the evolving multimodal management plan for postoperative ileus: improving time to bowel recovery...
TRANSCRIPT
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The Evolving Multimodal Management Plan for Postoperative Ileus:
Improving Time to Bowel Recovery
ASHP Chapter Meeting Content
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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
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Postoperative Ileus (POI)
A temporary impairment of GI motility that occurs for a variable period after
abdominal surgery
Kehlet H, Holte K. Am J Surg. 2001;182 (5A Suppl):3S-10S. Holte K, Kehlet H. Drugs. 2002;62:2603-2615.
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Postoperative Ileus (POI)
• Results in a functional inhibition of propulsive bowel activity, irrespective of pathogenetic mechanisms
– Primary POI: such cessation occurring in the absence of any precipitating complication
– Secondary POI: that occurring in the presence of a precipitating complication (infection, anastomotic leak, etc.)
• Paralytic ileus: form of POI lasting > 5 days after open and > 3 days after laparoscopic colectomy
Livingston EH, Passaro EP Jr. Dig Dis Sci. 1990;35:121-132. Delaney CP, et al. Clinical Consensus Update in General Surgery. 2006.
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There Are Numerous Risk Factors for POI
POI Is Expected to Affect Almost
Every Patient Who Undergoes
Abdominal Surgery
Surgical Site
Extent ofBowel
Manipulation
Operation Time
PatientHealth
Systemic Infections
Amount of Opioids
PatientAge,
Gender, Race
Resnick J, et al. Am J Gastroenterol. 1997;92:751-762. Resnick J, et al. Am J Gastroenterol. 1997;92:934-940.Senagore AJ. Am J Health-Syst Pharm. 2007;64(suppl 13):S3-S7. Senagore AJ, et al. Surgery. 2007;142:478-486. Woods MS. Perspect Colon Rectal Surg. 2000;12:57-76.
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POI: Pathogenesis Is Multifactorial
Endogenous opioids = endorphins, enkephalins, and dynorphins.
1. Holte K, et al. Drugs. 2002;62:2603-2615. 2. Behm AJ, et al. Clin Gastroenterol Hepatol. 2003;1:71-80.3. Bauer B, et al. Curr Opin Crit Care. 2002;8:152-157.
Opioids1-3
Endogenous and exogenous opioids reduce propulsive activity in GI tract
InflammatoryMediators1
Release of nitric oxide, vasoactive intestinal peptide, calcitonin gene-related peptide, substance P, andprostaglandins contributes to POI
Inhibitory NeuralReflexes1,2
Stimulation of somatic and visceral fibers inhibits GI motility
Minimizing the effects of 1 or more of these factors could potentially shorten the duration of POI and reduce the incidence of morbidity
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Origins of Postoperative IleusNeural 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. 1996;334:1106-1115.
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Moore B, et al. Sem Col Rect Surg. 2005;16(4):184-187.
Inflammatory Pathways of Postoperative Ileus
Intestinal Surgery
Motility
Inflammatory cytokinesAdhesion moleculesProstanoids
NO
NO (iNOS)PGs (COX – 2)
Cytokines (IL – 6)
ROIs and Proteases
Macrophages
Muscularis Externa
Sympathetic EfferentsPrimary Afferents
Mast Cells
PMN
Monocytes
“Barrier Function Disruption”
iNOS
Vagalacetylcholine
iNOSα-adrenergic
COX-2 (prostanoids)
α-7 receptorJAK / STAT
Anti-Inflammatory HO-1 (CO/Biliverdin)
Macrophage(inhibition)
HO-1: heme oxygenase-1; NO: nitric oxide; iNOS: inducible nitric oxide synthase; PGs: prostaglandins; ROIs: reactive oxygen intermediates
Lumenal Colo-Lymphatic Factors Activate Leukocytes
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Pharmacologic ClinicalDecreased 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
GI Effects of Opioids
Pappagallo M. Am J Surg. 2001;182 (suppl):11S-18S.Vanegas G, et al. Cancer Nurs. 1998;21:289-297. Kurz A, Sessler DI. Drugs. 2003;63:649-671.
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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.
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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.
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Hospital Discharge Associated With Recovery of GI Function
GI-2 = Recovery of bowel movement and toleration of solid food
Delaney CP, et al. Am J Surg. 2006;191:315-319.
Pat
ien
ts (
%)
0
5
10
15
20
25
0 1 2 3 4 5 6 7 8 9 10
Postoperative Day
GI-2 recovery
Hospital discharge
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There Is an Overall Health Care Burden Associated With POI
Prolonged hospitalization
POI
Beds occupied for
more time
Increased nursing time
Increased resource utilization
Schuster TG, Montie JE. Urology. 2002;59:465-471.Holte K, Kehlet H. Br J Surg. 2000;87:1480-1493.Chang SS, et al. J Urol. 2002;167:208-211.Sarawate CA, et al. Gastroenterology. 2003;124(4S1):A-828.
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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*
Senagore A, et al. American Society of Colon and Rectal Surgeons 2005 Annual Meeting (abstract). S22, p.165.
* P < 0.05 vs no coded POI; ** Based on APR-DRG severity levels
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Economic Burden of POI Associated With Abdominal Surgery
Goldstein J, et al. P&T. 2007;32(2):82-90.
Data from Premier’s Perspective Comparative Database,160 Hospitals, 2002
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
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What Are Current Management Strategies for POI?
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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.
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Nasogastric (NG) Intubation and POI
• Traditionally used at many institutions and is one of the mainstays of therapy along with IV hydration
• There are no data to support any beneficial effect of NG tubes on postoperative ileus
• Can delay feeding and thus recovery from POI
• May contribute to problems such as atelectasis, pneumonia, and fever
Kehlet H, et al. Am J Surg. 2001;182(S):3-10.Cheatam M, et al. Ann Surg. 1995;221:469-478.Sagar P, et al. Br J Surg. 1992;79(11):1127-1131.
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NG Tubes
• NG tubes routinely inserted for gastric decompression until return of bowel function
• Removal of NG intubation
– Meta-analysis of 28 trials (n = 4194) of abdominal surgery• Accelerated bowel recovery by 0.52 days (95% CI, 0.46-0.57; P
< 0.0001)
• Earlier flatulence by 0.53 days (95% CI, 0.28-0.78; P = 0.0004)
• Reduced vomiting (OR = 0.66 95% CI, 0.45-0.95; P = 0.03)
• Reduced pulmonary complications (RR = 1.45 95% CI, 1.08-1.92; P = 0.01)
• Shortened LOS by 1.21 days (95% CI, 0.56-1.86-1.94; P < 0.0001)
Person B, Wexner S. Curr Probl Surg. 2006;43:6-65.Nelson R, et al. Cochrane Database Syst Rev. 2007;CD004929.
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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
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Early Oral or Enteral Feeding• Convention is restriction of enteral intake• Early oral or enteral feeding (within 24 hours)
– Meta-analysis of 13 trials (n = 1173) of colorectal surgery • Less vomiting (RR = 1.27 95% CI, 1.01-1.61; P = 0.04)• Shortened LOS by 0.89 days (95% CI, 0.20-1.58-1.94; P = 0.01)• Reduced mortality (RR = 0.41 95% CI, 0.18-0.93; P = 0.03)
– Meta-analysis of three trials (n = 413) of abdominal gynecologic surgery
• Reduced nausea (RR = 1.79 95% CI, 1.19-2.71; P = 0.006)• Earlier bowel sounds by 0.50 days (95% CI 0.16-0.84)• Shortened time to intake of solid food by 1.47 days (95% CI,
0.69-2.26; P = 0.0004)• Shortened LOS by 0.73 days (95% CI, 0.07-1.52; P = 0.07)
Andersen HK et al. Cochrane Database Syst Rev. 2006;CD004080. Charoenkwan K et al. Cochrane Database Syst Rev. 2007;CD004508.
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RCTs of Early Postoperative Feeding vs Traditional Feedingb
Holte K, Kehlet H. Br J Surg. 2000;87:1480-1493.
D = defecation; F = flatus; C = combination score; I = ingest regular food
Early feeding
Traditional feeding (no oral intake until POI resolved)
Binderow et al.(1994)
Reissman et al.(1995)
Ortiz et al.(1996)
Schilder et al.(1997)
Stewart et al.(1998)
Pearl et al.(1998)
Cutillo et al.(1999)
Du
rati
on
of
Ileu
s (h
)
140
120
100
80
60
40
20
0
*
*
*
DFDIDCC
*P < 0.05
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Mobilization and Postoperative Ileus
• Important in helping to prevent postoperative complications such as clots, atelectasis, or pneumonia
• Ambulation thought to help increase blood flow to the GI and speed up recovery from POI
• Lack of studies showing any effect of mobilization (alone) to stimulate bowel function and decrease duration of POI
Waldhausen J, et al. Ann Surg. 1990;212:671-677.
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Effect of Surgical TechniqueMOA: Reduced activation of inhibitory reflexes and local inflammation due to reduced surgical trauma
MOA = mechanism of actionHolte K, Kehlet H. Br J Surg. 2000;87:1480-1493.Kehlet H, Holte K. Am J Surg. 2001;182(5A suppl):3S-10S.
*800
600
400
200
0Control Laparotomy Eventration Running Compression
Histogram of infiltrating polymorphonuclear neutrophils in muscularis whole mounts after different degrees of surgical manipulation. N = 5-7; *P < 0.05
*
*
*
Cel
ls/1
25 x
Mag
nif
icat
ion
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D = defecation; F = flatus; RCT = randomized clinical trial
.
Holte K, Kehlet H. Br J Surg. 2000;87:1480-1493.Kehlet H, Holte K. Am J Surg. 2001;182(5A suppl):3S-10S.
RCT: Laparoscopy vs Open Surgery
120
100
80
60
40
20
0
Du
rati
on
of
Ileu
s (h
)
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
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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
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Anesthetic Choice and Route• Almost all intraoperative inhaled or i.v. anesthetics
temporarily inhibit GI motility– Level of monitoring is important!
• Epidural anesthesia/analgesia synergistically block inhibitory sympathetic reflexes, prevent the release of afferent pain neurotransmitters, and increase splanchnic blood flow
• Epidural anesthetics dose-dependently block nociceptive and autonomic fibers first and motor and somatosensory fibers last
• Epidural analgesia reduces opioid adverse effects• Use of local anesthesia and nerve blocks further reduce
systemic exposure
Bonnet F, Marret E. Br J Anaesth. 2005;95:52-58.
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Epidural vs PCA Administration of Opioids
Epidural PCA
Pain controlAt restOn mobilization
+++++
+++/-
Adverse effectsIleusNausea and vomitingSedation Hypotension Urinary retention
Workload
Shortening--
+/-+/-+
Prolongation++++++
Postop morbidity reductionCardiovascular (CV)Respiratory
++
--
Bonnet F, Marret E. Br J Anaesth. 2005;95:52-58. PCA: patient-controlled analgesia
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Holte K, Kehlet H. Br J Surg. 2000;87:1480-1493.
Effect of Epidural Local Anesthetics vs Systemic Opioids on Postoperative Ileus
*P < 0.05
* ** *
**
0
50
100
150
200
Wallin1986
Scheinin 1987
Ahn1988
Wattwil1989
Bredtman1990
Riwar1991
Liu1995
Neudecker1999
Len
gth
of
PO
I (h
ou
rs)
Epidural local
anesthetics Systemic opioid
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Opioid-Sparing Analgesia
• 40 colectomy patients– Correlation between
morphine PCA dose and first bowel sounds (P = 0.001), flatulence, (P = 0.003), and first bowel movement (shown, P = 0.002)
– No correlation between incision length and morphine dose
Hours to First Bowel Movement
R = 0.48P = 0.002
Total Morphine (mg) 350.0
300.0
250.0
200.0
150.0
100.0
50.0
0
40 60 80 100 120 140 160 180
• ICD-9-CM coded POI correlates with systemic morphine (OR = 12.1; 95% CI, 5.4-27.1)
Cali RL, et al. Dis Colon Rectum. 2000;43:163-168. Goettsch WG, et al. Pharmacoepidemiol Drug Saf. 2007;16:668-674.
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Opioid-Sparing Analgesia• Nonsteroidal anti-inflammatory drugs (NSAIDs)
– Reduce prostaglandin production– R, DB study of morphine PCA ± ketorolac in 79 colorectal surgeries showed 29% less
morphine use, earlier first bowel movement (1.5 [0.7-1.9] vs 1.7 [1-2.8] days, P < 0.05), and earlier ambulation (2.2 ± 1 vs 2.8 ± 1.2 days, P < 0.05) with NSAID use
– Similar results in other surgeries and epidural route– Concerns: platelet inhibition (bleeding)
• Cyclooxygenase-2 (COX-2) Inhibitors – Similar results as NSAIDs; safety?
• Surveys indicate patients prefer inadequate pain relief over adequate analgesia with associated bowel dysfunction
Person B. Wexner S. Curr Probl Surg. 2006;43:6-65.Chen JY. Acta Anaesthesiol Scand. 2005;49:546-51.
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Prokinetic Agents• Metoclopramide improves nausea but…
Jepsen S, et al. Br J Surg. 1986;73:290-291. Cheape JD, et al. Dis Colon Rectum. 1991;34:437-441. Tollesson PO, et al. Eur J Surg. 1991;157:355-358. Seta ML, et al. Pharmacotherapy. 2001;21:1181-1186. Chan DC, et al. World J Gastroenterol. 2005;11:4776-4781. Lightfoot AJ, et al. Urology. 2007;69:611-615.
0306090
120
Jepsen(n = 55)
Cheape(n = 93)
Tollesson(n = 20)
Seta(n = 32)
Chan(n = 32)
Lightfoot(n = 22)H
yp
om
oti
lity
(h
ou
rs)
Metoclopramide Placebo Erythromycin
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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.
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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.
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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.
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Methylnaltrexone Phase 2: Results Reported as Mean Time (hr) S.E.
EndpointMNTX
(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
Viscusi E, et al. Anesthesiology. 2005;103:A893.
*1-sided
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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.
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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.
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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 1, phase 2, and phase 3 trials have been completed3-8
• FDA approval May 20089
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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.
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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)
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Alvimopan POI Phase 3 Study Design
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 Surgery
Preop dose≥ 30 min and < 5 hr
POD0 1 7 10–30
Screening
Alvimopan 12* mg BID
Placebo BID
≤ 7 PODs or discharge
2 3 4 5 6 98 1211 1413
* In some studies, a 6 mg dose of alvimopan was also evaluated
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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
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Delaney CP, et al. Ann Surg. 2007;245:355-363.
Alvimopan in Bowel Resection: Pooled Analysis (Studies 302, 308, 313)
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Pooled Data From Phase III Studies of Alvimopan: Postoperative Morbidity
Studies 302, 308, 313
*P < 0.05; †P < 0.001; ‡P = 0.003
NGT = nasogastric tube; POI = postoperative ileus; SAE = serious adverse event; EPSBO = early postoperative small bowel obstructionDelaney CP, et al. Ann Surg. 2007;245:355-363.
Pa
tie
nts
, %
† †
12.2
6.7
9.2
1.2
*6.8
1.8
3.0
1.51.9
3.9
1.0
0
3
6
9
12
15
Postoperative NGT insertion
POI as an SAE EPSBO or POIas an SAE
Anastomotic leak
Placebo
Alvimopan 6 mg
Alvimopan 12 mg *
6.8
†‡
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Pooled Data From Phase III Studies of Alvimopan: Hospital Resource Use
Studies 302, 308, 313
*P = 0.024; †P < 0.001; ‡P = 0.040
DCO = discharge orderDelaney CP, et al. Ann Surg. 2007;245:355-363.
Prolonged hospital stay Readmission DCO written ≥ 7 days
Placebo
Alvimopan 6 mg
Alvimopan 12 mg
Pa
tie
nts
, %
‡* †
†
†
13.7 11.7
38.1
8.67.3
24.4
7.0 7.7
19.9
0
5
10
15
20
25
30
35
40
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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) --- < 0.001
LOS (days) 5.2 6.2 < 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 < 0.001) – Abdominal distention (placebo 20.3% vs alvimopan 17.6%; P = 0.42)
Ludwig K, et al. Arch Surg. 2008;143:1098-1105.
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Time to GI-2: Combined Data From 5 Alvimopan Studies (Bowel Resection)
Est
imat
ed P
rob
abili
ty o
f A
chie
vin
g G
I-2
Rec
ove
ry
Hours After End of Surgery
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.00 24 48 72 96 120 144 168 192 216 240 264
Alvimopan 12 mg
Placebo
1. Wolff BG, et al. Ann Surg. 2004;240:728-735.2. Delaney CP, et al. Dis Colon Rectum. 2005;48:1114-1125. 3. Viscusi E, et al. Surg Endosc. 2006;20:67-70.4. Ludwig K, et al. Arch Surg. 2008;143:1098-1105.5. Buchler M, et al. Aliment Pharmacol Ther. 28:312-325.Available at: http://www.entereg.com/pdf/prescribing-information.pdf. Accessed March 2009.
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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
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Alvimopan for Opioid-induced Bowel Dysfunction (OBD)
• 12-month study in patients taking opioids for chronic non-cancer pain– Alvimopan (0.5 mg) or placebo BID
• More reports of myocardial infarction in patients treated with alvimopan (1.3%) compared with placebo (0)– Serious cardiovascular adverse events in patients at high risk for
cardiovascular disease – Myocardial infarction did not appear to be linked to duration of
dosing– Not observed in other alvimopan studies, including POI studies
in patients undergoing bowel resection (12 mg dose BID for up to 7 days)
– Causal relationship between alvimopan and myocardial infarction has not been established
Available at: http://www.fda.gov/bbs/topics/NEWS/2008/NEW01838.html. and http://www.gsk.com/media/pressreleases/2007/2007_04_09_GSK1012.htm. Accessed March 2009.
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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.
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Multimodal/Fast Track Management
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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?
POI (the role ofthe pharmacist)
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.
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Multimodal Approach:Preoperative Components
• Education
• Stabilize coexisting diseases
• Optimize comfort (minimize anxiety)
• Ensure hydration, electrolytes, normothermia
• Appropriate use of prophylactic therapy (nausea, ileus, pain, antibiotic)
White PF, et al. Anesth Analg. 2007;104:1380-1396.
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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.
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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.
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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
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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.
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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
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Role of the Pharmacist• Medication protocol
– Comfort (minimize anxiety)
– Appropriate hydration, electrolytes, normothermia
– Appropriate use of prophylactic therapy (nausea, ileus, pain, antibiotic)
– Postoperative analgesia (with opioid minimization) and pain assessment
– Laxatives
Gannon RH. Am J Health-Syst Pharm. 2007;64(20Suppl 13):S8-12.
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Role of the Pharmacist (cont)
• Stabilize coexisting diseases
• Advocate diet
• Promote mobilization
• Team member and education of team
• Discharge planning
• Patient education and compliance assessment
Gannon RH. Am J Health-Syst Pharm. 2007;64(20Suppl 13):S8-12.
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The Future• Identification of risk factors for POI
• Patient-centered care– Hydration and electrolytes
– Opioid regimen and opioid-sparing therapies
– Anxiolytic and anti-emetic therapies
• Pharmacologic modification of the “stress response”
• Multidisciplinary PACUs
• Clinical pathways
• Outreach services for rehabilitation
White PF, et al. Anesth Analg. 2007;104:1380-1396.
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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
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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