The Evolving Multimodal Management Plan for Postoperative Ileus: Improving Time to Bowel Recovery

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

3
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. 2001182 (5A
Suppl)3S-10S. Holte K, Kehlet H. Drugs.
2002622603-2615.
4
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 gt 5 days
  after open and gt 3 days after laparoscopic
  colectomy

Livingston EH, Passaro EP Jr. Dig Dis Sci.
199035121-132. Delaney CP, et al. Clinical
Consensus Update in General Surgery. 2006.
5
There Are Numerous Risk Factors for POI
Resnick J, et al. Am J Gastroenterol.
199792751-762. Resnick J, et al. Am J
Gastroenterol. 199792934-940. Senagore AJ. Am J
Health-Syst Pharm. 200764(suppl 13)S3-S7.
Senagore AJ, et al. Surgery. 2007142478-486.
Woods MS. Perspect Colon Rectal Surg.
20001257-76.
6
POI Pathogenesis Is Multifactorial
Minimizing the effects of 1 or more of these
factors could potentially shorten the duration of
POI and reduce the incidence of morbidity
Inhibitory Neural Reflexes1,2 Stimulation of
somatic and visceral fibers inhibits GI motility
Inflammatory Mediators1 Release of nitric oxide,
vasoactive intestinal peptide, calcitonin
gene-related peptide, substance P,
and prostaglandins contributes to POI
Opioids1-3 Endogenous and exogenous opioids
reduce propulsive activity in GI tract
Endogenous opioids endorphins, enkephalins, and
dynorphins. 1. Holte K, et al. Drugs.
2002622603-2615. 2. Behm AJ, et al. Clin
Gastroenterol Hepatol. 2003171-80. 3. Bauer B,
et al. Curr Opin Crit Care. 20028152-157.
7
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 homeostaticbalance
  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.
19963341106-1115.
8
Inflammatory Pathways of Postoperative Ileus
Anti-Inflammatory HO-1 (CO/Biliverdin)
Macrophages
Intestinal Surgery
Muscularis Externa
Inflammatory cytokines
Prostanoids
Adhesion molecules
a
-
adrenergic
NO
iNOS
PMN
Sympathetic Efferents
Primary Afferents
NO (iNOS)
COX-2 (prostanoids)
PGs (COX 2)
Motility
Cytokines (IL 6)
ROIs and Proteases
Macrophage
Monocytes
(inhibition)
Mast Cells
iNOS
Vagal
Barrier Function Disruption
a
-
7 receptor
acetylcholine
Lumenal Colo-Lymphatic Factors Activate
Leukocytes
JAK
/ STAT
HO-1 heme oxygenase-1 NO nitric oxide iNOS
inducible nitric oxide synthase PGs
prostaglandins ROIs reactive oxygen
intermediates
Moore B, et al. Sem Col Rect Surg.
200516(4)184-187.
9
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 intestinal secretions. Increased absorption of water from bowel contents Hard, dry stool
Pappagallo M. Am J Surg. 2001182
(suppl)11S-18S. Vanegas G, et al. Cancer Nurs.
199821289-297. Kurz A, Sessler DI. Drugs.
200363649-671.
10
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
Total 1,661,729 8.5
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.
11
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.
12
Hospital Discharge Associated With Recovery of
GI Function
GI-2 recovery
25
Hospital discharge
20
15
Patients ()
10
5
0
0
1
2
6
7
8
9
10
3
4
5
Postoperative Day
GI-2 Recovery of bowel movement and toleration
of solid food
Delaney CP, et al. Am J Surg. 2006191315-319.
13
There Is an Overall Health Care Burden Associated
With POI
Schuster TG, Montie JE. Urology.
200259465-471. Holte K, Kehlet H. Br J Surg.
2000871480-1493. Chang SS, et al. J Urol.
2002167208-211. Sarawate CA, et al.
Gastroenterology. 2003124(4S1)A-828.
14
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 (n 175,992) Coded POI (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
Mean total costs 9,944 16,303
Severe or most severe illness () 20.7 48.4
P lt 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.
15
Economic Burden of POI Associated With Abdominal
Surgery
Coded POI Without Coded POI
Total number of procedures () 142,026 (8.5) 1,519,663 (91.5)
Average length of stay (days) 11.5 5.5
Cost per hospital stay 18,877 9,460
Number of readmissions () 5,113 (3.6) 304 (0.02)
Cumulative costs for coded POI (total
hospitalization readmission cost)
1,464,167,173
Data from Premiers Perspective Comparative
Database,160 Hospitals, 2002
Goldstein J, et al. PT. 200732(2)82-90.
16

• What Are Current Management Strategies for POI?

17
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.
18
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. 2001182(S)3-10. Chea
tam M, et al. Ann Surg. 1995221469-478. Sagar
P, et al. Br J Surg. 199279(11)1127-1131.
19
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 lt 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 lt 0.0001)

Person B, Wexner S. Curr Probl Surg.
2006436-65. Nelson R, et al. Cochrane Database
Syst Rev. 2007CD004929.
20
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

21
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.
2006CD004080. Charoenkwan K et al. Cochrane
Database Syst Rev. 2007CD004508.
22
RCTs of Early Postoperative Feeding vs
Traditional Feeding

• b

Early feeding Traditional feeding (no oral intake
until POI resolved)
140 120 100 80 60 40 20 0


Duration of Ileus (h)

D
F
D
I
D
C
C
Reissman et al.(1995)
Ortiz et al.(1996)
Schilder et al.(1997)
Stewart et al.(1998)
Pearl et al.(1998)
Cutillo et al.(1999)
Binderow et al.(1994)
P lt 0.05
D defecation F flatus C combination
score I ingest regular food
Holte K, Kehlet H. Br J Surg. 2000871480-1493.
23
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. 1990212671-677.
24
Effect of Surgical Technique

• MOA Reduced activation of inhibitory reflexes
  and local inflammation due to reduced surgical
  trauma

800 600 400 200 0



Cells/125 x Magnification

Control
Laparotomy
Eventration
Running
Compression
Histogram of infiltrating polymorphonuclear
neutrophils in muscularis whole mounts after
different degrees of surgical manipulation. N
5-7 P lt 0.05
MOA mechanism of action Holte K, Kehlet H. Br J
Surg. 2000871480-1493. Kehlet H, Holte K. Am J
Surg. 2001182(5A suppl)3S-10S.
25
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 RCT randomized
clinical trial
Holte K, Kehlet H. Br J Surg. 2000871480-1493. K
ehlet H, Holte K. Am J Surg. 2001182(5A
suppl)3S-10S.
26
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

27
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. 20059552-58.
28
Epidural vs PCA Administration of Opioids
Epidural PCA
Pain control At rest On mobilization /-
Adverse effects Ileus Nausea and vomiting Sedation Hypotension Urinary retention Workload Shortening - - /- /- Prolongation
Postop morbidity reduction Cardiovascular (CV) Respiratory - -
Bonnet F, Marret E. Br J Anaesth. 20059552-58.
PCA patient-controlled analgesia
29
Effect of Epidural Local Anesthetics vs Systemic
Opioids on Postoperative Ileus
Holte K, Kehlet H. Br J Surg. 2000871480-1493.
30
Opioid-Sparing Analgesia
Total Morphine (mg)

• 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

350.0 300.0 250.0 200.0 150.0 100.0 50.0 0
R 0.48P 0.002

• ICD-9-CM coded POI correlates with systemic
  morphine (OR 12.1
• 95 CI, 5.4-27.1)

40 60 80 100 120 140 160 180
Hours to First Bowel Movement
Cali RL, et al. Dis Colon Rectum.
200043163-168. Goettsch WG, et al.
Pharmacoepidemiol Drug Saf. 200716668-674.
31
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 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.
200549546-51.
32
Prokinetic Agents

• Metoclopramide improves nausea but

Metoclopramide
Placebo
Erythromycin
120
90
Hypomotility (hours)
60
30
0
Jepsen (n 55)
Cheape (n 93)
Tollesson (n 20)
Seta (n 32)
Chan (n 32)
Lightfoot (n 22)
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. Seta ML, et al.
Pharmacotherapy. 2001211181-1186. Chan DC, et
al. World J Gastroenterol. 2005114776-4781.
Lightfoot AJ, et al. Urology. 200769611-615.
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 Reported as
Mean Time (hr) ? S.E.
Endpoint MNTX (n 33) Placebo (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
1-sided
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 1, phase 2, and phase 3 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 POIPhase 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 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)

42
Alvimopan POI Phase 3 Study Design
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

Randomization
Preop dose 30 min and lt 5 hr
Alvimopan 12 mg BID
Screening
Placebo BID
7 PODs or discharge
0
1
7
10
30
2
3
4
5
6
9
8
12
11
14
13
POD
In some studies, a 6 mg dose of alvimopan was
also evaluated
43
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

44
Alvimopan in Bowel Resection Pooled Analysis
(Studies 302, 308, 313)
Delaney CP, et al. Ann Surg. 2007245355-363.
45
Pooled Data From Phase III Studies of Alvimopan
Postoperative MorbidityStudies 302, 308, 313
15
12.2
12
Placebo
Alvimopan 6 mg
9.2
9
Alvimopan 12 mg
6.8
6.8
Patients,
6.7

6

3.9


3.0
3
1.9
1.8
1.5
1.2
1.0
0
Postoperative NGT insertion
POI as an SAE
EPSBO or POI as an SAE
Anastomotic leak
P lt 0.05 P lt 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. 2007245355-363.
46
Pooled Data From Phase III Studies of Alvimopan
Hospital Resource Use Studies 302, 308, 313
38.1
40
35
Placebo

Alvimopan 6 mg
30
Alvimopan 12 mg
24.4

25
19.9
Patients,
20
13.7
15
11.7



8.6
10
7.7
7.3
7.0
5
0
Prolonged hospital stay
Readmission
DCO written 7 days
P 0.024 P lt 0.001 P 0.040 DCO
discharge order Delaney CP, et al. Ann Surg.
2007245355-363.
47
GI Tract Recovery in Patients Following Bowel
Resection Alvimopan 12 mg Study 314
Endpoint Alvimopan (n 317) Placebo (n 312) P-value
GI-2 (hr) 92.0 111.8 ---
GI-2 hazard ratio 1.53 (1.29, 1.82) --- lt 0.001
LOS (days) 5.2 6.2 lt 0.001
POI-related morbidity () 6.9 14.4 0.003
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 lt 0.001) Abdominal
distention (placebo 20.3 vs alvimopan 17.6 P
0.42)
Ludwig K, et al. Arch Surg. 20081431098-1105.
48
Time to GI-2 Combined Data From 5 Alvimopan
Studies (Bowel Resection)
1.0
Alvimopan 12 mg Placebo
0.9
0.8
0.7
0.6
Estimated Probability of Achieving GI-2 Recovery
0.5
0.4
0.3
0.2
0.1
0.0
0
24
48
72
96
120
144
168
192
216
240
264
Hours After End of Surgery

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.

Available at http//www.entereg.com/pdf/prescribi
ng-information.pdf. Accessed March 2009.
49
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

50
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. and http//www.gsk.com/media/p
ressreleases/2007/2007_04_09_GSK1012.htm.
Accessed March 2009.
51
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.
52
Multimodal/Fast Track Management
53
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 the pharmacist)
Laparoscopicsurgery
Epidural anesthetics
Early feeding, fluid management
Mobilization?
Mattei P. World J Surg. 2006301382-1391.
Person B, Wexner S. Curr Probl Surg.
2006436-65.
54
Multimodal ApproachPreoperative 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. 20071041380-1396.
55
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.
56
Multimodal ApproachPostoperative Components

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

White PF, et al. Anesth Analg. 20071041380-1396.
57
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.
58
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.
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
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.
200764(20Suppl 13)S8-12.
61
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.
200764(20Suppl 13)S8-12.
62
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. 20071041380-1396.

63
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

64
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