TG, Montie JE. Urology. 2002;59:465-471.
Holte K, Kehlet H. Br J Surg. 2000;87:1480-1493.
Chang SS, et al. J Urol. 2002;167:208-211.
Sarawate CA, et al. Gastroenterology. 2003;124(4S1):A-828.
Increased
nursing time
Postoperative Ileus:
Economic Consequences and LOS
• Hospital Claims Database Analysis, open laparotomy pts
• ICD-9 coded POI (560.1 = paralytic ileus; and 997.4 = digestive system
complications)
No Coded POI
Coded POI
(n = 175,992)
(n = 17,417)
Mean age (yrs)
50.8
59.8*
Mean OR time (hrs)
2.5
3*
Mean LOS (d)
5.4
10.6*
Opioid PCA (%)
31.3
41.8*
Opioid epidural (%)
2.8
3.7*
Mortality (%)
2.3
3.7*
$9,944
$16,303*
20.7
48.4*
Mean total costs
Severe or most severe illness (%)**
* P < 0.05 vs no coded POI; ** Based on APR-DRG severity levels
Senagore A, et al. American Society of Colon and Rectal Surgeons 2005 Annual Meeting (abstract). S22, p.165.
Economic Burden of POI Associated
With Abdominal Surgery
Total number of
procedures (%)
Average length of
stay (days)
Cost per hospital
stay
Number of
readmissions (%)
Coded POI
Without Coded POI
142,026 (8.5%)
1,519,663 (91.5%)
11.5
5.5
$18,877
$9,460
5,113 (3.6%)
304 (0.02%)
Cumulative costs for coded POI (total hospitalization + readmission cost) =
$1,464,167,173
Data from Premier’s Perspective Comparative Database,160 Hospitals, 2002
Goldstein J, et al. P&T. 2007;32(2):82-90.
What Are Current Management
Strategies for POI?
Preventive and Therapeutic
Management Options for POI
• Physical Options
• Anesthesia and Analgesia
– Nasogastric tube
– Early postoperative feeding
– Early ambulation
– Epidural
– NSAIDs
• Pharmacologic
– Prokinetic agents
– Opioid (PAMOR) antagonists
– Other agents
• Surgical Technique
– Laparoscopy
• Psychological
Perioperative Information
• Perioperative Care Plan(s)
PAMOR = peripherally acting µ-opioid receptor antagonist
Luckey A, et al. Arch Surg. 2003;138:206-214.
– Multimodal clinical pathways
– Fluid/sodium restriction?
Nasogastric (NG) Intubation and POI
• Traditionally used at many institutions and is one of the
mainstays of therapy along with IV hydration
• There are no data to support any beneficial effect of NG
tubes on postoperative ileus
• Can delay feeding and thus recovery from POI
• May contribute to problems such as atelectasis,
pneumonia, and fever
Kehlet H, et al. Am J Surg. 2001;182(S):3-10.
Cheatam M, et al. Ann Surg. 1995;221:469-478.
Sagar P, et al. Br J Surg. 1992;79(11):1127-1131.
NG Tubes
• NG tubes routinely inserted for gastric decompression until
return of bowel function
• Removal of NG intubation
– Meta-analysis of 28 trials (n = 4194) of abdominal surgery
• Accelerated bowel recovery by 0.52 days (95% CI, 0.46-0.57;
P < 0.0001)
• Earlier flatulence by 0.53 days (95% CI, 0.28-0.78; P = 0.0004)
• Reduced vomiting (OR = 0.66 95% CI, 0.45-0.95; P = 0.03)
• Reduced pulmonary complications (RR = 1.45 95% CI, 1.08-1.92;
P = 0.01)
• Shortened LOS by 1.21 days (95% CI, 0.56-1.86-1.94; P < 0.0001)
Person B, Wexner S. Curr Probl Surg. 2006;43:6-65.
Nelson R, et al. Cochrane Database Syst Rev. 2007;CD004929.
Rationale
• Why would NG tube removal improve
outcomes?
– Resumption of oral intake
• Why would early oral or enteral feeding improve
outcomes?
– Counteracts catabolism
– Improves immune function
– Hastens wound healing
Early Oral or Enteral Feeding
• Convention is restriction of enteral intake
• Early oral or enteral feeding (within 24 hours)
– Meta-analysis of 13 trials (n = 1173) of colorectal surgery
• Less vomiting (RR = 1.27 95% CI, 1.01-1.61; P = 0.04)
• Shortened LOS by 0.89 days (95% CI, 0.20-1.58-1.94; P = 0.01)
• Reduced mortality (RR = 0.41 95% CI, 0.18-0.93; P = 0.03)
– Meta-analysis of three trials (n = 413) of abdominal
gynecologic surgery
• Reduced nausea (RR = 1.79 95% CI, 1.19-2.71; P = 0.006)
• Earlier bowel sounds by 0.50 days (95% CI 0.16-0.84)
• Shortened time to intake of solid food by 1.47 days (95% CI,
0.69-2.26; P = 0.0004)
• Shortened LOS by 0.73 days (95% CI, 0.07-1.52; P = 0.07)
Andersen HK et al. Cochrane Database Syst Rev. 2006;CD004080.
Charoenkwan K et al. Cochrane Database Syst Rev. 2007;CD004508.
RCTs of Early Postoperative
Feeding vs Traditional Feeding
b
Early feeding
Traditional feeding (no oral intake until POI resolved)
Duration of Ileus (h)
140
120
*
100
*
80
60
*
40
20
C
C
D
I
D
F
D
0
Binderow et al. Reissman et al. Ortiz et al.
(1995)
(1996)
(1994)
Schilder et al.
(1997)
Stewart et al.
(1998)
*P < 0.05
D = defecation; F = flatus; C = combination score; I = ingest regular food
Holte K, Kehlet H. Br J Surg. 2000;87:1480-1493.
Pearl et al.
(1998)
Cutillo et al.
(1999)
Mobilization and Postoperative Ileus
• Important in helping to prevent postoperative complications
such as clots, atelectasis, or pneumonia
• Ambulation thought to help increase blood flow to the GI
and speed up recovery from POI
• Lack of studies showing any effect of mobilization (alone)
to stimulate bowel function and decrease duration of POI
Waldhausen J, et al. Ann Surg. 1990;212:671-677.
Effect of Surgical Technique
Cells/125 x Magnification
MOA: Reduced activation of inhibitory reflexes and local
inflammation due to reduced surgical trauma
*
800
*
600
*
400
*
200
0
Control
Laparotomy Eventration Running Compression
Histogram of infiltrating polymorphonuclear neutrophils in muscularis whole
mounts after different degrees of surgical manipulation. N = 5-7; *P < 0.05
MOA = mechanism of action
Holte K, Kehlet H. Br J Surg. 2000;87:1480-1493.
Kehlet H, Holte K. Am J Surg. 2001;182(5A suppl):3S-10S.
RCT: Laparoscopy vs Open Surgery
.
Laparoscopic
120
Duration of Ileus (h)
Open
100
80
*
60
40
20
*
*
F
D
D
F
0
Lacy et al.
(1995)
Schwenk et al.
(1998)
*P < 0.05
D = defecation; F = flatus; RCT = randomized clinical trial
Holte K, Kehlet H. Br J Surg. 2000;87:1480-1493.
Kehlet H, Holte K. Am J Surg. 2001;182(5A suppl):3S-10S.
Milsom et al.
(1998)
Leung et al.
(2000)
Why Would Laparoscopic Surgery
Improve Outcomes?
• Smaller incisions
• Less handling of intestine (particularly the colon) and less
inflammation
• Less pain = less opioid used
• Earlier ambulation
• Less exposure to air and endotoxin
• Improved immune consequences
• Fewer NG tubes and earlier diet
Anesthetic Choice and Route
• Almost all intraoperative inhaled or i.v. anesthetics
temporarily inhibit GI motility
– Level of monitoring is important!
• Epidural anesthesia/analgesia synergistically block
inhibitory sympathetic reflexes, prevent the release of
afferent pain neurotransmitters, and increase splanchnic
blood flow
• Epidural anesthetics dose-dependently block nociceptive
and autonomic fibers first and motor and somatosensory
fibers last
• Epidural analgesia reduces opioid adverse effects
• Use of local anesthesia and nerve blocks further reduce
systemic exposure
Bonnet F, Marret E. Br J Anaesth. 2005;95:52-58.
Epidural vs PCA Administration of Opioids
Pain control
At rest
On mobilization
Adverse effects
Ileus
Nausea and vomiting
Sedation
Hypotension
Urinary retention
Workload
Postop morbidity reduction
Cardiovascular (CV)
Respiratory
Bonnet F, Marret E. Br J Anaesth. 2005;95:52-58.
Epidural
PCA
+++
++
++
+/-
Shortening
+/+/+
Prolongation
++
+
+
+
+
+
+
PCA: patient-controlled analgesia
Effect of Epidural Local Anesthetics vs
Systemic Opioids on Postoperative Ileus
Epidural local
Length of POI (hours)
*P < 0.05
anesthetics
Systemic opioid
200
150
100
*
*
*
*
*
50
0
Wallin
1986
Scheinin
1987
Ahn
1988
Holte K, Kehlet H. Br J Surg. 2000;87:1480-1493.
Wattwil Bredtman
1989
1990
Riwar
1991
*
Liu
1995
Neudecker
1999
Opioid-Sparing Analgesia
• 40 colectomy patients
– Correlation between
morphine PCA dose and first
bowel sounds (P = 0.001),
flatulence, (P = 0.003), and
first bowel movement
(shown, P = 0.002)
– No correlation between
incision length and morphine
dose
• ICD-9-CM coded POI
correlates with systemic
morphine (OR = 12.1;
95% CI, 5.4-27.1)
Total Morphine (mg)
350.0
300.0
250.0
200.0
150.0
100.0
R = 0.48
P = 0.002
50.0
0
40
60
80
100
120
140
160
Hours to First Bowel Movement
Cali RL, et al. Dis Colon Rectum. 2000;43:163-168.
Goettsch WG, et al. Pharmacoepidemiol Drug Saf. 2007;16:668-674.
180
Opioid-Sparing Analgesia
• Nonsteroidal anti-inflammatory drugs (NSAIDs)
– Reduce prostaglandin production
– R, DB study of morphine PCA ± ketorolac in 79 colorectal surgeries
showed 29% less morphine use, earlier first bowel movement
(1.5 [0.7-1.9] vs 1.7 [1-2.8] days, P < 0.05), and earlier ambulation
(2.2 ± 1 vs 2.8 ± 1.2 days, P < 0.05) with NSAID use
– Similar results in other surgeries and epidural route
– Concerns: platelet inhibition (bleeding)
• Cyclooxygenase-2 (COX-2) Inhibitors
– Similar results as NSAIDs; safety?
• Surveys indicate patients prefer inadequate pain relief over
adequate analgesia with associated bowel dysfunction
Person B. Wexner S. Curr Probl Surg. 2006;43:6-65.
Chen JY. Acta Anaesthesiol Scand. 2005;49:546-51.
Prokinetic Agents
Hypomotility (hours)
• Metoclopramide improves nausea but…
Metoclopramide
120
90
60
30
0
Jepsen
(n = 55)
Cheape
(n = 93)
Placebo
Tollesson
(n = 20)
Jepsen S, et al. Br J Surg. 1986;73:290-291.
Cheape JD, et al. Dis Colon Rectum. 1991;34:437-441.
Tollesson PO, et al. Eur J Surg. 1991;157:355-358.
Seta ML, et al. Pharmacotherapy. 2001;21:1181-1186.
Chan DC, et al. World J Gastroenterol. 2005;11:4776-4781.
Lightfoot AJ, et al. Urology. 2007;69:611-615.
Seta
(n = 32)
Erythromycin
Chan
(n = 32)
Lightfoot
(n = 22)
POI: Peripheral Opioid Antagonism
• Most patients require opioids
• Opioids inhibit GI propulsive motility and secretion; the
GI effects of opioids are mediated primary by
µ-opioid receptors within the bowel
• Naloxone and naltrexone reduce opioid bowel
dysfunction but reverse analgesia
• An ideal POI treatment is a peripheral opioid receptor
antagonist that reverses GI side effects without
compromising postoperative analgesia
– Alvimopan
– Methylnaltrexone
Kurz A, Sessler DI. Drugs. 2003;63:649-671.
Taguchi A, et al. N Engl J Med. 2001;345:935-940.
Methylnaltrexone: A Novel, Quaternary
-Opioid Receptor Antagonist
Naltrexone
N-methylnaltrexone
+
CH3
• Poorly lipid soluble, does not penetrate the BBB, not demethylated to
significant extent in humans
• Does not antagonize the central (analgesic) effects of opioids or precipitate
withdrawal
Foss JF. Am J Surg. 2001;182 (5ASuppl):19S-26S.
Methylnaltrexone: MNTX 203 Methods
• Phase 2 study for reduction of postoperative bowel
dysfunction
• Randomized, double-blind, placebo-controlled
• 65 patients undergoing segmental colectomy
• MNTX 0.3 mg/kg or placebo i.v.
– First dose within 90 min of end of surgery, then every 6 hr
– Up to 24 hr after GI recovery, max of 7 days
• GI recovery: tolerated solid food plus bowel movement (BM)
Viscusi E, et al. Anesthesiology. 2005;103:A893.
Methylnaltrexone Phase 2:
Results Reported as Mean Time (hr)  S.E.
MNTX
Placebo
(n = 33)
(n = 32)
P-value*
Full liquids
70 ± 9
100 ± 19
0.05
1st BM
97 ± 6
120 ± 10
0.01
GI recovery
124 ± 9
151 ± 16
0.06
Discharge eligible
119 ± 7
149 ± 17
0.03
Actual discharge
140 ± 6
165 ± 16
0.09
Endpoint
*1-sided
Viscusi E, et al. Anesthesiology. 2005;103:A893.
Methylnaltrexone for POI: Phase 3 Studies
Segmental colectomy1,2 and ventral hernia repair3
 Treatment: IV methylnaltrexone (12 or 24 mg)
or placebo every 6 hours
 Primary endpoint: Reduction in time to recovery
of GI function compared with placebo
 Results: Treatment did not achieve primary or
secondary endpoints4-6
1. Available at: http://www.clinicaltrials.gov/ct2/show/NCT00387309. Accessed March 2009.
2. Available at: http://www.clinicaltrials.gov/ct2/show/NCT00401375. Accessed March 2009.
3. Available at: http://www.clinicaltrials.gov/ct2/show/NCT00528970. Accessed March 2009.
4. Available at: http://www.wyeth.com/news/archive?nav=display&navTo=/wyeth_html/home/news/pressreleases/2008/
1205322072160.html. Accessed March 2009.
5. Available at: http://www.progenics.com/releasedetail.cfm?ReleaseID=311785. Accessed March 2009.
6. Available at: http://www.progenics.com/releasedetail.cfm?ReleaseID=370543. Accessed July 2009.
Alvimopan: A Novel, Quaternary -Opioid
Receptor Antagonist
Moderately Large MW (461 Da)
Alpha vi mu opioid peripheral antagonist
Fentanyl
Schmidt WK. Am J Surg. 2001;182(5A suppl):27S-38S.
Alvimopan
• Peripherally acting µ-opioid receptor antagonist1
• Highly selective for µ-opioid receptor over  and κ
receptors1,2
• Higher potency at µ-opioid receptor than morphine and
methylnaltrexone2
• Because of large molecular weight and polarity, does not
readily cross the blood-brain barrier; thus, does not block
central opioid receptors2
• Phase 1, phase 2, and phase 3 trials have been completed3-8
• FDA approval May 20089
1.
2.
3.
4.
5.
6.
7.
8.
9.
Azodo IA, et al. Curr Opin Investig Drugs. 2002;3:1496-1501.
Schmidt WK. Am J Surg. 2001;182(5A suppl):27S-38S.
Taguchi A, et al. N Engl J Med. 2001;345:935-940.
Wolff BG, et al. Ann Surg. 2004;240:728-735.
Delaney CP, et al. Dis Colon Rectum. 2005;48:1114-1125.
Viscusi E, et al. Surg Endosc. 2006;20:67-70.
Ludwig K, et al. Arch Surg. 2008;143:1098-1105.
Buchler M, et al. Aliment Pharmacol Ther. 2008;28:312-325.
FDA approval available at: http://www.accessdata.fda.gov/scripts/cder/drugsatfda. Accessed March 2009.
Alvimopan for POI:
Phase 3 Clinical Trial Summary
Study
Surgery
N (MITT)
Alvimopan
Dose (mg)
Primary
Endpoint
Secondary
Endpoints
3131
Bowel resection or radical
hysterectomy
510 (469)
6, 12
GI-3
GI-2, DOW
3022
Partial colectomy or simple
or radical hysterectomy
451 (424)
6, 12
GI-3
GI-2, DOW
3083
Bowel resection or simple or
radical hysterectomy
666 (615)
6, 12
GI-3
GI-2, DOW
3144
Bowel resection
654 (629)
12
GI-2
GI-3, DOW
0015
Bowel resection
738 (705)
6, 12
GI-3
GI-2, DOW
GI-3: later time of first tolerated solid food and time for first flatus or bowel movement;
GI-2: later time of first tolerated solid food and time for bowel movement; DOW: time to discharge order written
All studies conducted in North America except 001, which was conducted in Europe and New Zealand
1.
2.
3.
4.
5.
Wolff BG, et al. Ann Surg. 2004;240:728-735.
Delaney CP, et al. Dis Colon Rectum. 2005;48:1114-1125.
Viscusi E, et al. Surg Endosc. 2006;20:67-70.
Ludwig K, et al. Arch Surg. 2008;143:1098-1105.
Buchler M, et al. Aliment Pharmacol Ther. 28:312-325.
Alvimopan for POI: Phase 3 Trials
• Men and women, ≥ 18 years old
• Partial small or large bowel resection with primary
anastomosis; total abdominal hysterectomy (in some
studies)
• General anesthesia
• Standardized postoperative care
– Pain Management
• Analgesia via IV opioid patient-controlled analgesia (PCA) (US)
• Opioids via IV or IM bolus or IV PCA (non-US)
– Nasogastric (NG) tube out at end of surgery or early on
postoperative day (POD) 1
– Liquids offered, ambulation encouraged on POD 1
– Solid food offered on POD 2
• Exclusions: Opioids within 1-4 weeks, epidural opioids,
local anesthetics, nonsteroidal antiinflammatory drugs
(NSAIDs), or severe concomitant disease(s)
Alvimopan POI Phase 3 Study Design
Randomization
Surgery
Treatment-emergent adverse reactions:
 Events occurring after first dose and ≤ 7 days
after last dose of study drug or those present
at baseline that increased in severity after start
of study drug
Preop dose
≥ 30 min and < 5 hr
Alvimopan 12* mg BID
Placebo BID
Screening
≤ 7 PODs or discharge
–30
0
1
2
3
4
5
6 7
POD
8
9 10 11 12 13 14
* In some studies, a 6 mg dose of alvimopan was also evaluated
Alvimopan Phase 3 Study Endpoints
• GI-3 (Primary endpoint studies 302, 308, 313, 001)
– Later time of:
 Upper GI recovery: time to tolerating solid food
 Lower GI recovery: first to occur of passed flatus or bowel
movement (BM)
• GI-2 (Primary endpoint study 314)
– Later time of:
 Upper GI recovery: time to tolerating solid food
 Lower GI recovery: time to first BM
• Time to discharge order (DCO) written
Alvimopan in Bowel Resection:
Pooled Analysis
(Studies 302, 308, 313)
Delaney CP, et al. Ann Surg. 2007;245:355-363.
Pooled Data From Phase III Studies of
Alvimopan: Postoperative Morbidity
15
Studies 302, 308, 313
12.2
Patients, %
12
Placebo
Alvimopan 6 mg
9.2
9
*
Alvimopan 12 mg
*
6.8 6.8
6.7
‡
6
3
† †
1.8 1.9
† 3.9
3.0
1.2
1.5
1.0
0
Postoperative NGT
POI as an SAE
EPSBO or POI
insertion
as an SAE
*P < 0.05; †P < 0.001; ‡P = 0.003
NGT = nasogastric tube; POI = postoperative ileus; SAE = serious adverse event;
EPSBO = early postoperative small bowel obstruction
Delaney CP, et al. Ann Surg. 2007;245:355-363.
Anastomotic leak
Pooled Data From Phase III Studies of
Alvimopan: Hospital Resource Use
Studies 302, 308, 313
40
38.1
35
Placebo
Alvimopan 6 mg
Patients, %
30
†
24.4
Alvimopan 12 mg
25
†
19.9
20
15
13.7
*
10
8.6
†
7.0
11.7
‡
7.3
7.7
5
0
Prolonged hospital stay
*P = 0.024; †P < 0.001; ‡P = 0.040
DCO = discharge order
Delaney CP, et al. Ann Surg. 2007;245:355-363.
Readmission
DCO written ≥ 7 days
GI Tract Recovery in Patients Following
Bowel Resection: Alvimopan 12 mg
Study 314
Alvimopan
(n = 317)
Placebo
(n = 312)
P-value
92.0
111.8
---
1.53 (1.29, 1.82)
---
< 0.001
LOS (days)
5.2
6.2
< 0.001
POI-related
morbidity (%)
6.9
14.4
0.003
Endpoint
GI-2 (hr)
GI-2 hazard ratio
3 Most Common Treatment-Emergent Adverse Events
– Nausea (placebo 66.2% vs alvimopan 57.8%; P = 0.003)
– Vomiting (placebo 24.6% vs alvimopan 14.0%; P < 0.001)
– Abdominal distention (placebo 20.3% vs alvimopan 17.6%; P = 0.42)
Ludwig K, et al. Arch Surg. 2008;143:1098-1105.
Estimated Probability of
Achieving GI-2 Recovery
Time to GI-2: Combined Data From 5
Alvimopan Studies (Bowel Resection)
1.0
0.9
0.8
0.7
0.6
Alvimopan 12 mg
Placebo
0.5
0.4
0.3
0.2
0.1
0.0
0
24
48
72
96
120 144 168 192 216
Hours After End of Surgery
1. Wolff BG, et al. Ann Surg. 2004;240:728-735.
2. Delaney CP, et al. Dis Colon Rectum. 2005;48:1114-1125.
3. Viscusi E, et al. Surg Endosc. 2006;20:67-70.
4. Ludwig K, et al. Arch Surg. 2008;143:1098-1105.
5. Buchler M, et al. Aliment Pharmacol Ther. 28:312-325.
Available at: http://www.entereg.com/pdf/prescribing-information.pdf. Accessed March 2009.
240 264
Alvimopan for POI Summary
• Treatment of patients undergoing bowel resection with
alvimopan compared with placebo:
– Accelerated return of bowel function
– Reduced the time to discharge order written
– Reduced postoperative ileus-related morbidity
• Alvimopan did not reverse postoperative analgesia
• Alvimopan was well tolerated; adverse events were
similar between placebo and alvimopan treatment
groups
Alvimopan for Opioid-induced Bowel
Dysfunction (OBD)
• 12-month study in patients taking opioids for chronic
non-cancer pain
– Alvimopan (0.5 mg) or placebo BID
• More reports of myocardial infarction in patients treated
with alvimopan (1.3%) compared with placebo (0)
– Serious cardiovascular adverse events in patients at high risk for
cardiovascular disease
– Myocardial infarction did not appear to be linked to duration of
dosing
– Not observed in other alvimopan studies, including POI studies
in patients undergoing bowel resection (12 mg dose BID for up
to 7 days)
– Causal relationship between alvimopan and myocardial
infarction has not been established
Available at: http://www.fda.gov/bbs/topics/NEWS/2008/NEW01838.html. and
http://www.gsk.com/media/pressreleases/2007/2007_04_09_GSK1012.htm. Accessed March 2009.
Alvimopan for POI:
Formulary Considerations
E.A.S.E.™ Program
• Distribution Program for ENTEREG (alvimopan)
• Alvimopan is available only to hospitals that enroll in the
E.A.S.E. Program
• To enroll in the E.A.S.E. Program, the hospital must
acknowledge that hospital staff who prescribe, dispense, or
administer alvimopan have been provided the educational
materials on:
– Limiting the use of alvimopan to short-term, inpatient use
– Patients will not receive more than 15 doses of alvimopan
– Alvimopan will not be dispensed to patients after they have been
discharged from the hospital
– Hospital will not transfer alvimopan to unregistered hospitals
E.A.S.E.: Entereg Access Support and Education. Available at: http://www.entereg.com/pdf/prescribinginformation.pdf. Accessed March 2009.
Multimodal/Fast Track Management
What Is “Fast-Track Recovery”?
• “An interdisciplinary multimodal concept to
accelerate postoperative convalescence and
reduce general morbidity (including POI) by
simultaneously applying several interventions”
• What are the
appropriate
choices in
constructing
fast-track,
multimodal
protocols?
NG tube
removal
Opioid sparing
Laxatives,
prokinetics
POI (the role of
Epidural
anesthetics
the pharmacist)
Mobilization?
Mattei P. World J Surg. 2006;30:1382-1391.
Person B, Wexner S. Curr Probl Surg. 2006;43:6-65.
Laparoscopic
surgery
Early feeding,
fluid
management
Multimodal Approach:
Preoperative Components
• Education
• Stabilize coexisting diseases
• Optimize comfort (minimize anxiety)
• Ensure hydration, electrolytes, normothermia
• Appropriate use of prophylactic therapy (nausea, ileus,
pain, antibiotic)
White PF, et al. Anesth Analg. 2007;104:1380-1396.
Multimodal Approach:
Intraoperative Components
• Anesthesia to optimize surgery and recovery
• Local anesthesia/analgesia (or thoracic epidural) if possible
• Laparoscopic surgery if possible (gentle handling of tissue)
White PF, et al. Anesth Analg. 2007;104:1380-1396.
Multimodal Approach:
Postoperative Components
• Remove NG tube
• Laxative, start oral feedings early
• Minimize opioids
• Ambulate
• Discharge criteria
White PF, et al. Anesth Analg. 2007;104:1380-1396.
Fast-Track Example (Colectomy)
Day
Standard
Fast-Track
Preoperative
Consent, epidural (local anesthetic
[LA] with opioid)
Consent and educate, anti-emetic,
anxiolytic, epidural (LA with opioid)
Day of
surgery
Admit to SICU, NG out with order, i.v.
fluids to body weight, continuous
epidural or PCA, anti-emetic, nothing
by mouth, sitting
Admit to floor post PACU, NG out with
extubation, limit i.v. fluid, continuous
epidural (limit systemic opioids), NSAID,
laxative, mobilize to chair, short walk,
soft foods
POD 1
Admit to floor, epidural or PCA, clear
oral liquids and i.v. fluids, out of bed,
remove drains and Foley
Transition to oral opioids or NSAIDs
(limit epidural and systemic opioids),
regular diet, mobilize > 8 hr, walk twice
daily, remove drains and Foley
POD 2
Epidural or PCA, laxative, mashed
food, out of bed
Remove epidural, plan discharge
POD 3
Transition to oral opioids (limit
epidural and systemic opioids), out of
bed
Oral opioids or NSAIDs, fully mobilize,
discharge
POD 7
Extract staples, discharge pending
orders
Outpatient clinic, extract staples
Raue W, et al. Surg Endosc. 2004;18:1463-1468.
SICU = surgical intensive care unit
PACU = postanesthetic care unit
Multimodal Outcomes
• Expedited gastrointestinal recovery
• Earlier oral nutrition
• Fewer complications
• Shortened hospital LOS
• Fewer readmissions
• Cost minimization
• Greater patient satisfaction?
• Best results with epidural anesthesia/ analgesia
Person B, Wexner S. Curr Probl Surg. 2006;43:6-65.
White PF, et al. Anesth Analg. 2007;104:1380-1396.
Raue W, et al. Surg Endosc. 2004;18:1463-1468.
Costs of POI?
Implementation
of multimodal
pathways
• Decreased length of
hospital stay
• Decreased incidence of
prolonged hospital stay
• Decreased readmission
• Decreased need for
supportive care
• Decreased personnel use
• Decreased laboratory tests
• Decreased radiological studies
• Increased hospital bed
availability
Role of the Pharmacist
• Medication protocol
– Comfort (minimize anxiety)
– Appropriate hydration, electrolytes, normothermia
– Appropriate use of prophylactic therapy (nausea, ileus, pain,
antibiotic)
– Postoperative analgesia (with opioid minimization) and pain
assessment
– Laxatives
Gannon RH. Am J Health-Syst Pharm. 2007;64(20Suppl 13):S8-12.
Role of the Pharmacist (cont)
• Stabilize coexisting diseases
• Advocate diet
• Promote mobilization
• Team member and education of team
• Discharge planning
• Patient education and compliance assessment
Gannon RH. Am J Health-Syst Pharm. 2007;64(20Suppl 13):S8-12.
The Future
• Identification of risk factors for POI
• Patient-centered care
– Hydration and electrolytes
– Opioid regimen and opioid-sparing therapies
– Anxiolytic and anti-emetic therapies
•
•
•
•
Pharmacologic modification of the “stress response”
Multidisciplinary PACUs
Clinical pathways
Outreach services for rehabilitation
White PF, et al. Anesth Analg. 2007;104:1380-1396.
POI: Summary
• POI affects between 4% and 20% of abdominal surgical
patients annually and has a detrimental effect on clinical
outcomes and costs of care
• Accelerating recovery of GI function improves clinical
outcomes, enhances patient comfort, and shortens hospital
length of stay
• Treatment options for POI include both pharmacologic and
nonpharmacologic approaches
POI: Summary (cont)
• Laparoscopy, NSAIDs, and peripheral opioid-receptor
antagonists show promise in reducing the incidence of POI
– Thoracic epidurals with local anesthetics may help to reduce POI
without adversely affecting pain relief
– NSAIDs may reduce the requirement for opioids
– Peripheral opioid-receptor antagonists appear to reduce the
adverse GI side effects of opioids while preserving their analgesic
benefits
• There is an evolving consensus that a multimodal approach
using both nonpharmacologic and pharmacologic options is
the most consistent and effective strategy for managing POI