multimodal approach for managing postoperative · pdf filemultimodal approach for managing...

Multimodal Approach for Managing Postoperative Ileus:

Role of Health-System Pharmacists

A podcast educational activity based on a symposium presented at the

42nd ASHP Midyear Clinical Meeting and Exhibition

December 2007 Las Vegas, Nevada

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

Multimodal Approach for Managing Postoperative Ileus: Role of Health-System Pharmacists

A G E N D A Part 1 Postoperative Ileus: A Multifaceted Health Problem Brian L. Erstad, Pharm.D., FCCM, FASHP, FCCP, BCPS, Program Chair Part 2 Managing Postoperative Ileus Robert MacLaren, Pharm.D., FCCM, FCCP Part 3 New and Emerging Options for Managing Postoperative Ileus: Clinical Research and Potential Implications for Pharmacists Michael D. Kraft, Pharm.D. P R O G R A M F A C U L T Y Brian L. Erstad, Pharm.D., FCCM, FASHP, FCCP, BCPS, Program Chair Professor The University of Arizona College of Pharmacy Tucson, Arizona Michael D. Kraft, Pharm.D. Clinical Assistant Professor University of Michigan College of Pharmacy Clinical Coordinator University of Michigan Health System Ann Arbor, Michigan Robert MacLaren, Pharm.D., FCCM, FCCP Associate Professor School of Pharmacy University of Colorado Denver Aurora, Colorado


P R O G R A M O V E R V I E W

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 delayed passage of gas and stool, as well as by abdominal pain, nausea and vomiting, and diminished appetite. Preventing or minimizing postoperative ileus is an important aspect of perioperative care because the condition may delay patient ambulation, increasing the risk for pulmonary and thromboembolic complications; POI can also 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 often exacerbates POI. While a cure for postoperative ileus has not yet been found, current management strategies use a multimodal approach consisting of careful selection of anesthesia and analgesic regimens, early mobilization and institution of enteral nutrition, and avoidance of nasogastric tube placement. Ongoing clinical research continues to evaluate the effectiveness of these management strategies, as well as to explore new and emerging pharmacologic options like μ-opioid receptor antagonists. Using a case-based format, this symposium will provide an overview of postoperative ileus, including its multifactorial etiology and impact on patient and economic outcomes. Current treatment options for POI will be presented, focusing on the role of health-system pharmacists in the multidisciplinary care of perioperative patients. The results of current clinical research exploring new and emerging pharmacologic options for preventing and managing postoperative ileus also will be presented. By being aware of POI, its ramifications, current management strategies, and emerging therapies, health-system pharmacists will not only be able to provide high quality patient care for postoperative patients but also assume a leadership role on the multidisciplinary team responsible for establishing therapy guidelines during the perioperative period.

P R O G R A M O B J E C T I V E S At the conclusion of this program, participants should be able to

• Describe the pathophysiology of postoperative ileus (POI).

• Identify at least three clinical and economic consequences of POI.

• Describe the rationale for at least three components included in the multimodal approach for managing POI.

• Describe the role of health-system pharmacists in preventing and managing POI.

• Given pertinent patient information, recommend strategies for preventing or minimizing the impact of POI.

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


C O N T I N U I N G E D U C A T I O N A C C R E D I T A T I O N

The American Society of Health-System Pharmacists is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education. The program provides 2.5 hours (0.25 CEUs) of

continuing education credit (program number 204-000-07-450-H01P). F O R M A T and M E T H O D 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 2.5 hours. This activity is provided free of charge.

Instructions for Taking Post-Tests and Receiving Your CE Statements Online for Podcast Activities

The online ASHP Advantage CE Testing Center allows participants to obtain their CE statements conveniently and immediately using any computer with an Internet connection.* To take the post-test and obtain your CE statement for this ASHP Advantage Podcast activity, please follow these steps: 1. Type www.ashp.org/advantage/ce/ in your internet browser. 2. If you have previously logged in to the ASHP Advantage site, then you need only

enter your e-mail address and password.

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 Pharmacists section as “Multimodal Approach for Managing Postoperative Ileus: Role of Health-System Pharmacists.

4. Click on the radio button next to the correct answer for each question. Once you are

satisfied with your selections, click “Finish CE” to process your test and complete the remaining steps to complete the program evaluation and print your CE statement.

If you have any problems processing your CE, contact ASHP Advantage at [email protected]. *Except that this site does not support the AOL Web browser.


D I S C L O S U R E S T A T E M E N T

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: Brian L. Erstad declares that he has no relationships pertinent to this activity. Michael E. Kraft declares that he has served as a speaker and consultant for Adolor Corporation and GlaxoSmithKline and as a consultant for Wyeth. Robert MacLaren declares that he has no relationships pertinent to this activity. Carla J. Brink declares that she has no relationships pertinent to this activity.


Brian L. Erstad, Pharm.D., FCCM, FASHP, FCCP, BCPS, Program Chair Professor The University of Arizona College of Pharmacy Tucson, Arizona Brian L. Erstad, Pharm.D., is Professor in the Department of Pharmacy Practice and Science at The University of Arizona College of Pharmacy in Tucson. He carries out his clinical responsibilities at the University Medical Center in Tucson, where he is a member of the nutritional support team. Dr. Erstad also is on the faculty for the Center for Health Outcomes and PharmacoEconomic Research in the College of Pharmacy. Dr. Erstad earned his Bachelor of Science degree in pharmacy from South Dakota State University and then worked as a staff pharmacist for approximately eight years in community hospital practice. He subsequently earned his Doctor of Pharmacy degree from The University of Arizona and completed a residency at the University Medical Center in Tucson. Dr. Erstad also graduated from the Arizona Clinical Research Training Program, which was funded by an NIH K30 Clinical Research Curriculum Award. His research interests pertain to critical care medicine with an emphasis on blood product derivatives, blood conservation strategies, infectious diseases, and related outcomes. He has authored more than 100 peer-reviewed articles and book chapters. Dr. Erstad is a board-certified pharmacotherapy specialist, and he has received recognition as a Fellow by the following organizations: American College of Critical Care Medicine, American Society of Health-System Pharmacists, and the American College of Clinical Pharmacy. He has received the ACCP Clinical Practice Award for substantial and outstanding contributions to clinical pharmacy practice, and, in October 2007, he received the ACCP Education Award.


Brian L. Erstad, Pharm.D., FCCM, FASHP, FCCP, BCPS P R E S E N T A T I O N

Postoperative Ileus: A Multifaceted Health Problem A B S T R A C T

The role of the pharmacist has evolved throughout history from an initial focus on the product through the trading and selling of drugs to the current focus on the patient with interdisciplinary practice models. In the health-system setting, pharmacists are involved in the choice of medications for formularies, medication-use evaluations, clinician and patient education regarding medications, specialized clinical teams dealing with medications and nutrition support, and research activities. The pharmacists’ involvement in all of these areas is important as new therapies are investigated that are intended to prevent the complications associated with postoperative ileus (POI). A general knowledge of gastrointestinal tract anatomy, physiology, and function is necessary for understanding the actions of medications currently under development. To complicate matters, the terminology associated with POI has changed over time. Currently, POI refers to a non-mechanical obstruction or dysfunction that lasts beyond the normal time to return to full function after a major stressful event, such as surgery. The pathophysiology and causes of POI are multifactorial, and the signs and symptoms may vary substantially. There is no single diagnostic test for POI or for defining when gastrointestinal function has returned as POI resolves. The health care burden associated with POI is substantial, so it is important to identify and ameliorate causative or aggravating factors, such as opioid analgesics. L E A R N I N G O B J E C T I V E S

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

• List three classes of medications that decrease gastrointestinal propulsive movements or motility.

• Describe the normal anatomy and physiology of the gastrointestinal tract.

• List the order in which organs of the gastrointestinal tract return their function as postoperative ileus resolves.

• Describe how ileus differs from obstruction.

• Describe how postoperative ileus is usually diagnosed.

• Discuss the difficulties in documenting the resolution of postoperative ileus.

1/31/2008

1

Postoperative Ileus:A Multifaceted Health Problem

Brian L. Erstad, Pharm.D.,FCCM, FASHP, FCCP, BCPS

ProfessorThe University of Arizona College of Pharmacy

Tucson, Arizona

Pharmacy Then and Now

Several medications are at various stages of development for use in reducing the duration of postoperative ileus (POI). In addition to the role of the pharmacist in drugthe role of the pharmacist in drug development, what roles are there for pharmacists as the drugs near approval and after they are released?

Pharmacy Then• Apothecarius referred to in 10th century

• Trading in spices and drugs in London in 11th century taken over by grocers

• By 12th century some healers focused on• By 12th century, some healers focused on drugs (apothecaries)

• New profession: barber surgeons

New Profession circa 1960s: Butcher Barbers

Turf Battles: 13th Century• 13th Century: distinction between

physicians and apothecaries for first time– Only physicians allowed to administer

therapies or counsel patients– Surgeons could perform manual tasks

(phlebotomy); apothecaries could dispense

• 16th – 17th Century: apothecaries and grocers united, then later separated

Apothecary“Even into the sixteenth century, the apothecary was legally required to maintain the following in stock: wood lice, rain worms, ants, vipers, scorpions, frogs and crabs; also the skull of a dead person who was not buried, the bone from the heart of a bat, sparrow brains and hare brains, teeth of wild pigs and elephant skin, frog hearts, fox lungs, wolf intestines, human fat, and so on”

Preuss J. Julium Preuss’ Biblical and Talmudic Medicine. Rosner F, ed., 1978.

1/31/2008

2

Institute of Medicine• To Err is Human: Building a Safer Health

System• Crossing the Quality Chasm: A New Health

System for the 21st Century• Preventing Medication Errorsg

• Interdisciplinary effort with interdisciplinary recommendations for education and practice

“Just give what I ordered…”“Physicians who need me the least…”

Institute of Medicine. Crossing thequality chasm: the IOM health care quality initiative (URL in reference list).

Pharmacy Now

• Pharmacy and therapeutics (P&T) committee involvement including pharmacoeconomic analyses

• Evaluations (e.g., medication-use evaluations) of t dagents used

• Clinician and patient education with recommendations regarding medications that may cause or aggravate POI

• Nutritional support recommendations• Participation in research activities

P&T Involvement

• Pharmacist involvement either on P&T committees or for expertise with specific drugs

• Increasing use of pharmacoeconomics by P&T committees– Survey of pharmacy directors

• 92.1% of respondents indicated pharmacoeconomic analyses were used in formulary management process

• 66% indicated quality of life (QOL) information was used

. Pedersen CA et al. Am J Health-Syst Pharm. 2001; 58:2251-66.

Evaluations

Approximately 3-month evaluation of metoclopramide use in medical and surgical intensive care units

Mean time to first bowel movement 1.7 + 1.4 daysMean duration of therapy 10.7 + 7.1 daysMean duration of therapy for ileus 11.5 + 7.3 days

Bolesta S et al. Hosp Pharm. 2002; 37:949-52.

Education on Medications• Sympathomimetics decrease propulsive contractions

and tone through alpha and beta receptors– e.g., dopamine, dobutamine, epinephrine, norepinephrine,

phenylephrine

• Opioids decrease propulsive contractions and p p pincrease nonpropulsive contractions especially in upper gastrointestinal (GI) tract– e.g., morphine, meperidine, fentanyl

• Miscellaneous drugs suppress motility – e.g., anesthetics, atropine, calcium channel antagonists,

clonidine, loperamide, phenothiazines, somatostatin (octreotide) in higher doses?, tricyclic antidepressants

Kurz A et al. Drugs. 2003; 63:649-71.

Education on MedicationsMost of the following cause adverse effects on GI tract, often as extensions of pharmacologic actions• Antibiotics

– Allow selective increase in bacteria

• Sorbitol (drug product additive), lactulose– Osmolar laxatives

• Antacids (e.g., magnesium as poorly absorbed cation)

• Other laxatives– Varying mechanisms

1/31/2008

3

Nutritional Support• Oral and nasoenteral (ND or NJ) feedings• Systematic review and meta-analysis of randomized

controlled trials comparing nothing by mouth vs. feedings within 24 hours of elective surgeryP i t i f f l f di• Primary outcomes in favor of early feedings: anastomotic dehiscence (RR= 0.53, 95% CI= 0.26 to 1.08), infections (RR= 0.72, 95% CI= 0.54 to 0.98)

• Incidence of vomiting was higher in feeding group (RR= 1.27, 95% CI= 1.01 to 1.61)

• Indirect evidence that ileus is reduced with early feedings but influence of pain control not studied

Lewis SJ et al. Br Med J. 2001; 323:773-7.

VariableOdds Ratio 95% CI p-value

Stimulant/osmotic 26.599 3.201-221.013 0.002Prokinetic 4.424 0.694-28.19 0.116

Multiple Logistic Regression Analysis of Bowel Movements and Patient Characteristics

Research

Docusate 1.438 0.285-7.248 0.66Age 1.004 0.958-1.053 0.863Apache II 0.836 0.704-0.992 0.04Diet 0.86 0.124-5.957 0.879Log. Morphine 0.756 0.586-0.967 0.027Gender (male) 0.699 0.137-1.053 0.667Vasopressors 11.097 1.102-111.72 0.041

Patanwala A et al. Pharmacotherapy. 2006; 26:896-902.

Ileus: Case Report

• 63-year-old man s/p bowel resection has been receiving morphine 4 mg/hr for three days by patient-controlled analgesia (PCA)

• Began on PCA morphine one week agoBegan on PCA morphine one week ago with 2 mg i.v. bolus with 10-minute lock-out interval

• Patient started oral feedings today

• M.D. wants to convert patient to oral medications and discharge tomorrow

Options• Take an extended lunch break and hope

the patient gets transferred to another hospital

• Say you’re sick and go homeSay you re sick and go home

• Dump it on the new hire

• Dump it on the student

• Just do it, because that’s what the shoe commercial says

Gastrointestinal Anatomy and Physiology

• Stomach• Small intestine• Large intestine• Large intestine

Stomach

1/31/2008

4

Small Intestine Large Intestine

Gastrointestinal Control

Interactions of various components• Neuronal • Hormonal• Mechanical• Immunomodulation

Neuronal

• Acetylcholine and norepinephrine key roles• Extrinsic nervous system in continuous

communication with intrinsic system• Intrinsic (enteric) nervous system• Intrinsic (enteric) nervous system

– Nerve cell bodies grouped into ganglia– Ganglia connected to form plexuses (network)– Auerbach’s (myenteric) plexus– Meissner’s (submucosal) plexus– Nonganglionated plexuses

Hormonal

Gastrointestinal peptides

• Affect blood flow, motility, secretions

Some act as growth factors• Some act as growth factors

• Some mediate signals to central nervous system

Hormonal• Endocrine peptides: secreted in blood

– Cholecystokinin, gastrin, gastric inhibitory polypeptide, glucagon, insulin, motilin, neurotensin, peptide YY, secretin, somatostatin, urogastrone

• Neurocrine peptides: affect cells in contact with nerve terminalsnerve terminals– Multiple, including calcitonin gene-related peptide,

cholecystokinin, galanin, motilin, neurotension, neuropeptide Y, pancreastatin, peptides HM and YY, opioids, somatostatin, substance P, vasoactive intestinal peptide (VIP)

• Paracrine peptides: affect local cells (more widespread than neurocrine, less than endocrine)– Peptide YY, somatostatin

1/31/2008

5

Mechanical

• Propulsion and mixing, hopefully well-coordinated

• Varies in fed versus fasting states and after stressful events, such as surgerystressful events, such as surgery

• Smooth muscle regulated by– Calcium and contractile proteins

– Electrical, neurohormonal regulation

– Humoral factors produced by smooth muscle (adenosine, eicosanoids, histamine, serotonin)

Immunomodulation• Complex interactions between brain and

gastrointestinal tract• Gastrointestinal tract must be able to

differentiate beneficial substances fromdifferentiate beneficial substances from infectious and toxic substances

• Gut-associated lymphoid tissue (GALT) has developed specific adaptive properties to deal with this differentiation

• Prostaglandins and cytokines secreted

Ileus• Ileus- Greek for twisted

• Until late19th – early 20th century, the term “ileus” was ill-defined

• Often referred to intussusception, volvulusp ,

• Term now refers to non-mechanical obstruction (dysfunction but surgery not needed)

• Usual return of GI function (longer if abdominal/pelvic)

– Stomach 24-48 hours

– Small bowel 12-24 hours

– Colon 48-72 hrsBallantyne GH. Am J Surg. 1984; 148:252-6.

IleusIntestinal transit time can be measured (usually for research purposes)

• Scintigraphy

• Radiopaque markers

• Nonabsorbable markers

• Passage of 51Cr3 in stool

• Less invasive or non-radiation measurements– Food coloring

– Lactulose breath hydrogen testing

Compher C et al. JPEN J Parenter Enter Nutr. 2007; 31:240-5.

What Ileus Isn’t Constipation vs. Ileus: Terminology

Constipation: inability to pass feces easily“Golden age of purgation in 1920–1930s”• Enemas

Irrigations• Irrigations• Stimulators• Abdominal massage• Abdominal support belts• Rectal dilators

Whorton J. West J Med. 2000; 173:424-7.

1/31/2008

6

Small Bowel Obstruction (SBO)• Approximately 60% of cases associated with

adhesions secondary to abdominal or pelvic surgery (upper GI less common)

• Others due to cancer, Crohn’s disease, and hernias

• May be partial or complete; strangulation is life-threatening form of SBO

• Both CT and ultrasound have very high specificity; CT somewhat higher sensitivity

• Treatment– Watchful waiting vs. surgery

Nobie BA et al. Obstruction, small bowel (URL in reference list).

Large Bowel Obstruction• Pseudo-obstruction (aka Ogilvie’s)

– Autonomic imbalance due to various causes; may result in complications like ischemia or perforation

• True obstruction– Medical emergency due to cancer (≈60%) and

diverticulum (≈20%) in which complications are eminent or present

• Treatment– Usually watchful waiting for pseudo-obstruction and

surgery for true obstruction

McCowan C. Obstruction, large bowel (URL in reference list).

Ileus Pathophysiology• Likely multifactorial due to alteration of the

normal control systems– Neuronal (e.g., increased sympathetic

activity)– Hormonal (e.g., VIP)Hormonal (e.g., VIP)– Mechanical (e.g., bowel manipulation if

surgery)– Immunomodulation (e.g., stress response with

release of various cytokines)– Pharmacologic (e.g., exogenous opioids that

alter some of the control systems listed above)

Ileus: Causes• Any major stressful event or a variety of factors

that affect intestinal regulation– Surgery, trauma, severe infections, burns, myocardial

infarction– Fluid, hormonal, and metabolic derangements

Intestinal inflammation or injury– Intestinal inflammation or injury– Medications, particularly opioids

• Three major non-drug factors associated with postoperative ileus– Large incisions– Degree of physical manipulation of bowel– Exposure of peritonium to irritants, such as blood

Mattei P et al. World J Surg. 2006; 20:1382-91.

Postoperative Ileus (POI)• Ileus expected after surgery, particularly

abdominal or pelvic surgery

• Some use “adynamic” or “paralytic” to refer to a more prolonged ileus (e g 3 days)to a more prolonged ileus (e.g., 3 days)

• Prevalence depends on definition– For drug studies, ileus assumed to follow

partial bowel resection and hysterectomy (number of cases/year ≈ 1 million)

• Definition of bowel recovery is tricky

POI: Signs, Symptoms, and Diagnosis

• Not all patients have signs and symptoms– Anorexia, nausea (less commonly vomiting),

pain, and cramping may occurTypically no flatus or bowel movements– Typically no flatus or bowel movements

• No single diagnostic test rules in or out– Absence of bowel sounds not necessarily

indicative of ileus– Scans and contrast studies mostly useful for

ruling out obstruction and other complicationsMattei P et al. World J Surg. 2006; 20:1382-91.

1/31/2008

7

Resolution of POI• Should have resolution of signs and symptoms if

present during ileus• No single diagnostic test for resolution• Time withholding liquids or food after abdominal

surgeries varies among surgeons (little evidencesurgeries varies among surgeons (little evidence to substantiate prolonged delays)

• No substitute for a trial of oral or enteral feedings with potential risk for vomiting– May not see intolerance within hours in form of

vomiting; may see as abdominal distention or lack of bowel movements over time

Mattei P et al. World J Surg. 2006; 20:1382-91.Mangesi L et al. Cochrane Database Syst Rev. 2002; (3):CD003516.

Health Care Burden Associated with POI

Prolonged hospitalization

POI

Prolonged hospitalization

Beds occupied for more time

Increased nursing time

Increased resource use

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; 167:208-11;

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

22 million surgical procedures annually

2.7 million procedures lead to POI (> 1 day)

750 000 patients discharged 1 day earlier

Economic Consequences:Hospital Discharge Data, 1980-19931,2

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

Potential savings of $1.1 billion/year

1Woods MS. Perspect Colon Rectal Surg. 2000; 12:57-76;2Moss G et al. Surgery. 1986; 99:206; 3Holte K et al. Br J Surg. 2000; 87:1480-93; 4Sarawate CA et al. Gastroenterology. 2003; 124(Suppl 1):A-828; 5Leslie JB. Ann Pharmacother. 2005; 39:1502-10.

• Others suggest increase in length of stay (LOS) of 2–3 days, incremental costs of ~ $4100-$8800 per hospitalization3-5

Postoperative Ileus: Economic Consequences and LOS

• Hospital claims database analysis, open laparotomy patients• ICD-9 coded POI (560.1 = paralytic ileus; and 997.4 = digestive system

complications) No Coded POI (n=175,992)

Coded POI (n=17,417)

Mean age (yr) 50.8 59.8*

Mean OR time (hr) 2 5 3*Mean OR time (hr) 2.5 3

Mean LOS (day) 5.4 10.6*

Opioid PCA (%) 31.3 41.8*

Opioid epidural (%) 2.8 3.7*

Mortality (%) 2.3 3.7*

Mean total costs $9,944 $16,303*

Severe or most severe illness (%)** 20.7 48.4*

Senagor A et al. Dis Colon Rectum. 2005; 48:618-9. Abstract.

*p < 0.05 vs. no coded POI; ** Based on APR-DRG severity levels

Opium

• Word opion (opium) in 1st century A.D.• Used in various oral, rectal, inhaled, and topical

forms• Poppy head on coin 2nd century A.D.Poppy head on coin 2 century A.D.

Kritikos PG et al. The history of the poppy and of opium and their expansion in antiquity in the eastern Mediterranean area (URL in reference list).

Herbal Products: Middle Ages

• Alternative medicine was in by public (physicians and classic medicine out)

• Example– Soporific sponge: opium henbane and variousSoporific sponge: opium, henbane, and various

seeds, berries, and juices, including hemlock

• Concoction boiled then dried• Sponge dipped in hot water• Put under nose• Vinegar used to awaken

1/31/2008

8

Medications: 19th Century• Pharmaceutical industry in U.S. (Tilden &

Company, and Parke, Davis and company)

• Morphine isolated by Serturner in 1803

• Experiments begin with anesthetic agents• Experiments begin with anesthetic agents including NO and ether

• Syringe developed in 1850s

NO = nitrous oxide

Opioid Receptors• Opioids continue as key agents for severe pain• G-protein–linked receptor superfamily• Receptor subtypes

– mu (μ1, μ2)– delta (δ1, δ2)– kappa (κ1, κ2, κ3)

• Several subtypes have been cloned, and related receptors with ligands have been identified, allowing for research at molecular and pharmacologic levels

Ding YQ et al. J Comp Neurol. 1996; 367:375-402.Corbett AD et al. Br J Pharmacol. 2006; 147(Suppl 1):S153-S162.

Waldhoer M et al. Annu Rev Biochem. 2004; 73:953-90.

Opioid Receptors• Peripheral, spinal, and supraspinal opioid

receptors exist– Relative contributions to pharmacologic effects still

being investigated

• Centrally, μ-opioid receptors are located in the spinal dorsal horns, periaqueductal gray matter, cerebral cortex, and other locations mainly postsynaptically

• Peripherally, μ-opioid receptor activation (myenteric/submucosal plexuses, lymphocytes) inhibits GI motility and secretion

Ding YQ et al. J Comp Neurol. 1996; 367:375-402.Corbett AD et al. Br J Pharmacol. 2006; 147(Suppl 1):S153-S162.

Waldhoer M et al. Annu Rev Biochem. 2004; 73:953-90.

Receptor Subtypes and EffectsReceptor/Agonist Subclass Major Effect

Mu μ1

μ2

Supraspinal analgesia, euphoria, miosis, prolactin release

Spinal analgesia, inhibition of intestinal motility, respiratory depression

Delta δ1

δ2

Spinal analgesia, inhibition of smooth muscle

Supraspinal analgesia

Kappa κ1

κ2 and κ3

Miosis (weak), sedation, spinal analgesia

Supraspinal analgesia, dysphoria, hallucinations

Corbett AD et al. Br J Pharmacol. 2006; 147(Suppl 1):S153-S162.Waldhoer M et al. Annu Rev Biochem. 2004; 73:953-90.

Ileus: Case Report• 63-year-old man s/p bowel resection has been

receiving morphine 4 mg/hr for three days by PCA• Began on PCA morphine one week ago with 2 mg i.v.

bolus with 10-minute lock-out interval• Patient began oral feedings today• M.D. wants to convert patient to oral medications and

discharge tomorrow

Examples of wrong answers without more information– Acetaminophen as needed– Sustained-release morphine– Opioid without bowel regimen

End of Presentation

• You have reached the end of this presentation.

• Please select another presentation from the left menuthe left menu.


S E L E C T E D R E F E R E N C E S

1. Ballantyne GH. The meaning of ileus: its changing definition over three millennia. Am J Surg. 1984; 148:252-6.

2. Bolesta S, Erstad BL. The use of metoclopramide in ileus: a look at duration of

therapy. Hosp Pharm. 2002; 37:949-52. 3. 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. 4. Compher C, Rubesin S, Kinosian B et al. Noninvasive measurement of transit time in

short bowel syndrome. JPEN J Parenter Enteral Nutr. 2007; 31:240-5. 5. Corbett AD, Henderson G, McKnight AT et al. 75 years of opioid research: the

exciting but vain quest for the Holy Grail. Br J Pharmacol. 2006; 147(Suppl 1):S153-S162.

6. Ding YQ, Kaneko T, Nomura S et al. Immunohistochemical localization of mu-opioid

receptors in the central nervous system of the rat. J Comp Neurol. 1996; 367:375-402.

7. Holte K, Kehlet H. Postoperative ileus: a preventable event. Br J Surg. 2000;

87:1480-93. 8. Institute of Medicine. Crossing the quality chasm: the IOM health care quality

initiative. http://www.iom.edu/?id+21805 (accessed 2007 Nov 5). 9. Kritikos PG, Papadaki SP. The history of the poppy and of opium and their

expansion in antiquity in the eastern Mediterranean area. http://www.poppies.org/2001/07/13/the-early-history-of-the-poppy-and-opium/ (accessed 2007 Sep 24).

10. Kurz A, Sessler DI. Opioid-induced bowel dysfunction: pathophysiology and potential

new therapies. Drugs. 2003; 63:649-71. 11. Leslie JB. Alvimopan for the management of postoperative ileus. Ann Pharmacother.

2005; 39:1502-10. 12. Lewis SJ, Egger M, Sylvester PA et al. Early enteral feeding versus "nil by mouth"

after gastrointestinal surgery: systematic review and meta-analysis of controlled trials. Br Med J. 2001; 323:773-6.

13. Mangesi L, Hofmeyr GJ. Early compared with delayed oral fluids and food after

caesarean section. Cochrane Database Syst Rev. 2002; (3):CD003516. 14. Mattei P, Rombeau JL. Review of the pathophysiology and management of

postoperative ileus. World J Surg. 2006; 20:1382-91.


15. McCowan C. Obstruction, large bowel. http://www.emedicine.com/emerg/topic65.htm

(accessed 2007 Sep 24). 16. Moss G, Regal ME, Lichtig L. Reducing postoperative pain, narcotics, and length of

hospitalization. Surgery. 1986; 99:206-10. 17. Nobie BA, Khalsa SS. Obstruction, small bowel.

http://www.emedicine.com/emerg/topic66.htm (accessed 2007 Sep 24). 18. Patanwala A, Abarca J, Huckleberry Y et al. Pharmacologic management of

constipation in the critically ill patient. Pharmacotherapy. 2006; 26:896-902. 19. Pedersen CA, Schneider PJ, Santell JP. ASHP national survey of pharmacy practice

in hospital settings: prescribing and transcribing – 2001. Am J Health-Syst Pharm. 2001; 58:2251-66.

20. Person B, Wexner SD. The management of postoperative ileus. Curr Probl Surg.

2006; 43:6-65. Review. 21. Preuss J. Julius Preuss’ Biblical and Talmudic Medicine, 2nd ed. Translated and

edited by Fred Rosner. New York: Hebrew Publishing Co.; 1978. 22. 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.

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

59:465-71. 24. Senagor A, Delaney C, Wang PF et al. Economic burden and risk factors associated

with ICD-9 coded postoperative ileus (POI): results from US hospital data during 2002. Dis Colon Rectum. 2005; 48:618-9. Abstract.

25. Waldhoer M, Bartlett SE, Whistler JL. Opioid receptors. Annu Rev Biochem. 2004;

73:953-90. 26. Whorton J. Civilization and the colon. West J Med. 2000; 173:424-7. 27. Woods MS. Postoperative ileus: dogma versus data from bench to bedside. Perspect

Colon Rectal Surg. 2000; 12:57-76.


Robert MacLaren, Pharm.D., FCCM, FCCP Associate Professor School of Pharmacy University of Colorado Denver Aurora, Colorado Robert MacLaren, Pharm.D., is Associate Professor in the Department of Clinical Pharmacy at the University of Colorado Denver School of Pharmacy in Aurora, Colorado. In addition, he is a clinical pharmacist in the medical intensive care unit at the University of Colorado Hospital, which is also located on the Anschutz Medical Campus in Aurora. Dr. MacLaren also serves as co-director of the critical care residency at the University of Colorado. After completing his undergraduate degree in pharmacy at the University of British Columbia in Vancouver, Canada, Dr. MacLaren earned his Doctor of Pharmacy degree at the University of Utah in Salt Lake City and completed a critical care specialty residency in Memphis at the University of Tennessee and Baptist Memorial Hospital. He worked for two years as a critical care specialist at the Queen Elizabeth II Health Sciences Centre in Halifax, Canada, before joining the faculty at the University of Colorado. Dr. MacLaren is a fellow of the American College of Clinical Pharmacy and the Society of Critical Care Medicine. His clinical research interests include gastrointestinal motility dysfunction associated with critical illness and the use of intravenous glutamine as a supplement to parenteral nutrition. He conducts animal studies of acetaminophen toxicity and has been involved with outcomes research of pharmacologic therapies and the impact of pharmacists in the intensive care unit. He has authored several articles relating to the pharmacologic and nutritional therapies of critically ill patients and has been an invited speaker at national and international meetings.


Robert MacLaren, Pharm.D., FCCM, FCCP P R E S E N T A T I O N

Managing Postoperative Ileus A B S T R A C T

In the past, the mainstay of preventing and treating postoperative ileus (POI) involved nasogastric decompression and bowel rest. However, novel approaches contradict these methods and include rapid nasogastric extubation and early feeding. Other therapies shown to be effective include the use of less invasive surgical techniques, such as laparoscopy; minimization of systemic opioid administration; epidural anesthesia/analgesia; and sham feeding. This presentation will illustrate the clinical application of these proven therapies and will also include a brief review of unproven therapies, such as prokinetic agents, early mobilization, preoperative hydration, and sympathetic suppression. While no single therapy can eliminate POI, the combined application of these modalities is effective. An interdisciplinary concept to accelerate postoperative convalescence and reduce general morbidity by simultaneously applying several interventions is termed multimodal care and produces a fast-track treatment approach. This presentation will develop strategies for implementing multimodal, fast-track care with an emphasis on involving the pharmacist. L E A R N I N G O B J E C T I V E S


• Describe the rationale and clinical outcomes for at least three components included in the multimodal approach of preventing and treating postoperative ileus.

• Describe the role of the health-system pharmacist in preventing and managing postoperative ileus.

• Given pertinent patient information, recommend strategies for preventing and treating postoperative ileus.

1/7/2008

1

Managing Postoperative Ileus

Robert MacLaren, Pharm.D., FCCM, FCCPAssociate ProfessorSchool of Pharmacy

University of Colorado DenverAurora, Colorado

Learning Objectives• Describe the rationale and clinical

outcomes for the components included in the multimodal approach of preventing and treating postoperative ileus (POI)

• Describe the role of the health-system pharmacist in preventing and managing POI

• Given pertinent patient information, recommend strategies for preventing and treating POI

Ileus: Case Revisited• 63-year-old man s/p bowel resection has

been receiving morphine 4 mg/hr for three days by patient-controlled analgesia (PCA)Began PCA morphine one week ago with• Began PCA morphine one week ago with 2-mg i.v. bolus with 10-minute lock-out interval

• Patient just started oral feedings today• M.D. wants to convert patient to oral

medications and discharge tomorrow

Prevention and Management of POIPreoperative measures

– Hydration and premedication

Intraoperative measures– Surgical techniques

– Anesthetic choice and route

Postoperative measures– Opioid route – Remove nasogastric (NG) tube– Early oral or enteral feeding– Fluid management– Opioid-sparing analgesics– Mobilization (ambulation)

P ki ti t l ti– Anesthetic choice and route – Prokinetic agents, laxatives, neostigmine

– Others• Sham feeding• Hyperbaric oxygen• Electrical stimulation,

psychological suggestion, mechanical message, acupuncture, herbals

• Avoid medications that reduce gastrointestinal (GI) motility

“Multimodal Care” = “Fast-Track” Recovery

Mattei P et al. World J Surg. 2006; 30:1382-91.Person B et al. Curr Probl Surg. 2006; 43:6-65.

What is “Fast-Track Recovery”?• “An interdisciplinary multimodal concept to

accelerate postoperative convalescence and reduce general morbidity (including POI) by simultaneously applying several interventions.”

• What are the appropriate

NG tuberemovalappropriate

choices in constructing fast-track, multimodal protocols?

POI (the role ofthe pharmacist)

Opioid sparing

Laparoscopicsurgery

Early feeding,fluid

managementMobilization?

Epidural anesthetics

Laxatives,prokinetics

Mattei P. World J Surg. 2006;30:1382-91; Person B et al. Curr Probl Surg. 2006; 43:6-65.

Preoperative Measures• Hydration

– Preoperative administration of glucose containing fluids reduces postoperative insulin resistance and catabolic response BUT keeps normoglycemia

• PremedicationAnxiolytic agents (benzodiazepines) reduce sympathetic– Anxiolytic agents (benzodiazepines) reduce sympathetic-related complications and catabolic response

– Clonidine and β-blockers reduce intraoperative hemodynamic fluctuations AND have analgesia-sparing properties while optimizing analgesia

• R, DB study of 29 colorectal cases showed propranolol 4 mg i.v. every 12 hr starting 30 min before surgery reduced time to first bowel movement (82 ± 11 vs. 110 ± 9 hr, p < 0.01)

White PF et al. Anesth Analg. 2007; 104:1380-96.Hallerback B. Scand J Gastroenterol. 1987; 22:149-55.

R, DB= randomized, double blind

1/7/2008

2

Intraoperative Measures:Laparoscopic Surgery

• Meta analysis of 22 trials (n=2965) of colorectal surgery– Reduced blood loss of 71.8 mL (95% CI, 30.8-113 mL;

p=0.0006)– Reduced postoperative pain by 9.3/100 (95% CI, 5.4-

13.2; p<0.0001)– Earlier flatulence by 1 day (95% CI, 0.76-1.3; p<0.0001)– Earlier bowel movement by 0.9 days (95% CI, 0.74-1.13;

p<0.0001)– Lessened ileus (RR=0.40 95% CI, 0.22-0.73; p=0.003)– Reduced wound infections (RR=0.56 95% CI, 0.39-0.89;

p=0.002)– Shortened hospital length of stay (LOS) by 1.5 days (95%

CI, 1.12-1.94; p<0.0001)Schwenk W et al. Cochrane Database Syst Rev. 2005; CD003145.

Intraoperative Measures:Laparoscopic Surgery (cont)

• Another meta analysis of 49 trials (n=6438) of colorectal surgery– Reduced pain and opioid requirements by 16-35%

E li fl t l b l t t l ti– Earlier flatulence, bowel movement, or tolerating diet by 1.2-1.6 days (26-37% shorter)

– Shortened LOS by 3.5 days (18.8%)

Abraham NS et al. ANZ J Surg. 2007; 77:508-16.

Why Would Laparoscopic Surgery Improve Outcomes?

• Smaller incisions• Less handling of intestine (particularly the

colon) and less inflammationL i l i id d• Less pain = less opioid used

• Earlier ambulation• Less exposure to air and endotoxin• Improved immune consequences• Fewer NG tubes and earlier diet

Intraoperative Measures:Surgical Techniques

• Level of surgical training impacts GI motility– Multivariate regression analysis of 124 colorectal

surgeriesFactor contributing to delayed flatulence was lack of– Factor contributing to delayed flatulence was lack of fellowship training (OR=3.32; p=0.001)

– Factors contributing to delayed bowel movements• Lack of fellowship training (OR=3.13; p=0.002)• Systemic opioids (OR=2.62; p=0.01)

Gervaz P. Int J Colorectal Dis. 2006; 21:542-6.

Anesthetic Choice and Route• Almost all intraoperative inhaled or i.v. anesthetics

temporarily inhibit GI motility– Level of monitoring is important!

• Epidural anesthesia/analgesia synergistically block inhibitory sympathetic reflexes, prevent the release of afferent pain neurotransmitters, and increase splanchnic p , pblood flow

• Epidural anesthetics dose-dependently block nociceptive and autonomic fibers first and motor and somatosensory fibers last

• Epidural analgesia reduces opioid adverse effects• Use of local anesthesia and nerve blocks further reduce

systemic exposureBonnet F et al. Br J Anaesth. 2005; 95:52-8.

Postoperative Measures

1/7/2008

3

Epidural vs. PCA Administration of OpioidsEpidural PCA

Pain controlAt restOn mobilization

+++++

+++/-

Adverse effectsIleus Shortening ProlongationNausea and vomitingSedation Hypotension Urinary retentionWorkload

g--

+/-+/-+

g++++++

Postop morbidity reductionCardiovascular (CV)Respiratory

++

--

Bonnet F et al. Br J Anaesth. 2005; 95:52-8.

Epidural vs. Parenteral

• Meta analysis of 16 trials (n=806) of colorectal surgery– Reduced postop pain by 15-18/100 (95% CI,

10-26; p<0.001)– Earlier bowel function by 1.6 days (95% CI,Earlier bowel function by 1.6 days (95% CI,

0.84-2.3; p<0.001)– Also saw…

• Increased hypotension (OR=13.5 95% CI, 4-57.7; p<0.001)

• Pruritus (OR=4.8 95% CI, 1.3-17; p=0.02)• Urinary retention (OR=4.3 95% CI, 1.2-15.9;

p=0.03)Marret E et al. Br J Surg. 2007; 94:665-73.

Epidural vs. Parenteral (cont)

• BUT…Studies consistently show– Epidural anesthesia/analgesia at T8-10 is more

effective than PCA for analgesia with fewer adverse effects

– Morphine is hydrophilic and may reduce epidural-associated adverse events (except pruritus)associated adverse events (except pruritus)

• AND…Epidural anesthesia reduces time to GI recovery– By 37 hr (19-56) compared with systemic opioids– By 24 hr (10-39) compared with epidural opioids– But, analgesia better by 20/100 (8.4-31.5) with

epidural anesthesia/analgesia

Jorgensen H et al. Cochrane Database Syst Rev. 2000; CD001893.

NG Tubes• NG tubes routinely inserted for gastric

decompression until return of bowel function• Early removal of NG intubation

– Meta analysis of 28 trials (n=4194) of abdominal surgery

• Accelerated bowel recovery by 0 52 days (95% CI 0 46• Accelerated bowel recovery by 0.52 days (95% CI, 0.46-0.57; p<0.0001)

• Earlier flatulence by 0.53 days (95% CI, 0.28-0.78; p=0.0004)• Reduced vomiting (OR=0.66 95%CI, 0.45-0.95; p=0.03)• Reduced pulmonary complications (RR=1.45 95% CI, 1.08-

1.92; p=0.01)• Shortened LOS by 1.21 days (95% CI, 0.56-1.86-1.94;

p<0.0001)

Person B et al. Curr Probl Surg. 2006; 43:6-65.Nelson R et al. Cochrane Database Syst Rev. 2007; CD004929.

Early Oral or Enteral Feeding• Convention is restriction of enteral intake• Early oral or enteral feeding (within 24 hours)

– Meta analysis of 13 trials (n=1173) of colorectal surgery • Less vomiting (RR=1.27 95% CI, 1.01-1.61; p=0.04)• Shortened LOS by 0.89 days (95% CI, 0.20-1.58-1.94; p=0.01)• Reduced mortality (RR=0 41 95% CI 0 18-0 93; p=0 03)Reduced mortality (RR 0.41 95% CI, 0.18 0.93; p 0.03)

– Meta analysis of three trials (n=413) of abdominal gynecologic surgery

• Reduced nausea (RR=1.79 95% CI, 1.19-2.71; p=0.006)• Earlier bowel sounds by 0.50 days (95% CI 0.16-0.84)• Shortened time to intake of solid food by 1.47 days (95% CI,

0.69-2.26; p=0.0004)• Shortened LOS by 0.73 days (95% CI, 0.07-1.52; p=0.07)

Andersen HK et al. Cochrane Database Syst Rev. 2006; CD004080. Charoenkwan K et al. Cochrane Database Syst Rev. 2007; CD004508.

Rationale

• Why would NG tube removal improve outcomes? – Resumption of oral intake

• Why would early oral or enteral feeding improve outcomes? – Counteracts catabolism– Improves immune function– Hastens wound healing

1/7/2008

4

Fluid Management• 20 patients with colonic resection randomized to receive

postoperative daily intake of ≥ 3L water and 154 mEq sodium vs. ≤ 2L and 77 mEq sodium for 4-5 days

Standard (n = 10) Restricted (n = 10)Net estimated water balance L over 5 days

3.7 (2.4-5.8) 0.2 (-0.9-1.2)*balance, L over 5 days

Passing flatulence, days 4 (4-5) 3 (2-3)*Bowel movement, days 6.5 (5.8-8) 4 (3-4)*Enteral intake, days 6.5 (5.5-7) 4 (4-4.3)*Adverse events, n (%) 7 (70%) 1 (10%)*Hospital LOS, days 9 (7.8-14.3) 6 (5-7)*

Lobo DN et al. Lancet. 2002; 359:1812-8.Reported as median (IQR); *p ≤ 0.01

Goal: Euvolemia without dehydration and electrolyte abnormalities

Opioid-Sparing Analgesia

• 40 colectomy patients– Correlation between

morphine PCA dose and first bowel sounds (p=0.001), flatulence, (p=0 003) and first bowel

Total Morphine (mg) 350.0

300.0

250.0

200.0

150 0(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

150.0

100.0

50.0

040 60 80 100 120 140 160 180

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

Cali RL et al. Dis Colon Rectum. 2000; 43:163-8.Goettsch WG et al. Pharmacoepidemiol Drug Saf. 2007; 16:668-74.

Opioid-Sparing Analgesia (cont)

• Surveys indicate patients prefer inadequate pain relief over adequate analgesia with associated bowel dysfunction

Person B. Curr Probl Surg. 2006; 43:6-65.

Opioid-Sparing Analgesia (cont)• Nonsteroidal anti-inflammatory drugs (NSAIDS),

such as ketorolac– Reduce prostaglandin production– R, DB study of morphine PCA and ketorolac compared

with morphine PCA alone in 79 colorectal surgeries • 29% less morphine usep• Earlier first bowel movement (1.5 [0.7-1.9] vs. 1.7 [1-2.8] days,

p<0.05)• Earlier ambulation (2.2 ± 1 vs. 2.8 ± 1.2 days, p<0.05)

– Similar results in other surgeries and epidural route– Concerns: platelet inhibition (bleeding)

• Cyclooxygenase-2 (COX-2) inhibitors– Similar results as NSAIDS but…

Person B. Curr Probl Surg. 2006; 43:6-65.Chen JY. Acta Anaesthesiol Scand. 2005; 49:546-51.

Mobilization (Ambulation)• Important for preventing postoperative

thrombi and pneumonia• Thought to increase gastrointestinal blood

flow to enhance motility– Gastrointestinal electrical recording of 34

laparotomy cases (ambulation day 1 vs. day 4) showed no differences in myoelectrical activity along any segment

• Fast-track programs incorporating early mobilization show mixed results

Person B. Curr Probl Surg. 2006; 43:6-65.Waldhausen JHT. Ann Surg. 1990; 212:671-7.

Prokinetic Agents• Metoclopramide improves nausea but…

6090

120

mot

ility

(hou

rs) metoclopramide placebo erythromycin

030

Jeps

en (n

=55)

Cheap

e (n=

93)

Tolles

son (

n=20

)

Seta (n

=32)

Chan (

n=32

)

Lightf

oot (n

=22)

Hyp

om

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; Seta ML et al. Pharmacotherapy. 2001; 21:1181-6; Chan DC et al. World J Gastroenterol. 2005; 11:4776-81; Lightfoot AJ et al. Urology. 2007; 69:611-5.

1/7/2008

5

Laxatives and Neostigmine

• Only one randomized study of 20 colectomy cases of bisacodyl vs. placebo suppositories– By postoperative day (POD) 3 all patientsBy postoperative day (POD) 3, all patients

taking bisacodyl defecated vs. 3 patients taking placebo (p<0.001)

– LOS: 8.5 ± 2.7 vs. 10.4 ± 5.3 days

• Neostigmine not studied and too many adverse events

Wiriyakosol S et al. Asian J Surg. 2007; 30:167-71.

Sham Feeding• Meta analysis of 5 trials (n=158) of colorectal

surgery– Earlier flatulence by 20.8 hours (95% CI, 8.9-32.6;

p=0.0006)– Earlier bowel movement by 33.3 hours (95% CI, 15.7-

50.8; p=0.0002)50.8; p 0.0002)– Shortened LOS by 2.44 days (95% CI, 1.77-3.1;

p<0.0001)– Fewer complications (OR=0.45 95% CI, 0.2-1; p=0.05)

• Why would sham feeding improve outcomes? – Stimulation of the vagal reflex to enhance cholinergic

motility– Secretion of GI hormones and enzymes

Chan MK et al. Dis Colon Rectum. 2007 Aug 21 [Epub ahead of print].

Other Postoperative Measures• Hyperbaric oxygen therapy may prevent and

treat POI (case series)• Electrical stimulation via intermittent

transcutaneous “pacing” or electromagnetic energy– Earlier return of bowel sounds but not function (case

series and small studies)

• Randomized study of light massage of the abdominal wall after colectomy in 50 patients– Earlier flatulence (1.8 vs. 3.6 days, p<0.01)– Lower pain scores and opioid use

Person B et al. Curr Probl Surg. 2006; 43:6-65.Ambiru S et al. Gastroenterology. 2007 Jun 25 [Epub ahead of print].

Other Postoperative Measures (cont)

• Randomized study of acupuncture restored normal bowel function within 72 hours of colectomy in 12/13 vs. 6/13 patients (p=0.009)

• Randomized study of Dai-kenchu-to and Keish-Randomized study of Dai kenchu to and Keishbukuryo-gan after colectomy in 66 patients– Earlier flatulence and tolerance of diet

– Shortened hospital LOS

Person B et al. Curr Probl Surg. 2006; 43:6-65.Suehiro T et al. Hepatogastroenterology. 2005; 52:97-100.

Summary:Therapies with Proven Benefit

• Laparoscopic surgery

• Epidural anesthesia/analgesia at T8-10

• NG tube removal

• Early oral or enteral feeding while maintaining euvolemia

• Minimization of opioid administration (opioid-sparing)

• Sham feeding

Summary:Therapies with NO Proven Benefit

• Early mobilization

• Prokinetic agents

1/7/2008

6

Summary:Therapies Yet to be Proven

• Preoperative hydration and pharmacologic therapies

• Level of surgical trainingLaxatives• Laxatives

• Others– Hyperbaric oxygen– Electrical stimulation– Light abdominal massage– Acupuncture– Herbal agents

Ileus: Case Revisited• What could have been done differently?

– Preoperative care and education– Epidural anesthesia/analgesia– Minimize opioids (rather than escalating)– NG tube removalNG tube removal– Laxative– Early oral or enteral feeding– Sham feeding if oral feeding not possible

• How could the process improve to ensure efficiency?– Multimodal, fast-track care

Multimodal Components:Preoperative Components

• Provide patient education• Stabilize coexisting diseases• Optimize comfort (minimize anxiety)Optimize comfort (minimize anxiety)• Ensure hydration, normalized electrolytes,

normoglycemia, and normothermia• Ensure appropriate use of prophylactic

therapy (nausea, ileus, pain, antibiotic)

White PF et al. Anesth Analg. 2007; 104:1380-96.

Multimodal Components: Intraoperative Components

• Anesthesia to optimize surgery and recovery

• Local anesthesia/analgesia (or thoracicLocal anesthesia/analgesia (or thoracic epidural) if possible

• Laparoscopic surgery if possible (gentle handling of tissue)


Multimodal Components:Postoperative Components

• Remove NG tube

• Laxative, start oral feedings early (vs. sham feedings)g )

• Minimize opioids

• Ambulate

• Discharge criteria


Fast-Track Example (Colectomy)Day Standard Fast-Track

Pre-operative

Consent, epidural (local anesthetic [LA] with opioid)

Consent and educate, anti-emetic, anxiolytic, epidural (LA with opioid)

Day of surgery

Admit to SICU, NG out with order, i.v. fluids to body weight, continuous epidural or PCA, anti-emetic, nothing by mouth, sitting

Admit to floor post PACU, NG out with extubation, limit i.v. fluid, continuous epidural (limit systemic opioids), NSAID, laxative, mobilize to chair, short walk, soft foods

POD 1 Admit to floor epidural or PCA clear Transition to oral opioids or NSAIDSPOD 1 Admit to floor, epidural or PCA, clear oral liquids and i.v. fluids, out of bed, remove drains and Foley

Transition to oral opioids or NSAIDS (limit epidural and systemic opioids), regular diet, mobilize > 8 hr, walk twice daily, remove drains and Foley

POD 2 Epidural or PCA, laxative, mashed food, out of bed

Remove epidural, plan discharge

POD 3 Transition to oral opioids (limit epidural and systemic opioids), out of bed

Oral opioids or NSAIDS, fully mobilize, discharge

POD 7 Extract staples, discharge pending orders

Outpatient clinic, extract staples

Raue W et al. Surg Endosc. 2004; 18:1463-8.SICU = surgical intensive care unitPACU = postanesthetic care unit

1/7/2008

7

Multimodal Outcomes• Expedited gastrointestinal recovery

• Earlier oral nutrition

• Fewer complications

• Shortened hospital LOSp

• Fewer re-admissions

• Cost minimization

• Greater patient satisfaction?

• Best results with epidural anesthesia/analgesiaPerson B. Curr Probl Surg. 2006; 43:6-65.

White PF et al. Anesth Analg. 2007; 104:1380-96.Raue W et al. Surg Endosc. 2004; 18:1463-8.

Role of the Pharmacist

• Medication protocol– Comfort (minimize anxiety)

– Appropriate hydration, normalized electrolytes, normoglycemia, and normothermianormoglycemia, and normothermia

– Appropriate use of prophylactic therapy (nausea, ileus, pain, antibiotic)

– Postoperative analgesia (with opioid minimization) and pain assessment

– Laxatives

Gannon RH. Am J Health-Syst Pharm. 2007; 64(Suppl 13):S8-12.

Role of the Pharmacist (cont)

• Stabilize coexisting diseases

• Advocate diet

• Promote mobilization

• Team member and education of team

• Discharge planning

• Patient education and compliance assessment


The Future• Identification of risk factors for POI• Patient-centered care

– Hydration and electrolytes– Opioid regimen and opioid-sparing therapies– Anxiolytic and anti-emetic therapies

• Pharmacologic modification of the “stress response”• Multidisciplinary PACUs• Clinical pathways• Outreach services for rehabilitation• Hyperbaric oxygen therapy, electrical stimulation,

acupuncture• New agents: peripherally active selective opioid antagonists

(methylnaltrexone, alvimopan), motilin agonists (atilmotin)


• Classic view: Postoperative ileus is an inevitable response to major surgery that prolongs hospitalization and causes significantly diminished patient quality of life

Time to Change the WayWe Think About POI!

s g ca y d s ed pa e qua y o e

• New view: Pharmacists can participate in the proactive prevention and treatment of postoperative ileus to help facilitate hospital discharge, lower hospitalization costs, and improve patient outcomes


End of Presentation

• You have reached the end of this presentation.

• Please select another presentation from the left menuthe left menu.


S E L E C T E D R E F E R E N C E S 1. Abraham NS, Byrne CM, Young JM et al. Meta-analysis of non-randomized

comparative studies of the short-term outcomes of laparoscopic resection for colorectal cancer. ANZ J Surg. 2007; 77:508-16.

2. Ambiru S, Furuyama N, Kimura F et al. Hyperbaric oxygen therapy as a prophylactic

and treatment against ileus and recurrent intestinal obstruction soon after surgery to relieve adhesive intestinal obstruction. J Gastroenterol Hepatol. 2007 Jun 25 [Epub ahead of print].

3. Andersen HK, Lewis SJ, Thomas S. Early enteral nutrition within 24h of colorectal

surgery versus later commencement of feeding for postoperative complications. Cochrane Database Syst Rev. 2006 Oct 18;(4):CD004080. Review.

4. Bonnet F, Marret E. Influence of anaesthetic and analgesic techniques on outcome

after surgery. Br J Anaesth. 2005; 95:52-8. 5. 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. 6. Chan DC, Liu YC, Chen CJ et al. Preventing prolonged post-operative ileus in gastric

cancer patients undergoing gastrectomy and intra-peritoneal chemotherapy. World J Gastroenterol. 2005; 11:4776-81.

7. Chan MK, Law WL. Use of chewing gum in reducing postoperative ileus after

elective colorectal resection: a systematic review. Dis Colon Rectum. 2007 Aug 21 [Epub ahead of print].

8. Charoenkwan K, Phillipson G, Vutyavanich T. Early versus delayed (traditional) oral

fluids and food for reducing complications after major abdominal gynaecologic surgery. Cochrane Database Syst Rev. 2007 Oct 17;(4):CD004508. Review.

9. Cheape JD, Wexner SD, James K. Does metoclopramide reduce the length of ileus

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

10. Chen JY, Wu GJ, Mok MS et al. Effect of adding ketorolac to intravenous morphine

patient-controlled analgesia on bowel function in colorectal surgery patients—a prospective, randomized, double-blind study. Acta Anaesthesiol Scand. 2005; 49:546-51.

11. Gannon RH. Current strategies for preventing or ameliorating postoperative ileus: a

multimodal approach. Am J Health-Syst Pharm. 2007; 64(Suppl 13):S8-12. 12. Gervaz P, Bucher P, Scheiwiller A et al. The duration of postoperative ileus after

elective colectomy is correlated to surgical specialization. Int J Colorectal Dis. 2006; 21:542-6.


13. Goettsch WG, Sukel MP, van der Peet DL et al. In-hospital use of opioids increases

rate of coded postoperative paralytic ileus. Pharmacoepidemiol Drug Saf. 2007; 16:668-74.

14. Hallerbäck B, Carlsen E, Carlsson K et al. Beta-adrenoceptor blockade in the

treatment of postoperative adynamic ileus. Scand J Gastroenterol. 1987; 22:149-55. 15. 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.

16. Jørgensen H, Wetterslev 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. Review.

17. Lightfoot AJ, Eno M, Kreder KJ et al. Treatment of postoperative ileus after bowel

surgery with low-dose intravenous erythromycin. Urology. 2007; 69:611-5. 18. 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.

19. Marret E, Remy C, Bonnet F; Postoperative Pain Forum Group. Meta-analysis of

epidural analgesia versus parenteral opioid analgesia after colorectal surgery. Br J Surg. 2007; 94:655-73. Review.

20. Mattei P, Rombeau JL. Review of the pathophysiology and management of

postoperative ileus. World J Surg. 2006; 30:1382-91. 21. Nelson R, Edwards S, Tse B. Prophylactic nasogastric decompression after

abdominal surgery. Cochrane Database Syst Rev. 2007 Jul 18;(3):CD004929. Review.


2006; 43:6-65. Review. 23. Raue W, Haase O, Junghans T et al. 'Fast-track' multimodal rehabilitation program

improves outcome after laparoscopic sigmoidectomy: a controlled prospective evaluation. Surg Endosc. 2004; 18:1463-8.

24. Schwenk W, Haase O, Neudecker J et al. Short term benefits for laparoscopic

colorectal resection. Cochrane Database Syst Rev. 2005 Jul 20;(3):CD003145. Review.

25. Seta ML, Kale-Pradhan PB. Efficacy of metoclopramide in postoperative ileus after

exploratory laparotomy. Pharmacotherapy. 2001; 21:1181-6.


26. Suehiro T, Matsumata T, Shikada Y et al. The effect of the herbal medicines dai-

kenchu-to and keishi-bukuryo-gan on bowel movement after colorectal surgery. Hepatogastroenterology. 2005; 52:97-100.

27. Tollesson PO, Cassuto J, Faxén A et al. Lack of effect of metoclopramide on colonic

motility after cholecystectomy. Eur J Surg. 1991; 157:355-8. 28. Waldhausen JH, Schirmer BD. The effect of ambulation on recovery from

postoperative ileus. Ann Surg. 1990; 212:671-7. 29. White PF, Kehlet H, Neal JM et al. The role of the anesthesiologist in fast-track

surgery: from multimodal analgesia to periooperative medical care. Anesth Analg. 2007; 104:1380-96.

30. Wiriyakosol S, Kongdan Y, Euanorasetr C et al. Randomized controlled trial of

bisacodyl suppository versus placebo for postoperative ileus after elective colectomy for colon cancer. Asian J Surg. 2007; 30:167-71.


Michael D. Kraft, Pharm.D. Clinical Assistant Professor University of Michigan College of Pharmacy Clinical Coordinator University of Michigan Health System Ann Arbor, Michigan

Michael D. Kraft, Pharm.D., is Clinical Assistant Professor at the University of Michigan College of Pharmacy in Ann Arbor, Michigan. His practice site is at the University of Michigan Health-System, where he serves as Clinical Coordinator and Clinical Pharmacist in Surgery and Nutrition. He earned his Doctor of Pharmacy degree from the University of Michigan College of Pharmacy, and then completed a specialty residency in critical care and nutrition support at the University of Tennessee at Memphis before returning to his alma mater as a faculty member. At the college, Dr. Kraft teaches several topics, including fluids and electrolyte pathophysiology, acid-base pathophysiology, and parenteral nutrition support. His research interests include nutrition support, drug-nutrient interactions, infectious diseases in surgical and critically ill patients, drug and nutrition therapy during continuous renal replacement therapy, adverse drug events, gastrointestinal dysfunction in critically ill patients, and postoperative ileus. He has authored several articles and book chapters, and his writings have appeared in Pharmacotherapy, American Journal of Health-System Pharmacy, Nutrition in Clinical Practice, Journal of Pediatric Pharmacology and Therapeutics, and Chemical Research in Toxicology. He regularly makes presentations at local, regional, and national conferences on postoperative ileus, perioperative nutrition support, nutrition support in critically ill patients, sepsis, treatment of nosocomial pneumonia, and appropriate empiric antibiotic therapy and antibiotic resistance. Dr. Kraft is an active member of several professional associations, including the American Society of Health-System Pharmacists, American Society for Parenteral and Enteral Nutrition (ASPEN), Michigan Society for Parenteral and Enteral Nutrition (MSPEN), American College of Clinical Pharmacy (ACCP), Society of Critical Care Medicine (SCCM), and Michigan Pharmacists Association (MPA). He currently serves as the President of MSPEN, Secretary/Treasurer of the Pharmacy Practice Section of ASPEN, and member of the Professional Affairs Committee of MPA.


Michael D. Kraft, Pharm.D. P R E S E N T A T I O N

New and Emerging Options for Managing Postoperative Ileus: Clinical Research and Potential Implications for Pharmacists A B S T R A C T

The ideal drug therapy for treating postoperative ileus (POI) would selectively antagonize the inhibitory effects on the gastrointestinal (GI) tract of all of the potential factors implicated in the pathophysiology of POI. The most promising target to date is inhibition of the μ-opioid receptors in the GI tract and the adverse GI effects of endogenous and exogenous opioids. Opioid analgesics are an important part of the postoperative care of surgical patients, and endogenous opioids are released as part of the stress response, especially after abdominal surgery. Selective inhibition of μ-opioid receptors in the GI tract—without reversing centrally-mediated opioid-induced analgesia—may be beneficial in reducing POI. The nonselective opioid antagonists naloxone and nalmefene may cross the blood-brain barrier and reverse analgesic effects of opioids and, therefore, are not appropriate for preventing or treating POI. They have not been evaluated in any prospective, randomized studies for POI. The peripherally-selective opioid antagonist methylnaltrexone may shorten the duration of POI and the length of hospital stay based on results from a phase 2 study. Phase 3 studies with methylnaltrexone are ongoing. Alvimopan is a more extensively studied peripherally-selective opioid antagonist, and several phase 3 studies have shown that it reduces the duration of POI, incidence of postoperative nausea and vomiting, and length of hospital stay compared with placebo. Preliminary results of a long-term alvimopan safety study, however, revealed some potential safety concerns, including adverse cardiovascular events. The significance of these adverse events must be understood before determining the most appropriate role of alvimopan in patient care. Should these new agents receive FDA approval, criteria for their optimal use will need to be developed. These therapies will need to be incorporated into preoperative and postoperative policies, procedures, and protocols; initiatives, such as restricting prescribing to certain prescribers or to types of patients or surgeries or both, may be appropriate. Other considerations in the formulary review process will be the safety profile of the agents and the potential cost savings if reduced patient length of hospital stay can be realized. L E A R N I N G O B J E C T I V E S


• Describe the potential role of methylnaltrexone and alvimopan in reducing postoperative ileus and the potential impact on clinical outcomes.

• List and discuss issues that pharmacists must consider when evaluating formulary status of new drug therapies for postoperative ileus.

New and Emerging Options for New and Emerging Options for Managing Postoperative Managing Postoperative IleusIleus::

Clinical Research andPotential Implications for Pharmacists

Michael D. Kraft, Pharm.D.Clinical Assistant Professor

University of Michigan College of PharmacyAnn Arbor, Michigan

The “Ideal” Anti-Postoperative Ileus(POI) Drug

• Selective for inhibitory mediators on gastrointestinal (GI) tract– Opioid inhibition appears most promising– Lack of central nervous system (CNS)

penetration

• Easy to administer• Well-tolerated; limited or no adverse

effects

The “Ideal” Anti-POI Drug (cont)

• Available in oral and parenteral forms• Limited systemic absorption when given

by mouth (p.o.)• No drug or disease interactions• Inexpensive

Agents Studied

• Nonselective compounds (tertiary opioidantagonists)– Naloxone

– Nalmefene

• Selective compounds (quaternary opioidantagonists)– Methylnaltrexone (MNTX)

– Alvimopan

Naloxone*• Naloxone effectively reverses effects of opioids

• Naloxone readily crosses the blood brain barrier (BBB)– Reversal of opioid-mediated analgesia– May produce withdrawal

• Dose required to reverse opioid effects is patient-specific, highly variable

• Study by Liu and Wittbrodt– Nine patients with chronic opioid-induced constipation– Naloxone 2 mg, 4 mg, or placebo 3 times daily for 3 weeks– All patients experienced improved bowel frequency– 3/9 had reversal of analgesia (1 total), several days to return to

baseline

Liu M et al. J Pain Symptom Manag. 2002; 23:48-53.

*Not FDA approved for POI

Nalmefene*• Not selective for peripheral (gut) opioid receptors

– Nalmefene glucuronide shows selectivity in rodents

• Study by Cheskin et al.– Ascending doses of nalmefene glucuronide given to 5

patients maintained on chronic oral methadone

– Drug stopped when either laxation or withdrawal occurred

– Withdrawal symptoms observed in all 5 patients

– Possibly due to biotransformation of glucuronide form back to the parent compound

Cheskin LJ et al. Drug Alcohol Depend. 1995; 39:151-4. Kurz A et al. Drugs. 2003; 63:649-71.

*Not FDA approved for POI

Peripherally Selective µ-Opioid Receptor Antagonists

MethylnaltrexoneMethylnaltrexone**

AlvimopanAlvimopan**

*Investigational agents, not FDA approved

MethylnatrexoneMethylnatrexone

Naltrexone N-methylnaltrexone

CH3

+

Methylnaltrexone: A Novel, Quaternaryμ-Opioid Receptor Antagonist

• Addition of methyl group to naltrexone, a naloxone-derived tertiary antagonist

Foss JF. Am J Surg. 2001; 182(Suppl):19S-26S.

Methylnaltrexone (MOA-728)

• Poorly lipid soluble, does not penetrate the BBB• Pharmacokinetics

– Limited oral absorption, half-life ~ 2 – 4 hr (p.o. and i.v.)

• ~ 30 – 50% recovered in urine after i.v.• ~ <1% recovered in urine after oral

– Steady-state: no accumulation, minimal change in pharmacokinetics

– Not demethylated to substantial extent in humans

Yuan CS et al. Clin Pharmacol Ther. 1996; 59:469-75;Yuan CS et al. Clin Pharmacol Ther. 1997; 61:467-75; Yuan CS et al. JAMA. 2000; 283:367-72; Yuan CS et al. Clin Pharmacol Ther. 2000; 67:398-404; Yuan CS et al. J Clin Pharmacol. 2005;

45:538-46; Foss JF. Am J Surg. 2001; 182(Suppl):19S-26S.

Methylnaltrexone (MOA-728) (cont)

• Reverses opioid-induced slowing of gut transit time

• Does not antagonize the central (analgesic) effects of opioids or precipitate withdrawal

• Reported to be well-tolerated, no significant adverse effects– Diarrhea, mild-moderate abdominal cramping

Yuan CS et al. Clin Pharmacol Ther. 1996; 59:469-75; Yuan CS et al. Clin Pharmacol Ther. 1997; 61:467-75; Yuan CS et al. JAMA. 2000; 283:367-72; Yuan CS et al. Clin Pharmacol Ther. 2000;

67:398-404; Yuan CS et al. J Clin Pharmacol. 2005; 45:538-46; Foss JF. Am J Surg. 2001; 182(Suppl):19S-26S.

Methylnaltrexone: Three Dosage Forms Being Evaluated

• Intravenous and subcutaneous– Completed two phase 3 trials (subcutaneously) for

opioid-induced bowel dysfunction (OBD)– Completed a phase 2 trial (i.v.) for POI

• Oral– Completed two phase 1 studies in healthy

volunteers (uncoated and enteric-coated)– Will initiate two phase 2 trials soon

Foss JF. Am J Surg. 2001; 182(Suppl):19S-26S;Yuan CS et al. Clin Pharmacol Ther. 2000; 67:398-404;

Progenics Pharmaceuticals. Methylnaltrexone (URL in reference list); Wyeth. Product pipeline (URL in reference list); U.S. National Library of Medicine (NLM). ClinicalTrial.gov (URL in

reference list); Progenics Pharmaceuticals. 2007 Oct 15. Press release (URL in reference list).

Methylnaltrexone: MNTX 203 Methods

• Phase 2 study for reduction of postoperative bowel dysfunction

• Randomized, double-blind, placebo-controlled• 65 patients undergoing segmental colectomy• MNTX 0.3 mg/kg or placebo i.v.

– First dose within 90 min of end of surgery, then every 6 hr

– Up to 24 hr after GI recovery, max of 7 days • GI recovery: tolerated solid food plus bowel

movement (BM)

Viscusi E et al. Anesthesiology. 2005; 103:A893. Abstract.

Methylnaltrexone: MNTX 203 Results Reported as mean time (hr) + S.E.

EndpointMNTX (n=33)

Placebo (n=32) p value*

Full liquids 70 ± 9 100 ± 19 0.05

1st BM 97 ± 6 120 ± 10 0.01

GI recovery 124 ± 9 151 ± 16 0.06

Discharge eligible 119 ± 7 149 ± 17 0.03

Actual discharge 140 ± 6 165 ± 16 0.09

Viscusi E et al. Anesthesiology. 2005; 103:A893. Abstract.*1-sided

Clinical Trials of Methylnaltrexone

• MNTX 203: Phase 2 trial, MNTX i.v. in the prevention of postoperative ileus

• Three ongoing Phase 3 trials, MNTX i.v. for reduction of POI– MNTX 3301, 3200L2-300: open laparotomy and

segmental colectomy

– 3200L2-301: ventral hernia repair

– Primary outcome: time between end of surgery and first BM

U.S. NLM. ClinicalTrials.gov (URL in reference list).Wyeth. Clinical trial listings (URL in reference list).

Progenics Pharmaceuticals. Postoperative (IV) (URL in reference list).

AlvimopanAlvimopan

Alvimopan: A Novel, Quaternary μ-Opioid Receptor Antagonist

Moderately large molecular weight (461 Da)

Fentanyl

• Unique pharmacologic profile– Limited oral bioavailability (dogs ~ 0.03%, humans ~ 6%)– Majority excreted in the feces, minimal renal excretion

after oral dosing (~ 0.4%)– Similar in elderly

• High binding affinity for μ-opioid receptor– Ki<1 nmol/L– 10-100 times less affinity for delta (δ) and kappa (κ)

opioid receptorsZimmerman DM et al. J Med Chem. 1994; 37:2262-5;

Schmidt WK. Am J Surg. 2001; 182(Suppl 5A):27S-38S; Foss J et al. Clin Pharmacol Ther.2005; 77:P74. Abstract; Foss J et al. Pharmacotherapy. 2005; 25:1505. Abstract 325;

Holzer P. Neurosci Lett. 2004; 361:192-5; Kurz A et al. Drugs. 2003; 63:649-71;Leslie JB. Ann Pharmacother. 2005; 39:1502-10; Taguchi A et al. N Engl J Med. 2001; 345:935-40.

Alvimopan

Alvimopan (cont)

• Does not reverse opioid analgesia

• Reduces oral-cecal transit time

• Reverses morphine-induced constipation

• Data for efficacy in reducing opioid-induced bowel dysfunction

• Data for efficacy in reducing the duration of POI after bowel resection

Liu SS et al. Clin Pharmacol Ther. 2001; 69:66-71; Schmidt WK. Am J Surg. 2001; 182(Suppl 5A):27S-38S; Holzer P. Neurosci Lett. 2004; 361:192-5; Kurz A et al. Drugs. 2003; 63:649-71;

Leslie JB. Ann Pharmacother. 2005; 39:1502-10; Taguchi A et al. N Engl J Med. 2001; 345:935-40.

Study Total and MITT (n) Population (% MITT)

14CL 302 Total = 451MITT = 424

Colon resection (68%)Radical hysterectomy (7%)Simple hysterectomy (22%)

14CL 308 Total = 666MITT = 510

Large/small bowel resection (68%)Radical hysterectomy (17.4%)Simple hysterectomy (14.6%)

14CL 313 Total = 510MITT = 469

Large/small bowel resection (96%)Radical hysterectomy (4%)

14CL 306 Total = 519MITT = 510 Simple hysterectomy

Alvimopan for POI: Phase 3 Trials*

Delaney CP et al. Dis Colon Rectum. 2005; 48:1114-29; Viscusi ER et al. Surg Endosc. 2006; 20:64-70; Wolff BG et al. Ann Surg. 2004; 240:728-35; Herzog TJ et al. Am J Obstet Gynecol. 2006; 195:445-53.

*Multicenter, prospective, randomized, double-blind, placebo-controlled trials; patients underwent open laparotomy/open surgical procedureMITT = modified intent-to-treat

Alvimopan for POI: Phase 3 Trials• Alvimopan 6 mg or 12 mg orally or placebo for 1

dose ≥ 2 hours preop, then twice daily until discharge or up to 7 days

• Primary endpoint (GI-3) was later time of– First tolerated solid food and– Time patient first passed flatus or had BM

• Secondary endpoint (GI-2) was later time of– First tolerated solid food– Time patient first had BM

• Time to discharge order (DCO) writtenDelaney CP et al. Dis Colon Rectum. 2005; 48:1114-29; Wolff BG et al.

Ann Surg. 2004; 240:728-35; Viscusi ER et al. Surg Endosc. 2006; 20:64-70.

Alvimopan for POI: Phase 3 Trials• Men and women, ≥ 18 years old• Standardized postoperative care

– Analgesia via opioid patient-controlled analgesia (PCA)– Nasogastric (NG) tube out at end of surgery

postoperative day (POD) 1– Liquids offered, ambulation encouraged on POD 1– Solid food offered on POD 2

• Exclusions: Opioids within 1-4 weeks, epidural opioids, local anesthetics, nonsteroidalantiinflammatory drugs (NSAIDs), or severe concomitant disease(s)

Delaney CP,et al. Dis Colon Rectum. 2005; 48:1114-29; Wolff BG et al.Ann Surg. 2004; 240:728-35; Viscusi ER et al. Surg Endosc. 2006; 20:64-70.

Delaney CP et al. Dis Colon Rectum. 2005; 48:1114-29.Wolff BG et al. Ann Surg. 2004; 240:728-35.

Viscusi ER et al. Surg Endosc. 2006; 20:64-70.

Other Variables of Interest

• Visual analogue scale (VAS) pain scores

• Daily postoperative opioid consumption

• Incidence of NG tube insertion after surgery

• Safety

Alvimopan Study 14CL 313

Alvimopan 14CL 313: Patient Demographics (MITT)

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

Placebon = 149

Alvimopan6 mg

(n = 155)

Alvimopan12 mg

(n = 165)

Totaln = 469

Mean (range) age, yr

60.9(20-87)

59.3(19-88)

61.3(20-89)

60.5(19-89)

Mean (median) surgery duration, hr 2.2 (1.9) 2.1 (1.9) 2.1 (1.9) 2.1 (1.9)

Intraoperativeopioid use, mgPostoperative opioid use, mg

26.5

27

28.1

33.6*

25.5

27.1

--

*Significantly higher vs. placebo and 12 mg

Alvimopan 14CL 313: Results


Endpoint/ Treatment n

Censored n (%)

Mean, hr (Δ vs.

placebo)Hazard Ratio

(95% CI)p

valueFirst solid food + BM/flatus (GI-3)- Placebo- Alvimopan 6 mg- Alvimopan 12 mg

149155165

26 (17.4)16 (10.3)16 (9.7)

120105 (-15)98 (-22)

--1.28 (1.0-1.64)1.54 (1.21-1.96)

--<0.05<0.001

First solid food + BM (GI-2)- Placebo- Alvimopan 6 mg- Alvimopan 12 mg

149155165

39 (26.2)25 (16.1)25 (15.2)

133113 (-20)105 (-28)

--1.38 (1.07-1.79)1.67 (1.30 -2.15)

--0.013<0.001

Alvimopan 14CL 313: Results (cont)

Endpoint/ Treatment n

Censored n(%)

Mean, hr(Δ vs.

placebo)Hazard Ratio

(95% CI)p

valueHospital DCO written- Placebo- Alvimopan 6 mg- Alvimopan 12 mg

149155165

18 (12.1)10 (6.5)9 (5.5)

146133 (-13)126 (-20)

--1.25 (0.98-1.58)1.42 (1.12-1.79)

--0.0700.003


Alvimopan 14CL 313: Adverse Events


Adverse Event

Placebon = 165

Alvimopan 6 mgn = 169

Alvimopan 12 mgn = 176

Nausea 64.2 % 60.9 % 54.5 %Vomiting 25.5 24.3 19.9Hypotension 13.9 13.6 13.6Oliguria 15.2 11.8 13.1Hypertension 10.9 11.8 12.5Pyrexia 13.9 14.2 10.8Abdominal distention 15.2 11.8 10.8Tachycardia 13.9 13.0 10.8Hypokalemia 17.0 10.7 9.7

Alvimopan 14CL 313: Morbidity• Reduced incidence of postoperative NG tube

insertion vs. placebo– 4.8% alvimopan 12 mg vs. 14.8% placebo; p = 0.004

• Significant reduction of “delayed” POI vs. placebo– 8.3% alvimopan 6 mg vs. 6.3% alvimopan 12 mg vs.

15.8% (placebo); p < 0.05

• Decreased readmission rates (within 10 days)– 4% alvimopan-treated patients– 8% placebo


Alvimopan Phase 3 Pooled Analyses

Meta-Analysis: Alvimopan vs. Placebo• Included 5 trials, 2195 patients

– Alvimopan = 1521, placebo = 674– Bowel resection ~ 56%, total abdominal hysterectomy (TAH) ~ 44%

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

Outcome HR p valueGI-3 (alvimopan 12 mg vs. placebo) 1.30 <0.001

GI-3 (alvimopan 6 mg vs. placebo) 1.50 0.003

GI-2 (alvimopan 12 mg vs. placebo) 1.61 <0.001


Time ready for DC (alvimopan 12 mg) 1.26 <0.001

Time ready for DC (alvimopan 6 mg) 1.40 <0.001

• No significant reduction in nausea, vomiting, prolonged POI, abdominal distention

DC = discharge

Alvimopan: Pooled Analysis of Patients with Bowel Resection

• Included 3 trials, 1165 patients (MITT)– Alvimopan 12 mg = 397, alvimopan 6 mg = 385, placebo = 383

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

Outcome HR p valueGI-3 (alvimopan 12 mg vs. placebo) 1.38 <0.001

GI-3 (alvimopan 6 mg vs. placebo) 1.28 0.001



Time to DCO written (alvimopan 12 mg) 1.43 <0.001

Time to DCO written (alvimopan 6 mg) 1.36 <0.001

• Alvimopan significantly reduced nausea (12 mg), NG tube reinsertion, prolonged POI, readmit, or prolonged LOS

Alvimopan Study 14CL 314

Alvimopan Study 14CL 314: Methods

• Phase 3 study, 654 patients scheduled for large or small bowel resection; MITT = 629

• Alvimopan 12 mg twice daily vs. placebo, first dose given 30-90 minutes before surgery– Primary endpoint: GI-2

– Secondary endpoints: GI-3, time to first BM, time to ready for DC, time to DCO written, time to hospital departure

Leslie J et al. Anesthesiology. 2006; 105:A122. Abstract.

Alvimopan Study 14CL 314: Results

EndpointAlvimopan

(n=317)Placebo (n=312) p value*

GI-2 (hr) 92.0 111.8 ---

GI-2 hazard ratio 1.53 (1.29, 1.82) --- <0.001

LOS (days) 5.2 6.2 <0.001

POI-related morbidity (%) 6.9 14.4 0.003

• Generally well tolerated- Nausea (placebo 66.2% vs. alvimopan 57.8%; p = 0.03)- Vomiting (placebo 24.6% vs. alvimopan 14.0%; p < 0.001)- Abdominal distention (placebo 20.3% vs. alvimopan 17.6%; p = 0.425)

Leslie J et al. Anesthesiology. 2006; 105:A122. Abstract.

Alvimopan Study 014Safety Concerns

Alvimopan: FDA Approvable Letter

• Alvimopan study 014 safety concerns – 805 patients (alvimopan = 538, placebo = 267)

GlaxoSmithKline and Adolor. 2007 Apr 9. Press release (URL in reference list).

Outcome Alvimopan PlaceboMyocardial infarction (MI) 7 (1.3%) 0All cardiovascular (CV) severe adverse events (SAEs) 14 (2.6%) 3 (1.12%)

Neoplasms (benign, malignant, unspecified)

15 (2.8%)4 serious

2 (0.7%)1 serious

• Also an increase in fracture events alvimopan vs. placebo• CV events in patients with established or high risk for CV disease• 5 of 7 MIs occurred at two sites; incidence of MI not linked to

duration

Ileus: Case Report

• 63-yr-old man s/p bowel resection has been receiving morphine 4 mg/hr for three days by patient-controlled analgesia (PCA)

• Began PCA morphine 1 week ago with 2-mg i.v. bolus with 10-minute lock-out interval

• Patient just started oral feedings today• Physician wants to convert patient to oral

medications and discharge tomorrow

Emerging Drug Therapies for Postoperative Ileus:

Formulary Considerations

If either methylnaltrexone or alvimopanreceive FDA approval, in which patients would they be appropriate?

• Exploratory laparotomy with bowel resection

• Likely to receive opioids via PCA

• Other abdominal surgeries (e.g., TAH)?

• Surgeries other than exploratory or open laparotomy? Laparoscopic – seems unlikely to benefit

• Safety concerns? Patients with CV disease?

• Has your institution developed other pathways to reduce POI (e.g., multimodal or fast-track pathway)?

When and how should the drug be administered?• Alvimopan: up to 30 – 90 min preoperatively

• What if a patient does not receive a preoperative dose of alvimopan? According to rats, less effective!1

• Methylnaltrexone: postoperatively?

• Is this the best way to dose these agents (i.e. “prophylaxis”)?

• More pharmacokinetics and pharmacodynamics data??• Where to administer? In hospital

• Route of administration

• DOSING!! Dose for opioid-induced constipation and OBD will likely be lower than for POI

1Fukuda H et al. Brain Res. 2006; 1102:63-70.

How will these agents affect resources? How should they be used to realize the maximum benefit with the least impact on resources and budget?

• Drug cost unknown

• Restrict to prescriber types (e.g., GI surgeons) or specific procedures or both?

• Decrease in actual LOS vs. time to DCO written?

• Can the reduced LOS be realized?

• Reduction in morbidity?

We can improve upon the “old way”of doing things!

Conclusions• Methylnaltrexone and alvimopan are promising

agents for the reduction of POI after bowel resection

• Methylnaltrexone phase 3 studies are underway, multiple dosage forms also being investigated

• Alvimopan is the most extensively studied agent for the reduction of POI– Decreased duration of POI – Reduced time to DCO written, possibly LOS– Must await further safety data and analysis

• These novel agents may become an important component of perioperative care

End of Presentation

• You have reached the end of this presentation

• Please return to the Program Overview to take the program post-test

• Or select another presentation from the left menu


R E F E R E N C E S

1. Cheskin LJ, Chami TN, Johnson RE et al. Assessment of nalmefene glucuronide as a selective gut opioid antagonist. Drug Alcohol Depend. 1995; 39:151-4.

2. 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; 48:1114-29.

3. 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. 4. Foss JF. A review of the potential role of methylnaltrexone in opioid bowel

dysfunction. Am J Surg. 2001; 182(Suppl):19S-26S. 5. Foss J, Marbury TC, Melikian A et al. Pharmacokinetics of alvimopan, a novel, oral,

peripherally acting mu-opioid receptor (PAM-OR) antagonist, and its primary metabolite in the elderly. Pharmacotherapy. 2005; 25:1505. Abstract 325.

6. Foss J, Schmith V, Wallin B et al. Alvimopan (Entereg™), a novel opioid antagonist,

achieves active systemic concentrations. Clin Pharmacol Ther. 2005; 77:P74. Abstract.

7. Fukuda H, Suenaga K, Tsuchida D et al. The selective mu opioid receptor antagonist,

alvimopan, improves delayed GI transit of postoperative ileus in rats. Brain Res. 2006; 1102:63-70.

8. GlaxoSmithKline and Adolor Corporation. GSK and Adolor announce preliminary

results from Phase 3 Safety study of Alvimopan (Entereg/Entrareg®). 2007 Apr 9. Press release. http://www.gsk.com/media/archive.htm (accessed 2007 Oct 17).

9. Herzog TJ, Coleman RL, Guerrieri JP et al. A double-blind, randomized, placebo-

controlled phase III study of the safety of alvimopan in patients who undergo simple total abdominal hysterectomy. Am J Obstet Gynecol. 2006; 195:445-53.

10. Kurz A, Sessler DI. Opioid-induced bowel dysfunction: pathophysiology and potential

new therapies. Drugs. 2003; 63:649-71. 11. Leslie JB. Alvimopan for the management of postoperative ileus. Ann Pharmacother.

2005; 39:1502-10. 12. Leslie J, Steinbrook R, Viscusi E et al. Alvimopan oral dosing 30-90 minutes before

and BID after bowel resection accelerates GI recovery. Anesthesiology. 2006; 105:A122. Abstract. http://www.asaabstracts.com/strands/asaabstracts/abstract.htm;jsessionid=FDE0375B62BA3CE1FFE7313651CDD094?year=2005&index=11&absnum=1630 (accessed 2007 Oct 16).

13. Liu M, Wittbrodt E. Low-dose oral naloxone reverses opioid-induced constipation and

analgesia. J Pain Symptom Manage. 2002; 23:48-53.


14. Liu SS, Hodgson PS, Carpenter RL et al. ADL 8-2698, a trans-3,4-dimethyl-4-(3-

hydroxyphenyl) piperidine, prevents gastrointestinal effects of intravenous morphine without affecting analgesia. Clin Pharmacol Ther. 2001; 69:66-71.

15. Progenics Pharmaceuticals. Methylnaltrexone.

http://www.progenics.com/prod_methyl.cfm (accessed 2007 Oct 16). 16. Progenics Pharmaceuticals. Postoperative (IV).

http://www.progenics.com/postop.cfm (accessed 2007 Oct 16). 17. Progenics Pharmaceuticals. Wyeth and Progenics to initiate phase 2 trials of oral

methylnaltrexone in chronic-pain setting. 2007 Oct 15. Press release. http://www.progenics.com/releasedetail.cfm?ReleaseID=268975 (accessed 2007 Oct 16).

18. Schmidt WK. Alvimopan (ADL 8-2698) is a novel peripheral opioid antagonist. Am J

Surg. 2001; 182(Suppl 5A):27S-38S. 19. Taguchi A, Sharma N, Saleem RM et al. Selective postoperative inhibition of

gastrointestinal opioid receptors. N Engl J Med. 2001; 345:935-40. 20. 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. 21. U.S. National Library of Medicine. ClinicalTrials.gov. http://www.clinicaltrials.gov

(accessed 2007 Oct 16). 22. Viscusi ER, Goldstein S, Witkowski T et al. Alvimopan, a peripherally acting mu-

opioid receptor antagonist, compared with placebo in postoperative ileus after major abdominal surgery. Surg Endosc. 2006; 20:64-70.

23. Viscusi E, Rathmell J, Fichera A et al. A double-blind, randomized, placebo-

controlled trial of methylnaltrexone (MNTX) for post-operative bowel dysfunction in segmental colectomy patients. Anesthesiology. 2005; 103:A893. Abstract. http://www.asaabstracts.com/strands/asaabstracts/abstract.htm;jsessionid=115F34A273578F2AFCA2365449EDFA68?year=2005&index=11&absnum=1630 (accessed 2007 Oct 16).

24. 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.

25. Wyeth. Clinical trial listings: post operative bowel dysfunction.

http://www.wyeth.com/ClinicalTrialListings_hcp?query=Post%20operative%20bowel%20dysfunction (accessed 2007 Oct 16).

26. Wyeth. Product pipeline. http://www.wyeth.com/research_hcp/pipeline_hcp

(accessed 2007 Oct 14).


27. Yuan CS, Doshan H, Charney MR et al. Tolerability, gut effects, and

pharmacokinetics of methylnaltrexone following repeated intravenous administration in humans. J Clin Pharmacol. 2005; 45:538-46.

28. Yuan CS, Foss JF, O’Connor M et al. Methylnaltrexone prevents morphine-induced

delay in oral-cecal transit time without affecting analgesia: a double-blind randomized placebo-controlled trial. Clin Pharmacol Ther. 1996; 59:469-75.

29. Yuan CS, Foss JF, O’Connor M et al. Methylnaltrexone for reversal of constipation

due to chronic methadone use. JAMA. 2000; 283:367-72. 30. Yuan CS, Foss JF, O’Connor M et al. Effects of enteric-coated methylnaltrexone in

preventing opioid-induced delay in oral-cecal transit time. Clin Pharmacol Ther. 2000; 67:398-404.

31. Yuan CS, Foss JF, Osinski J et al. The safety and efficacy of oral methylnaltrexone

in preventing morphine-induced delay in oral-cecal transit time. Clin Pharmacol Ther. 1997; 61:467-75.

32. Zimmerman DM, Gidda JS, Cantrell BE et al. Discovery of a potent, peripherally

selective trans-3,4-dimethyl-4-(3-hydroxyphenyl) piperidine opioid antagonist for the treatment of gastrointestinal motility disorders. J Med Chem. 1994; 37:2262-5.

A D D I T I O N A L R E F E R E N C E S

1. Beattie DT, Cheruvu M, Mai N et al. The in vitro pharmacology of the peripherally restricted opioid receptor antagonists, alvimopan, ADL 08-0011 and methylnaltrexone. Naunyn Schmiedebergs Arch Pharmacol. 2007; 375:205-20.

2. Foss JF, O’Connor MF, Yuan CS et al. Safety and tolerance of methylnaltrexone in

healthy humans: a randomized, placebo-controlled, intravenous, ascending-dose, pharmacokinetic study. Clin Pharmacol. 1997; 37:25-30.

3. Foss JF, Fisher DM, Schmith VD. Pharmacokinetics of alvimopan and its metabolite

in healthy volunteers and patients in postoperative ileus trials. Clin Pharmacol Ther. 2007; Jul 25 [Epub ahead of print].

4. Holzer P. Opioids and opioid receptors in the enteric nervous system: from a

problem in opioid analgesia to a possible new prokinetic therapy in humans. Neurosci Lett. 2004; 361:192-5.

5. Kotake AN, Kuwahara SK, Burton E et al. Variations in demethylation of N-

methylnaltrexone in mice, rats, dogs, and humans. Xenobiotica. 1989; 19:1247-54. 6. Kraft MD. Emerging pharmacologic options for treating postoperative ileus. Am J

Health-Syst Pharm. 2007; 64(Suppl 13):S13-20. 7. Livingston EH, Passaro EP. Postoperative ileus. Dig Dis Sci. 1990; 35:121-32.


8. Paulson DM, Kennedy DT, Donovick RA et al. Alvimopan: an oral, peripherally acting,

μ-opioid receptor antagonist for the treatment of opioid-induced bowel dysfunction—a 21-day treatment-randomized clinical trial. J Pain. 2005; 6:184-92.


2006; 43:6-65. Review. 10. Yuan CS. Clinical status of methylnaltrexone, a new agent to prevent and manage

opioid-induced side effects. J Support Oncol. 2004; 2:111-7.


S E L F – A S S E S S M E N T Q U E S T I O N S

1. In the normal gastrointestinal tract, what percent of nutrient absorption occurs in the jejunum? a. 20%. b. 40%. c. 70%. d. 90%.

2. According to Dr. Erstad, the four components of gastrointestinal control are a. Neuronal, hormonal, antibacterial, and immunomodulation. b. Neuronal, hormonal, mechanical, and immunomodulation. c. Hormonal, mechanical, psychological, and immunomodulation. d. Neuronal, hormonal, mechanical, and behavorial.

3. Which of the following terms is used to describe a non-mechanical obstruction of the

gastrointestinal tract? a. Perforated bowel. b. Constipation. c. Strangulation. d. Ileus.

4. Small bowel obstruction occurring after abdominal surgery is a type of postoperative

ileus. a. True. b. False.

5. Which of the following nondrug factors is associated with developing postoperative

ileus? a. Physical manipulation of bowel. b. Short incisions during abdominal surgery. c. Enteral feedings given shortly after surgery. d. Laparoscopic surgery.

6. Which of the following statements best describes the diagnostic criteria for postoperative ileus? a. The absence of bowel sounds is almost always indicative of ileus. b. Patients are very ill and experience anorexia, nausea, and vomiting. c. There is no single diagnostic test to diagnose postoperative ileus or rule it out. d. Scans and contrast studies are routinely performed to differentiate postoperative

ileus from small bowel obstruction and other complications. 7. Based on the reliability of indicators of restored bowel function after postoperative

ileus, which of the following patients most likely has resolution of postoperative ileus? a. A patient with a normal CT scan of the colon. b. A patient with a normal ultrasound of the abdomen. c. A patient with bowel sounds and no abdominal pain. d. An asymptomatic patient on goal rate tube feedings.


8. The primary economic burden associated with postoperative ileus is prolonged

hospitalization. a. True. b. False.

9. Which of the following statements best describes the “multimodal, fast-track approach” of caring for surgical patients? a. An interdisciplinary concept to expedite therapy of surgical patients in an effort to

reduce postoperative complications. b. An interdisciplinary concept to accelerate postoperative convalescence and

reduce general morbidity by simultaneously applying several interventions. c. An interdisciplinary concept to accelerate procedures in an effort to streamline

care and decrease costs. d. An interdisciplinary concept to facilitate patient flow through the health care

system after surgery.

10. Compared with conventional surgical techniques, laparoscopic colorectal surgery has been associated with reduced postoperative pain, earlier flatulence, and earlier bowel movement. a. True. b. False.

11. All of the following are positive effects of epidural anesthesia/analgesia in patients undergoing abdominal surgery except a. Synergistically blocks inhibitory sympathetic reflexes, prevents the release of

afferent pain neurotransmitters, and increases blood flow to the gut. b. Provides a deep level of anesthesia associated with greater inhibition of

gastrointestinal motility. c. Reduces adverse effects of opioids. d. Provides dose-dependent response in which nociceptive and autonomic fibers

are blocked at lower doses and motor and somatosensory fibers are blocked at higher doses.

12. According to Dr. MacLaren, the goal of fluid management during the perioperative

period is a. Euvolemia without dehydration and electrolyte abnormalities. b. Intake of less than 2 liters water daily for 4-5 days after surgery. c. Intake of at least 3 liters water daily for 4-5 days after surgery. d. Urine output of at least 2 liters daily.

13. A 68-year-old woman just underwent a partial colectomy and was transferred to the

surgical intensive care unit after mechanical ventilation was removed. Epidural analgesia is being provided, and a nasogastric (NG) tube is in place. Which of the following options would be most beneficial for this patient in preventing or managing postoperative ileus? a. Start a laxative. b. Administer neostigmine. c. Remove the NG tube. d. Encourage mobilization.


14. All of the following have been shown to be beneficial in managing postoperative ileus

except a. Early oral or enteral feeding. b. Administration of prokinetic agents like metoclopramide and erythromycin. c. Sham feeding. d. Reducing the amount of opioids administered by incorporating nonsteroidal anti-

inflammatory agents in the pain regimen. 15. A multimodal approach to perioperative care can result in which of the following

outcomes? a. Delayed oral nutrition. b. Shortened hospital length of stay. c. Delayed gastrointestinal recovery. d. Greater number of re-admissions.

16. All of the following are ways in which pharmacists can contribute to the multimodal,

fast-track care of surgical patients except a. Develop medication protocols. b. Provide patient education and compliance assessment. c. Aid in discharge planning. d. Recommend maximum scheduled doses of opioids to minimize pain.

17. Which of the following drugs is a tertiary opioid antagonist that readily crosses the

blood brain barrier? a. Methylnaltrexone. b. Naloxone. c. Meperidine. d. Alvimopan.

18. Which of the following statements best describes the results of clinical studies

evaluating methylnaltrexone for postoperative ileus? a. It may reverse centrally-mediated opioid analgesia. b. It may reduce the time to first bowel movement in patients undergoing bowel

resection via open laparotomy. c. It may accumulate in patients after multiple doses. d. It was associated with shortened time to bowel recovery and length of stay after

open laparotomy and bowel resection in several phase 3 studies.

19. Based on available clinical studies, alvimopan and methylnaltrexone are administered only by the oral route. a. True. b. False.

20. The results of phase 3 clinical studies comparing alvimopan with placebo suggest that alvimopan is associated with all of the following outcomes following major abdominal surgery except a. Increased postoperative nausea and vomiting. b. Shortened time to bowel recovery. c. Reduced incidence of postoperative nasogastric tube insertion. d. Reduced time to discharge order written.


21. When making formulary decisions regarding new drug therapies for reducing postoperative ileus, all of the following could be potentially useful to consider except a. Limit their use to patients at least 50 years old. b. Limit their use to patients undergoing procedures for which phase 3 data have

demonstrated potential benefit. c. Review all potential safety issues associated with the use of these agents. d. Develop a medication administration protocol, including the timing of the first

dose relative to the start of surgery, as well as the most appropriate dose, route, and duration of therapy.

22. Based on the results of phase 2 studies (and pending phase 3 studies and further

data and analysis on safety), which of the following patients could be the best candidate to receive methylnaltrexone? a. 60-year-old man 2 hours before undergoing a large bowel resection via open

laparotomy. b. 50-year-old woman 6 days after undergoing a total abdominal hysterectomy who

has not had return of bowel function (i.e. no flatus, no bowel movement, nothing by mouth).

c. 65-year-old woman 1 hour after undergoing a large bowel resection via open laparotomy.

d. 14-year-old girl 1 hour before undergoing a laparoscopic appendectomy. 23. Based on the results of phase 3 studies (and pending further data and analysis on

safety), all of the following patients could be a candidate for receiving alvimopan except a. A 62-year-old woman 1 hour before undergoing a large bowel resection via open

laparotomy. b. A 45-year-old man 3 hours before undergoing a small bowel resection via open

laparotomy. c. A 53 year-old man 45 minutes before undergoing an exploratory (open)

laparotomy and planned bowel resection for likely bowel perforation. d. A 38-year-old woman 4 days after a large bowel resection via open laparotomy

who has not had return of bowel function (i.e. no flatus, no bowel movement, nothing by mouth).

multimodal approach for managing postoperative · pdf filemultimodal approach for managing...

Documents