ACS Chapter Meeting Content

The Evolving Multimodal Management Plan for Postoperative Ileus:

Improving Time to Bowel Recovery

• 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

Educational Activity Learning Objectives

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

Postoperative Ileus Management Council

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 surgery1-

3

– Small intestine: 0-24 hours

– Stomach: 24-48 hours

– Colon: 48-120 hours

1. Luckey A, et al. Arch Surg. 2003;138:206-214.2. Livingston EH, Passaro EP Jr. Dig Dis Sci. 1990;35:121-132.3. 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.

Sympathetic Nervous System1,2 Inhibitory neural reflexes

Neuropeptide and Hormonal Factors1,2 Calcitonin gene-related peptide, endogenous opioid peptides, corticotropin-releasing factor

Pharmacologic2

Exogenous opioids

Multiple Pathways

Enteric Nervous System2

Nitric oxideVasoactive intestinal peptide

Substance P

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.

Pathogenesis of POI Is Multifactorial

Kalff J, et al. Ann Surg. 1998;228:652-663.

Intestinal contractility Leukocyte infiltration into intestinal mucosa

* P < 0.05

Effect of Surgical Manipulation

*

** *

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ControlLaparotomyEventrationRunningCompression

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. 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.

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

Delayed recovery

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.

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

0

5

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Abdominal Hysterectomy

Large Bowel Resection

Small Bowel Resection

Appendectomy Chole-cystectomy

Nephro-ureterectomy

Other Procedures

Co

ded

PO

I (%

)

Delaney C, et al. Clinical Consensus Update in General Surgery. 2006.

HCFA Data 1999-2000

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)

Salvador CG, et al. P&T. 2005;30:590-595.

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)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

Indications for Readmission

Kariv Y, et al. Am J Surg. 2006;191:364-371.

33%

23%

24% 20%

Surgical site septiccomplications (SSSC)

Ileus/small bowelobstruction (SBO)

Medicalcomplications

Other

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 capacityCOPDPostoperative fever Postoperative ileusStoma 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)

Factors Associated With Readmission Cause

Kariv Y, et al. Am J Surg. 2006;191:364-371.

RD = readmission within 30 days of dischargeSSSC: surgical site septic complications; SBO: small bowel obstruction

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– 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. 2003;138:206-214.

Management Options for POINonpharmacologic 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

N = 31 CREAD patientsN = 33 traditional postop care patientsDelaney C, et al. Dis Col Rect. 2003;46:851-859.

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.

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.

RCT: Laparoscopy vs Open Surgery

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Lacy et al. (1995)

Schwenk et al.(1998)

Milsom et al.(1998)

Laparoscopic

Open

F D D F

*

*

*

Leung et al.(2000)

*P < 0.05

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 POIPharmacologic 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-2selective 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. 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 (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

Epidural Thoracic Anesthetics

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

Adapted from Person B, Wexner S. Curr Probl Surg. 2006;43:12-65.

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 < 0.05

Ahn et al, 1988 Colorectal Yes Yes < 0.001

Bredtmann et al, 1990 Colonic --- Yes < 0.001

Jayr et al, 1993 Major abdominal Yes --- < 0.05

Morimoto et al, 1995 Proctocolectomy/IPAA --- Yes < 0.01

Liu et al, 1995 Colonic Yes Yes < 0.005

Scott et al, 1996 Proctocolectomy/IPAA Yes Yes < 0.05

Bradshaw et al, 1998 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

*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

D = defecation; F = flatus; I = ingestion of solid food

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Cheape et al. (1991)

Tollesson et al. (1991)

Metoclopramide

Placebo

F I D

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.

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.

Naltrexone N-methylnaltrexone

+

CH3

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. 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 MNTX N = 33

Placebo N = 32

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200

Full Liquids 1st BM GI Recovery DischargeEligible

ActualDischarge

Tim

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*

*

*

*P < 0.05Viscusi, 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.

Fentanyl

Alpha vi mu opioid peripheral antagonist

Alvimopan: A Novel, Quaternary-Opioid Receptor Antagonist

Moderately Large MW (461 Da)

Schmidt WK. Am J Surg. 2001;182(5A suppl):27S-38S.

Alvimopan

1. Azodo IA, et al. Curr Opin Investig Drugs. 2002;3:1496-1501. 2. Schmidt WK. Am J Surg. 2001;182(5A suppl):27S-38S.3. Taguchi A, et al. N Engl J Med. 2001;345:935-940.4. Wolff BG, et al. Ann Surg. 2004;240:728-735.5. Delaney CP, et al. Dis Colon Rectum. 2005;48:1114-1125. 6. Viscusi E, et al. Surg Endosc. 2006;20:67-70.7. Ludwig K, et al. Arch Surg. 2008;143:1098-1105.8. Buchler M, et al. Aliment Pharmacol Ther. 2008;28:312-325.9. FDA approval available at: http://www.accessdata.fda.gov/scripts/cder/drugsatfda. Accessed March 2009.

• 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

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

3083Bowel 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 writtenAll studies conducted in North America except 001, which was conducted in Europe and New Zealand

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.

Alvimopan POI Phase 3 Study Design

Surgery

Randomization

Placebo BID

Alvimopan 6 mg BID

Pre-op dose ≥ 30 min and < 5 hrs before surgery Endpoints: GI-2, GI-3,

Time to discharge order written,safety

Treatment until discharge or up to 7 days

Upper and Lower GI RecoveryGI-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 12 mg BID

Alvimopan Phase 3 Studies – GI Recovery

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Study 313 Study 302 Study 308 Study 314 Study 001

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Studies 313, 302, 308 include bowel resection and hysterectomy; Studies 314, 001 bowel resection only

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.

** *

*P < 0.001; #P < 0.01; §P < 0.02;

§

##

#

§

Alvimopan Phase 3 Studies: Discharge Orders Written

-25

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-10

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0Study 313 Study 302 Study 308 Study 314 Study 001

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6 mg Alvimopan 12 mg Alvimopan

P = 0.003

P < 0.001 P = 0.008P = 0.015

P < 0.001

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

Delaney C, et al. Ann Surg. 2007;245:355-363. Studies 302, 308, 313

GI-3

GI-2

Ready for HD

DOW

Alvimopan 6 mgAlvimopan 12 mg

2.52 1.5 10.50

In favor of alvimopanIn favor of placebo

P value

0.001< 0.001

< 0.001< 0.001

< 0.001< 0.001

< 0.001< 0.001

1.28

1.38

1.34

1.46

1.37

1.48

1.36

1.43

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

Alvimopan POI-Related MorbidityBowel Resection Pooled Analysis‡

Wolff B, et al. J Am Coll Surg. 2007;204:609-616.*P ≤ 0.001‡Studies 302, 308, 313, 314

0

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18

Overall POM Post-op NGTInsertion

Overall POIComplications

POI ComplicationsResulting in

Prolonged Stay

POI ComplicationsResulting in Readmission

Pat

ien

ts (

%)

Placebo N = 695

Alvimopan 12 mg N = 714

**

* *

POM: postoperative morbidity; NGT: nasogastric tube; POI: postoperative ileus

Treatment-Emergent Adverse Reaction

Bowel Resection Patients All Surgical Patients

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

Worldwide POI Safety Population

Available at: http://www.entereg.com/pdf/prescribing-information.pdf. Accessed March 2009.

Alvimopan SafetyTreatment-emergent Adverse Events Reported in ≥ 3%

Alvimopan-treated Patients and for Which the Rate for Alvimopan was ≥ 1% than Placebo

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/prescribing-information.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”

• What are the appropriate choices in constructing fast-track, multimodal protocols?

Opioid sparing

Laparoscopicsurgery

Early feeding,fluid

managementMobilization?

Epidural anesthetics

Laxatives, prokinetics

NG tuberemoval

Mattei P. World J Surg. 2006;30:1382-1391. Person B, Wexner S. Curr Probl Surg. 2006;43:6-65.

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

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 > 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 unitPACU = 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)

Mea

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osp

ital

S

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s)

*P < 0.05 for coded POI vs no coded POI

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Senagore A, et al. American Society of Colon and Rectal Surgeons 2005 Annual Meeting (abstract). S22, p.165.

5.4

10.6

0

5

10

15No coded POI (N = 175,992)

Coded POI (N = 17,417)

9.9

16.3

0

5

10

15

20

25*

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

• 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

Time to Change the WayWe Think About POI!

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