Oxford American Pocket Notes Postoperative Ileus

O A P N OX F O R D A M E R I C A N P O C K E T N O T E S

Postoperative ileus

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O A P N

OX F O R D A M E R I C A N P O C K E T N O T E S

Postoperative ileus By Conor P. Delaney, MD, MCh, PhD, FRCSI, FACS Professor of Surgery, Case Western Reserve University Chief, Division of Colorectal Surgery Vice-Chairman, Department of Surgery Director, Institute for Surgery and Innovation University Hospitals, Case Medical Center Cleveland, OH

1

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POSTOPERATIVE STATIN GUIDE ILEUS

FOREWORD

Postoperative ileus is a condition that has recently come to prominence in our clinical care for patients. For many years, patients undergoing abdominal surgery were known to take 4 or 5 days to recover gastrointestinal function and to be able to maintain adequate hydration and nutrition. This was accepted as a normal part of recovery after intestinal surgery. Approximately 10% of patients are known to develop a more significant form of ileus, often requiring prolonged nasogastric intubation and intravenous nutrition. Increasing pressure on provision of care, with reduced reimbursement and reduced nursing resources, has increased the emphasis on providing care efficiently. Over the past decade, perioperative care has improved and patients now stay 4 to 7 days after open abdominal surgery, instead of the 7 to 12 days that used to be required. These new benchmarks have been further accelerated by laparoscopic intestinal surgery, and in some institutions patients now return home within 1 or 2 days of surgery. Thus, as care has evolved, clinicians have realized that while a period of postoperative ileus is mandatory, a shorter ileus is not harmful and simply accelerates recovery. In this book, Dr. Gan reviews all of the salient points related to postoperative ileus. Defi nitions, clinical features, and the magnitude of the clinical problem are reviewed. Precipitating factors and pathophysiology are described. Protocols to optimize perioperative care and minimize ileus are reviewed, and fi nally pharmacologic

OAPN management and prevention are discussed in detail. In short, this handbook briefly reviews all the points that the clinical practitioner needs to know about the management and prevention of postoperative ileus. I have no doubt it will be a useful tool for those looking after patients at risk of, and who have developed, this troubling and common condition.

POSTOPERATIVE ILEUS CORONARY STENTING

TABLE OF CONTENTS

Introduction 1 Defi nitions 2 Prevalence 2 Economic burden in the hospital setting 4 Risk factors 5 Causes and pathophysiology 6 Diagnosis and clinical features 11 Diagnostic tests and imaging 12 Differential diagnosis 12 Prevention 13 Nasogastric intubation 13 Fluid administration 13 Surgical technique 14 Anesthetic techniques 14 Psychological factors 15 Current pharmacological options for treatment and management 16 Nonsteroidal anti-inflammatories and other anti-inflammatory agents 16 Symptom relief with hydration and nasogastric tube 16 Prokinetic agents 16 Chewing gum 19

OAPN Anticholinergic or cholinergic drugs 19 Laxatives 20 P-opioid antagonists 20 Other drugs 20 Nonpharmacological therapies 21 Early feeding 21 Fast-track recovery protocol 21 Emerging pharmacotherapies 23 Peripherally acting μ-opioid antagonists 23 Conclusions 26

POSTOPERATIVE ILEUS

DISCLOSURES

Dr. Gan has received research support or honoraria from Aspect Medical System, Baxter, Durect, Eisai, Fresenius, GSK and Hospira.

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POSTOPERATIVE ILEUS

Introduction

Postoperative ileus (POI) is one of the most common complications after elective abdominal surgery. It prolongs the hospital stay, causes patient discomfort, and presents a significant economic burden to the society in terms of increased health-care resource utilization and cost as well as lost productivity. In a recent study, 50% of the complications after elective major surgery in the hospital were due to gastrointestinal (GI) dysfunction.1 POI is the most common reason for delayed discharge after abdominal surgery. The GI tract goes through a period of quiescence after STATIN GUIDE abdominal surgery. Colonic motility appears to be the last to recover. Studies in which bowel motility is measured in real time suggest that the small bowel returns to normal peristaltic function within 12 to 24 hours, the stomach within 24 to 48 hours, and the colon in 3 to 5 days.2 Many factors are associated with the development of POI, such as surgical manipulation, anesthesia, fluid administration, preexisting GI disease, and opioid use. Successful management of POI requires identifying and reducing avoidable risk factors and taking a comprehensive, multimodal approach to the prevention and treatment of the condition.

1

OAPN DEFINITIONS Ileus —Functional inhibition of propulsive bowel activity, irrespective of pathogenic mechanisms. Paralytic Ileus —Form of POI lasting for more than 5 days after

surgery. Postoperative Ileus (POI) —Transient cessation of coordinated

bowel motility after surgical intervention that prevents effective transit of intestinal contents or tolerance of oral intake. Primary Postoperative Ileus —Postoperative ileus occurring in the absence of any precipitating complication. Secondary OAPN Postoperative Ileus—Postoperative ileus occurring in

the presence of a precipitating complication. PREVALENCE

GI tract dysfunction occurs predictably after major abdominal operations but can occur after operations on other parts of the body or occasionally even after minor surgical procedures. A recent study suggests that 50% of the complications after elective major surgery in the hospital were due to GI dysfunction.1 In general, surgery that involves the bowel, a larger surgical incision, and more extensive bowel manipulation; the presence of pus; and preexisting medical conditions make the development of POI more likely. POI is characterized by a lack of coordinated intestinal activity and a substantial overall reduction in peristalsis. Table 1 outlines the type of surgical procedures and the frequency of POI. The incidence quoted is likely to be an underestimate, however, as the data are based on the POI cases being coded as the primary cause for complication. 2

POSTOPERATIVE ILEUS

Table 1. The Number of Surgical Procedures and the Incidence of POI Procedure Description

Number of Procedures

Cases with POI (%)

Small bowel resection

48,824

19.2

Large bowel resection

257,336

14.9

Radical cystectomy

9787

18

Nephroureterectomy

44,808

Cholecystectomy

81,013

8.9 8.5

Appendectomy

175,964

6.2

Abdominal hysterectomy

456,292

Other procedures

597,492

STATIN GUIDE

4.1

9.0

Colonic motility is usually the last function of the GI tract to return after abdominal surgery. Fifty percent of patients undergoing open abdominal bowel surgery had not recovered GI function at 4.5 days; 25% of patients had not recovered GI function after more than 6 days. Figure 1 demonstrates the time course of POI.

3

OAPN 1.0 0.9

Percentile of patients

0.8 0.7

After ⬎ 6 days, 25% of patients had not recovered GI function

0.6 0.5 0.4 0.3 0.2

0.1 OAPN 0.0 0

24

48

72 96 120 144 168 192 216 240 Time to recovery of GI function (h)

Figure 1. Time to recovery of GI function in patients undergoing open abdominal colorectal surgery. Adapted from Wolff BG, Michelassi F, Gerkin TM, et al. Alvimopan Postoperative Ileus Study G: 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;240:728–734.

ECONOMIC BURDEN IN THE HOSPITAL SETTING

In the United States, length of stay for patients undergoing bowel resection ranges from 5 to 14 days. Mean cost per hospital stay has been estimated to be approximately $6000 more for patients with coded POI compared with patients without coded POI.3,4 4

POSTOPERATIVE ILEUS

Annual POI-related health-care costs in the United States are estimated to be $750 million to $1 billion5 due to: ■

Nasogastric insertion

■

Intravenous hydration and nutrition

■

Extra nursing care

■

Longer hospital stay

■

Additional laboratory testing

RISK FACTORS

STATIN GUIDE

Many risk factors are associated with POI. Certain risk factors may be avoidable, and with careful management the incidence and duration of POI may be reduced. Risk factors include the following: ■

Surgery, particularly abdominal surgery

■

Surgical technique and manipulation of the bowel

■

Presence of pus, infection, and sepsis

■

Extended opioid use

■

Inhaled anesthesia

■

Preexisting GI disease

■

Stress and inflammatory mediators (in addition to the physiologic stress of surgery)

■

Inactivity

5

OAPN Causes and Pathophysiology

The enteric nervous system (ENS) is the neural network that supplies the digestive tract and mediates the complex reflex activity in the GI tract independently of the central nervous system (CNS). The ENS processes information from sensory receptors, regulates neural reflex activities, and coordinates the complex motor patterns in the GI tract that are responsible for mixing and propulsive movements and the secretory functions. Extrinsic neural pathways also connect with the ENS and modulate OAPN its function. Extrinsic sensory neurons travel in spinal and vagal afferent nerves, transmitting information to the CNS. Efferent fibers of the sympathetic (inhibitory) and parasympathetic (excitatory) nervous systems synapse with nerve fibers in the ENS and modulate motor activity. Therefore, because of its complex interconnecting neural networks and sophisticated functions, the ENS is often referred to as the brain of the GI tract.6,7 Three types of neurons mediate the regulation of ENS functions: sensory neurons, interneurons, and motor neurons (Fig. 2). Enteric sensory neurons receive sensory information from sensory receptors in the intestinal epithelium, mucosa, and muscle.6,8 Interneurons serve as conduits between the sensory and motor neurons and between different motor neurons to allow the ENS to function as an intercommunicating network in the intestinal plexuses. Excitatory and inhibitory motor neurons work in concert to mediate effective peristalsis through interaction and control of smooth muscle cells, epithelial cells, glands, and blood 6

POSTOPERATIVE ILEUS

Central nervous system Central autonomic neural network

Nodose ganglia

Dorsal-root ganglia Sympathetic ganglia

Parasympathetic nervous system

Sympathetic nervous system

STATIN GUIDE

Parasympathetic ganglia

Enteric nervous system (myenteric plexus, submucous plexus)

Intermediate cells

Effector systems (muscle, secretory epithelium, endocrine cells, vasculature)

Figure 2. Innervation of the gastrointestinal tract. Reprinted with permission from Goyal RK, Hirano I. The enteric nervous system. N Engl J Med. 1996;334:1106–1115.

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OAPN vessels. The inflammatory response to manipulation of the intestines during abdominal surgery can also influence GI motility.6–8 Common causes of POI include the following: Activation of inhibitory spinal reflex arcs. This results in an imbalance between the efferent fibers of the sympathetic (inhibitory) and parasympathetic (excitatory) nervous systems and the nerve fibers in the ENS, resulting in reduced bowel contraction.9 Surgical stress response and generation of endocrine OAPN and inflammatory mediators. Numerous chemical mediators and neurotransmitters are found in the ENS; more than 20 candidates have been identified (Table 2). Neurotransmitter functions have been clearly defined in some of them, including acetylcholine, substance P, vasoactive intestinal polypeptide, and nitric oxide.6 Surgical manipulation of the bowel. Extensive surgical manipulation is often associated with a greater likelihood of POI. A longer duration of surgery, especially in the presence of infection and sepsis, increases the risk for developing POI. Stimulation of opioid receptors. Endogenous opioids are released as part of the stress response in the postoperative period. Exogenous opioids are the most potent and commonly used analgesics for the control of postoperative pain. Both types of opioids activate the same receptor sites and affect a variety of GI functions, including motility, secretion, and transport of electrolytes and fluids. Opioids 8

POSTOPERATIVE ILEUS

Table 2. Chemical Mediators and Neurotransmitters Found in the Enteric Nervous System Amines Acetylcholine Norepinephrine Serotonin (5-hydroxytryptamine) Amino acids γ-Aminobutyric acid Purines ATP Gases Nitric oxide Carbon monoxide

STATIN GUIDE

Peptides Calcitonin gene–related peptide Cholecystokinin Gastrin-releasing peptide Neuropeptide Y Neurotensin Opioids ■

Dynorphin

■

Enkephalins

■

Endorphins

Somatostatin Substance P Vasoactive intestinal polypeptide

9

OAPN have been shown to profoundly inhibit peristaltic activity and delay gastric emptying and intestinal transit, and they play an important role in precipitating prolonged POI. Receptor-binding studies and advances in recombinant DNA methods have led to the identification of three main classes of opioid receptors—μ, δ, and k—as well as subtypes within each class. The activation of μ receptors in the brain (μ1) and spinal cord (μ2) is responsible for the analgesia induced by morphine and most other opioids used clinically. In addition, μ2 receptors are present in the brain stem as well as in the GI tract; they mediate the OAPN side-effect profile. Activation of μ2 receptors results in respiratory depression and reduced GI motility.9,10

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POSTOPERATIVE ILEUS

Diagnosis and Clinical Features

Symptoms include the following: ■

Abdominal pain and cramping

■

Delayed passage of flatus and stool

■

Increased postoperative pain and cramping

■

Increased nausea and vomiting

■

Increased risk of aspiration

■

Delay in resuming oral intake and possible need for parenteral nutrition

■

Delay in postoperative mobilization

STATIN GUIDE

Signs include the following: ■

Abdominal distension

■

Abdominal discomfort

■

Absence of bowel sounds

■

Tympany on abdominal percussion

■

Tachycardia and oliguria due to sequestration of fluid in the gut

■

Delayed absorption of oral medications

■

Delayed nourishment resulting in hypoalbuminemia, poor wound healing, and reduced immune function

11

OAPN DIAGNOSTIC TESTS AND IMAGING

A plain radiograph may be helpful. It may show dilated, airfi lled loops of small and large bowel, but this is a nonspecific fi nding and by no means diagnostic. Computed axial tomography (CT) and/or upper GI contrast studies as well as endoscopy are useful in the rare situation that it becomes necessary to differentiate an ileus from a mechanical bowel obstruction. Laboratory fi ndings are usually unremarkable but may show metabolic acidosis. OAPN DIFFERENTIAL DIAGNOSIS It is important to rule out other conditions that may mimic POI. Evidence of newly developed bowel obstruction due to adhesions, inflammation, or intussusception warrants rapid assessment and management. Other differential diagnoses include sepsis and Ogilvie syndrome (pseudo-obstruction).

12

POSTOPERATIVE ILEUS

Prevention NASOGASTRIC INTUBATION

Although traditionally the mainstay of treatment, recent studies have shown that nasogastric decompression does not shorten time to fi rst bowel movement or decrease time to adequate oral intake. Furthermore, inappropriate use may contribute to postoperative complications such as fever, pneumonia, and atelectasis.11 FLUID ADMINISTRATION

STATIN GUIDE

Goal-directed fluid administration, fluid restriction, and the type of fluid have been shown to affect postoperative bowel function. Goal-directed fluid administration during the perioperative period has been shown to shorten the time to resumption of bowel function.12 In a clinical study, goaldirected fluid therapy targeting maximum stroke volume was shown to shorten the time to tolerance of an oral solid regimen by an average of 2 days, with a subsequent shorter hospital stay.13 Another study found better GI mucosal perfusion using a goal-directed fluid administration approach.14 Interestingly, some recent studies have found that “fluid restriction” was associated with more rapid recovery of bowel function after colorectal surgery.15,16 Holte et al.,17 on the other hand, found that a “liberal” fluid regimen led to a transient improvement in pulmonary function and postoperative hypoxemia; patients tended to have lower morbidity rates and a shorter total hospital stay. This apparent discrepancy may be related to the defi nition of terms used. 13

OAPN SURGICAL TECHNIQUE

Laparoscopic procedures offer the theoretical advantage of decreased tissue trauma compared with open procedures, which may lead to faster recovery of postoperative bowel function. Delaney et al.18 found that laparoscopic colectomy, compared with open colectomy, was associated with shorter intensive care unit and total hospital stays, fewer complications, lower mortality rates, fewer readmissions, and less use of skilled nursing facilities after discharge. However, there was a small but significant increase in reoperation rates and OAPN costs with laparoscopic colectomy. in-hospital ANESTHETIC TECHNIQUES

The use of inhalational agents for general anesthesia can inhibit bowel motility. In addition, the use of anticholinergics (e.g., atropine) can also contribute to impairment of bowel motility. However, it is less clear whether the effects delay recovery of bowel function in the postoperative period. An epidural with local anesthetics can block afferent and efferent inhibitory reflexes, increase splanchnic blood flow, and have anti-inflammatory properties. It also blocks the afferent stimuli that trigger the endocrine metabolic stress response to surgery and thus inhibit the catabolic activity.19 The site of the epidural and the drug choice delivered via the epidural route appear to be important factors. Midthoracic epidurals with bupivacaine significantly reduced ileus compared to systemic opioid therapy in patients undergoing laparoscopic and open colectomy 14

POSTOPERATIVE ILEUS

procedures.20 However, lumbar epidural administration has not been shown to have beneficial effects on postoperative ileus. Local anesthesia (bupivacaine) alone reduces the duration of postoperative ileus. In contrast, epidural opioids may not block transmission in somatic or sympathetic nerves and may thus be intrinsically less effective in reducing ileus than local anesthetics. Furthermore, epidural opioids may directly inhibit GI motility.19 A recent meta-analysis of 16 trials showed the efficacy of epidurals in improving analgesia and decreasing POI after colorectal surgery; however, there was also an increased incidence of pruritus, urinary GUIDE retention, and hypotension, with no differenceSTATIN in the length in hospital stay.21 PSYCHOLOGICAL FACTORS

Several studies have attested to the value of psychological preparation for patients undergoing major bowel procedures. One study showed that preoperative positive suggestions reduced both POI and the hospital stay.22

15

OAPN Current Pharmacological Options for Treatment and Management

Table 3 summarizes treatment options for POI. NONSTEROIDAL ANTI-INFLAMMATORIES AND OTHER ANTI-INFLAMMATORY AGENTS

Nonsteroidal anti-inflammatory drugs (NSAIDs) may improve POI by reducing the amount of opioid needed by 20% to 40%. The reduction in opioid use translates into a reduction in opioid-related side effects (e.g., nausea and vomiting, OAPN pruritus, and bowel dysfunction).23 SYMPTOM RELIEF WITH HYDRATION AND NASOGASTRIC TUBE

Because oral ingestion of fluid is not possible, intravenous fluid administration is necessary to maintain adequate hydration. Although the insertion of a nasogastric tube has not been proven to be an effective way of treating POI, it is often used to decompress the bowel and provide symptomatic relief. PROKINETIC AGENTS

Metoclopramide hydrochloride is a prokinetic agent that acts as a cholinergic agonist and a dopamine antagonist. However, almost all of the trials conducted to date have failed to show any benefit in the treatment of POI.24,25 Erythromycin, a macrolide antibiotic, is a motilin receptor agonist that binds to GI smooth muscle membrane receptors, 16

POSTOPERATIVE ILEUS

Table 3. Treatments for Postoperative Ileus Treatment

Benefits

Nasogastric tube

■

Possible relief of vomiting and bloating

Drawback ■

■

Early postoperative feeding

■

■

Stimulates reflex for propulsive bowel motility Earlier resumption of bowel function and earlier hospital discharge

■

Does not affect the duration of POI May contribute to fever and atelectasis Patients may not tolerate feeding

STATIN GUIDE

Laparoscopic procedures

■

Earlier return of bowel function and earlier hospital discharge

■

Not all surgical procedures are amenable to the laparoscopic approach

Goal-directed fluid administration

■

Earlier return of bowel function and earlier hospital discharge

■

May need additional hemodynamic monitoring

Local epidural anesthetic/ analgesics

■

Reduced duration of ileus compared to epidural and systemic morphine Increases splanchnic blood flow Blocks afferent and efferent sympathetic inhibitory input Anti-infl ammatory

■

Complications associated with epidural catheters

May shorten duration of POI Inexpensive

■

Clinical data proving effectiveness are lacking

■

■

■

Laxatives

■

■

17

OAPN

Table 3. continued Treatment

Benefits

Nonsteroidal anti-infl ammatory drugs

■

Drawback

Decreased amount of opioid needed for postoperative pain management May increase motility by acting as an anti-infl ammatory

■

Possible increased risk of postoperative bleeding and renal dysfunction in high-risk patients

Inexpensive Some studies show reduction in POI

■

■

Clinical data proving effectiveness are lacking

Prokinetic agents (cisapride, erythromycin, metoclopramide)

■

Inexpensive

■

Clinical data proving effectiveness are lacking

Gum chewing

■

May shorten duration of POI Simple, inexpensive, few side effects

■

Does not defi nitively reduce length of hospital stay

Inexpensive

■

Clinical data proving effectiveness are lacking

■

Clinical data proving effectiveness are lacking Potential side effects

■

Therapeutic suggestions

■

OAPN

■

Anticholinergic

■

Others (ceruletide, octreotide) P eripheral opioid antagonists (alvimopan, methylnaltrexone)

■

■

■

Do not cross blood– brain barrier and thus do not antagonize analgesia Favorable side-effect profi le when used in short term

■

Early studies show promise: reduced duration of POI, lower incidence of nasogastric tube reinsertion, and earlier hospital discharge

Adapted from Luckey A, Livingston E, Tache Y. Mechanisms and treatment of postoperative ileus. Arch Surg. 2003;138:206–214.

18

POSTOPERATIVE ILEUS

displacing the endogenous ligand motilin. In prospective, randomized clinical trials, erythromycin did not appear to resolve POI.26,27 Cisapride is a serotonin agonist that facilitates acetylcholine release from the intrinsic plexus. Its effectiveness in the treatment of POI is equivocal, and it has been withdrawn from the market due to deleterious side effects.28 CHEWING GUM

Gum chewing provides the benefits of GI stimulation without STATIN GUIDE the complications associated with feeding. The use of gum chewing to reduce POI had been studied in a few randomized, controlled trials, and the results were confl icting. Two recent systematic reviews concluded that gum chewing significantly reduces the time to fi rst flatus and bowel opening and showed a trend toward a shorter hospital stay.29,30 ANTICHOLINERGIC OR CHOLINERGIC DRUGS

Neostigmine is a reversible inhibitor of acetylcholinesterase and as such has been investigated as a potential treatment for POI. Kreis et al.31 found that neostigmine therapy significantly increased colonic motility in the early postoperative period in patients undergoing colorectal surgery. However, a recent systematic review concluded that more studies are needed to confi rm the fi nding.28

19

OAPN LAXATIVES

Laxatives may shorten the duration of POI, but good clinical evidence for their efficacy is lacking. μ-OPIOID ANTAGONISTS

Nonselective μ-opioid receptor antagonists have not been shown to reduce POI. Moreover, their readiness to cross the blood–brain barrier may antagonize analgesia, and hence their use is limited.32 OAPN

OTHER DRUGS

Ceruletide is a synthetic peptide that may enhance GI motility by acting as a cholecystokinin antagonist. It can cause nausea and vomiting, which may limit its clinical effectiveness.33 Octreotide is an analogue of somatostatin that is known to inhibit the secretion of many GI hormones. Octreotide therapy shortens the duration of ileus in animal models, but clinical studies are needed to prove its efficacy in humans.34

20

POSTOPERATIVE ILEUS

Nonpharmacological Therapies EARLY FEEDING

Early postoperative enteral feeding via oral or nasogastric administration has been suggested as a way to decrease the duration of POI. The rationale for early enteral feeding is that food intake can potentially stimulate a reflex that produces coordinated propulsive activity and elicit the secretion of GI hormones, causing an overall positive effect on bowel motility. The role of early enteral feeding remains unclear, although a recent fast-track approach incorporating early STATIN GUIDE feeding appears to be beneficial.35 Fast-Track Recovery Protocol Numerous studies have shown that multimodal fast-track recovery protocols reduce the incidence and duration of POI and shorten length of hospital stay. These protocols may include the use of the laparoscopic approach, or a transverse or curved surgical incision in an open procedure, preoperative carbohydrate loading, a midthoracic epidural using local anesthetic infusion, reduced opioid use by incorporating analgesic adjuncts (e.g., NSAIDs, acetaminophen, gabapentin, pregabalin, ketamine, and dexmedetomidine), early postoperative enforced feeding, laxative use, and early mobilization the day after surgery.35,36 Younger patient age and increased surgeon experience appear to lead to better results using a fast-track recovery pathway.37

21

OAPN Concerns about fast-track recovery protocols include an increased risk of readmission and the potential transfer of health-care burden to home nurses and family doctors. However, recent data suggest that planned discharge on the third day after segmental colonic resection can reduce the readmission rate, and postoperative fatigue can be reduced by early resumption of normal activities after fast-track colonic resection, without an increased need for other health-care support.35 OAPN

22

POSTOPERATIVE ILEUS

Emerging Pharmacotherapies PERIPHERALLY ACTING μ-OPIOID ANTAGONISTS

The peripherally acting μ-opioid receptor antagonists alvimopan and methylnaltrexone were designed to mitigate the peripheral GI-related adverse effects of opioids while preserving analgesia centrally. At clinically relevant concentrations, alvimopan and methylnaltrexone do not readily cross the blood–brain barrier into the CNS. Alvimopan is a high-molecular-weight zwitterion with high polarity and binds with avid affi nity to μ-opioid receptors. STATIN GUIDE Compared with methylnaltrexone it has a higher affi nity for and slower dissociation rate from the μ-opioid receptor in vitro (Fig. 3). It is given orally at 12 mg twice a day. Alvimopan has limited bioavailability and is rapidly absorbed after oral administration. It is converted by intestinal microflora to an active metabolite, which is not required for its efficacy. It is excreted into the bile and is then eliminated in the feces. The efficacy of alvimopan in GI recovery after laparotomy for bowel resection or hysterectomy has been examined in a number of clinical trials. Alvimopan 12 mg when administered preoperatively was associated with an accelerated recovery of bowel function (time to fi rst toleration of solid food and fi rst bowel movement) by about 24 hours. Average length of stay was 1 day shorter in patients who received alvimopan, and the proportion of patients with postoperative nasogastric tube insertion was lower in the alvimopan-treated group than in the placebo group (5.0% vs. 14.8%).38,39 23

OAPN H

A

N HCI HO

O

HO B

O

D

HO N⫹

OH

O

OAPN

Me N

OH O

C

HO

O

NH OH

N O

O H

HO

Figure 3. Structural formulas of (A) naltrexone, (B) methylnaltrexone, (C) morphine, and (D) alvimopan. Copyright © 2000, 2001, 2002, Free Software Foundation, Inc.,51 Franklin St, Fifth Floor, Boston, MA 02110–1301, USA.

24

POSTOPERATIVE ILEUS

Methylnaltrexone is a highly polar derivative of the opioid antagonist naltrexone. Unlike naltrexone, methylnaltrexone does not readily cross the blood–brain barrier because of the substitution of a polar methyl group. Methylnaltrexone can be metabolized to naltrexone by demethylation; however, this does not appear to occur appreciably in humans at clinical doses. Approximately 40% to 60% of methylnaltrexone is excreted in the urine within 24 hours of intravenous administration. A recent preliminary study suggests that the mean time to fi rst toleration of solid food or fi rst bowel movement was STATIN GUIDE accelerated by 27 hours and the mean time to eligibility for hospital discharge was accelerated by 30 hours in the methylnaltrexone group compared with the placebo group.40 The drug (0.3 mg/kg) was mixed with saline and administered by an intravenous infusion over 20 minutes starting in the recovery room QID. Both these drugs were well tolerated, and side effects such as abdominal cramps and distension were self-limiting. There was no increase in the use of opioids in the presence of alvimopan or methylnaltrexone. Alvimopan has recently been approved in the United States for the prophylactic treatment of in-hospital POI in open colorectal surgery. The administration of a pill is a simple and appealing approach to the treatment of POI. Methylnaltrexone is currently in Phase III clinical development programs and is not available for use in POI. As these drugs are new, their defi nitive role in the management of POI will be more clearly defi ned with more clinical trials and experience. 25

OAPN Conclusions

POI is an important health-care problem that causes significant morbidity and is associated with prolonged hospital stays. Because the etiology of POI is multifactorial, the most successful approach for managing POI may be a multimodal fast-track approach that could include a variety of components, such as early mobilization and feeding, enhanced anesthetic and surgical techniques, and pharmacologic agents (e.g., thoracic epidurals, opioid-sparing techniques, laxatives, and the use of peripheral opioid antagonists). Peripheral opioid antagonists are an emerging class of drugs; OAPN in clinical tests to date they appear well tolerated and did not appear to compromise centrally mediated opioid analgesia. Achieving an effective management strategy for POI requires the involvement of a multidisciplinary team including surgeons, anesthesiologists, nurses, and other healthcare personnel. REFERENCES 1. Bennett-Guerrero E, Welsby I, Dunn TJ, et al. The use of a postoperative morbidity survey to evaluate patients with prolonged hospitalization after routine, moderate-risk, elective surgery. Anesth Analg. 1999;89:514–519. 2. Livingston EH, Passaro EPJ. Postoperative ileus. Dig Dis Sci. 1990;35:121–132. 3. Healthcare Cost and Utilization Project (HCUP). 2003 National Statistics. 4. Senagore AJ. Pathogenesis and clinical and economic consequences of postoperative ileus. Am J Health System Pharm. 2007;64:S3–7. 26

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