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Therapeutic Update on Management of Postoperative Ileus

A podcast educational activity based on a live symposium Available at www.postopileus.org

Sunday, October 7, 2007 New Orleans, Louisiana

This activity is planned and coordinated by ASHP Advantage and supported by an educational grant from Adolor Corporation and GlaxoSmithKline

Therapeutic Update on Management of Postoperative Illeus

Agenda Part 1 Enhanced Recovery Surgery: State of the Art Anthony Senagore, M.D., M.S., M.B.A., FACS, FASCRS Part 2 Impact of Anesthesia and Analgesia on Postoperative Ileus: A View from “Above the Screen” T.J. Gan, M.B., B.S., FRCA Part 3 Emerging Pharmacologic Options for Managing Postoperative Ileus Conor P. Delaney, M.D., M.Ch., Ph.D., FRCSI, FACS

Faculty Anthony Senagore, M.D., M.S., M.B.A., FACS, FASCRS, Program Chair Vice President of Research and Medical Education Spectrum Health Professor of Surgery Michigan State University Grand Rapids, Michigan Conor P. Delaney, M.D., M.Ch., Ph.D., FRCSI, FACS Professor of Surgery, Case Western Reserve University Chief, Division of Colorectal Surgery Vice-Chairman, Department of Surgery Director, Institute for Surgery and Innovation University Hospitals of Cleveland, Case Medical Center Cleveland, Ohio T. J. Gan, M.B., B.S., FRCA Professor and Vice Chair for Clinical Research Department of Anesthesiology Duke University Medical Center Durham, North Carolina

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Overview One of the most common causes of extended length of hospital stay following abdominal surgery is postoperative ileus (POI), which is temporary impairment of gastrointestinal motility characterized by abdominal distension and pain, delayed passage of gas and stool, nausea and vomiting, and diminished appetite. The condition may delay patient ambulation, increasing the risk for pulmonary and thromboembolic complications, and it may delay enteral feedings or resumption of a solid diet, resulting in poor nutrition with delayed wound healing. The use of opioid analgesics for postoperative pain relief often exacerbates POI. Current management strategies consist of careful selection of anesthetic and analgesic choices before, during, and after surgery, along with the avoidance of nasogastric tube feedings and the use of supportive therapies. State-of-the-art enhanced-recovery surgery protocols incorporate these management strategies to improve patient recovery, shorten length of stay related to postoperative ileus, and reduce resource consumption. This symposium will provide an update on the therapeutic management of postoperative ileus, beginning with an overview of the components of enhanced-recovery surgery protocols. The impact of choice of surgery type, anesthesia, and analgesia on POI will be presented, emphasizing the multidisciplinary responsibility for managing POI. The results of current clinical research exploring the potential use of peripherally selective µ-opioid receptor antagonists following major abdominal surgery as a means to prevent and minimize the impact of POI will also be presented.

Learning Objectives At the conclusion of this symposium, participants should be able to

• Describe the pathophysiology of postoperative ileus.

• Describe the rationale for at least three components of enhanced-recovery surgery protocols.

• Describe the relative benefits of balanced anesthesia and epidural analgesia with respect to postoperative ileus.

• Identify two options for optimizing postoperative analgesia while minimizing opioid-related adverse effects.

• Describe recent clinical research into new and emerging pharmacologic options for preventing and managing postoperative ileus.

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Continuing Education Accreditation

The American Society of Health-System Pharmacists is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. ASHP designates this educational activity for a maximum of 2.0 AMA PRA Category 1 CreditsTM. Physicians should only claim credit commensurate with the extent of their participation in the

activity. Podcast activity #08703.

Format and Method This activity consists of audio, post-test, and activity evaluation tool. Participants must listen to the entire presentation, take the activity post-test, and complete the course evaluation to receive continuing education credit. A minimum score of 70% is required on the test for credit to be awarded, and participants may print their official statements of continuing education credit immediately. The estimated time required to complete this activity is two hours. This activity is provided free of charge.

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If you have not logged in to the ASHP Advantage site before, click on “Create Account” and follow the brief instructions to set up a user account and password. You will only need to create your account once to have access to register, take CE tests, and process CE online from ASHP Advantage in the future.

3. After logging in, you will see the list of activities for which CE is available. To process CE for one of the activities in the list, click on the “Start” button next to the title of the activity. This activity is listed in the CE Activities for Physicians section as “Therapeutic Update on Management of Postoperative Ileus.”

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Disclosure Statement

In accordance with the Accreditation Council for Continuing Medical Education’s Standards for Commercial Support, ASHP Advantage requires that all individuals involved in the development of program content disclose their relevant financial relationships. A person has a relevant financial relationship if the individual or his or her spouse/partner has a financial relationship (e.g., employee, consultant, research grant recipient, speakers bureau, or stockholder) in any amount occurring in the last 12 months with a commercial interest whose products or services may be discussed in the CME activity content over which the individual has control. The existence of these relationships is provided for the information of participants and should not be assumed to have an adverse impact on presentations. All faculty and planners for ASHP Advantage education activities are qualified and selected by ASHP Advantage and required to disclose any relevant financial relationships with commercial interests. ASHP Advantage identifies and resolves conflicts of interest prior to an individual’s participation in development of content for an educational activity. The faculty and planners report the following relationships: Conor P. Delaney, M.D., M.Ch., Ph.D., FRCSI, FACS Conor P. Delaney declares that he has served as a speaker and consultant for and has received a research grant from Adolor Corporation and Covidien; he has also served as a speaker for and received a research grant from Ethicon Endo-Surgery, Inc. T.J. Gan, M.B., B.S., FRCA Dr. Gan declares that he has received a research grant from Progenics Pharmaceuticals, Inc. Anthony Senagore, M.D., M.S., M.B.A., FACS, FASCRS, Program Chair Dr. Senagore declares that he has served on the advisory board for Adolor Corporation and Ethicon Endo-Surgery, Inc. Carla J. Brink, M.S., R.Ph. Ms. Brink declares that she has no relationships pertinent to this activity.

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Anthony Senagore, M.D., M.S., M.B.A., FACS, FASCRS Program Chair

Vice President of Research and Medical Education Spectrum Health

Professor of Surgery Michigan State University Grand Rapids, Michigan

Anthony Senagore, M.D., is Vice President of Research and Medical Education at Spectrum Health, a not-for-profit health system in West Michigan. He also serves as Professor of Surgery at Michigan State University (MSU) and as staff surgeon for Michigan Medical, P.C. Dr. Senagore earned his Doctor of Medicine degree from MSU, followed by a residency in general surgery at the Butterworth Hospital/MSU program in Grand Rapids. He then completed a research fellowship and colon and rectal surgery residency at Ferguson Hospital on the Grand Rapids and East Lansing campuses of MSU. He continued his education and later received his Master of Science degree in physiology from MSU and Master in Business Administration from the University of Phoenix on the San Francisco campus. Before assuming his current position, Dr. Senagore served as Krause-Lieberman Chair in laparoscopic colorectal surgery at The Cleveland Clinic. While at the Clinic, he was also Medical Director in the Office of Medical Operations and Associate Chief of Staff. He served as the Chairman of the Department of Surgery at the University of Toledo, College of Medicine. Dr. Senagore is board certified in general surgery and colon and rectal surgery. He is a fellow in the American College of Surgeons (ACS) and the American Society of Colon and Rectal Surgeons (ASCRS). He is a member of numerous organizations, including the Association for Academic Surgery, Central Surgical Association, Society of Critical Care Medicine, Midwest Surgical Association, International Society of University Colon and Rectal Surgeons, and the Society of American Gastrointestinal Endoscopic Surgeons. He currently serves as President-Elect for the American Society of Colon and Rectal Surgeons. Dr. Senagore specializes in laparoscopic bowel resection, surgical management of Crohn’s disease and ulcerative colitis, sphincter-preserving surgery for rectal cancer, treatment of anal incontinence and constipation, and management of anorectal disorders. Among his many clinical and research interests are surgical innovations in laparoscopic bowel surgery, molecular and genetic changes in colorectal cancer, and new surgical treatments for incontinence and constipation. He has lectured on various topics related to colon and rectal surgery, edited a textbook in colon and rectal surgery, and authored more than 100 peer-reviewed publications and 15 textbook chapters. Dr. Senagore is a national and international speaker on colorectal surgical topics.

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Overview Traditionally, postoperative stay following major gastrointestinal surgery has been 5-10 days, with recent Medicare data revealing a mean length of stay of 11.3 days for DRG 148. The emphasis on reducing resource use brought about by transitions in payment for medical services, coupled with improved understanding of perioperative physiology, have substantially reduced the length of hospitalization after colectomy. Another factor contributing to the reduced length of stay has been the greater use of minimally invasive surgical techniques, which have been associated with postoperative stays of 2.1 to 4.5 days. A variety of factors contribute to the length of stay following major gastrointestinal surgery, including inadequate analgesia, nausea and vomiting, delay in ileus resolution, and stress-induced organ dysfunction. In addition, iatrogenic factors, such as the use of nasogastric tubes, transabdominal drains, and enforced malnutrition and bed rest, adversely affect patient recovery after colectomy. This presentation will provide an overview of components of “enhanced-recovery” surgery protocols that permit rapid recovery and early discharge from the hospital without adverse events related to the accelerated nature of the postoperative care. The pathophysiology of postoperative ileus will be discussed, as well as how enhanced-recovery surgery protocols can help prevent and manage POI. Our experience indicates that the use of enhanced-recovery protocols is well tolerated by all patient cohorts regardless of co-morbidity or complexity of procedure, and a key component of success is patient education. When the principles of enhanced-recovery care and daily benchmarks, including discharge criteria, are shared with patients before admission and reinforced daily during hospitalization, patients enthusiastically accept the process. The ability of the modern abdominal surgeon to embrace these concepts of enhanced recovery after surgery has the potential of allowing patients to be discharged substantially earlier from the hospital, reducing rates of nosocomial infection, allowing more efficient use of hospital beds, and reducing hospital costs.

Presentation Objectives At the conclusion of this presentation, participants should be able to

• Describe the pathophysiology of postoperative ileus (POI). • Explain the importance of improving recovery of perioperative bowel function. • Identify patients who are at greatest risk of developing opioid-induced bowel dysfunction

and POI. • Describe the rationale for at least three components of enhanced-recovery surgery

protocols. • Define the pharmacoeconomic benefits of enhanced management of POI.

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Enhanced Recovery Surgery:State of the Art

Anthony J. Senagore, M.D., M.S., M.B.A., FACS, FASCRS

Vice President of Research and Medical EducationSpectrum Health

Professor of SurgeryMichigan State UniversityGrand Rapids, Michigan

Clinical Case

A 73-year-old man underwent open sigmoid colectomy with node dissection

• Early postoperative course (POD 0 to <6): NPO, nausea and vomiting, adequate pain control with PCA using morphine, “quiet” abdominal sounds, mild distension, no flatus passage

• POD 6: Patient still unable to eat, family concerned

POI following open sigmoid colectomy

Cause for concern and intervention?POD = postoperative day, PCA = patient-controlled analgesia

Diagnosis: POI• POD 6: POI managed conservatively

I.V. fluids, nasogastric tube reinsertion, increased ambulation, parenteral nutrition considered

• POI gradually resolves over 3 days• POD 9: Flatus passed, clear liquids started• POD 12: Discharge to home

Have you seen patients like this? Could the extended hospital stay have been avoided?

Clinical CasePOI following open sigmoid colectomy

POI: Definition• Ileus: functional inhibition of propulsive bowel activity,

irrespective of pathogenetic mechanisms1

• POI: transient cessation of coordinated bowel motility after surgical intervention, which prevents effective transit of intestinal contents and/or tolerance of oral intake2

– Primary POI: such cessation occurring in the absence of any precipitating complication

– Secondary POI: that occurring in the presence of a precipitating complication

• Paralytic ileus: form of POI lasting >5 days after surgery

1Livingston EH et al. Dig Dis Sci. 1990; 35:121-32.2Delaney CP et al. for the PIMC. http://www.ClinicalWebcasts.com/PIMC.htm

(accessed 2007 Sept 7).

Primary POI: Response by Different Intestinal Segments

Average time to resolution of POI after major abdominal surgery– Small intestine: 0-24 hours– Stomach: 24-48 hours– Colon: 48-120 hours

Luckey A et al. Arch Surg. 2003; 138:206-14.Livingston EH et al. Dig Dis Sci. 1990; 35:121-32.

Delaney CP et al. for the PIMC. http://www.ClinicalWebcasts.com/PIMC.htm(accessed 2007 Sept 7).

Risk Factors for POI

• Surgery, particularly abdominal surgery• Surgical technique• Extended opioid use• Inhaled anesthesia• Pre-existing gastrointestinal (GI) disease• Stress (in addition to physiologic stress of

surgery)?• Inactivity?

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Manifestations and 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 parenteralnutrition

• Poor wound healing• Delay in postoperative

mobilizationDelaney CP et al. for the PIMC. http://www.ClinicalWebcasts.com/PIMC.htm

(accessed 2007 Sept 7).

Manifestations and Consequences of Prolonged POI (cont)

• Increased risk of other postoperative complications

– Deconditioning– Pulmonary complications– Other nosocomial infections

• Prolonged hospitalization• Decreased patient satisfaction• Increased health care costs


Incidence of POI for Common Abdominal Surgeries

Procedure Description Procedures, n POI Cases, %Abdominal hysterectomy 456,292 4.1Large bowel resection 257,336 14.9Small bowel resection 48,824 19.2Appendectomy 175,964 6.2Cholecystectomy 81,013 8.5Nephroureterectomy 44,808 8.9Other procedures 597,492 9.0Total 1,661,729 8.5

HCFA data (Medicare, 1999-2000), evaluating 161,000 major intestinal and colorectal resections from 150 U.S. hospitals


How Long Can POI Last?

Adapted with permission from Steinbrook RA. Contemp Surg. 2005; March(Suppl):4-7; based on data from Wolff BC et al. Ann Surg. 2004; 240:728-35.

A long time for a majority of abdominal surgery patients

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 definitely contribute to the pathogenesis of POI, as do several other mechanisms, pathways, and mediators

Goyal RK et al. N Engl J Med. 1996; 334:1106-15. Copyright © 1996 Massachusetts Medical Society. All rights reserved.

POI: Pathogenesis Is Multifactorial

1Holte K et al. Drugs. 2002; 62:2603-15; 2Behm B et al. Clin GastroenterolHepatol. 2003; 1:71-80; 3Bauer AJ et al. Curr Opin Crit Care. 2002; 8:152-7.

Opioids1-3

Endogenous and exogenous opioids reduce propulsive activity in GI tract

InflammatoryMediators1

Release of nitric oxide, vasoactiveintestinal 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 one or more of these factors could potentially shorten the duration of POI and reduce the incidence of morbidity

Endogenous opioids = endorphins, enkephalins, and dynorphins

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Possible Mechanisms of POIMechanism Factors InvolvedAutonomic nervous system Sympathetic inhibitory pathways

Enteric nervous system Substance P, nitric oxide

Hormonal or neuroendocrine system

Vasoactive intestinal peptide; corticotropin-releasing factor ligands; calcitonin gene-related peptide ligands

Inflammation Macrophage and neutrophil infiltration; cytokines, other inflammatory mediators

Anesthesia General anesthetics

Pain Exogenous and endogenous (endorphins, enkephalins, dynorphins) opioids

Delaney CP et al. for the PIMC. http://www.ClinicalWebcasts.com/PIMC.htm (accessed 2007 Sept 7).

Opioids and their Effects on GI Function

• Endogenous opioids are released as part of the stress response in the postoperative period1

• Exogenous opioids are the most potent and commonly used analgesics for control of postoperative pain1

• Both types of opioids activate the same receptor sites and affect a variety of GI functions, including1,2

– Motility– Secretion– Transport of electrolytes and fluids

• Opioids have been shown to2

– Profoundly inhibit peristaltic activity– Delay gastric emptying and intestinal transit– Play an important role in precipitating prolonged POI

1Prasad M et al. Gastroenterology. 1999; 117:489-92.2Bauer AJ et al. Neurogastroenterol Motil. 2004; 16(Suppl 2):54-60.

Cali RL et al. Dis Colon Rectum. 2000; 43:163-8; adapted with permission.

Morphine or Incision Length Correlated with Return of Bowel Function?

Colectomy patients (n = 40)● Primarily left colon and

rectal procedures

Return of bowel function?● Correlation between

morphine PCA dose and first bowel sounds (P=0.001), flatus (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

040 60 80 100 120 140 160 180

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 and sodium restriction?

Luckey A et al. Arch Surg. 2003; 138:206-14. Person B et al. Curr Probl Surg. 2006; 43:6-65. Review.

NSAIDs = nonsteroidal anti-inflammatory drugsPAMOR = peripherally acting mu-opioid receptor

Components of a Multimodal Enhanced-Recovery Protocol for POI

• Surgical management– Laparoscopic approach

• Pain management– Epidural (local)

analgesia– Opioid-sparing

techniques– Minimize opioid PCA

• Supportive patient care elements– Avoidance of nasogastric tube (NGT)– Fluid restriction– Early oral feeding– Early ambulation

• Pharmacologic management– PAMOR antagonist

Nasogastric Intubation• Selective vs. routine NGT was compared in a meta-analysis

of 26 randomized clinical trials (3964 patients)– Patients without nasogastric (NG) tubes

• Had a significantly lower rate of fever, atelectasis, and pneumonia

• Were able to tolerate an oral diet significantly earlier• Experienced abdominal distension and vomiting

more frequently– “For every patient requiring insertion of a NGT in the

postoperative period, at least 20 patients will not require NG decompression…”

– “Routine NG decompression is considered detrimental by meta-analysis of the literature.”

Cheatham ML et al. Ann Surg. 1995; 221:469-76; discussion 476-8.

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RCTs of Early Postoperative Feeding vs. Traditional Feedingb

Holte K et al. Br J Surg. 2000; 87:1480-93.

RCTs = randomized controlled trials; 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)

Dur

atio

n of

Ileu

s (h

)

140

120

100

80

60

40

20

0

*

**

DFDIDCC

*P < 0.05

Laxatives• Only 1 RCT, involving 20 patients, in literature1

• Commonly used in combination with prokinetic agents and with other multimodal treatments (e.g., epidural, early feeding, early ambulation)2-4

– Stimulant laxatives: most commonly used senna compounds and bisacodyl

– Bulking agents and nonabsorbable compounds: lactulose can cause bloating

– Osmotic laxatives (poorly absorbable ions magnesium or phosphate) can cause metabolic disturbances, particularly in presence of renal impairment

1Fanning J et al. Gynecol Oncol. 1999; 73:412-4.2Basse L et al. Br J Surg. 2001; 88:1498-1500.

3Basse L et al. Br J Surg. 2002; 89:446-53.4Xing JH et al. Dis Colon Rectum. 2001; 44:1201-9. Review.

Surgical Technique (“Scope”)MOA: Reduced activation of inhibitory reflexes and local

inflammation due to reduced surgical trauma

Holte K et al. Br J Surg. 2000; 87:1480-93.Kehlet H et al. 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

nific

atio

n

MOA = mechanism of action D = defecation; F = flatus

.

Holte K et al. Br J Surg. 2000; 87:1480-93.Kehlet H et al. Am J Surg. 2001; 182(5A Suppl):3S-10S.

RCTs of Laparoscopy vs. Open Surgery

120

100

80

60

40

20

0

Dur

atio

n of

Ileu

s (h

ours

)

Lacy et al.(1995)

Schwenk et al.(1998)

Milsom et al.(1998)

LaparoscopicOpen

F D D F

*

*

*

Leung et al.(2000)

*P < 0.05

Metoclopramide• MOA: combined cholinergic and serotonergic agonist,

and dopaminergic antagonist – limited to the proximal gut

• 6 prospective, randomized, blinded, placebo-controlled trials1-4

– 16-115 patients per trial up to 5 days– Metoclopramide started on day of surgery– Doses: 10 mg i.v. every 6 hours to 20 mg every 8 hours

• None of the studies showed any benefit from metoclopramide as a POI therapy in any outcome(s)

• Adverse effects in 15-20% of patients– Drowsiness, dystonic reactions, agitation– More common in patients <30 years

1Davidson ED et al. Ann Surg. 1979; 190:27-30;2Lykkegaard-Nielsen M et al. Dis Colon Rectum. 1984; 27:288-9; 3Seta ML et al. Pharmacotherapy. 2001; 21:1181-6; 4Holte K et al. Br J Surg. 2000; 87:1480-93.

Effect of Metoclopramide on POI

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

120

100

80

60

40

20

0

Dur

atio

n of

ileu

s (h

)

Jepsen et al. (1986)

Cheape et al. (1991)

Tollesson et al. (1991)

Metoclopramide

Placebo

F I D

Jepsen S et al. Br J Surg. 1986; 73:290-1. Cheape JD et al. Dis Colon Rectum. 1991; 34:437-41.

Tollesson PO et al. Eur J Surg. 1991; 157:355-8.Holte K et al. Br J Surg. 2000; 87:1480-93.

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RCT: Fast Track vs. Traditional CareFast track

(n = 32)P

ValueTraditional

(n = 33)

4.7 0.01

0.0013.8

3.1 0.79

0.818.1

LOS for patients <70 yr (days)

LOS for patients treated by‘enhanced-recovery’ surgeons (days)

Pain score on discharge

Satisfaction with stay

Readmissions 0.453

5.8

5.0

3.1

8.2

6

Delaney CP et al. Dis Colon Rectum. 2003; 46:851-9.Delaney CP et al. Br J Surg. 2001; 88:1533-8.

LOS = length of stay (counting day of surgery as day 0)

Short-term Outcomes of Laparoscopic Resection after Colorectal Cancer

• Meta-analysis of RCTs up to 2002• 2512 cases in 12 trials,* random effects model

Relative improvements with laparoscopyFlatus ↓ 34% (25-37)Toleration of diet ↓ 24% (0-34)Pain at 6 h ↓ 35% at rest, ↓ 34% coughingPain at 3 days ↓ 63% at rest, ↓ 40% coughingNarcotic use at 48 h ↓ 37% (13-72)

Abraham NS et al. Br J Surg. 2004; 91:1111-24.

*Patients were not subjected to the same postoperative regimens

Economic Considerations with POI• Most common reason for delayed discharge after

abdominal surgery1

• Annual U.S. healthcare costs estimated to be $750 million to $1 billion, due to2

– Nasogastric intubation– I.V. hydration and nutrition– Extra nursing care– Longer hospital stay– Additional laboratory testing

• Possible benefits of effective POI management for selected patients due to3

– Shortened hospital stay– Reduced use of resources– Fewer complications– Fewer readmissions

1Luckey A et al. Arch Surg. 2003;138:206-14; 2Livingston EH et al. Dig Dis Sci.1990; 35:121-32; 3Leslie JB. Ann Pharmacother. 2005; 39:1502-10.

Clinical Impact of POI

Woods MS. Perspect Colon Rectal Surg. 2000; 12:57-76.Kehlet H et al. Am J Surg. 2001; 182(5A Suppl):3S-10S.Behm B et al. Clin Gastroenterol Hepatol. 2003; 1:71-80.

Leslie JB. Ann Pharmacother. 2005; 39:1502-10.

• Increased postoperative pain• Increased nausea and vomiting

– Increased risk of aspiration• Prolonged time to regular diet

– Delayed wound healing– Increased risk of malnutrition or catabolism

• Prolonged time to mobilization– Increased pulmonary complications

• Prolonged hospitalization– Increased healthcare costs

Delayed recovery

Economic Burden of POI

• Nasogastric (NG) intubation• I.V. hydration• Additional nursing care• Lab tests• Increased hospital days

Livingston EH et al. Dig Dis Sci. 1990; 35:121-32.Collins TC et al. Ann Surg. 1999; 230:251-9.

Sarawate CA et al. Gastroenterology. 2003; 124(Suppl 1):A-828.

Overall Healthcare Burden Associated with POI

Beds occupied for more time

Increased resourceuse

Increased nursing time

Prolonged hospitalization

Decreased patientsatisfaction

Steinbrook RA. Contemp Surg. 2005; March(Suppl):4-7; Schuster TG et al. Urology.2002; 59:465-71; Holte K et al. Br J Surg. 2000; 87:1480-93; Chang SS et al. J Urol.

2002; 67:208-11; Sarawate CA et al. Gastroenterology. 2003; 124(Suppl 1):A-828.

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Estimate of Potential Savings

22 million inpatient surgical procedures annually

2.7 million procedures lead to POI (>1 day)

750,000 patients discharged 1 day earlier (with effective management of POI)

Potential savings of $1.1 billion/year

Woods MS. Perspect Colon Rectal Surg. 2000;12:57.

Resources Used by Major Intestinal or Rectal Resection Annually

• Between October 1999 and September 2000, 161,000 Medicare patients underwent this type of surgery

• They stayed approximately 1.8 million days in hospital and consumed $1.75 billion

Delaney CP. Neurogastroenterol Motil. 2004; 16(Suppl 2):61-6.

Keeping Track of (Coding for) POIICD-9- CM code 997.4• Digestive system complications

– Complications of intestinal (internal anastomosis and bypass not elsewhere classified, except that involving the urinary tract)

ICD-9- CM code 560.1• Adynamic ileus; ileus (of intestine) (of bowel) (of

colon); paralysis of intestine or colon

ICD-9- CM code 564.4• Other postoperative functional disorders

– Diarrhea following gastrointestinal surgery

Recorded Rate and Economic Burden Associated with Postoperative Ileus

Saunders WB et al. ASHP Midyear Clinical Meeting (MCM). Orlando, FL: 2004 Dec 7. Abstract P440E.

• Studied POI prevalence, consequent economic burden in 2002

• Data from Premier’s PerspectiveTM Comparative Database (includes 5 million discharges annually)

• 806,081 surgical patients identified for evaluation of rate of POI– Open laparotomies, incisional procedures, non-incisional procedures,

orthopedics, thoracic surgeries, etc. (645 primary surgery codes)• POI identified using ICD-9 diagnosis codes 560.1 and 997.4

– “Comparison with estimates of incidence in published literature suggest that in practice, POI may not be routinely coded and therefore, the overall recorded rate and economic burden of illness found in our study may be underestimated.”


Coded POI Associated with Selected Surgical ProceduresCoded POI Associated with Selected Surgical Procedures

Saunders WB et al. ASHP MCM. Orlando, FL: 2004 Dec 7. Abstract P440E.

1.44

9.01

3.61

1.57 2.39

4.25

0123456789

10

% experiencing POI

OrthopedicproceduresOpenlaparotomyIncisionalproceduresThoracicproceduresNon-incisionalproceduresAverage



0

25

50

75

100

Orthopedic Open lap Incisional Thoracic Nonincisional Average

Coded POI Associated with Selected Surgical ProceduresCoded POI Associated with Selected Surgical Procedures

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Hospitalization Outcomes of Patients with and without POIHospitalization Outcomes of Patients with and without POI

9.3

5.3

0123456789

10

Hospital stay, days


p < 0.001

POI Non-POI

18,000

11,700

02,0004,0006,0008,000

10,00012,00014,00016,00018,000

Hospital cost, in thousands of $

p < 0.001

PPOI Incidence

Mean Time to Dx of PPOI

(days)

Time from Dx to

Discharge (days)

Mean LOS (days)

Total Mean Cost

TAH (n=43)

18.2 % 3.1 3.8 6.9 vs. 3.71 $4,5122 ⇑⇑

HC (n=40)

30.2 % 2.5 NA 20.3 vs. 8.43 $17,7064 ⇑⇑

Clinical and Economic Outcomes of Patients with Prolonged POI Undergoing Hysterectomy and

Hemicolectomy at an Academic Medical Institution

1Compared with a sample of TAH patients who did not have PPOI2Compared with total average costs for those without PPOI3Compared with a sample of HC patients who did not have PPOI4Compared with total average costs for those without PPOI

Salvador CG et al. 46th MCM. Orlando, FL: 2004 Dec 7. Abstract P402E.

PPOI = prolonged POI; TAH = total abdominal hysterectomy; HC = hemicolectomy

Surgeons’ Roles…• What is our role in the multimodal

approach to the prevention and management of POI?

Enhanced-Recovery SurgeryProtocols

• Form multidisciplinary team• Re-evaluate procedures to ensure all

components of fast-track surgery are implemented

• Evaluate entire perioperative period

Patient Education

• Medication protocol• Postoperative expectations • Benefits of early ambulation• Hydration• Resuming diet

Pain Management Education

• Preoperative pain assessment

• Pain management– Descriptive pain scales

• Techniques to decrease opioid burden

• Selective opioid-receptor antagonists– Mitigate adverse GI effects of opioids

– Preserve analgesia

14

Patient Advocacy

• Provide patient with necessary information

• Assess patient’s understanding of and potential compliance with preoperative and postoperative instructions

Patient Satisfaction• Enhance the patient’s perianesthesia

experience– Optimize patient care, satisfaction, and

comfort

• Reduce the patient’s postoperative length of stay– Ensure efficient and cost-effective patient

evaluation

Conclusions

• POI affects between 4% and 20% of patients undergoing abdominal surgery annually and has a detrimental effect on clinical outcomes and costs of care

• Accelerating recovery of GI function by using enhanced-recovery programs improves clinical outcomes, enhances patient comfort, and shortens hospital length of stay

• Enhanced-recovery surgery protocols should include both pharmacologic and nonpharmacologic approaches for managing POI

End of Presentation

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15


Selected References

1. Abraham NS, Young JM, Solomon MJ et al. Meta-analysis of short-term outcomes after laparoscopic resection for colorectal cancer. Br J Surg. 2004; 91:1111-24.

2. Basse L, Madsen JL, Kehlet H. Normal gastrointestinal transit after colonic resection using

epidural analgesia, enforced oral nutrition and laxative. Br J Surg. 2001; 88:1498-500. 3. Basse L, Raskov HH, Hjort Jakobsen D et al. Accelerated postoperative recovery

programme after colonic resection improves physical performance, pulmonary function and body composition. Br J Surg. 2002; 89:446-53.

4. Bauer AJ, Boeckxstaens GE. Mechanisms of postoperative ileus. Neurogastroenterol Motil.

2004; 16(Suppl 2):54-60. 5. Bauer AJ, Schwarz NT, Moore BA et al. Ileus in critical illness: mechanisms and

management. Curr Opin Crit Care. 2002; 8:152-7. 6. Behm B, Stollman N. Postoperative ileus: etiologies and interventions. Clin Gastroenterol

Hepatol. 2003; 1:71-80. 7. Cali RL, Meade PG, Swanson MS et al. Effect of morphine and incision length on bowel

function after colectomy. Dis Colon Rectum. 2000; 43:163-8. 8. Chang SS, Baumgartner RG, Wells N et al. Causes of increased hospital stay after radical

cystectomy in a clinical pathway setting. J Urol. 2002; 167:208-11. 9. Cheape JD, Wexner SD, James K et al. Does metoclopramide reduce the length of ileus

after colorectal surgery? A prospective randomized trial. Dis Colon Rectum. 1991; 34:437–41.

10. Cheatham ML, Chapman WC, Key SP et al. A meta-analysis of selective versus routine

nasogastric decompression after elective laparotomy. Ann Surg. 1995; 221:469-76; discussion 476-8.

11. Collins TC, Daley J, Henderson WH et al. Risk factors for prolonged length of stay after

major elective surgery. Ann Surg. 1999; 230:251-9. 12. Davidson ED, Hersh T, Brinner RA et al. The effects of metoclopramide on postoperative

ileus: a randomized double-blind study. Ann Surg. 1979; 190:27-30. 13. Delaney CP. Clinical perspective on postoperative ileus and the effect of opiates.

Neurogastroenterol Motil. 2004; 16(Suppl 2):61-6. 14. Delaney CP, Fazio VW, Senagore AJ et al. 'Fast track' postoperative management protocol

for patients with high co-morbidity undergoing complex abdominal and pelvic colorectal surgery. Br J Surg. 2001; 88:1533-8.

16


15. Delaney CP, Kehlet H, Senagore AJ et al. for the Postoperative Ileus Management Council

(PIMC) National Experts’ Clinical Consensus Panel. Postoperative ileus: profiles, risk factors, and definitions—a framework for optimizing surgical outcomes in patients undergoing major abdominal and colorectal surgery. 2006 May 1. http://www.ClinicalWebcasts.com/PIMC.htm (accessed 2007 Sept 7).

16. Delaney CP, Zutshi M, Senagore AJ et al. Prospective, randomized, controlled trial between

a pathway of controlled rehabilitation with early ambulation and diet and traditional postoperative care after laparotomy and intestinal resection. Dis Colon Rectum. 2003; 46:851-9.

17. Fanning J, Yu-Brekke S. Prospective trial of aggressive postoperative bowel stimulation

following radical hysterectomy. Gynecol Oncol. 1999; 73:412-4. 18. Goyal RK, Hirano I. The enteric nevous system. N Engl J Med. 1996; 334:1106-15. 19. Holte K, Kehlet H. Postoperative ileus: a preventable event. Br J Surg. 2000; 87:1480-93. 20. Holte K, Kehlet H. Postoperative ileus: progress towards effective management. Drugs.

2002; 62:2603-15. 21. Jepsen S, Klaerke A, Nielsen PH et al. Negative effect of metoclopramide in postoperative

adynamic ileus. A prospective, randomized, double blind study. Br J Surg. 1986; 73:290-1. 22. Kehlet H, Holte K. Review of postoperative ileus. Am J Surg. 2001; 182(5A Suppl):3S-10S. 23. Leslie JB. Alvimopan for the management of postoperative ileus. Ann Pharmacother. 2005;

39:1502-10. 24. Livingston EH, Passaro EP Jr. Postoperative ileus. Dig Dis Sci. 1990; 35:121-32. 25. Luckey A, Livingston E, Taché Y. Mechanisms and treatment of postoperative ileus. Arch

Surg. 2003; 138:206-14. 26. Lykkegaard-Nielsen M, Madsen PV, Nielsen OV. Ceruletide vs.metoclopramide in

postoperative intestinal paralysis: a double-blind clinical trial. Dis Colon Rectum. 1984; 27:288-9.

27. Person B, Wexner SD. The management of postoperative ileus. Curr Probl Surg. 2006;

43:6-65. Review. 28. Prasad M, Matthews JB. Deflating postoperative ileus. Gastroenterology. 1999; 117:489-92. 29. Salvador CG, Sikirica M, Evans A et al. Clinical and economic outcomes of patients with

prolonged postoperative ileus undergoing hysterectomy and hemicolectomy at an academic medical institution. Presented at the ASHP Midyear Clinical Meeting. Orlando, FL: 2004 Dec 7. Abstract P402E.

17


30. Sarawate CA, Lin SL, Walton SM et al. Economic burden of postoperative ileus (POI) in

abdominal surgical procedures. Gastroenterology. 2003; 124(Suppl 1):A-828. Abstract M2239.

31. Saunders WB, Bowers B, Moss B et al. Recorded rate and economic burden associated

with postoperative ileus. Presented at the ASHP Midyear Clinical Meeting. Orlando, FL: 2004 Dec 7. Abstract P440E.

32. Schuster TG, Montie JE. Postoperative ileus after abdominal surgery. Urology. 2002;

59:465-71. 33. Seta ML, Kale-Pradhan PB. Efficacy of metoclopramide in postoperative ileus after

exploratory laparotomy. Pharmacotherapy. 2001; 21:1181-6. 34. Steinbrook RA. Postoperative ileus: why we should treat. Contemp Surg. 2005; March

(Suppl):4–7. www.contemporarysurgery.com/pages.asp?aid=47 (accessed 2007 Sept 1). 35. Tollesson PO, Cassuto J, Faxen A et al. Lack of effect of metoclopramide on colonic motility

after cholecystectomy. Eur J Surg. 1991; 157:355-8. 36. Wolff BG, Michelassi F, Gerkin TM et al. Alvimopan, a novel, peripherally acting mu opioid

antagonist: results of a multicenter, randomized, double-blind, placebo-controlled, phase III trial of major abdominal surgery and postoperative ileus. Ann Surg. 2004; 240:728-35.

37. Woods MS. Postoperative ileus: dogma versus data from bench to bedside. Perspect Colon

Rectal Surg. 2000; 12:57-76. 38. Xing JH, Soffer EE. Adverse effects of laxatives. Dis Colon Rectum. 2001; 44:1201-9.

Review.

18


T. J. Gan, M.B., B.S., FRCA Professor and Vice Chair for Clinical Research

Department of Anesthesiology Duke University Medical Center

Durham, North Carolina T. J. Gan, M.B., B.S., FRCA, is Professor and Vice Chairman for Clinical Research in the Department of Anesthesiology at Duke University Medical Center in Durham, North Carolina. He also serves on the faculty at the Duke Clinical Research Institute and as a Senior Research Fellow at the Duke Center for Integrative Medicine. Dr. Gan has received numerous awards, including the Society of Ambulatory Anesthesia Young Investigator Award and the International Anesthesia Research Society (IARS) Clinical Scholar Research Award. He is a member of several professional organizations, including the American Society of Anesthesiologists and the International Anesthesia Research Society. Dr. Gan is the President Elect of International Society of Anesthetic Pharmacology and The Society of Ambulatory Anesthesia. He serves on the editorial board of Anesthesia Analgesia, Acute Pain, and Clinical Research, and he is a reviewer for many scientific journals. Dr. Gan has served as an invited speaker for many national and international professional conferences and as principal investigator or co-investigator for many clinical trials. His research explores a variety of topics, such as prevention of postoperative nausea and vomiting, opioids, fluid management during surgery, intravenous anesthesia, and postoperative pain. He is the author or co-author of more than 100 scientific articles in peer-reviewed medical journals, as well as numerous abstracts, reviews, and textbook chapters.

19


Overview

In the United States, length of stay for patients undergoing bowel resection ranges from 5–14 days. Cost per hospital stay has been estimated to be approximately $8000 more for patients with postoperative ileus (POI) compared with patients without POI. Moreover, POI is associated with increased postoperative morbidity and prolonged hospital stays. Therefore, accelerating GI recovery after bowel resection via patient management or pharmacologic approaches would represent a clinically important addition to the standard of care. Anesthetic and perioperative factors have a significant impact on the incidence and severity of POI, as well as on other postoperative outcomes. These factors can include opioid use, type and volume of fluid administration, anesthetic techniques, and other drugs used in the perioperative period. This presentation discusses the perioperative factors of interest and presents strategies that have been demonstrated to reduce the incidence and severity of POI and other related postoperative adverse events.

Presentation Objectives

At the conclusion of this presentation, participants should be able to

• Describe the impact of anesthetic and perioperative factors on postoperative ileus.

• Identify effective perioperative management strategies for reducing the incidence and severity of postoperative ileus and minimizing opioid-related adverse effects.

20

Impact of Anesthesia and Analgesia on Postoperative Ileus:

A View from “Above the Screen”

T.J. Gan, M.B., B.S., FRCAProfessor and Vice ChairmanDepartment of Anesthesiology

Duke University Medical CenterDurham, North Carolina

Outline• Incidence of postoperative gastrointestinal

dysfunction• Anesthetic and analgesic factors

– Opioids– Inhalational agents and nitrous oxide– Fluid administration

• Multimodal management strategy– Preoperative education– Combination analgesics– Epidural– Peripheral opioid antagonists

Incidence of POI in SurgeriesAbdominal Surgery

Procedure Description Procedures, N POI Cases, %Abdominal hysterectomy 456,292 4.1Large bowel resection 257,336 14.9Small bowel resection 48,824 19.2Appendectomy 175,964 6.2Cholecystectomy 81,013 8.5Nephroureterectomy 44,808 8.9Other procedures 597,492 9.0Total 1,661,729 8.5

Other SurgeryProcedure Description Procedures, N POI Cases, %Total hip and knee

arthroplasties2949 2.1

Radical cystectomy 304 18HCFA data (Medicare, 1999-2000), evaluating 161,000 major intestinal and colorectal resections from 150 U.S. hospitals; POI = postoperative ileus

Delaney CP et al. http://www.ClinicalWebcasts.com/PIMC.htm;Berend KR et al. J Arthroplasty. 2004;19(7 Suppl 2):82-6; Chang SS et al. J Urol. 2002;167:2012-6.

0

10

20

30

40

50

60

GI Renal Pain Pulmonary Infectious

POD 5 POD 15

Postoperative Complications%

of

% o

f P a

t ien t

s

Bennett-Guerro E et al. Anesth Analg. 1999; 89:514-9.

POD = postoperative dayGI = gastrointestinal

Possible Mechanisms of POIMechanism Factors InvolvedAutonomic nervous system Sympathetic inhibitory pathways

Enteric nervous system Substance P, nitric oxide

Hormonal or neuroendocrinesystem

Vasoactive intestinal peptide; corticotropin-releasing factor ligands; calcitonin gene-related peptide ligands

Inflammation Macrophage and neutrophilinfiltration; cytokines, other inflammatory mediators

Anesthesia General anesthetics

Pain Exogenous and endogenous (endorphins, enkephalins, dynorphins) opioids

Delaney CP et al. http://www.ClinicalWebcasts.com/PIMC.htm.

Opioids and their Effects on GI Function

• Endogenous opioids are released as part of the stress response in the postoperative period

• Both types of opioids activate the same receptor sites and affect a variety of GI functions, including

– Motility– Secretion– Transport of electrolytes and fluids

• Opioids have been shown to– Profoundly inhibit peristaltic activity– Delay gastric emptying and intestinal transit– Precipitating prolonged POI

Coley KC et al. J Clin Anesth. 2002; 14:349-53.

21

Effects of Opioids on the Gastrointestinal Tract

Pharmacologic action Clinical effect• ↓ Gastric motility and

emptying• ↓ Appetite, ↑ gastro-

esophageal reflux• ↓ Pyloric tone • Nausea and vomiting• ↓ Enzymatic secretion • Delayed digestion;

hard, dry stools• Inhibition of small and

large bowel propulsion• Delayed absorption,

straining, bloating, abdominal distension, constipation

Kurz A et al. Drugs. 2003; 63:649-71; Bates JJ et al. Anesth Analg. 2004; 98:116-22.

Pharmacologic action Clinical effect

• Increased fluid and electrolyte absorption

• Hard, dry stools

• Increased nonpropulsivesegmental contractions

• Spasms, abdominal cramps, pain

• Increased anal sphincter tone

• Incomplete evacuation

Effects of Opioids on the Gastrointestinal Tract (cont)

Kurz A et al. Drugs. 2003; 63:649-71; Bates JJ et al. Anesth Analg. 2004; 98:116-22.

Patient Preferences for Treatment of Acute Pain

Gan TJ et al. Br J Anaesth. 2004; 92:681-8.

Pain control41%

Setting and route of administration

12%

Side effect severity19%

Side effect type28%

Patients prefer avoiding side effects Patients prefer avoiding side effects over complete pain controlover complete pain control

47%

Symptom Distress Score (SDS) Questionnaire

Joshi GP et al. Anesth Analg. 2004; 98:336-42.Gan TJ et al. Acta Anaesthesiol Scand. 2004; 48:1194-207.

Symptom Distress Score (SDS) Questionnaire

Joshi GP et al. Anesth Analg. 2004; 98:336-42.Gan TJ et al. Acta Anaesthesiol Scand. 2004; 48:1194-207.

Opioid Dose and Clinically Meaningful Opioid-related Adverse Events

Zhao SZ et al. J Pain Symp Manage. 2004; 28:35-46.

0 5 10 15 20 25

Num

ber o

f CM

Eson

day

1 a

fter

lapa

rosc

opic

cho

lecy

stec

tom

y

≥3 events

2 events

1 event

No event

Morphine equivalent dose in 24 hours (mg)

–33%

Reduction in clinically meaningful

opioid-related AE

CME = clinically meaningful eventAE = adverse event

22

Cali RL et al. Dis Colon Rectum. 2000; 43:163-8; adapted with permission.

Morphine or Incision Length Correlated With Bowel Function Return?

Colectomy patients (n = 40)● Primarily left colon and

rectal procedures

Return of bowel function?● Correlation between

morphine PCA dose and first bowel sounds (P = 0.001), flatus (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

040 60 80 100 120 140 160 180

PCA = patient-controlled analgesia

Management Strategies for POI

• Prevention– Anesthetic choice– Surgical techniques– Opioid-sparing

analgesics

• Supportive care– NG tube insertion– Mobilization– Early oral feeding– Fluid management– Prokinetic agents

• Cisapride*• Erythromycin• Metoclopramide

NG = nasogastric*Not available in the United States

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 antagonists– Other agents

• Perioperative care plan(s)– Multimodal clinical pathways– Fluid/sodium restriction?

Luckey A et al. Arch Surg. 2003; 138:206-14. Person B et al. Curr Probl Surg. 2006; 45:6-65. Review.

NSAIDs = nonsteroidal anti-inflammatory agents

Analgesics and the Pain Pathway

DorsalDorsalhornhorn

Ascending inputAscending input(spinothalamic (spinothalamic

tract)tract)

Dorsal rootDorsal rootganglionganglion

PeripheralPeripheralnervenerve

PeripheralPeripheralnociceptorsnociceptors

TraumaTrauma

Adapted from Gottschalk A et al. Am Fam Physician. 2001; 63:1979-84.

Descending Descending modulationmodulation

PainPain

Opioids Opioids αα22 agonists agonists

Centrally acting analgesicsCentrally acting analgesicsAntiAnti--inflammatory agents inflammatory agents Calcium channel blockersCalcium channel blockers

NMDA antagonistsNMDA antagonists

Local anestheticsLocal anestheticsOpioids Opioids

αα22 agonistsagonistsNSAIDs and COXNSAIDs and COX--2 inhibitors2 inhibitors

Local anestheticsLocal anesthetics

Local anesthetics Local anesthetics AntiAnti--inflammatory agents inflammatory agents

(selective COX(selective COX--2 inhibitors, 2 inhibitors, nonselectivenonselective--NSAIDs)NSAIDs)

NMDA = N-methyl-D-aspartate; COX-2 = cyclooxygenase-2

Kehlet H et al. Anesth Analg. 1993; 77:1048-56.Playford RJ et al. Digestion. 1991; 49:198-203.

Multimodal or Balanced Analgesia

• ⇓ Doses of each analgesic

• Improved anti-nociception due to synergistic/additive effects

• May ⇓ severity of adverse effects of each drug

Potentiation

Opioid

Conventional NSAIDs/COX-2 inhibitors,

acetaminophen,nerve blocks

Morphine Consumption – 24 hours

Elia N et al. Anesthesiology. 2005; 103:1296-304.

23

Thoracic EpiduralAnesthesia/Analgesia

• All anesthetics may depress GI motility

• Reduced ileus is a significant benefit of thoracic epidural anesthesia and analgesia vs. general anesthesia and systemic opiates– GI function may return 2-3 days earlier!

Moraca RJ et al. Ann Surg. 2003; 238:663-73; Steinbrook RA. Anesth Analg. 1998; 86:837-44; Liu SS et al. Anesthesiology. 1995; 83:757-65.

Thoracic EpiduralAnesthesia/Analgesia (cont)

• Mechanisms by which thoracic epidural anesthesia may promote GI motility– Blockade of nociceptive afferent nerves– Blockade of thoracolumbar sympathetic

efferent nerves– Unopposed parasympathetic efferent nerves– Reduced need for postoperative opiates– Increased GI blood flow– Systemic absorption of local anesthetic

Moraca RJ et al. Ann Surg. 2003; 238:663-73; Steinbrook RA. Anesth Analg. 1998; 86:837-44; Liu SS et al. Anesthesiology. 1995; 83:757-65.

RCTs of Epidural Anesthesia/Analgesiavs. Systemic Opiates b

RCTs = randomized controlled trialsC = combination score; D = defecation; F = flatus

Holte K et al. Br J Surg. 2000; 87:1480-93.

Epidural local anestheticSystemic opioid

Wailin et al.

(1986)

Scheinin et al.

(1987)

Ahn et al.

(1988)

Wattwil et al.

(1989)

Bredtmann et al.

(1990)

Riwar et al.

(1991)

Liu et al.

(1995)

Dur

atio

n of

Ileu

s (h

) 200

150

100

50

0

*

D

* * *

* *

Neudecker et al.

(1999)

C D D D D F D

*P < 0.05

Advice on Epidural to Prevent POI

• Epidural must be in place before surgical stress and nociceptive afferent stimulation begin

• Catheter should be placed to cover T5 to L2 dermatomes to affect both upper and lower GI innervation

• Epidural local anesthetics with opioids should be included and administered postoperatively until bowel function returns

Nitrous Oxide and Bowel Dysfunction

Akca O et al. Acta Anaesthesiol. 2004; 48:894-8.Jensen AG et al. Can J Anaesth. 1992; 39:938-43.

24

• 100 ASA II and III patients

• Surgery with expected blood loss > 500 mL

• Intraoperative goal-directed fluid management vs. control

• Background crystalloid infusion and colloid bolus

• Fluid management algorithm with EDM

• Primary outcome: length of stay (LOS)

Gan TJ et al. Anesthesiology. 2002; 97:820-6.

ASA II and III = American Society of Anesthesiology grade II and IIIEDM = esophageal Doppler monitor

Goal-Directed Fluid Management

0

1

2

3

4

5

6

7

Tolerating Solids LOS

Control Therapy

*

* p < 0.05

*

Gan TJ et al. Anesthesiology. 2002; 97:820-6.

Days

Perioperative Plasma Volume Expansion Reduces the Incidence of Gut Mucosal Hypoperfusion during

Cardiac Surgery

• 60 ASA III patients• Protocol and control groups• Fluid optimization with EDM in protocol group• Standard practice in control group• 200 mL 6% hetastarch to maintain maximum

stroke volume (SV)

Mythen MG et al. Arch Surg. 1995; 130:423-9.

Perioperative Plasma Volume Expansion Guided by EDM

Mythen MG et al. Arch Surg. 1995; 130:423-9.

pHi = gastric mucosa pH; ICU = intensive care unit

Control Protocol P value

pHi <7.32 56% 7% <0.001

Complications 6 0 0.01

ICU Days 1.7 1 0.02

Hospital Days 10.1 6.4 0.01

I.V. Fluid Restriction• MOA: salt/water

restriction improves canine gastric emptying time

• Lobo et al. compared standard (>3 L/day fluids, 154 mmol/day sodium) with restricted (<2 L/day fluids, 77 mmol/day sodium) protocols after open hemicolectomy

• Significantly more complications in standard treatment

Solid and liquid phase gastric emptying times (T50). Solid lines are medians, shaded areas interquartile ranges, and whiskers extreme values.

P values derived with the Mann-Whitney U test.

Differences between medians for solid and liquid phase T50 were 56 min (95% CI: 12-132) and 52 min (95% CI: 9-95), respectively.

250

200

150

100

50

0

n = 10n = 10

P = 0.028

Standard group Restricted group

Solid Phase Gastric Emptying Time(T50 min)

200

150

100

50

0

n = 10n = 10

P = 0.017

Standard group Restricted group

Liquid Phase Gastric Emptying Time(T50 min)

Lobo DN et al. Lancet. 2002; 359:1812-8.

MOA = mechanism of action

• Elective intraabominal surgery• Crystalloid: lactated Ringer’s solution• Randomized into 2 groups

– Liberal fluid regimen: 10 mL/kg followed by 12 mL/kg/hr

– Restricted regimen: 4 mL/kg/hr• Primary outcome: death or

complicationsNisanevich V et al. Anesthesiology. 2005; 103:25-32.

25

Liberal Group Restrictive Group P Value

Volume received (mL) 3878 ± 1170 1408 ± 946 –

Patients with complications

31% 17% 0.046

Time to bowel movement (days)

6 (4-9) 4 (3-9) <0.001

Hospital stay (days) 9 (7-24) 8 (6-21) 0.01

Nisanevich V et al. Anesthesiology. 2005; 103:25-32.Brandstrup B et al. Ann Surg. 2003; 238:641-8.

Brandstrup B et al. Ann Surg. 2003; 238:641-8. Bellamy M. Br J Anaesth. 2006; 97:755-7.

Bellamy M. Br J Anaesth. 2006; 97:755-7.

Restricted Liberal

Bellamy M. Br J Anaesth. 2006; 97:755-7.

Control GDT

26

Bellamy M. Br J Anaesth. 2006; 97:755-7.Moretti EW et al. Anesth Analg. 2003; 96:611-7.

Intraoperative Volumes of Fluids

0

1000

2000

3000

4000

5000

6000

7000

Colloid/Cryst (HS-LR) Crystalloid (LR)

Colloid Crystalloid

mL

Moretti EW et al. Anesth Analg. 2003; 96:611-7.

HS-LR = 6% hetastarch and lactated Ringer’s solutionLR = lactated Ringer’s solution

Colloids vs. Crystalloid

01020304050607080

Nausea Vomiting Antiemetic

Hetastarch/LR

LR

% of Patients*p < 0.05*

* *


Colloids vs. Crystalloid

05

10152025303540

Severe Painon coughing

Periorbitaledema

Doublevision

Hetastarch/LR LR

% of Patients *p < 0.05

*

*

*


Total Total Body FluidBody Fluid

45 L45 L

Intracellular

30 LPV

3 L

Different Body Fluid SpacesDifferent Body Fluid Spaces

GlucoseGlucoseColloidColloid

SalineSaline

RBC2 LInterstitial

10 L

Grocott M et al. Anesth Analg. 2005; 100:1093-106.

27

Plasma Volume Expansion Effect 90 min after Fluid Administration

Vol

u me

(mL )

Lamke LO et al. Resuscitation. 1976; 5:93-102.

0100200300400500600700800900

1000

6% HS 5% Albumin Gelatin Saline

HS = hetastarch Disbrow EA et al. West J Med. 1993; 158:488-92.

Disbrow EA et al. West J Med. 1993; 158:488-92.

Conclusion• POI affects between 4% and 20% of abdominal

surgical patients annually and has a detrimental effect on clinical outcomes and costs of care

• There are important anesthetic factors that can have an impact on POI

• Epidural anesthetic agents, analgesic adjuncts, preoperative education, and peripheral opioid-receptor antagonists can potentially reduce the incidence of POI

• A multimodal approach using both nonpharmacologic and pharmacologic options is most effective

End of Presentation


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28


Selected References 1. Akca O, Lenhardt R, Fleischmann E et al. Nitrous oxide increases the incidence of bowel

distension in patients undergoing elective colon resection. Acta Anaesthesiol. 2004; 48:894-8.

2. Bates JJ, Foss JF, Murphy DB. Are peripheral opioid antagonists the solution to opioid side

effects? Anesth Analg. 2004; 98:116-22. 3. Bellamy MC. Wet, dry or something else? Br J Anaesth. 2006; 97:755-7. 4. Bennett-Guerro E, Welsby I, Dunn TJ et al. The use of a postoperative morbidity survey to

evaluate patients with prolonged hospitalization after routine, moderate risk, elective surgery. Anesth Analg. 1999; 89:514-9.

5. Berend KR, Lombardi AV Jr, Mallory TH et al. Ileus following total hip or knee arthroplasty is

associated with increased risk of deep venous thrombosis and pulmonary embolism. J Arthroplasty. 2004;19(7 Suppl 2):82-6.

6. Brandstrup B, Tønnesen H, Beier-Holgersen R et al. Effects of intravenous fluid restriction

on postoperative complications: comparison of two perioperative fluid regimens: a randomized assessor-blinded multicenter trial. Ann Surg. 2003; 238:641-8.

7. Cali RL, Meade PG, Swanson MS et al. Effect of morphine and incision length on bowel

function after colectomy. Dis Colon Rectum. 2000; 43:163-8. 8. Chang SS, Cookson MS, Baumgartner RG et al. Analysis of early complications after radical

cystectomy: results of a collaborative care pathway. J Urol. 2002; 167:2012-6. 9. Coley KC, Williams BA, DaPos SV et al. Retrospective evaluation of unanticipated

admissions and readmissions after same day surgery and associated costs. J Clin Anesth. 2002; 14:349-53.



11. Disbrow EA, Bennett HL, Owings JT. Effect of preoperative suggestion on postoperative

gastrointestinal motility. West J Med. 1993; 158:488-92. 12. Elia N, Lysakowski C, Tramèr MR. Does multimodal analgesia with acetaminophen,

nonsteroidal anti-inflammatory drugs, or selective cyclooxygenase-2 inhibitors and patient-controlled analgesia morphine offer advantages over morphine alone? Meta-analyses of randomized trials. Anesthesiology. 2005; 103:1296-304.

29


13. Gan TJ, Joshi GP, Zhao SZ et al. Presurgical intravenous parecoxib sodium and follow-up

oral valdecoxib for pain management after laparoscopic cholecystectomy surgery reduces opioid requirements and opioid-related adverse effects. Acta Anaesthesiol Scand. 2004; 48:1194-207.

14. Gan TJ, Lubarsky DA, Flood EM et al. Patient preferences for acute pain treatment. Br J

Anaesth. 2004; 92:681-8. 15. Gan TJ, Soppitt A, Maroof M et al. Goal-directed intraoperative fluid administration reduces

length of hospital stay after major surgery. Anesthesiology. 2002; 97:820-6. 16. Gottschalk A, Smith DS. New concepts in acute pain therapy: preemptive analgesia. Am

Fam Physician. 2001; 63:1979-84. 17. Grocott M, Mythen M, Gan TJ. Perioperative fluid management. Anesth Analg. 2005;

100:1093-106. 18. Holte K, Kehlet H. Postoperative ileus: a preventable event. Br J Surg. 2000; 87:1480-93. 19. Jensen AG, Kalman SH, Nyström PO et al. Anaesthetic technique does not influence

postoperative bowel function: a comparison of propofol, nitrous oxide and isoflurane. Can J Anaesth. 1992; 39:938-43.

20. Joshi GP, Viscusi ER, Gan TJ et al. Effective treatment of laparoscopic cholecystectomy

pain with intravenous followed by oral COX-2 specific inhibitor. Anesth Analg. 2004; 98:336-42.

21. Kehlet H, Dahl JB. The value of “multimodal” or “balanced analgesia” in postoperative pain

treatment. Anesth Analg. 1993; 77:1048-56.

22. Kurz A, Sessler DI. Opioid-induced bowel dysfunction: pathophysiology and potential new therapies. Drugs. 2003; 63:649-71.

23. Lamke LO, Liljedahl SO. Plasma volume changes after infusion of various plasma

expanders. Resuscitation. 1976; 5:93-102. 24. Liu SS, Carpenter RL, Mackey DC et al. Effects of perioperative analgesic technique on rate

of recovery after colon surgery. Anesthesiology. 1995; 83:757-65. 25. Lobo DN, Bostock KA, Neal KR et al. Effect of salt and water balance on recovery of

gastrointestinal function after elective colonic resection: a randomised controlled trial. Lancet. 2002; 359:1812-8.

26. Luckey A, Livingston E, Taché Y. Mechanisms and treatment of postoperative ileus. Arch

Surg. 2003; 138:206-14. 27. Moraca RJ, Sheldon DG, Thirlby RC. The role of epidural anesthesia and analgesia in

surgical practice. Ann Surg. 2003; 238:663-73.

30


28. Moretti EW, Robertson KM, El-Moalem H et al. Intraoperative colloid administration reduces

postoperative nausea and vomiting and improves postoperative outcomes compared with crystalloid administration. Anesth Analg. 2003; 96:611-7.

29. Mythen MG, Webb AR. Perioperative plasma volume expansion reduces the incidence of

gut mucosal hypoperfusion during cardiac surgery. Arch Surg. 1995; 130:423-9. 30. Nisanevich V, Felsenstein I, Almogy G et al. Effect of intraoperative fluid management on

outcome after intraabdominal surgery. Anesthesiology. 2005; 103:25-32. 31. Person B, Wexner SD. The management of postoperative ileus. Curr Probl Surg. 2006;

43:6-65. Review. 32. Playford RJ, Vesey DA, Haldane S et al. Dose-dependent effects of fentanyl on

indomethacin-induced gastric damage. Digestion. 1991; 49:198-203. 33. Steinbrook RA. Epidural anesthesia and gastrointestinal motility. Anesth Analg. 1998;

86:837-44; 34. Zhao SZ, Chung F, Hanna DB et al. Dose-response relationship between opioid use and

adverse effects after ambulatory surgery. J Pain Symp Manage. 2004; 28:35-46.

31


Conor P. Delaney, M.D., M.Ch., Ph.D., FRCSI, FACS Professor of Surgery, Case Western Reserve University

Chief, Division of Colorectal Surgery Vice-Chairman, Department of Surgery

Director, Institute for Surgery and Innovation University Hospitals of Cleveland, Case Medical Center

Cleveland, Ohio Conor P. Delaney, M.D., M.Ch., Ph.D., FRCSI, FACS, is Chief of the Division of Colorectal Surgery and Vice Chairman of the Department of Surgery at Case Medical Center in Cleveland, Ohio. He is also Professor of Surgery at Case Western Reserve University School of Medicine in Cleveland. Dr. Delaney earned a Master of Surgery (M.Ch.) degree and a specialty degree in medicine from the University College Dublin in Dublin, Ireland. His postgraduate education included an internship at Mater Misericordiade Hospital Dublin 7 and residency at the Royal College of Surgeons Ireland, both of which are located in Dublin, Ireland. He also completed fellowships at the Royal College of Surgeons, University of Pittsburgh, and The Cleveland Clinic. Dr. Delaney’s clinical interests include laparoscopic colorectal surgery; carcinoma of the colon, rectum, and anus; Crohn’s disease and ulcerative colitis; sphincter-saving surgery; re-operative abdominal surgery; and colonoscopy. He has given numerous lectures nationally and internationally and has published widely in peer-reviewed journals and book chapters on topics relating to colorectal surgery, laparoscopic colorectal surgery, and pre- and postoperative management in bowel surgery. Dr. Delaney has received numerous prizes, scholarships, and awards over the course of his career in training, education, and research, including the New England Society of Colon and Rectal Surgeons Award in 2004. He is a member of several professional societies, including the American College of Surgeons, Crohn’s and Colitis Foundation of America, and the American Society of Colon and Rectal Surgeons. He serves on the editorial board of Reality Surgery published in Dublin, Ireland, and is a manuscript reviewer for many journals. Dr. Delaney is also actively involved in a number of professional committees for the American Society of Colorectal Surgeons, Society of American Gastrointestinal and Endoscopic Surgeons, and the Midwest Surgical Association.

32


Overview

Surgery on the gastrointestinal (GI) tract is associated with a mandatory period of cessation of intestinal function, deemed postoperative ileus (POI). Time spent in the hospital after abdominal surgery has been related to several factors, including pain, postoperative fatigue, the presence of mechanical factors like drains, and the persistence of POI. There is now increasing evidence that clinical pathways reduce the length of time spent in the hospital after abdominal surgery. The effect of epidural anesthesia on POI has been studied for many years. Unfortunately, epidurals have been used with extreme variability, sometimes as lumbar, sometimes as thoracic, with and without opiates, and using different clinical endpoints. The time spent in the hospital has not been reproducibly shortened. Laparoscopy has also been used for colorectal surgery in recent years. Most studies show a significant reduction in time to recovery of bowel function and usually a hospital stay shortened by two days compared with open surgery. Part of the reduction in length of stay is thought to be related to a reduction in time to recovery of bowel function. Most recently some new pharmacologic agents have been suggested as a means of accelerating recovery of bowel function. The best studied agents are in a new class of drugs called µ-opioid receptor antagonists. Several recent studies have suggested that alvimopan showed a significant reduction in time to recovery of ileus, number of nausea and vomiting episodes, and time to hospital discharge. More recent data with another drug in this group called methylnaltrexone suggest similar findings. Although neither agent has yet been FDA approved, it is likely that they will be a component of postoperative care pathways in the future.

Presentation Objectives

At the conclusion of this presentation, participants should be able to

• Summarize factors associated with postoperative ileus. • Describe the rationale for using opioid-receptor antagonists in the management of

postoperative ileus. • Describe recent clinical research into new and emerging pharmacologic options for

preventing and managing postoperative ileus.

33

Emerging Pharmacologic Options for Managing Postoperative Ileus

Conor P. Delaney, M.D., Ph.D.Professor and Chief

Division of Colorectal SurgeryVice Chairman, Department of Surgery

Case Western Reserve UniversityUniversity Hospitals, Case Medical Center

Cleveland, Ohio

Ileus

• ….but we don’t really know….

• Some people recover after extensive manipulation

• Some patients with easy, quick, straightforward cases don’t recover for prolonged times…

Stomach: 24-48 hours

Small intestine:12-24 hours

Large intestine:72-120 hours

Usual Organ Recovery Times

Delaney CP, Kehlet H, Senagore AJ, Chairs. New York: 2005 Sept 23-24.

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 IleusManagementCouncil (PIMC)

POI = postoperative ileus

34

– Primary POI occurs in the absence of any precipitating complication

– Secondary POI occurs in the presence of a precipitating complication (infection, anastomotic leak, etc.)

Consensus Panel Definitions POI: Profiles, Risk Factors and Definitions -Consensus Document

Delaney CP et al. for the PIMC. http://www.clinicalwebcasts.com/PIMC.htm(accessed 2007 Sept 7).

Hospital Discharge Associated with Recovery of GI Function

GI = gastrointestinalGI-2 = recovery of bowel movement and toleration of solid food

Delaney CP et al. Am J Surg. 2006; 191:315-9.

Patie

nts

(%)

N=383

0

5

10

15

20

25

0 1 2 3 4 5 6 7 8 9 10

Postoperative day

GI-2 recoveryHospital discharge

Readmission and Prolongation of Hospital StayPa

tient

s (%

)

SAE = serious adverse eventEPSBO = early postoperative small bowel obstruction

Delaney CP et al. Am J Surg. 2006; 191:315-9.

N=383N=383

With standardized, multimodal postoperative care protocols after open laparotomy and bowel resection

11.713.7

24.4

9.2

0

5

10

15

20

25

30

Hospitalreadmission

Prolongedhospital stay

Prolongedhospital stay or

readmission

POI as an SAEand/or EPSBO

Cochrane Review - Summary• Epidural LA (no opiate) reduces POI,

compared with systemic (36 h) or epidural (24 h) opioids, with comparable analgesia

• Epidural LA plus opioid may provide better analgesia than LA alone (VAS 15 mm), while the effect on GI function is unclear

• No significant difference in postoperative nausea and vomiting (PONV)

Jørgensen H et al. Cochrane Database Syst Rev. 2000;(4):CD001893.

LA = local anesthetic; VAS = visual analog pain score

Jørgensen H et al. Cochrane Database Syst Rev. 2000;(4):CD001893.

Epi LA vs syst op: P=0.0001

Subgroups: Return of GI function

Epi LA vs epi op: P=0.0009

Epi LA vs epi LA/op: P=0.15

35

CREAD Epidural vs. PCA

PCAPCA((nn=28)=28)

LOS LOS

pp

5.0 (4.05.0 (4.0--8.5)8.5)

EpiduralEpidural((nn=31)=31)

5.0 (4.05.0 (4.0--7.0)7.0) 0.940.94

Pain score at 48 hPain score at 48 h 3.33.3 2.52.5 0.010.01

Pain score on dischargePain score on discharge 3.1 3.1 ++ 2.02.0 3.1 3.1 ++ 2.42.4 0.790.79

Costs ($)Costs ($) 0.140.1445864586 38083808

AgeAge 4747 4444 0.520.52

Pain score at all other times Pain score at all other times -- identicalidentical

CREAD = Controlled rehabilitation with early ambulation and dietPCA = patient-controlled analgesiaLOS = length of stay in days

Zutshi M et al. Am J Surg. 2005; 189:268-72.

Laparoscopic Colectomy:RCT of Epidural vs. PCA

• 21 patients per group• Thoracic epidural vs. i.v. PCA• Identical dietary management

• Hospital stay 2.3 vs. 2.4 days• Nausea / vomiting 28% both groups• No nasogastric (NG) tubes required

Senagore AJ et al. Br J Surg. 2003; 90:1195-9.

RCT = randomized controlled trial

New Pharmacologic Agents

Fedotozine

• Peripheral opioid agonist (К-receptor)– 51-Cr test meal in rats, laparotomy and peritonitis models,

inhibiting motility and migrating myoelectrical complexes (MMC) for 3 h

• μ-agonist potentiated ileus• δ-agonist made no difference• К-agonist reversed ileus

(3 mg/kg i.v.; 10 mg/kg s.c.)

Rivière PJ et al. Gastroenterology. 1993; 104:724-31.

Opioids interact with μ-opioid receptors in the CNS to induce analgesia

Opioids interact with μ-opioid receptors in the

gut to inhibit function

Opioid Receptors in the Bowel Suppress Motility

(Courtesy, Dr. Carston Gutt, Heidelberg)

Narcoticanalgesicpain relief

Narcotic adverse effects • Sedation • Respiratory depression • Addiction

Pain Pain and and

NarcoticNarcoticAnalgesicsAnalgesics

Opioid bowel dysfunction

Central opioid receptors

Peripheralopioid receptors in bowel

Narcotic analgesics • Morphine• Codeine • Hydrocodone• Oxycodone• Fentanyl

36

Peripheralopioidantagonist

Alvimopan selectively antagonizes GI opioid receptors; no effect on CNS opioid receptors

Narcoticanalgesicpain reliefPain Pain

and and NarcoticNarcotic

AnalgesicsAnalgesics

Central opioid receptors

Peripheralopioid receptors in bowel

Narcotic analgesics • Morphine• Codeine • Hydrocodone• Oxycodone• Fentanyl

Narcotic adverse effects • Sedation • Respiratory depression • Addiction

Naloxone• Competitive µ-opioid receptor antagonist

• Readily crosses the blood-brain barrier when given i.v.

• Reverses the centrally-mediated effects of opiates (CNS depression, analgesia, respiratory depression)

• May precipitate opioid withdrawal

• No current data showing benefit in POI

Kurz A et al. Drugs. 2003; 63:649-671.

Methylnaltrexone• µ-opioid receptor antagonist

• Does not readily cross the blood-brain barrier

• If given i.v., its effects are limited mainly to GI tract

• Has been shown to decrease opioid-induced constipation without affecting pain control or precipitating opioid withdrawal

• Is being evaluated in the postoperative settingLuckey A et al. Arch Surg. 2003; 138:206-14; Person B et al. Curr Probl Surg. 2006; 43:6-

65. Review; Thomas J et al. Presented at American Society of Clinical Oncologists. Orlando, FL; 2005 May 13-17; Yuan CS et al. JAMA. 2000; 283:367-72; Viscusi ER et

al. Presented at Society of Surgical Oncology. Washington, DC: 2007 Mar 16.

Methylnaltrexone inOpioid-Induced Constipation (OIC)

• OIC in advanced medical illness (n=154)• Multicenter, phase III randomized double-blind

placebo-controlled trial• Compared placebo, methylnaltrexone 0.15

mg/kg, and methylnaltrexone 0.3 mg/kg given s.c.• Laxation within 4 hours of study drug

– Placebo 13%– 0.15 mg/kg 62% p < 0.0001*– 0.30 mg/kg 58% p < 0.0001*

• 30-40% had cramps, and 1-15% flatulenceThomas J et al. Presented at American Society of

Clinical Oncologists. Orlando, FL: 2005 May 13-17.*Cochran-Mantel-Haenszel

Methylnaltrexone forSegmental Colectomy

• I.V. peripheral µ-opioid receptor antagonist• 0.3 mg/kg every 6 h, within 90 min of surgery, max 7

days• 65 colectomies

Methylnaltrexone Placebo pToleration liquids (h) 68 97 0.12Toleration solids (h) 97 124 0.21First BM (h) 98 118 0.04GI recovery (h) 115 137 0.26Discharge eligible (h) 116 149 0.049Time to discharge (h) 138 164 0.16

Viscusi ER et al. Presented at Society of Surgical Oncology. Washington, DC: 2007 Mar 16.

BM = bowel movement

Alvimopan

NH+

CH3

NH

O-

O

O

CH3

HO

. 2 H2O

37

Alvimopan

1Azodo IA et al. Curr Opin Investig Drugs. 2002; 3:1496-501;2Schmidt WK. Am J Surg. 2001; 182(5A Suppl):27S-38S; 3Taguchi A et al.

N Engl J Med. 2001; 345:935-40; 4Wolff BG et al. Ann Surg. 2004; 240:728-35; 5Delaney CP et al. Dis Colon Rectum. 2005; 48:1114-25.

• Peripherally acting µ-opioid receptor antagonist1

• Highly selective for µ-opioid receptor over δ and κreceptors1,2

• 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

• Following positive phase I and phase II3 trials, phase III trials have been completed;4,5 under FDA review for management of POI following bowel resection

Monoclonal antibodies to mu-opioid receptor – present in small bowel, stomach, and colonISMOR Colon Q1241.Left: ISMOR (40X mag). Reactive Meissner’s plexus (blue arrows) in sub-mucosa.Right: ISMOR (40X mag). Staining of basal ganglia (blue arrow and bracket) adjacent to crypt epithelium (red arrows).

NN = 1,627= 1,627

Scheduled Scheduled for BR or for BR or

TAHTAH

Alvimopan Phase III Trial Design

3 Double-blind, multicenter, placebo-controlled trials

Alvimopan 12 mg (n = 544)

Alvimopan 6 mg (n = 541)

Placebo (n = 542)

*Administered orally at least 2 hours before surgery, then twice daily until hospital discharge for up to 7 days

Dosing*Dosing* Hospital Hospital dischargedischarge

BR = bowel resection; TAH = total abdominal hysterectomy

Primary Endpoint:Primary Endpoint:Time to GI Recovery (GITime to GI Recovery (GI--3)3)

1.01.0

0.90.9

0.80.8

0.70.7

0.60.6

0.50.5

0.40.4

0.30.3

0.20.2

0.10.1

0.00.000 2424 4848 7272 9696 120120 144144 168168 192192 216216 240240 264264

Cox proportional Cox proportional hazard estimateshazard estimates

Time to GI recovery, hoursTime to GI recovery, hours

Patie

nts

achi

evin

g en

dpoi

nt, %

Patie

nts

achi

evin

g en

dpoi

nt, %

HRHR PP valuevalueMean,*Mean,*hours hours

PlaceboPlacebo —— —— 100100ALV 12 mgALV 12 mg 1.281.28 0.0590.059 9393 ((--8)8)††ALV 6 mgALV 6 mg 1.451.45 0.0030.003 8686 ((--14)14)††

ΔΔ vsvsplaceboplacebo

*By Kaplan-Meier estimates†Mean difference in hours from placeboHR = hazard ratio; ALV = alvimopan

Delaney CP et al. Dis Colon Rectum. 2005; 48:1114-25.GI-3 = recovery of BM, passage of flatus, and toleration of solid food

Primary Endpoint: Time to Recovery of GI Function (GI-3)

Cox PH - Estimates

KM - Estimates

Cumulative Distributions for MITT Population—Overall

Alvimopan

98(-22)

105(-15)

120Mean (h)*(Δ vs. placebo)

<0.0010.046—P-value

1.54(1.21, 1.96)

1.28(1.00, 1.64)

—HR (95% CI)

12 mg(N=165)

6 mg(N=155)

Placebo(N=149)

*Kaplan-Meier estimatesMITT = modified intent to treat

Readmission rate reduced:8% to 4%

Wolff BG et al. Ann Surg. 2004; 240:728-35.

Postoperative Morbidity

*Statistically significant compared with placebo (p < 0.05)NGT = nasogastric tube; EPSBO = early postoperative small bowel obstruction

Patie

nts,

%

**

**

**

**

Delaney CP et al. Dis Colon Rectum. 2005; 48:1114-25.

9.6

5.4

2.6

0.9

5.5

1.91.3 1.1

5.6

1.5 1.9

0.7

0

3

6

9

12

15

Postoperative NGTinsertion

POI as an SAE EPSBO Anastomotic leak

Placebo Alvimopan 6 mg Alvimopan 12 mg

38

Hospital Resource Use

*Statistically significant compared with placebo (p < 0.05)DCO = discharge order

Patie

nts,

%

**** ****

****

≥≥

Delaney CP et al. Dis Colon Rectum. 2005; 48:1114-25.

12.011.0

29.3

7.0 6.6

18.8

7.1 7.1

15.7

0

5

10

15

20

25

30

Prolonged hospital stay Readmission DCO written 7 days

Placebo Alvimopan 6 mg Alvimopan 12 mg

Alvimopan in Bowel Resection: Pooled Analysis

• Elective intestinal resection• Randomized to three groups

– Placebo– Alvimopan 6 mg– Alvimopan 12 mg

• 400 patients per group

• Endpoints of GI recovery, hospital discharge• Complications and treatment emergent event

Delaney CP et al. Ann Surg. 2007; 245:355-63.

Alvimopan: A Meta-analysis

• 2512 bowel resections in 5 trials

• Recovery of GI-2 and GI-3, significantly improved

• Time to discharge order significantly improved

Tan EK et al. Aliment Pharmacol Ther. 2007; 25:47-57.

Alvimopan in Bowel Resection: Pooled Analysis


Alvimopan in Bowel Resection: Pooled Analysis (cont)


Alvimopan in Bowel Resection: Pooled Analysis (cont)


Placebo 6 mg 12 mg p

Prolonged POI 6.7% 1.8% 1.9% <0.001

EPSBO/POI 9.2% 3.0% 3.9% <0.001

NG tube insertion 12% 6.8% 6.8% <0.001

Readmission 11.7% 7.3% 7.7% 0.05Prolonged stay 13.7% 8.6% 7.0% 0.02Combined 24.4% 13.6% 14% <0.001

39

Alvimopan in Bowel Resection: Adverse Events in Pooled Analysis


TEAE Placebo 6 mg 12 mg

Nausea 60.2% 54.5% 51.1%*

Vomiting 26.1% 22.4% 19.6%

Pruritus 13.5% 11.1% 9.4%*

POI 13.9% 7.%* 8.0%*

• Nausea most common TEAE reported• Majority of AEs resulting in prolonged hospital stay were GI-

related in placebo group and non-GI-related in alvimopan groups

*p > 0.05 compared with placeboTEAE = treatment-emergent AE, defined as AE occurring after 1st dose of study medication and up to 7 days after the last dose

Outcome of Unplanned Readmission (UR)

• 553 resections in 6 months; 56 URs (10%)• UR had more perioperative steroids (32 vs. 17%, p=0.03)• Matched non-readmitted cases had shorter primary LOS

(median 6 vs. 5 days, p=0.04)

• No predictors (complications, WBC, Hb, antibiotics, co-morbidity, fever, urgency, stoma, length of stay)

• No adverse event related to delayed diagnosis

• Conclusion: UR is unpredictable, not related to LOS, doesn’t affect overall outcome

Kiran RP et al. J Am Coll Surg. 2004; 198:877-83.

Indications for Readmission

Kariv Y et al. Am J Surg. 2006; 191:364-71.

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 Reoperation

12.8 (0.98, 167.2)16.9 (1.05, 272.6)

Medical complications

Functional capacityCOPDPostoperative fever Postoperative ileusStoma at discharge

1.53 (1.11, 2.12)11.0 (1.39, 87.4)5.6 (1.78, 17.5)3.33 (1.08, 10.3)4.12 (1.35, 12.6)

Ileus/SBO Prior PE/DVTPrior 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; 191:364-71.

RD = readmission within 30 days of discharge

Alvimopan: Postoperative Morbidity (Phase III Pooled Data)

Patie

nts,

%

† †

*P<0.05; †P<0.001; ‡P=0.003

12.2

6.7

9.2

1.2

*6.8

1.83.0

1.51.9

3.9

1.0

0

3

6

9

12

15

Postoperative NGTinsertion

POI as an SAE EPSBO or POIas an SAE

Anastomotic leak

Placebo

Alvimopan 6 mg

Alvimopan 12 mg *

6.8

†‡


Alvimopan: Hospital Resource Use (Phase III Pooled Data)

*P=0.024; †P<0.001; ‡P=0.040; ¶P=0.059.

Prolonged hospital stay Readmission DCO written ≥7 days

Placebo

Alvimopan 6 mg

Alvimopan 12 mg

Patie

nts,

%

‡* ¶†

†

†

13.7 11.7

38.1

8.6 7.3

24.4

7.0 7.7

19.9

0

5

10

15

20

25

30

35

40


40

Conclusions• POI occurs variably in all patients

• Contributed to by standard opiates, which are currently necessary agents for adequate analgesia

• Postoperative care pathways and laparoscopy are useful adjuncts to treatment

• New medications are likely to be available in the near future

End of Presentation


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41


Selected References 1. Azodo IA, Ehrenpreis ED. Alvimopan (Adolor/GlaxoSmithKline). Curr Opin Investig Drugs.

2002; 3:1496-501. 2. Jørgensen H, Wettersley J, Møiniche S et al. Epidural local anaesthetics versus opioid-

based analgesic regimens on postoperative gastrointestinal paralysis, PONV and pain after abdominal surgery. Cochrane Database Syst Rev. 2000;(4):CD001893.

3. Delaney C, Kehlet H, Senagore AJ, Guest Eds. Postoperative ileus. Semin Colon Rectal

Surg. 2005; 16(4). 4. Delaney CP, Kehlet H, Senagore AJ, Chairs. The Postoperative Ileus Management Council

(PIMC) National Experts’ Consensus Panel and Scientific Roundtable: the complete challenges of defining, measuring, and predicting postoperative ileus (POI)—an evidence based analysis and recommendations for surgical management. New York, NY: Sept 23-24, 2005.



6. Delaney CP, Senagore AJ, Viscusi ER et al. Postoperative upper and lower gastrointestinal

recovery and gastrointestinal morbidity in patients undergoing bowel resection: pooled analysis of placebo data from 3 randomized controlled trials. Am J Surg. 2006; 191:315-9.

7. Delaney CP, Weese JL, Hyman NH et al. Phase III trial of alvimopan, a novel, peripherally

acting, mu opioid antagonist, for postoperative ileus after major abdominal surgery. Dis Colon Rectum. 2005; 48:1114-25.

8. Delaney CP, Wolff BG, Viscusi ER et al. Alvimopan, for postoperative ileus following bowel

resection: a pooled analysis of phase III studies. Ann Surg. 2007; 245:355-63. 9. Rivière PJ, Pascaud X, Chevalier E et al. Fedotozine reverses ileus induced by surgery or

peritonitis: action at peripheral kappa-opioid receptors. Gastroenterology. 1993; 104:724-31. 10. Kariv Y, Wang W, Senagore AJ et al. Multivariable analysis of factors associated with

hospital readmission after intestinal surgery. Am J Surg. 2006; 191:364-71. 11. Kiran RP, Delaney CP, Senagore AJ et al. Outcomes and prediction of hospital readmission

after intestinal surgery. J Am Coll Surg. 2004; 198:877-83. 12. Kurz A, Sessler DI. Opioid-induced bowel dysfunction: pathophysiology and potential new

therapies. Drugs. 2003; 63:649-71. 13. Luckey A, Livingston E, Taché Y. Mechanisms and treatment of postoperative ileus. Arch

Surg. 2003; 138:206-14.

42


14. Person B, Wexner SD. The management of postoperative ileus. Curr Probl Surg. 2006;

43:6-65. Review. 15. Schmidt WK. Alvimopan*(ADL 8-2698) is a novel peripheral opioid antagonist. Am J Surg.

2001; 182(5A Suppl):27S-38S. 16. Senagore AJ, Delaney CP, Mekhail N et al. Randomized clinical trial comparing epidural

anaesthesia and patient-controlled analgesia after laparoscopic segmental colectomy. Br J Surg. 2003; 90:1195-9.

17. Taguchi A, Sharma N, Saleem RM et al. Selective postoperative inhibition of gastrointestinal

opioid receptors. N Engl J Med. 2001; 345:935-40. 18. Tan EK, Cornish J, Darzi AW et al. Meta-analysis: alvimopan vs. placebo in the treatment of

post-operative ileus. Aliment Pharmacol Ther. 2007; 25:47-57. 19. Thomas J, Lipman A, Slatkin N et al. A phase III double-blind placebo-controlled trial of

methylnaltrexone (MNTX) for opioid-induced constipation (OIC) in advanced medical illness (AMI). Presented at the American Society of Clinical Oncologists Annual Meeting. Orlando, FL; 2005 May 13-17 (abstract 8003). http://www.asco.org/portal/site/ASCO/menuitem.34d60f5624ba07fd506fe310ee37a01d/?vgnextoid=76f8201eb61a7010VgnVCM100000ed730ad1RCRD&vmview=abst_detail_view&confID=34&abstractID=32585 (accessed 2007 Sept 20).

20. Viscusi ER. Methylnaltrexone bromide administered postoperatively to patients following

segmental colectomy may accelerate GI recovery and hospital discharge without affecting opioid analgesia. Presented at Society of Surgical Oncology Annual Cancer Symposium. Washington, DC: Mar 16, 2007.

21. Wolff BG, Michelassi F, Gerkin TM et al. Alvimopan, a novel, peripherally acting mu opioid

antagonist: results of a multicenter, randomized, double-blind, placebo-controlled, phase III trial of major abdominal surgery and postoperative ileus. Ann Surg. 2004; 240:728-35.

22. Yuan CS, Foss JF, O-Connor M et al. Methylnaltrexone for reversal of constipation due to

chronic methadone use: a randomized controlled trial. JAMA. 2000; 283:367-72. 23. Zutshi M, Delaney CP, Senagore AJ et al. Randomized controlled trial comparing the

controlled rehabilitation with early ambulation and diet pathway versus the controlled rehabilitation with early ambulation and diet with preemptive epidural anesthesia/analgesia after laparotomy and intestinal resection. Am J Surg. 2005; 189:268-72.

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Self-Assessment Test This program is located at www.postopileus.org (Activity #08703 podcast).

This self-assessment test has been provided as a study aid only. At the conclusion of the internet-based program, click on “Take CE Test” to proceed to the ASHP Advantage CE Testing Center and take the online program post-test. You may print your CME statement immediately after successful completion of the post-test.

1. Primary postoperative ileus (POI) is now assumed to be a natural sequelae of abdominal

surgical procedures and is described as a transient cessation of coordinated bowel motility that prevents effective transit of intestinal contents or tolerance of oral intake

a. Occurring in the presence of a precipitating complication, such as intraabdominal abcess

or anastomotic leak. b. Occurring in the absence of any precipitating complication. c. Lasting more than five days after surgery. d. Lasting more than nine days after surgery.

2. Risk factors for postoperative ileus include all of the following except

a. Surgical technique. b. Extended opioid use. c. Inactivity. d. Initiation of solid food diet on postoperative day 2.

3. According to recent Medicare data, postoperative ileus occurs most frequently after which of

the following procedures?

a. Abdominal hysterectomy and appendectomy. b. Hip arthroplasty and cholecystectomy. c. Small bowel resection and large bowel resection. d. Cholecystectomy and nephroureterectomy.

4. The primary pathogenesis of postoperative ileus involves inflammatory mediators.

a. True. b. False.

5. Supportive patient-care elements in enhanced-recovery surgery protocols aimed at

minimizing postoperative ileus include all of the following components except

a. Avoidance of nasogastric (NG) intubation. b. Fluid restriction. c. Early oral feeding. d. Delayed ambulation.

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6. Dr. Senagore would not recommend including metoclopramide in a multimodal approach to

managing postoperative ileus because

a. Well-controlled studies indicated no benefit in any outcomes related to postoperative ileus.

b. Its combined dopaminergic agonist and cholinergic antagonist actions are limited to the proximal gut.

c. Adverse effects occur in 25-30% of patients. d. Postoperative patients often cannot tolerate the oral dosage form.

7. Studies by Delaney et al. evaluating outcomes of patients undergoing abdominal surgeries

using enhanced-recovery protocols compared with traditional care showed that patients treated using enhanced-recovery protocols

a. Reported less satisfaction with care during their hospitalization. b. Had higher pain scores on discharge. c. Had shorter lengths of stay. d. Had more readmissions.

8. Both exogenous and endogenous opioids have which of the following pharmacologic effects on the gastrointestinal tract?

a. Increased gastric motility and emptying resulting in decreased appetite and increased

gastroesophageal reflux. b. Decreased enzymatic secretion resulting in delayed digestion and hard, dry stools. c. Decreased fluid and electrolyte absorption resulting in hard, dry stools. d. Decreased nonpropulsive segmental contractions resulting in incomplete evacuation.

9. A survey conducted by Gan et al. of patients undergoing major abdominal surgery using

patient-controlled analgesia showed that many patients preferred avoiding adverse effects of opioids over complete pain control.

a. True. b. False.

10. Which of the following is a centrally acting analgesic that has been shown to decrease the postoperative opioid requirement and help prevent long term chronic pain following abdominal surgery?

a. Gabapentin. b. Aspirin. c. Celecoxib. d. Acetaminophen.

11. All of the following are benefits of a balanced postoperative analgesia regimen that includes

a combination of opioids and other analgesics except

a. Decreased doses of each analgesic. b. Early ambulation. c. Improved anti-nociception due to synergistic or additive effects. d. Less severe adverse effects of each analgesic.

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12. Thoracic epidural anesthesia/analgesia promotes gastrointestinal motility by

a. Blocking nociceptive afferent nerves. b. Stimulating thoracolumbar sympathetic efferent nerves. c. Decreasing gastrointestinal blood flow. d. Increasing need for postoperative opiates.

13. According to Dr. Gan, which of the following statements best describes the use of epidurals to manage postoperative ileus?

a. The epidural should not be placed until after surgery begins. b. The catheter should be placed at about T7 or T8 so that it can expand to cover T5 to L2. c. The most effective solution for the epidural is a local anesthetic. d. The epidural should be administered postoperatively for a maximum of 24 hours.

14. According to Dr. Gan, fluid management is an important aspect of enhanced recovery after abdominal surgery because

a. Optimizing the volume of fluids administered and using a combination of colloids and

crystalloids have been shown to have a positive influence on postoperative outcomes. b. Restricting intraoperative fluid administration to 500 mL or less results in decreased

postoperative morbidity. c. Colloid administration results in edema caused by pooling of colloids in interstitial

spaces. d. Goal-directed intraoperative fluid management has been shown to increase length of

stay.

15. Fedotozine is a peripheral _______________ that has been shown to reverse ileus in animal models.

a. Mu-opioid receptor agonist. b. Delta-opioid receptor agonist. c. Kappa-opioid receptor agonist. d. Mu-opioid receptor antagonist.

16. Opioids interact with peripheral mu-opioid receptors in the gastrointestinal tract to inhibit

function.

a. True. b. False.

17. Which of the following statements best describes the effects of naloxone for postoperative

ileus?

a. Current data indicate it is beneficial in POI. b. It does not reverse the centrally-mediated effects of opiates, such as central nervous

system depression, analgesia, and respiratory depression. c. It readily crosses the blood-brain barrier when administered intravenously. d. It does not precipitate opioid withdrawal.

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18. Methylnaltrexone is a peripheral mu-opioid receptor antagonist that has been shown to

decrease opioid-induced constipation without affecting pain control or precipitating opioid withdrawal. a. True. b. False.

19. Preliminary results of a study comparing intravenous administration of methylnaltrexone with

placebo in patients undergoing segmental colectomy indicate that a. Methylnaltrexone was associated with shorter time to first bowel movement and time to

be eligible for discharge. b. Methylnaltrexone must be initiated before surgery to be effective. c. The optimal regimen is 0.6 mg/kg every 3 hours for at least 7 days. d. Methylnaltrexone has little potential role in the postoperative setting.

20. Alvimopan is a peripherally acting mu-opioid receptor antagonist that

a. Has equipotency at mu-opioid receptor compared with morphine and methylnaltrexone. b. Blocks central opioid receptors. c. Is highly selective for mu-opiod receptor over delta and kappa receptors. d. Readily crosses the blood-brain barrier.

21. Clinical trials evaluating alvimopan in patients undergoing abdominal surgery have

documented all of the following outcomes except

a. Reduced time to passage of flatus and stool. b. Reduced time to hospital discharge. c. Reduced readmission rates. d. Increased anastomotic leak rates.

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