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The Evolving Multimodal Management
Plan for Postoperative Ileus:
Improving Time to Bowel Recovery
Educational Activity 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
Management Council
Definition of POI
• Transient cessation of coordinated bowel
motility after surgical intervention, which
prevents effective transit of intestinal
contents and/or tolerance of oral intake
Delaney CP, et al. Clinical Consensus Update in General Surgery. 2006.
Primary POI: Response by Different
Intestinal Segments
Average time to
resolution of POI after
major abdominal surgery13
– Small intestine: 0-24 hours
– Stomach: 24-48 hours
– Colon: 48-120 hours
1.
2.
3.
Luckey A, et al. Arch Surg. 2003;138:206-214.
Livingston EH, Passaro EP Jr. Dig Dis Sci. 1990;35:121-132.
Delaney CP, et al. Clinical Consensus Update in General Surgery. 2006.
Pathophysiology of POI:
Multifactorial
• The major causes of POI
–
–
–
–
Surgical trauma and manipulation of the bowel
Other surgeries such as hysterectomy, knee, thoracic
Stress
Stimulation of GI opioid receptors by endogenous and
exogenous opioids
• POI has been generally regarded as a usual and
inevitable response to surgery
Kehlet H, Holte K. Am J Surg. 2001;182 (5A Suppl):3S–10S.
Holte K, Kehlet H. Drugs. 2002;62:2603-2615.
Pathogenesis of POI Is Multifactorial
Sympathetic Nervous System1,2
Inhibitory neural reflexes
Enteric Nervous System2
Nitric oxide
Vasoactive intestinal peptide
Substance P
Neuropeptide and
Hormonal Factors1,2
Multiple
Pathways
Inflammatory Mediators1,2
Macrophage and neutrophil
infiltration, IL-1, IL-6
IL = interleukin
1. Luckey A, et al. Arch Surg. 2003;138:206-214.
2. Behm B, et al. Clin Gastroenterol Hepatol. 2003;1:71-80.
Calcitonin gene-related
peptide, endogenous
opioid peptides,
corticotropin-releasing
factor
Pharmacologic2
Exogenous opioids
Effect of Surgical Manipulation
Intestinal contractility
Contractility
1
0.8
0.6
Control
Laparotomy
Eventration
Running
Compression
0.4
0.2
0
0 0.1
1
10 100 300
Bethanechol uM
Kalff J, et al. Ann Surg. 1998;228:652-663.
Leukocyte infiltration
into intestinal mucosa
* P < 0.05
800
600
400
200
0
* *
*
*
Inhibitory Effects of Opioids
on Bowel Function
Endogenous Opioids
• Released in response
to surgical trauma/
manipulation
• Higher degrees of
surgical
trauma/manipulation
→ Greater
inflammation
→ Greater gut
paralysis
Brix-Christensen V, et al. Int J Cardiol. 1997;62:191-197.
Yoshida S, et al. Surg Endosc. 2000;14:137-140.
Kalff JC, et al. Ann Surg. 1998;228:652-663.
Cali R, et al. Dis Colon Rectum. 2000;43:163-168.
Exogenous Opioids
• Commonly
administered for
postoperative pain
• Relationship between
amount of opioid
administered and
time to return of
bowel function
Risk Factors for Postoperative Ileus
•
•
•
•
•
•
Abdominal surgery
Surgical technique
Prolonged opioid analgesia
Preexisting gastrointestinal disease
Physiological stress from surgery
Physical inactivity pre/post surgery
Senagore A. Am J Health-Syst Pharm. 2007;64(S13):S3-7.
Clinical Impact of POI
• Increased postoperative pain
• Increased nausea and vomiting
– Increased risk of aspiration
• Prolonged time to regular diet
– Delayed wound healing
– Increased risk of malnutrition/catabolism
• Prolonged time to mobilization
– Increased pulmonary complications
• Prolonged hospitalization
– Increased health care costs
Kehlet H, Holte K. Am J Surg. 2001;182(5A suppl):3S-10S.
Leslie JB. Ann Pharmacother. 2005; 39:1502-1510.
Behm B, Stollman N. Clin Gastroenterol Hepatol. 2003;1:71-80.
Delayed
recovery
How Long Can POI Last?
Figure from Steinbrook RA. Contemp Surg. 2005; March(suppl):4-7.
Wolff B, et al. Ann Surg. 2004;240:728-734.
POI and Abdominal Surgery
25
Coded POI (%)
20
15
10
5
0
Abdominal Large Bowel Small Bowel
CholeAppendectomy
Hysterectomy Resection
Resection
cystectomy
HCFA Data 1999-2000
Delaney C, et al. Clinical Consensus Update in General Surgery. 2006.
NephroOther
ureterectomy Procedures
Economic Burden of POI
•
•
•
•
•
Nasogastric (NG) intubation
IV hydration
Additional nursing care
Lab tests
Increased hospital days
Livingston E, Passaro E Jr. Dig Dis Sci. 1990;35:121-132.
Collins TC, et al. Ann Surg. 1999;230:251-259.
Sarawate CA, et al. Gastroenterology. 2003;124:A-828.
Postoperative Ileus: Economic Consequences
and Length of Stay (LOS)
• Prolonged POI at an Academic Medical Center (ICD-9
codes 564.4 and 997.4)
• Total of 83 patients (total abdominal hysterectomy &
hemicolectomy)
Avg
Avg time
Incidence time to from Dx Avg LOS vs
of PPOI
Dx (d) to D/C (d) no PPOI (d)
Increase in
total average
costs
(vs no PPOI)
TAH
(n = 43)
18.2%
3.1
3.8
6.9 vs 3.7
$4,512
HC
(n = 40)
24.5%
2.5
15.6
16.6 vs 8.6
$12,416
Salvador CG, et al. P&T. 2005;30:590-595.
Indications for Readmission
24%
20%
Surgical site septic
complications (SSSC)
Ileus/small bowel
obstruction (SBO)
Medical
complications
23%
33%
Kariv Y, et al. Am J Surg. 2006;191:364-371.
Other
Factors Associated With Readmission Cause
Indication for RD First-admission factor
OR (95% CI)
SSSC
Bowel perforation
Re-operation
12.8 (0.98, 167.2)
16.9 (1.05, 272.6)
Medical
complications
Functional capacity
COPD
Postoperative fever
Postoperative ileus
Stoma at discharge
3.58 (2.28, 10.0)
11.0 (1.39, 87.4)
5.6 (1.78, 17.5)
3.33 (1.08, 10.3)
3.15 (0.98, 10.1)
Ileus/SBO
Prior PE/DVT
Prior abdominal surgery
11.8 (1.48, 93.3)
2.6 (1.12, 6.02)
RD = readmission within 30 days of discharge
SSSC: surgical site septic complications; SBO: small bowel obstruction
Kariv Y, et al. Am J Surg. 2006;191:364-371.
Options to Reduce LOS
• Change discharge criteria
• Change postoperative care plans
• Altered surgical technique
– Laparoscopy vs Open
– Different incisions
• Enhance postoperative recovery
– Better analgesia
– “Anti-ileus” adjuncts
– Early ambulation
Current Management Strategies for
Postoperative Ileus
Preventive and Therapeutic
Management Options for POI
• Physical Options
• Anesthesia and Analgesia
– Nasogastric tube
– Early postoperative feeding
– Early ambulation
– Epidural
– NSAIDs
• Pharmacologic
• Surgical Technique
– Prokinetic agents
– Opioid (PAMOR) antagonists
– Other agents
– 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?
Management Options for POI
Nonpharmacologic Options
Management
Potential Mechanism
Comments
NG tube
Gastric/small bowel
decompression
Helps symptoms of POI, but
no evidence NG tubes reduce
duration of POI; may increase
pulmonary postoperative
complications
Early feeding
Stimulates GI motility by
eliciting reflex response
and stimulating release
of hormonal factors
Appears safe, well tolerated;
some, but not all, studies
suggest decrease in POI
Early
ambulation
Possible mechanical
stimulation; possible stimulation
of intestinal function
No significant change in
duration of POI, but may
decrease other postoperative
complications
Laparoscopic
surgery
Decreased opiate requirements,
decreased pain, less abdominal
wall trauma, less intestinal
manipulation
Most studies find decreased
duration of POI
Holte K, Kehlet H. Drugs. 2002;62:2603-2615.
Behm B, Stollman N. Clin Gastroenterol Hepatol. 2003;1:71-80.
Luckey A, et al. Arch Surg. 2003;138:206-214.
Prophylactic Nasogastric Decompression
Following Abdominal Surgery
• Meta-analysis
– 33 Studies, N = 5,240 patients
– Patients without routine NG tube use had:
 Earlier return of bowel function (P < 0.00001)
 Decrease in pulmonary complications (P = 0.01)
 Trend toward increase risk of wound infection (P = 0.22)
 Shorter length of stay
– No difference in anastomotic leak between patients with
vs without NG tubes (P = 0.70)
– “Routine nasogastric decompression does not
accomplish any of its intended goals and should be
abandoned in favor of selective use of the nasogastric
tube”
Nelson R, et al. Cochrane Database Syst Rev. 2007;Jul 18;(3):CD004929.
Early Oral/Enteral Nutrition Within 24
Hours of Intestinal Surgery
• Meta-analysis of 13 clinical trials, N = 1,173 patients
– Mortality – reduced with early post-op feeding
 RR (95% CI): 0.41 (0.18, 0.93)
– Data suggestive of reduced
 Wound Infections – RR (95% CI): 0.77 (0.48, 1.22)
 Pneumonia - RR (95% CI): 0.76 (0.36, 1.58)
 Length of Stay - RR (95% CI): -0.60 (-0.66, -0.54)
– Anastomotic Dehiscence – little evidence of benefit or harm
 RR (95% CI): 0.69 (0.36, 1.32)
– Overall conclusion: no benefit for restricting postoperative
oral/enteral nutrition
Lewis S, et al. J Gastrointest Surg. 2009;13:569-575.
Mobilization and Postoperative Ileus
• Important in helping to prevent postoperative
complications, ie, 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.
Controlled Rehabilitation with Early
Ambulation and Diet (CREAD)
Laparotomy & Intestinal Resection
• Compared with traditional postoperative care:
– CREAD patients spent less total time in the hospital
following surgery (5.4 vs 7.1 days, P = 0.02)
– Patients < 70 years had greater benefits than overall
study group
– No adverse effect on patient satisfaction, pain scores,
complications, or readmission rates
– Increased surgeon experience with CREAD
associated with improved outcome
Delaney C, et al. Dis Col Rect. 2003;46:851-859.
N = 31 CREAD patients
N = 33 traditional postop care patients
Surgical Technique - Laparoscopy
• Duration of ileus is shortened after less invasive surgery
• Progression to a solid diet and discharge is faster
• Several studies have shown favorable results
• Possible rationale
– Reduced surgical trauma leads to less sympathetic activation
and inflammation
– Smaller incisions, less pain (therefore less opiate use)
– Earlier ambulation, earlier tolerance of feeding, less NGT use
Holte K, Kehlet H. Drugs. 2002;62:2603-2615.
Person B, Wexner S. Curr Probl Surg. 2006;43:12-65.
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)
Milsom et al.
(1998)
*P < 0.05
D = defecation; F = flatus; RCTs = randomized clinical trials.
Holte K, Kehlet H. Br J Surg. 2000;87:1480-1493.
Kehlet H, Holte K. Am J Surg 2001;182(5A suppl):3S-10S.
Leung et al.
(2000)
Intraoperative Measures:
Laparoscopic Surgery
• Meta-analysis of 22 trials (n = 2965) of colorectal surgery
– Reduced blood loss of 71.8 mL (95% CI, 30.8-113 mL; P = 0.0006)
– Reduced postoperative pain by 9.3/100 (95% CI, 5.4-13.2; P < 0.0001)
– Earlier flatulence by 1 day (95% CI, 0.76-1.3; P < 0.0001)
– Earlier bowel movement by 0.9 days (95% CI, 0.74-1.13; P < 0.0001)
– Lessened ileus (RR = 0.40 95% CI, 0.22-0.73; P = 0.003)
– Reduced wound infections (RR = 0.56 95% CI, 0.39-0.89; P = 0.002)
– Shortened hospital length of stay (LOS) by 1.5 days (95% CI, 1.12-1.94;
P < 0.0001)
Schwenk W, et al. Cochrane Database Syst Rev. 2005;CD003145.
Management Options for POI
Pharmacologic Options
Treatment or
Prevention
Potential Mechanism
Comments
Epidural
anesthesia with
only local
anesthetics
NSAIDs
Inhibits sympathetic reflex at
cord level; opioid-sparing
analgesia
Several RCTs suggest benefit
in preventing POI; most
effective when inserted at
thoracic level
Opiate-sparing analgesia,
inhibits COX-mediated
prostaglandin synthesis
Probable benefit; COX-2
selective medications need
further evaluation
Metoclopramide
Dopamine antagonist,
cholinergic agonist
Majority of RCTs suggest no
benefit
Peripherally
selective mureceptor
antagonists
Block enteric mu-receptors
and minimize opiate effects
on GI function, without
impacting CNS-mediated
analgesia
Clinical trials with alvimopan
demonstrate reduced duration
of POI, time to discharge
order written
Holte K, Kehlet H. Drugs. 2002;62:2603-2615.
Behm B, Stollman N. Clin Gastroenterol Hepatol. 2003;1:71-80.
Luckey A, et al. Arch Surg. 2003;138:206-214.
Becker G, Blum H. Lancet. 2009;373(9670):1198-1206..
Epidural Thoracic Anesthetics
• Epidural (epi) anesthesia with local anesthetics (LA)
– Suppression of inhibitory neural responses
• Randomized trials demonstrate decreased POI
duration compared with systemic opioids
• epi-LA vs systemic opioid =  POI
• epi-LA vs epi-opioid =  POI
• epi-LA/opioid vs systemic opioid =  POI (less than
epi-LA)
• Location of catheter important: thoracic application
more effective than lumbar or low-thoracic
Jorgensen H, et al. Br J Anaesthesia. 2001;87:577-583.
Steinbrook R. Anesth Analg.1998;86:837-844.
Holte K, Kehlet H. Br J Surg. 2000;87:1480-1493.
Jorgensen H, et al. Cochrane Database Syst Rev. 2001;(1):CD001893.
Epidural Analgesia and Duration
of Postoperative Ileus
Study
Surgery
Earlier Gas
Earlier Stool
*P-value
Hjortso et al, 1985
Major abdominal
No
No
NS
Wallin et al, 1986
Major abdominal
No
No
NS
Colonic
---
Yes
< 0.05
Colorectal
Yes
Yes
< 0.001
Colonic
---
Yes
< 0.001
Major abdominal
Yes
---
< 0.05
Proctocolectomy/IPAA
---
Yes
< 0.01
Colonic
Yes
Yes
< 0.005
Proctocolectomy/IPAA
Yes
Yes
< 0.05
Colorectal
Yes
Yes
< 0.001
Welch et al, 1998
Gastrointestinal
No
No
NS
Neudecker et al, 1999
Laparoscopic
sigmoidectomy
---
No
NS
Carli et al, 2001
Colorectal
Yes
Yes
< 0.001
Carli et al, 2002
Colonic
Yes
Yes
< 0.01
Steinberg et al, 2002
Colonic
Yes
Yes
< 0.002
Scheinin et al, 1987
Ahn et al, 1988
Bredtmann et al, 1990
Jayr et al, 1993
Morimoto et al, 1995
Liu et al, 1995
Scott et al, 1996
Bradshaw et al, 1998
Adapted from Person B, Wexner S. Curr Probl Surg. 2006;43:12-65.
*Compared with systemic analgesic regimens;
IPAA: ileal pouch anal anastomosis
Opioid-Sparing Analgesia
• Nonsteroidal anti-inflammatory drugs (NSAIDs)
– Reduce prostaglandin production
– Randomized, double-blind 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;49:546-551.
Effect of Metoclopramide on POI
120
Duration of Ileus (h)
Metoclopramide
100
Placebo
80
60
40
20
0
F
Jepsen et al.
(1986)
I
Cheape et al.
(1991)
D
Tollesson et al.
(1991)
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.
Holte K, Kehlet H. Br J Surg. 2000;87:1480-1493.
D = defecation; F = flatus; I = ingestion of solid food
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
200
MNTX N = 33
Placebo N = 32
180
160
Time (hours)
140
*
120
100
*
*
80
60
40
20
0
Full Liquids
1st BM
Viscusi, E et al. Anesthesiology. 2005;103:A893.
GI Recovery
Discharge
Eligible
Actual
Discharge
*P < 0.05
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 I, phase II, and phase III 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 POI Phase 3 Study Design
Placebo BID
Randomization
Alvimopan 6 mg BID
Treatment until discharge or up to 7 days
Alvimopan 12 mg BID
Pre-op dose
≥ 30 min and < 5 hrs
before surgery
Surgery
Endpoints: GI-2, GI-3,
Time to discharge order written,
safety
Upper and Lower GI Recovery
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
Alvimopan Phase 3 Studies – GI Recovery
140
Time to GI-2 (hours)
120
100
Placebo
§
*
#
6 mg Alvimopan
12 mg Alvimopan
§
#
*
*
#
80
60
40
20
0
Study 313
Study 302
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.
Study 308
Study 314
Study 001
*P < 0.001; #P < 0.01; §P < 0.02;
Studies 313, 302, 308 include bowel resection and hysterectomy;
Studies 314, 001 bowel resection only
Reduction in Time to Discharge Order Written
Compared with Placebo
(hours)
Alvimopan Phase 3 Studies:
Discharge Orders Written
0
Study 313
Study 302
Study 308
Study 314
Study 001
-5
-10
-15
P < 0.001
P = 0.008
P = 0.015
P < 0.001
-20
P = 0.003
6 mg Alvimopan
12 mg Alvimopan
-25
Studies 313, 302, 308 include bowel resection and hysterectomy;
Studies 314, 001 bowel resection only
All studies conducted in North America except 001, which was conducted in Europe and New Zealand
Alvimopan Bowel Resection
Pooled Analysis
P value
GI-3
GI-2
0
1.38
1.46
1.37
< 0.001
< 0.001
1.48
1.36
< 0.001
< 0.001
0.5
Alvimopan 6 mg
Alvimopan 12 mg
1.34
< 0.001
< 0.001
Ready for HD
DOW
1.28
0.001
< 0.001
1.43
1
In favor of placebo
1.5
2
2.5
In favor of alvimopan
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;
HD: ready for hospital discharge based on GI recovery;
DOW: discharge order written
Delaney C, et al. Ann Surg. 2007;245:355-363.
Studies 302, 308, 313
Alvimopan POI-Related Morbidity
Bowel Resection Pooled Analysis‡
18
16
Placebo N = 695
Patients (%)
14
Alvimopan 12 mg N = 714
12
10
8
*
*
6
4
*
2
*
0
Overall POM
Post-op NGT
Insertion
Overall POI
Complications
POM: postoperative morbidity; NGT: nasogastric tube; POI: postoperative ileus
Wolff B, et al. J Am Coll Surg. 2007;204:609-616.
POI Complications
Resulting in
Prolonged Stay
POI Complications
Resulting in
Readmission
*P ≤ 0.001
‡Studies 302, 308, 313, 314
Alvimopan Safety
Treatment-emergent Adverse Events Reported in ≥ 3%
Alvimopan-treated Patients and for Which the Rate for Alvimopan
was ≥ 1% than Placebo
Worldwide POI Safety Population
TreatmentEmergent
Adverse
Reaction
Anemia
Bowel Resection Patients
Placebo
Alvimopan
(N = 986)
(N = 999)
%
%
4.2
5.2
All Surgical Patients
Placebo
Alvimopan
(N = 1365)
(N = 1650)
%
%
5.4
5.4
Constipation
3.9
4.0
7.6
9.7
Dyspepsia
4.6
7.0
4.8
5.9
Flatulence
4.5
3.1
7.7
8.7
Hypokalemia
8.5
9.5
7.5
6.9
Back pain
1.7
3.3
2.6
3.4
Urinary retention
2.1
3.2
2.3
3.5
Available at: http://www.entereg.com/pdf/prescribing-information.pdf. Accessed March 2009.
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;
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 for
Postoperative Ileus
What Is “Fast-Track Recovery”?
• “An interdisciplinary multimodal concept to accelerate
postoperative convalescence and reduce general
morbidity (including POI) by simultaneously applying
several interventions”
NG tube
removal
• What are the
appropriate
choices in
constructing
fast-track,
multimodal
protocols?
Opioid sparing
Laparoscopic
surgery
Laxatives,
prokinetics
Epidural
anesthetics
Mattei P. World J Surg. 2006;30:1382-1391.
Person B, Wexner S. Curr Probl Surg. 2006;43:6-65.
Mobilization?
Early feeding,
fluid
management
Engage the Multidisciplinary Team
•
•
•
•
•
Surgeons
Anesthesiologists
Med-surgical nurses
Hospital pharmacists
Rehabilitation personnel
Multimodal Approach:
Preoperative Components
• Education
• Stabilize coexisting diseases
• Optimize comfort (minimize anxiety)
• Ensure hydration, electrolyte, 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.
Economic Burden of POI
(2002 Premier’s Perspective Database)
No coded POI (N = 175,992)
Coded POI (N = 17,417)
*
10.6
10
5.4
5
0
Mean Hospital Costs per
Patient × $1,000
Mean Duration of Hospital
Stay (days)
15
25
*
20
16.3
15
10
9.9
5
0
*P < 0.05 for coded POI vs no coded POI
Senagore A, et al. American Society of Colon and Rectal Surgeons 2005 Annual Meeting (abstract). S22, p.165.
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
Time to Change the Way
We Think About POI!
• Classic view: Postoperative ileus is an inevitable
response to major surgery that prolongs hospitalization
and causes significantly diminished patient quality of life
• New view: Surgeons can participate in the proactive
prevention and treatment of postoperative ileus to help
facilitate hospital discharge, lower hospitalization costs,
and improve patient outcomes
Summary
• Postoperative ileus has a multifactorial pathophysiology
– Neurogenic, inflammatory, hormonal, pharmacologic components
• Selective nasogastric tube use, laparoscopic surgery,
epidural anesthesia/analgesia, and opioid sparing
techniques help to reduce the duration of POI
• Peripheral opioid receptor antagonism is a promising
approach for accelerating GI recovery in patients
following bowel resection
• Accelerating recovery of GI function improves clinical
outcomes, enhances patient comfort, and reduces
hospital length of stay
• A multimodal approach incorporating nonpharmacologic
and pharmacologic options is an effective strategy for
managing POI