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ole of Pharmacologic Agentsn Treating Postoperative Ileusnut Magne Augestad, MD,*,† Fabien Leblanc, MD,*,‡ and Conor P. Delaney, MD, PhD*

All patients develop postoperative ileus (POI) after major abdominal surgery, with approx-imately 10% developing a more severe form of prolonged ileus. POI represents the singlelargest factor influencing length of stay after abdominal surgery and has the great impli-cations for patients and resource use in health care. New methods to treat and decreasethe duration of POI are therefore of great importance. Up to the year 2000, severalpharmacologic agents had been studied to prevent POI, however none of these agentswere effective enough to become part of routine established practice. Over the pastdecade, significant progress has been made treating POI pharmacologically. This articleoutlines the different pharmacologic options that exist for POI, with emphasis on theresearch during the past decade and future perspectives.Semin Colon Rectal Surg 21:153-159 © 2010 Elsevier Inc. All rights reserved.

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ll patients undergoing bowel resection develop an oblig-atory period of postoperative ileus (POI).1-4 POI is char-

cterized by a transient cessation of bowel function with aariable reduction in motility sufficient to prevent effectiveransit of intestinal contents.5 POI is the single most impor-ant determinant of length of stay (LOS) after abdominalurgery and thus has significant implications for individualatients and hospital resource use.Surgeons have discussed POI for more than 2 centuries.6,7

n 1906, Finney divided POI into 3 subgroups according toathophysiology: mechanical, septic, and adynamic.8 After aentury of debate a consensus conference in 2006 proposed aefinition of POI as “transient cessation of coordinated bowelotility after surgical intervention, which prevents effective

ransit of intestinal contents or tolerance of oral intake.”5

rimary POI was defined as such cessation occurring in thebsence of any precipitating complication, whereas second-ry POI was defined as that occurring in the presence of arecipitating complication (anastomotic leak, pneumonia,

University Hospitals Case Medical Center, Division of Colorectal Surgery,Cleveland, OH.

University Hospital North Norway, Department of Digestive Surgery,Tromsø, Norway.

University Hospital of Bordeaux, Department of Surgery, Bordeaux,France.

inancial support: North Norwegian Health Authorities Research Fund.ddress reprint requests to Conor P. Delaney, MD, PhD, FRCSI, FACS,

Division of Colorectal Surgery, University Hospitals Case Medical Cen-ter, 11100 Euclid Avenue, Cleveland, OH 44106-5047. E-mail: conor.

fldelaney@UHhospitals.org

043-1489/$-see front matter © 2010 Elsevier Inc. All rights reserved.oi:10.1053/j.scrs.2010.05.006

tc.). Patients undergoing major abdominal surgery are atighest risk for developing POI.Clinically, POI is characterized by an inability to tolerate a

olid diet, delayed passage of flatus and formed stool, pain,nd abdominal distention, nausea, vomiting, and accumula-ion of gas or fluids in the intestine.9,10 Numerous surgical,nesthetic, and postoperative strategies have been exploredo limit POI. These include laparoscopic surgery, epiduralnesthesia, opioid-sparing regimens, early feeding, and earlymbulation. Often several interventions are combined into afast track protocol” that has been collectively shown to fur-her decrease POI and LOS.11 Up to the year 2000, severalharmacological agents had been studied in order to preventOI, however none of these agents were effective enough toecome part of routine established practice.12-24 Several phar-acologic agents, including albumin,25 �-blockers,26 eryth-

omycin,22 gum chewing,27-30 and metoclopramide,17 haveeen studied in this setting. Two new drugs, both peripheral-opioid receptor antagonists, methylnaltrexone and alvi-opan, have recently been evaluated for POI. The objective

f this article is to highlight the pharmacologic treatment ofOI, with a focus on past and present research.

athogenesis of POIharmacologic treatment of POI cannot be discussed withoutgood understanding of the physiology of POI. Normal

owel function involves a complex interaction between gas-rointestinal motility, mucosal transport, and defecation re-

exes. Motility of the intestines is dependent on the electro-

153

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154 K.M. Augestad, F. Leblanc, and C.P. Delaney

hysiologic activity of smooth muscle cells, neural inputrom the intrinsic and autonomic nervous system, hormonalnteractions, and coordinated smooth muscle activity.31 The

igrating motor complex (MMC) has a central position in theormal gut motility.32,33 The MMC is divided into 4 phasesnd regulates gut motility (contractile pattern) betweeneals.34 In addition, the nervous system (enteric and cen-

ral),35 hormones,36 and smooth muscle activity play roles.ngestion of food activates these mechanisms and turns offhe MMC contractile pattern. The interactions between theseegulatory components are complex and much is unknown.ontractions in the colon differ from the small intestine, with

rregular oscillations and contractile patterns.33,35 Althoughultiple factors are thought to contribute to the pathogenesis

f POI, 4 major pathways have been identified (Fig. 1): neu-ogenic, inflammatory, hormonal, and pharmacologic.

lvimopanlvimopan is an orally administered, selective peripherallycting �-opioid receptor antagonist. The medication blockshe peripheral �-receptor with high affinity, therefore mini-izing the paralytic effect opiates have on the intestines (Fig. 1).his molecule is large and polar and therefore does not cross

he blood-brain barrier or impair analgesia. During the last 5ears, a series of randomized controlled trials have been con-ucted to evaluate the effectiveness of lAvimopan at reducingOI.37-42 In each trial performed in the USA, recovery of theowel function was enhanced. In 1 trial performed in Eu-ope, no acceleration of gastrointestinal function occurred,ikely related to the lower opioid doses being used. The pri-

ary endpoints in these trials were time to recovery of gas-rointestinal function, measured as either GI-2 or GI-3, com-osite measures that were developed to track recovery ofpper and lower gastrointestinal function. In these trials GI-2

Figure 1 Pathogenesis of postoperative ileus. Four major pileus. Pharmacologic treatment must be aimed at thesbinding to �-receptors in the GI tract, result in disorganaddition, activation of opioid receptors, which occursrelease, reduces gastrointestinal motility, and has beenAlvimopan inhibits these effects by blocking the pherip

as defined as “the time that the patient first tolerated solid h

ood and had passed a bowel movement.” GI-3 was defineds “the time that the patient first tolerates solid food, and theatient first passes flatus or a bowel movement.” The USood and Drug Administration approved alvimopan in 2008Table 1). All the randomized controlled trials (RCT)hoose GI-3 as their primary endpoint for gastrointestinalecovery, except the study by Ludwig et al, as the collab-rative study group had noted GI-2 to be a more robustndpoint. GI-3 uses documentation of passage of flatus asn additional endpoint, which can be subject to consider-ble variability,43 since the patient has to be conscious andilling to report it. Thus, it was advocated that GI-2 is aore objective endpoint.37 In the trial by Ludwig et al,I-2 recovery was primarily driven by time to first bowelovement, as this was the later occurring of the 2 compo-ents of GI-2 recovery.37 In the RCT trials there are nobvious dose response curves for alvimopan, although aose of 12 mg provided somewhat more consistent resultshrough the trials and became the US Food and Drugdministration-approved dose (Table 1). This phenome-on is common for new drugs, particularly biologicalgents, where effects on a receptor are not directly relatedo the concentration of the agent. These discrepancies maylso be attributed to differing patient populations. How-ver, a pooled analysis has shown that a 12-mg dose pro-ided more consistent benefits across both sexes and allges.38

Alvimopan has had fewer side effects than placebo. Treat-ent adverse events reported in the published RCT trialsere most commonly nausea and vomiting, but these were

ess common in the alvimopan-treated groups.44 All studiesf alvimopan have been conducted for open abdominal sur-ery. Whether there is an additive effect on GI recovery oflvimopan in combination with laparoscopic surgery and en-

ys are identified as contributing factors of postoperativeways. **Primarily exogenous opioids, eg, morphine,nd nonpropulsive motility, and, thus, prolong ileus. Ining major abdominal surgery, inhibits acetylcholinestrated to play a key role in POI regulatory pathways.pioid � receptor.

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Role of pharmacologic agents in treating postoperative ileus 155

ethylnaltrexoneethylnaltrexone has been shown to antagonize the inhibi-

ory effects of opioids on GI transit without impairing anal-esia. Methylnaltrexone, like alvimopan, is a peripheral �-re-eptor antagonist. It was approved for the treatment ofpioid-induced constipation in patients who are receivingalliative care, when response to laxative therapy is insuffi-ient.45 It is contraindicated in patients who have known oruspected mechanical gastrointestinal obstruction. Whileethylnaltrexone significantly improved POI in a phase 2

tudy, it failed to meet its primary or secondary endpoints inphase 3 trials.45,46 Preliminary results from the two com-

leted trials indicate that methylnaltrexone was not betterhan placebo. Further analyses of these data, clinical trialesigns and the various dosage forms are necessary to deter-ine the potential role of methylnaltrexone in the treatment

f POI.47,48

hewing Gumhewing sugarless gum following elective intestinal resection

s associated with improved outcomes. Gum chewing ishought to promote physiologic simulation of the cephalic-agal axis, thereby increasing bowel motility and gastrointes-inal stimulation.29,30,49 There exist 2 meta-analyses analyzinghe effects of chewing gum28,50; however, all the includedrials in these meta-analyses were small, and only 2 trials hadn adequate sample size calculation.

The meta-analysis showed an improvement in first time toowel movement of 23 hours and a reduction in LOS of 1.1ays. An adequately powered, methodologically rigorousrial of gum chewing is required to confirm if there are anyenefits.51

lbuminhe use of albumin has been evaluated in 1 study.25 Patients

able 1 Overview of RCT Trials 2004-2008 of Alvimopan

AuthorNumber ofPatients

PrimaryEnd Point

GI-2Improvem

olff et al41 510 GI3 20a

28b

iscusi et al40 666 GI3 16.413.7

elaney et al39 451 GI3 15.210.5

udwig et al37 654 GI2 20b

uchler et al42 911 GI3 14.310.7

CO: discharge order; Hazard ratio: the ratio of 2 hazard rates (haznot available; GI-2: The time to recovery of GI function, a compothe patient first tolerated solid food and time that the patient firscomposite end point that represents full upper and lower recoverfirst passes flatus or a bowel movement.

6 mg Alvimopan.12 mg Alvimopan.

ndergoing abdominal aortic aneurysm resection or aor- e

oiliac or aortofemoral bypass grafts are almost uniformlyypoalbuminemic postoperatively and a prospective, ran-omized clinical study was undertaken to identify the role oferum albumin concentration on the length of POI in thisopulation. The study was single blind and did not include aower calculation in its design and a small sample size wassed (69 patients). Return of bowel function was measuredy first time to flatus (GI3), as well as the postoperative dayral intake was resumed. Mean values were determined forach group, and t tests did not reveal a significant differencen time to flatus or postoperative oral intake. Use of albuminid not appear to reduce the time to first flatus, time to firstral intake, or LOS. In addition, the study did not evaluatehe effect of albumin on time to first bowel movement (GI3),more objective endpoint.38

eta-Blockershe effect of beta-blockers on POI has been evaluated in twomall studies in patients undergoing cholecystectomy andolectomy.21,26 As inhibition of intestinal motility is thoughto be mediated in part by a- and b-adrenoceptors, and pro-ranolol had been found to enhance intraluminal pressure inealthy volunteers, it has been postulated that b-adrenocep-or antagonists might prevent POI following abdominal sur-ery. Patients were randomized to either placebo or propran-lol in different dosages. Propranonol shortened the meanime to first bowel movement but not the time to the passagef first flatus. In the study conducted upon patients under-oing cholecystectomy, treatment with a combination of pro-ranolol and neostigmine shortened the duration of postop-rative paralytic ileus. Despite the promising results, nourther surveys have been conducted on the effect of pro-ranolol on POI.

isacodylisacodyl is a laxative that stimulates colonic peristalsis. The

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7.5b 1.28b 7.2b

16b 1.5b 17b

8.5a 1.18a 8.1a

4.8b 1.37b 5.9b

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156 K.M. Augestad, F. Leblanc, and C.P. Delaney

le-blind, placebo-controlled trial involving 169 patients un-ergoing open or laparoscopic colorectal resection.52 Primaryndpoint was mean time to first flatus passed, first defecation,nd first solid food tolerated (GI3). Secondary endpointsere incidence and duration of nasogastric tube reinsertion,

ncidence of vomiting, length of hospital stay, and visualnalogue scores for pain, cramps, and nausea. Bisacodyl, sig-ificantly reduced the time to reach the GI-3 endpoint (me-ian 3.0 vs 3.7 days; P � 0.007) and time to first bowelovement (median 3.0 vs 4.0 days; P � 0.001) comparedith placebo. No significant difference in the secondary end-oints was seen. Morbidity and mortality did not differ be-ween groups. The longer duration of nasogastric tube rein-ertion in the treatment group suggests the need for furthertudies.

rythromycinrythromycin (EM), a macrolide antibiotic, has prokineticffects on the gut through binding to gastrointestinal tractotilin receptors.43 Three studies using intravenous erythro-ycin in the prevention of POI have been published.22,53,54

he studies were conducted in a range of surgeries, includingystectomy, colectomy, and cholecystectomy, all studiesere placebo controlled and 2 of these employed a double-lind design. Only 1 of the studies included a power calcu-

ation and this was based on a 2-day reduction in time to firstral intake with erythromycin. No significant difference wasound between EM and placebo with regard to the onset ofowel sounds, passage of flatus, passage of the first bowelovement, and the time to tolerate a general diet. These data

ndicate that erythromycin is not useful in improving post-perative bowel function.

scintudies have shown that escin accelerates gastrointestinalransit in mice and improves gastrointestinal motility in pa-ients after abdominal surgery. Escin, a natural mixture ofriterpene saponins, is extracted from plants, such as driedeeds of the horse chestnut. In China, escin is widely used forhe treatment of postoperative edema, cerebral edema, andhronic venous insufficiency, among other conditions. Re-ently, a randomized, double-blind study from China wasublished.55 Seventy-two patients were randomized to re-eive escin or placebo once daily administered by intrave-ous infusion. Time to passage of gas and time to bowelovement were significantly reduced in the escin group

from 72 to 84 h compared with the placebo group), and theffect was dose dependent. Given the small sample size in thisilot study, additional research is needed.

etoclopramideetoclopramide, a drug derived from procaine amide, has

een shown to be an effective antiemetic agent with proper-ies of enhancing gastrointestinal motility. Metoclopramide

timulates gastrointestinal motility through peripheral and a

entral mechanisms and has been shown to increase gastricontractions and gastric emptying by stimulating smoothuscle contractions in the small intestine, thereby decreasing

ntestinal transit time.43 Several studies with intravenous orntramuscular metoclopramide have been published.17,19,56

urgery included colectomy, cholecystectomy, aortoiliacrocedures, and gynecologic surgery. In addition, several ofhe studies did not assess the effect of metoclopramide onime to first bowel movement (GI2), an endpoint that is morebjective than time to first flatus (GI3). A study published in971 used a nonvalidated scoring system to assess efficacy.57

etoclopramide appears to have no effect upon POI as as-essed by time to first flatus, first bowel movement, and oralntake, as well as LOS.

osaprideosapride citrate (mosapride) is a serotonin 5-hydroxytryp-

amine 4-receptor agonist known to promote gastric empty-ng and large intestine motility by increasing the release ofcetylcholine at parasympathetic nerve-endings. It is com-ercially available only in Japan. A small RCT study evalu-

ted the effect of mosapride in patients undergoing hand-ssisted laparoscopic colectomy, including 40 patients.58

ompared with placebo, mosapride 15 mg 3 times daily byouth significantly reduced the time to first bowel move-ent (mean 48.5 vs 69.3 h; P � 0.015) and length of post-

perative hospital stay (6.7 vs 8.4 days; P � 0.040). Theethodology of this study is, however, disputed.59 It seems

hat although mosapride may be a promising agent, morehorough, placebo-controlled, and longer studies are neededefore scientifically valid conclusions about the efficacy andafety of mosapride in postoperative ileus can be drawn.

etotifenanipulation-induced mast cell activation is recognized as

n important pathophysiologic mechanism contributing toOI. Therefore, mast cell stabilization may represent a newherapeutic approach to shortening POI. In a recently pub-ished RCT, 60 patients undergoing major abdominal surgeryor gynecologic malignancy were randomized to treatmentith ketotifen 4 or 12 mg or placebo. Gastric emptying of

iquids, selected as a primary outcome parameter, was mea-ured 24 hours after surgery using scintigraphy. Ketotifenignificantly improved gastric emptying after abdominal sur-ery and warrants further exploration of mast cell stabilizerss putative therapy for POI.60 This is however the first initia-ive to test the drug in a clinical trial, and further research iseeded to determine the safety and efficacy of ketotifen.

hrelin Agonistshrelin and ghrelin mimetics stimulate appetite and enhanceastric motility. A study investigated whether ipamorelin, aelective growth hormone secretagogue and agonist of thehrelin receptor, would accelerate gastrointestinal transit and

meliorate the symptoms in a rodent model of POI. Fasted

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Role of pharmacologic agents in treating postoperative ileus 157

ale rats were subjected to laparotomy and intestinal manip-lation. At the end of surgery, a dye marker was infused inhe proximal colon to evaluate postsurgical colonic transitime, which was the time to the first bowel movement. Theesults suggest that postsurgical intravenous infusions ofpamorelin may ameliorate the symptoms in patients withOI.61 A first clinical has been published very recently, andhe data suggest that TZP-101, a ghrelin agonist, acceleratesecovery of GI function by 10-22 hours and accelerates timeo hospital discharge by up to 20 hours.62 Further studies areequired; however, the initial results of this dose-finding trialre promising.

ecent Advancesn Animal Modelsntestinal manipulation triggers an inflammatory cascadeithin the muscularis causing POI. In a recent published

tudy the aim was to investigate the recovery and therapeuticotential of interleukin-10 (IL-10) for POI. POI was inducedy bowel surgical manipulation in wild-type and recombi-ant murine IL-10-treated mice. In IL-10 knockout miceompared with the wild type, motility never recovered fromanipulation and mortality rate was 87.5%. In wild types,

omplete functional recovery occurred in 7 days with noortality. Delay in transit and suppression in jejunal circularuscle contractions were significantly improved by IL-10

reatment. Pre-emptive exogenous recombinant humanL-10 could be a treatment for the prevention of clinicalOI.63

ncorporating Theseesults Into Clinical Practice

he basis of all POI research over the past decade has been toeduce the risk of surgery and to minimize pain, require-ents for postoperative hospitalization and rehabilitation.

tandard elective colorectal resection is usually associatedith a complication rate of 20%-30% and a postoperative

able 2 Effect of Pharmacologic Treatment, Laparoscopic Sur

Trials Type of Study Interventio

oble, 200951 Meta-analysis Chewing guelaney, 200738 Pooled analysis Alvimopan

elaney, 200965 Observationalmulticenter study

Laparoscopsurgery

alter, 200964 Meta-analysis ERP

tandard elective open colorectal resection is usually associated wiERP have substantially decreased LOS after surgery.

OS: length of stay; NA: data not available.Defined as GI-3.Defined as GI-2.Discharge order written.

tay of 8-12 days.11 The introduction of pharmacologic treat-

ent, fast track protocols,64 and laparoscopic surgery65 havehanged this perspective, substantially decreasing hospitaltay (Table 2). Review of the pharmacologic options in therevention of POI suggest that gum chewing and alvimopanay be efficacious in patients undergoing colorectal resec-

ions, while albumin, �-blockers, erythromycin, metoclopra-ide, and methylnaltrexone lack data to support their use in

ny setting.66 Ketotifen, Mosapride, Escin, and Ghrelin havell shown promising results in small RCT trials, but furtheresearch is needed to determine the efficacy and safety ofhese drugs.

Although alvimopan is the best studied agent, with repro-ucible results for open surgery, there is still much debatebout using this in clinical practice, and its incorporation intoractice has been less than might be expected.67,68 Several

mportant questions remain unresolved, particularly the ef-ect of alvimopan after laparoscopic surgery and in combina-ion with ERP protocols. Alvimopan requires a significantnvestment per case, and while the number needed to treat,nd financial analyses suggest its use is rational, practicinghysicians have been reluctant to use it widely. In contrast,he cost of acquiring gum is substantially lower, although itsse is supported by far less evidence. Both alvimopan andum have several practical issues around procurement, stor-ge, and administration, and neither has compelling dataemonstrating a reduction in nondrug costs, including LOS.uture POI research should address pharmacologic treat-ent, fast track protocols and laparoscopic surgery, and the

ptimal combination of these interventions, as the complexnterplay of physiologic processes which cause POI likely

ean that its routine and effective prevention will be with aultistep approach.

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ImprovementPassageFlatus (h)

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Movement (h)Decrease in

LOS

14 23 1.1 d12a (6 mg) 15b (6 mg) 18.4 hc

15a (12 mg) 18b (12 mg)NA 0.7 da 1.7 dc

NA NA 3.64 d

of 8-12 days. Pharmacologic treatment, laparoscopic surgery, and

gery,

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ic

th LOS

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8. Delaney CP, Wolff BG, Viscusi ER, et al: Alvimopan, for postoperativeileus following bowel resection: A pooled analysis of phase III studies.Ann Surg 245:355-363, 2007

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