ACS Chapter Meeting Content

1
ACS Chapter Meeting Content
The Evolving Multimodal Management Plan for
Postoperative Ileus Improving Time to Bowel
Recovery
2
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

3
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.
4
Primary POI Response by Different Intestinal
Segments

• Average time to resolution of POI after major
  abdominal surgery1-3
• Small intestine 0-24 hours
• Stomach 24-48 hours
• Colon 48-120 hours

1. Luckey A, et al. Arch Surg. 2003138206-214.
2. Livingston EH, Passaro EP Jr. Dig Dis Sci.
   199035121-132.
3. Delaney CP, et al. Clinical Consensus Update in
   General Surgery. 2006.

5
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. 2001182 (5A
Suppl)3S10S. Holte K, Kehlet H. Drugs.
2002622603-2615.
6
Pathogenesis of POI Is Multifactorial
Sympathetic Nervous System1,2 Inhibitory neural
reflexes
Neuropeptide and Hormonal Factors1,2 Calcitonin
gene-related peptide, endogenous opioid peptides,
corticotropin-releasing factor
Enteric Nervous System2 Nitric oxide Vasoactive
intestinal peptideSubstance P
Multiple Pathways
Inflammatory Mediators1,2 Macrophage and
neutrophil infiltration, IL-1, IL-6
Pharmacologic2 Exogenous opioids
IL interleukin 1. Luckey A, et al. Arch Surg.
2003138206-214. 2. Behm B, et al. Clin
Gastroenterol Hepatol. 2003171-80.
7
Effect of Surgical Manipulation
Leukocyte infiltration into intestinal mucosa
Intestinal contractility
P lt 0.05

800

600

400

200
0
Control
Running
Compression
Eventration
Laparo...
Kalff J, et al. Ann Surg. 1998228652-663.
8
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
Exogenous Opioids
Commonly administered for postoperative pain Relationship between amount of opioid administered and time to return of bowel function
Brix-Christensen V, et al. Int J Cardiol.
199762191-197. Yoshida S, et al. Surg Endosc.
200014137-140. Kalff JC, et al. Ann Surg.
1998228652-663. Cali R, et al. Dis Colon
Rectum. 200043163-168.
9
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.
200764(S13)S3-7.
10
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. 2001182(5A
suppl)3S-10S. Leslie JB. Ann Pharmacother. 2005
391502-1510. Behm B, Stollman N. Clin
Gastroenterol Hepatol. 2003171-80.
11
How Long Can POI Last?
Figure from Steinbrook RA. Contemp Surg. 2005
March(suppl)4-7. Wolff B, et al. Ann Surg.
2004240728-734.
12
POI and Abdominal Surgery
25
20
15
Coded POI ()
10
5
0
Abdominal Hysterectomy
Large Bowel Resection
Small Bowel Resection
Chole- cystectomy
Nephro- ureterectomy
Other Procedures
Appendectomy
HCFA Data 1999-2000
Delaney C, et al. Clinical Consensus Update in
General Surgery. 2006.
13
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.
199035121-132. Collins TC, et al. Ann Surg.
1999230251-259. Sarawate CA, et al.
Gastroenterology. 2003124A-828.
14
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)

Incidence of PPOI Incidence of PPOI Avg time to Dx (d) Avg time from Dx to D/C (d) Avg LOS vs no PPOI (d) Increase in total average costs (vs no PPOI)
TAH (n 43) TAH (n 43) 18.2 3.1 3.8 6.9 vs 3.7 4,512
HC (n 40) HC (n 40) 24.5 2.5 15.6 16.6 vs 8.6 12,416
Salvador CG, et al. PT. 200530590-595.
15
Indications for Readmission
Kariv Y, et al. Am J Surg. 2006191364-371.
16
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. 2006191364-371.
17
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

18
Current Management Strategies for Postoperative
Ileus
19
Preventive and Therapeutic Management Options
for POI

• Physical Options
• Nasogastric tube
• Early postoperative feeding
• Early ambulation
• Surgical Technique
• Laparoscopy
• Psychological Perioperative Information

• Anesthesia and Analgesia
• Epidural
• NSAIDs
• Pharmacologic
• Prokinetic agents
• Opioid (PAMOR) antagonists
• Other agents
• Perioperative Care Plan(s)
• Multimodal clinical pathways
• Fluid/sodium restriction?

PAMOR peripherally acting µ-opioid receptor
antagonist Luckey A, et al. Arch Surg.
2003138206-214.
20
Management Options for POI
Nonpharmacologic Options Nonpharmacologic Options 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. 2002622603-2615.
Behm B, Stollman N. Clin Gastroenterol Hepatol.
2003171-80. Luckey A, et al. Arch Surg.
2003138206-214.
21
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 lt 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.
2007Jul 18(3)CD004929.
22
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.
200913569-575.
23
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. 1990212671-677.
24
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 lt 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

N 31 CREAD patients N 33 traditional postop
care patients
Delaney C, et al. Dis Col Rect. 200346851-859.
25
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. 2002622603-2615. Perso
n B, Wexner S. Curr Probl Surg. 20064312-65.
26
RCT Laparoscopy vs Open Surgery

• .

120 100 80 60 40 20 0

Duration of Ileus (h)


F
D
D
F
Lacy et al. (1995)
Schwenk et al. (1998)
Milsom et al. (1998)
Leung et al. (2000)
P lt 0.05
D defecation F flatus RCTs randomized
clinical trials.
Holte K, Kehlet H. Br J Surg. 2000871480-1493. K
ehlet H, Holte K. Am J Surg 2001182(5A
suppl)3S-10S.
27
Intraoperative MeasuresLaparoscopic 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 lt 0.0001)
• Earlier flatulence by 1 day (95 CI, 0.76-1.3 P
  lt 0.0001)
• Earlier bowel movement by 0.9 days (95 CI,
  0.74-1.13 P lt 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 lt 0.0001)

Schwenk W, et al. Cochrane Database Syst Rev.
2005CD003145.
28
Management Options for POI
Pharmacologic Options Pharmacologic Options Pharmacologic Options
Treatment or Prevention Potential Mechanism Comments
Epidural anesthesia with only local anesthetics Inhibits sympathetic reflex at cord level opioid-sparing analgesia Several RCTs suggest benefit in preventing POI most effective when inserted at thoracic level
NSAIDs 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 mu-receptor 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. 2002622603-2615.
Behm B, Stollman N. Clin Gastroenterol Hepatol.
2003171-80. Luckey A, et al. Arch Surg.
2003138206-214. Becker G, Blum H. Lancet.
2009373(9670)1198-1206..
29
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.
200187577-583. Steinbrook R. Anesth
Analg.199886837-844. Holte K, Kehlet H. Br J
Surg. 2000871480-1493. Jorgensen H, et al.
Cochrane Database Syst Rev. 2001(1)CD001893.
30
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
Scheinin et al, 1987 Colonic --- Yes lt 0.05
Ahn et al, 1988 Colorectal Yes Yes lt 0.001
Bredtmann et al, 1990 Colonic --- Yes lt 0.001
Jayr et al, 1993 Major abdominal Yes --- lt 0.05
Morimoto et al, 1995 Proctocolectomy/IPAA --- Yes lt 0.01
Liu et al, 1995 Colonic Yes Yes lt 0.005
Scott et al, 1996 Proctocolectomy/IPAA Yes Yes lt 0.05
Bradshaw et al, 1998 Colorectal Yes Yes lt 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 lt 0.001
Carli et al, 2002 Colonic Yes Yes lt 0.01
Steinberg et al, 2002 Colonic Yes Yes lt 0.002
Compared with systemic analgesic regimens IPAA
ileal pouch anal anastomosis
Adapted from Person B, Wexner S. Curr Probl Surg.
20064312-65.
31
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 lt 0.05),
  and earlier ambulation (2.2 1 vs. 2.8 1.2
  days, P lt 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.
2006436-65. Chen JY. Acta Anaesthesiol Scand.
200549546-551.
32
Effect of Metoclopramide on POI
Jepsen S, et al. Br J Surg. 198673290-291.
Cheape JD, et al. Dis Colon Rectum.
199134437-441. Tollesson PO, et al. Eur J Surg.
1991157355-358. Holte K, Kehlet H. Br J Surg.
2000871480-1493.
D defecation F flatus I ingestion of
solid food
33
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. 200363649-671.Taguch
i A, et al. N Engl J Med. 2001345935-940.
34
Naltrexone
N-methylnaltrexone
Methylnaltrexone A Novel, Quaternary ?-Opioid
Receptor Antagonist

• 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. 2001182 (5ASuppl)19S-26S.
35
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. 2005103A893.
36
Methylnaltrexone Phase 2 Results
P lt 0.05
Viscusi, E et al. Anesthesiology. 2005103A893.
37
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/sh
ow/NCT00401375. Accessed March 2009. 3. Available
at http//www.clinicaltrials.gov/ct2/show/NCT0052
8970. Accessed March 2009. 4. Available at
http//www.wyeth.com/news/archive?navdisplaynavT
o/wyeth_html/home/news/pressreleases/2008/ 120532
2072160.html. Accessed March 2009. 5. Available
at http//www.progenics.com/releasedetail.cfm?Rel
easeID311785. Accessed March 2009. 6. Available
at http//www.progenics.com/releasedetail.cfm?Rel
easeID370543. Accessed July 2009.
38
Alvimopan A Novel, Quaternary?-Opioid Receptor
Antagonist
Moderately Large MW (461 Da)
Alpha vi mu opioid peripheral antagonist
Schmidt WK. Am J Surg. 2001182(5A suppl)27S-38S.
39
Alvimopan

• Peripherally acting µ-opioid receptor antagonist1
• Highly selective for µ-opioid receptor over ? and
  ? 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. Azodo IA, et al. Curr Opin Investig Drugs.
   200231496-1501.
2. Schmidt WK. Am J Surg. 2001182(5A
   suppl)27S-38S.
3. Taguchi A, et al. N Engl J Med. 2001345935-940.
4. Wolff BG, et al. Ann Surg. 2004240728-735.
5. Delaney CP, et al. Dis Colon Rectum.
   2005481114-1125.
6. Viscusi E, et al. Surg Endosc. 20062067-70.
7. Ludwig K, et al. Arch Surg. 20081431098-1105.
8. Buchler M, et al. Aliment Pharmacol Ther.
   200828312-325.
9. FDA approval available at http//www.accessdata.f
   da.gov/scripts/cder/drugsatfda. Accessed March
   2009.

40
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. Wolff BG, et al. Ann Surg. 2004240728-735.
2. Delaney CP, et al. Dis Colon Rectum.
   2005481114-1125.
3. Viscusi E, et al. Surg Endosc. 20062067-70.
4. Ludwig K, et al. Arch Surg. 20081431098-1105.
5. Buchler M, et al. Aliment Pharmacol Ther.
   28312-325.

41
Alvimopan POI Phase 3 Study Design
Placebo BID
Alvimopan 6 mg BID
Randomization
Treatment until discharge or up to 7 days
Alvimopan 12 mg BID
Pre-op dose 30 min and lt 5 hrs before surgery
Endpoints GI-2, GI-3, Time to discharge order
written, safety
Surgery
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
42
Alvimopan Phase 3 Studies GI Recovery
140
Placebo
6 mg Alvimopan
12 mg Alvimopan

120






100

80
Time to GI-2 (hours)
60
40
20
0
Study 313
Study 302
Study 308
Study 314
Study 001
Wolff BG, et al. Ann Surg. 2004240728-735. Delan
ey CP, et al. Dis Colon Rectum.
2005481114-1125. Viscusi E, et al. Surg
Endosc. 20062067-70. Ludwig K, et al. Arch
Surg. 20081431098-1105. Buchler M, et al.
Aliment Pharmacol Ther. 28312-325.
P lt 0.001 P lt 0.01 P lt 0.02
Studies 313, 302, 308 include bowel resection and
hysterectomy Studies 314, 001 bowel resection
only
43
Alvimopan Phase 3 Studies Discharge Orders
Written
Study 313
Study 302
Study 308
Study 314
Study 001
0
-5
-10
Reduction in Time to Discharge Order Written
Compared with Placebo
(hours)
P 0.008
-15
P lt 0.001
P 0.015
P lt 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
44
Alvimopan Bowel Resection Pooled Analysis
P value
1.28
0.001 lt 0.001
GI-3
1.38
Alvimopan 6 mg
Alvimopan 12 mg
1.34
GI-2
lt 0.001 lt 0.001
1.46
1.37
lt 0.001 lt 0.001
Ready for HD
1.48
1.36
lt 0.001 lt 0.001
DOW
1.43
2.5
2
1.5
1
0.5
0
In favor of alvimopan
In favor of placebo
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. 2007245355-363.
Studies 302, 308, 313
45
Alvimopan POI-Related MorbidityBowel Resection
Pooled Analysis
18
16
Placebo N 695
14
Alvimopan 12 mg N 714
12
10

Patients ()

8
6

4

2
0
Overall POM
Post-op NGT
Overall POI
POI Complications Resulting in Prolonged Stay
POI Complications Resulting in Readmission
Insertion
Complications
P 0.001 Studies 302, 308, 313, 314
POM postoperative morbidity NGT nasogastric
tube POI postoperative ileus
Wolff B, et al. J Am Coll Surg. 2007204609-616.
46
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
Treatment-Emergent Adverse Reaction Bowel Resection Patients Bowel Resection Patients All Surgical Patients All Surgical Patients
Treatment-Emergent Adverse Reaction Placebo (N 986) Alvimopan (N 999) Placebo (N 1365) Alvimopan (N 1650)
Anemia 4.2 5.2 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/prescribi
ng-information.pdf. Accessed March 2009.
47
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

48
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/2
008/NEW01838.html http//www.gsk.com/media/pressr
eleases/2007/2007_04_09_GSK1012.htm. Accessed
March 2009.
49
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/prescribi
ng-information.pdf. Accessed March 2009.
50
Multimodal/Fast Track Management for
Postoperative Ileus
51
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
Laparoscopicsurgery
Laxatives, prokinetics
Early feeding, fluid management
Epidural anesthetics
Mobilization?
Mattei P. World J Surg. 2006301382-1391.
Person B, Wexner S. Curr Probl Surg.
2006436-65.
52
Engage the Multidisciplinary Team

• Surgeons
• Anesthesiologists
• Med-surgical nurses
• Hospital pharmacists
• Rehabilitation personnel

53
Multimodal ApproachPreoperative 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. 20071041380-1396.
54
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. 20071041380-1396.
55
Multimodal ApproachPostoperative Components

• Remove NG tube
• Laxative, start oral feedings early
• Minimize opioids
• Ambulate
• Discharge criteria

White PF, et al. Anesth Analg. 20071041380-1396.
56
Fast-Track Example (Colectomy)
Day Standard Fast-Track
Pre-operative 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 gt 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
SICU surgical intensive care unit PACU
postanesthetic care unit
Raue W, et al. Surg Endosc. 2004181463-1468.
57
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.
2006436-65. White PF, et al. Anesth Analg.
20071041380-1396. Raue W, et al. Surg Endosc.
2004181463-1468.
58
Economic Burden of POI (2002 Premiers
Perspective Database)
No coded POI (N 175,992)
15
Coded POI (N 17,417)
25


10.6
20
10
16.3
Mean Duration of Hospital Stay (days)
Mean Hospital Costs per Patient 1,000
15
5.4
9.9
10
5
5
0
0
P lt 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.
59
Costs of POI?

• Implementation of multimodalpathways

• 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

60
Time to Change the WayWe 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

61
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