Transcript There Are Numerous Risk Factors for POI

Pathogenesis of POI Is Multifactorial
Sympathetic Nervous System
Inhibitory neural reflexes
Enteric Nervous System
Nitric oxide
Vasoactive intestinal peptide
Substance P
Neuropeptide and
Hormonal Factors
Multiple
Pathways
Inflammatory Mediators
Macrophage and neutrophil
infiltration, IL-1, tumor necrosis
factor, IL-6
IL = interleukin
Luckey A, et al. Arch Surg. 2003;138:206-214.
Holte K, Kehlet H. Drugs. 2002;62(18):2603-2615.
Person B, Wexner S. Curr Probl Surg. 2006;43:12-65.
Calcitonin gene-related
peptide, endogenous
opioid peptides,
corticotropin-releasing
hormone
Pharmacologic
Exogenous opioids
There Are Numerous Risk Factors for POI
Surgical
Site
Patient
Factors
Extent of
Bowel
Manipulation
POI Is Expected to
Affect Almost
Every Patient Who
Undergoes
Abdominal Surgery
Operation
Time
Patient
Health
Amount of
Opioids
Systemic
Infections
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.
POI and Abdominal Surgery
25
Coded POI (%)
20
15
10
5
0
Abdominal Large Bowel Small Bowel
CholeNephroOther
Appendectomy
Cystectomy
Hysterectomy Resection
Resection
cystectomy ureterectomy Procedures
Based on HCFA Data 1999-2000 for all surgeries except cystectomy; cystectomy data from Chang et al, 2002
Delaney C, et al. Clinical Consensus Update in General Surgery. 2006.
Chang S, et al. J Urol. 2002;167:2012-2016.
Clinical and Economic Impact of POI
DELAYED RECOVERY
•
•
•
•
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
Coded POI
Without Coded POI
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%)
Total number of
procedures (%)
Cumulative costs for coded POI
(total hospitalization + readmission cost) = $1,464,167,173
Kehlet H, Holte K. Am J Surg. 2001;182(5A suppl):3S-10S.
Person B, Wexner S. Curr Probl Surg. 2006;43:12-65.
Goldstein J, et al. P&T. 2007;32(2):82-90.
Preventive and Therapeutic
Management Options for POI
• Physical Options
–
–
–
–
Nasogastric tube
Early postoperative feeding
Sham feeding, gum chewing
Early ambulation
• Anesthesia and Analgesia
– Epidural
– NSAIDs
• Pharmacologic
– Prokinetic agents
– Opioid (PAMOR) antagonists
– Other agents
• Surgical Technique
– Laparoscopy
• Psychological
Perioperative Information
• Perioperative Care Plan(s)
PAMOR = peripherally acting µ-opioid receptor antagonist
Luckey A, et al. Arch Surg. 2003;138:206-214.
Person B, Wexner S. Curr Probl Surg. 2006;43:12-65.
– Multimodal clinical pathways
– Fluid/sodium restriction?
Management Options for POI
Nonpharmacologic Options
Management
NG tube
Early feeding
(including
sham feeding)
Early
ambulation
Laparoscopic
surgery
Potential Mechanism
Impact on Bowel Function,
Length of Stay
Gastric/small bowel
decompression
Removal of NG tube associated with
earlier return of bowel function,
reduction in pulmonary complications,
shorter length of stay
Stimulates GI motility by eliciting
reflex response
and stimulating release
of hormonal factors
Some studies report a reduction in
POI with early feeding, metaanalyses suggest a modest (nonsignificant) reduction in length of stay
Possible mechanical stimulation; No effect on duration of POI;
possible stimulation of intestinal beneficial for prevention of lower
function
extremity thromboembolism
Decreased opiate requirements,
decreased pain, less abdominal
wall trauma, less intestinal
manipulation
Nelson R, et al. Cochrane Database Syst Rev. 2007;(3):CD004929.
Holte K, Kehlet H. Br J Surgery. 2000;87:1480-1493.
Andersen H, et al. Cochrane Database Syst Rev. 2006;(4):CD004080.
Charoenkwan K, et al. Cochrane Database Syst Rev. 2007;(4):CD004508.
Earlier passage of flatus, earlier
bowel movement, shortened length of
stay
Lewis S, et al. J Gastrointest Surg. 2009;13:569-575.
Noble E, et al. Int J Surg. 2009;7:100-105.
Waldhausen J, et al. Ann Surg. 1990;212:671-677.
Zutshi M, et al. Colorectal Dis. 2004;6:477-480.
Schwenk W, et al. Cochrane Database Rev. 2005;(3):CD003145.
Management Options for POI
Pharmacologic Options
Treatment or
Prevention
Potential Mechanism
Impact on Bowel Function,
Length of Stay
Inhibits sympathetic reflex at cord
level; opioid-sparing analgesia
Earlier bowel movement, reduced
duration of POI compared with
systemic analgesic regimens
NSAIDs
Opiate-sparing analgesia, inhibits
COX-mediated prostaglandin
synthesis
Earlier bowel movement, earlier
ambulation, no change in length of stay
compared with morphine PCA
Metoclopramide
Dopamine antagonist, cholinergic
agonist, prokinetic agent
No benefit on the duration of POI
Erythromycin
Motilin receptor agonist,
prokinetic effect
No benefit on the duration of POI
Epidural (thoracic)
anesthesia/analgesia
Laxatives
Peripherally selective
mu-receptor antagonists
Help to induce bowel movement
Block enteric mu-receptors and
minimize opioid effects on GI
function, without impacting CNSmediated analgesia
Person B, Wexner S. Curr Probl Surg. 2006;43:12-65.
Chen JY, et al. Acta Anaesthesiol Scand. 2005;49:546-551.
Luckey A, et al. Arch Surg. 2003;138:206-214.
Becker G, Blum H. Lancet. 2009;373(9670):1198-1206.
Limited data from small
nonrandomized study suggests benefit;
additional study required
Clinical trials with alvimopan
demonstrated reduced time to recovery
of GI function, reduced time to
discharge order written compared with
placebo
POI: Peripheral Opioid Antagonism
• Most patients require opioids
• Opioids inhibit GI propulsive motility and secretion; the GI
effects of opioids are mediated primarily by µ-opioid
receptors within the bowel
• Naloxone and naltrexone reduce opioid bowel dysfunction
but can reverse analgesia in higher doses
• 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.
Becker G, Blum H. Lancet. 2009;373(9670):1198-1206.
Methylnaltrexone for POI: Phase 3 Studies
Segmental colectomy1,2 and ventral hernia repair3
 Treatment: IV methylnaltrexone (12 or 24 mg)
or placebo every 6 hours
 Primary endpoint: Reduction in time to recovery
of GI function compared with placebo
 Results: Treatment did not achieve primary or
secondary endpoints4-6
1. Available at: http://www.clinicaltrials.gov/ct2/show/NCT00387309. Accessed March 2009.
2. Available at: http://www.clinicaltrials.gov/ct2/show/NCT00401375. Accessed March 2009.
3. Available at: http://www.clinicaltrials.gov/ct2/show/NCT00528970. Accessed March 2009.
4. Available at: http://www.wyeth.com/news/archive?nav=display&navTo=/wyeth_html/
home/news/pressreleases/2008/1205322072160.html. Accessed March 2009.
5. Available at: http://www.progenics.com/releasedetail.cfm?ReleaseID=311785. Accessed March 2009.
6. Available at: http://www.progenics.com/releasedetail.cfm?ReleaseID=370543. Accessed July 2009.
Alvimopan Phase 3 Studies – GI Recovery
140
Time to GI-2 (hours)
120
100
Placebo
§
*
#
6 mg Alvimopan
12 mg Alvimopan
§
#
*
*
#
80
60
40
20
0
Bowel Resection, Bowel Resection,
Hysterectomy
Hysterectomy
Study 313
Study 302
Wolff BG, et al. Ann Surg. 2004;240:728-735.
Delaney CP, et al. Dis Colon Rectum. 2005;48:1114-1125.
Viscusi E, et al. Surg Endosc. 2006;20:67-70.
Ludwig K, et al. Arch Surg. 2008;143:1098-1105.
Büchler M, et al. Aliment Pharmacol Ther. 28:312-325.
Bowel Resection, Bowel Resection
Hysterectomy
Study 314
Study 308
Bowel Resection
Study 001
*P < 0.001; #P < 0.01; §P < 0.02;
Pooled Data From Phase III Studies of
Alvimopan: Hospital Resource Use
Studies 302, 308, 313
40
38.1
35
Placebo
Alvimopan 6 mg
Patients, %
30
†
24.4
Alvimopan 12 mg
25
†
19.9
20
15
13.7
*
10
8.6
†
7.0
11.7
‡
7.3
7.7
5
0
Prolonged hospital stay
*P = 0.024; †P < 0.001; ‡P = 0.040
DCO = discharge order
Delaney CP, et al. Ann Surg. 2007;245:355-363.
Readmission
DCO written ≥ 7 days
Alvimopan Safety
Worldwide POI Safety Population
TreatmentEmergent
Adverse
Reaction
Anemia
Bowel Resection Patients
All Surgical Patients
Placebo
(N = 986)
%
4.2
Alvimopan
(N = 999)
%
5.2
Placebo
(N = 1365)
%
5.4
Alvimopan
(N = 1650)
%
5.4
Constipation
3.9
4.0
7.6
9.7
Dyspepsia
4.6
7.0
4.8
5.9
Flatulence
Hypokalemia
4.5
3.1
7.7
8.7
8.5
9.5
7.5
6.9
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.entereg.com/pdf/prescribing-information.pdf. Accessed March 2009.
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.
E.A.S.E.: Entereg Access Support and Education. Available at: http://www.entereg.com/pdf/prescribing-information.pdf. Accessed March 2009.
Alvimopan for POI:
Formulary Considerations
E.A.S.E.™ Program
Distribution Program for ENTEREG® (alvimopan)
Alvimopan is available only to hospitals that enroll in the E.A.S.E.
Program. To enroll in the E.A.S.E. Program, the hospital must
acknowledge that hospital staff who prescribe, dispense, or administer
alvimopan have been provided the educational materials on:
– Limiting the use of alvimopan to short-term, inpatient use
– Patients will not receive more than 15 doses of alvimopan
– Alvimopan will not be dispensed to patients after they have been
discharged from the hospital
– Hospital will not transfer alvimopan to unregistered hospitals
E.A.S.E.: Entereg Access Support and Education. Available at: http://www.entereg.com/pdf/prescribinginformation.pdf. Accessed March 2009.
What Is “Fast-Track Recovery”?
• “An interdisciplinary multimodal concept to accelerate
postoperative convalescence and reduce general
morbidity (including POI) by simultaneously applying
several interventions”
NG tube
removal
• What are the
appropriate
choices in
constructing
fast-track,
multimodal
protocols?
Opioid sparing
Laparoscopic
surgery
Laxatives,
prokinetics
Epidural
anesthetics
*such as gum chewing
Mattei P. Rombeau J. World J Surg. 2006;30:1382-1391.
Person B, Wexner S. Curr Probl Surg. 2006;43:6-65.
Mobilization?
Early/sham*
feeding,
Optimal fluid
management
Fast-Track Example (Colectomy)
Day
Standard
Fast-Track
Preoperative
Consent, epidural (local anesthetic
[LA] with opioid)
Consent and educate, anti-emetic,
anxiolytic, epidural (LA with opioid)
Day of
surgery
Admit to SICU*, NG out with order,
i.v. fluids to body weight, continuous
epidural or PCA, anti-emetic, nothing
by mouth, sitting
Admit to floor post PACU, NG out with
extubation, limit i.v. fluid, continuous
epidural (limit systemic opioids), NSAID,
laxative, mobilize to chair, short walk,
soft foods
POD 1
Admit to floor, epidural or PCA, clear
oral liquids and i.v. fluids, out of bed,
remove drains and Foley
Transition to oral opioids or NSAIDs
(limit epidural and systemic opioids),
regular diet, mobilize > 8 hr, walk twice
daily, remove drains and Foley
POD 2
Epidural or PCA, laxative, mashed
food, out of bed
Remove epidural, plan discharge
POD 3
Transition to oral opioids (limit
epidural and systemic opioids), out of
bed
Oral opioids or NSAIDs, fully mobilize,
discharge
POD 8
Extract staples, discharge pending
orders
Outpatient clinic, extract staples
*Not all centers admit patients to the SICU under standard care
Raue W, et al. Surg Endosc. 2004;18:1463-1468.
SICU = surgical intensive care unit
PACU = postanesthetic care unit
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.