Mechanisms and Treatment of Postoperative Ileus

REVIEW ARTICLE Mechanisms and Treatment of Postoperative Ileus

Andrew Luckey, MD; Edward Livingston, MD; Yvette Tache´, PhD

Objective: To review the pathogenesis and treatment velopment of this entity. These factors include inhibitory of postoperative ileus. effects of sympathetic input; release of hormones, neurotransmitters, and other mediators; an inflammatory Data Sources: Data collected for this review were iden- reaction; and the effects of anesthetics and analgesics. Nu- tified from a MEDLINE database search of the English- merous treatments have been used to alleviate postop- language literature. The exact indexing terms were erative ileus without much success. “postoperative ileus,” “treatment,” “etiology,” and “patho- physiology.” Previous review articles and pertinent ref- Conclusions: The etiology of postoperative ileus can best erences from those articles were also used. be described as multifactorial. A multimodality treatment approach should include limiting the administra- Study Selection: All relevant studies were included. tion of agents known to contribute to postoperative il- Only articles that were case presentations or that men- eus (narcotics), using thoracic epidurals with local tioned postoperative ileus in passing were excluded. anesthetics when possible, and selectively applying nasogastric decompression. Data Synthesis: The pathogenesis of postoperative ileus is complex, with multiple factors contributing ei- ther simultaneously or at various times during the de- Arch Surg. 2003;138:206-214

LEUS IS DEFINED in Dorland’s Illus- end points, and each has its own weak- trated Medical Dictionary simply as ness. Bowel sounds are sometimes used as “obstruction of the intestines.”1 an end point, but they require frequent aus- However, the definition of post- cultation, their presence does not neces- operative ileus, the topic of this re- sarily indicate propulsive activity, and they view, is a bit less clear. In 1990, Living- can be the result of small-bowel activity and I 2 3 ston and Passaro defined ileus as “the not colonic function. Flatus also is not the functional inhibition of propulsive bowel ideal end point. It requires a conscious pa- activity, irrespective of pathogenetic mecha- tient who is comfortable reporting its oc- nisms.” They further defined postopera- currence to the investigator. Also, there is tive ileus as the “uncomplicated ileus oc- some question as to the correlation be- curring following surgery, resolving tween flatus and bowel movements.4 Bowel spontaneously within 2 to 3 days.” Fi- movements are seemingly the most reli- nally, the term paralytic postoperative ileus able end point, although they too may be was defined as that form of ileus lasting nonspecific, representing distal bowel 2 From the University of more than 3 days after surgery. Such a dis- evacuation as opposed to global gastrointes- California at San tinction was necessary because different tinal tract function. In the end, the health Francisco–East Bay, Oakland mechanisms are probably responsible for care provider should assess the patient as (Dr Luckey); the Departments the 2 types of postoperative ileus. It may a whole to determine the resolution of post- of Surgery (Dr Livingston) and be more correct to call postoperative ileus operative ileus. Medicine (Dr Tache´), The a primary ileus in that it is most likely an David Geffen School of inevitable response to surgical trauma. In HISTORY Medicine, and the Bariatric postoperative ileus, inhibition of small- Surgery Program bowel motility is transient, and the stom- The reduction in bowel motility after sur- (Dr Livingston), University of California at Los Angeles, and ach recovers within 24 to 48 hours, whereas gery has been described since the late 1800s. CURE: Digestive Diseases colonic function takes 48 to 72 hours to re- A multiplicity of studies have been pub- 2 Research Center, VA Greater turn. Determination of the end of postop- lished on postoperative ileus, but the patho- LA Healthcare System, erative ileus is somewhat controversial. The genesis remains an enigma (Table 1). Little Los Angeles (Dr Tache´). studies in the literature have used varying advancement in effective treatment regi-

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©2003 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/30/2021 mens has taken place since the introduction of nasogastric decompression. Ileus is a significant medical problem Table 1. Possible Mechanisms of Postoperative Ileus and constitutes the most common reason for delayed discharge from the hospital after abdominal surgery. The eco- Mechanisms Factors Involved nomic impact of ileus has been estimated to be $750 mil- Autonomic nervous system Sympathetic inhibitory pathways lion to $1 billion in the United States.5 More important Enteric nervous system Substance P, nitric oxide Hormones and Vasoactive intestinal peptide; than health care costs is patient discomfort. The symp- neuropeptides corticotropin-releasing factor ligands; toms of postoperative ileus range from cramping and ab- calcitonin gene−related peptide dominal pain to nausea and vomiting. ligands The presence of inhibitory spinal reflexes acting on Inflammation Macrophage and neutrophil infiltration; the bowel was first demonstrated in 1872 by Goltz.6 In cytokines, other inflammatory 7 mediators 1899, Bayliss and Starling determined that the ablation Anesthesia General anesthetics of splanchnic nerves would improve bowel motility af- Narcotics Opiates ter laparotomy. They discovered this by using a device termed the enterograph, which allowed them to study in- tact small-intestinal activity in the unanesthetized dog.7 During the past few decades, numerous reports have been published reaffirming the implication of sympathetic path- The musculature of the stomach is made of cells that ways in postoperative ileus. Over the years, experimen- are intimately associated, allowing them to conduct elec- tal models of postoperative ileus have been developed to trophysiologic functions. There are 3 distinctive electri- assess propulsive bowel motor function. Some of these cal potentials: resting potential; slow-wave or pacesetter models include gastric emptying, small- and large-bowel potential; and spike potential19 that trigger contractions. transit time, and stool pellet output as well as recording However, these potentials can only occur during the slow- changes in bowel motility.8-14 An experimental model us- wave frequency and thus are determined by the pace- ing strain gauge transducers in awake rats has been re- maker. Numerous gastrointestinal hormones affecting ported15 as a method of measuring gastrointestinal mo- gastrointestinal motility have been reviewed recently,20 and tility. Many new theories have been hypothesized to a detailed discussion of this topic is beyond the scope of explain the pathogenesis of postoperative ileus. this review. Gastric motility is thus determined by complex interactions among the electrophysiologic character- NORMAL PHYSIOLOGY istics, neural input, and gastrointestinal hormones. OF GASTROINTESTINAL MOTILITY The colon, whose main purpose is to absorb water and store feces, differs in structure and function from the Normal bowel motility results from complex interactions remainder of the bowel. Measured electrical activity in among the enteric nervous system, central nervous sys- the colon reveals irregular oscillations with varying am- tem, hormones, and local factors affecting smooth- plitude. Colonic smooth muscle does not contain gap muscle activity. Motility in the stomach and small intes- junctions and therefore does not act as a single unit. In tine varies based on whether one is in the fasting or fed humans, 3 electrical activities of colonic motility can be state. Compared with fasting, the fed pattern consists of distinguished: electrical control activity represents continuous low varying-amplitude, ungrouped contrac- smooth-muscle membrane potential oscillations, dis- tions whose number, intensity, and duration depend on crete electrical response activity consists of spike-wave the food ingested (amount and physical and chemical potentials superimposed on the oscillations, and con- composition). However, between meals, the migrating mo- tinuous electrical response activity is not related to os- tor complex (MMC) dictates the contractile pattern of the cillations but is involved with contractions that sweep bowel. The MMC, first described by Szurszewski,16 is be- luminal contents distally.21 lieved to serve a “housekeeper” function by propelling in- traluminal contents distally during the fasting state.17 In PATHOGENESIS humans, these contractions occur approximately once every 1 to 2 hours. Altered Gastrointestinal Motility Four phases are involved in the MMC in the fasted in Postoperative Ileus state. The first phase includes oscillating smooth- muscle membrane potentials without actual muscle In the stomach and the small intestines, normal basal elec- contractions. The occurrence of intermittent muscle trical activity is impaired after surgical procedures. Spe- contractions marks the transition to phase II. During cifically, in the stomach there is an irregular pattern of phase III, the contractions increase to the maximal con- gastric spike and slow-wave activity. In addition, after tractile frequency allowed by the slow wave (approxi- surgery, if patients are not being fed, MMC activity is mately 3 contractions per minute in the stomach and 11 thought to be the “only impetus to bowel contraction.”2 contractions per minute in the duodenum). Phase IV is Therefore, patients who are restricted from taking any- marked by cessation of contractions, and the bowel be- thing by mouth after surgery are also thought to have comes quiescent.18 Feeding is followed by interruption minimally propulsive bowel motility. Various anes- of the MMC and the appearance of a different pattern thetic agents can affect MMC activity. For example, ether consisting of sustained irregular phasic contractile and halothane are inhibitory, whereas enflurane is exci- activity. tatory.22,23 Incising the peritoneum likewise inhibits MMC

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©2003 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/30/2021 activity, and prolonged inhibition is observed after bowel mission, and N␻-nitro-L-arginine, an NO synthase inhibi- manipulation.2 tor, were given alone and in combination. When given The colon’s electrical activity is also disturbed as a re- alone, reserpine significantly increased gastrointestinal tran- sult of surgical procedures. After surgery in monkeys and sit in rats that underwent a skin incision, completely re- humans, there is disruption of the 3 electrical activities de- versed the inhibition caused by laparotomy alone, but only scribed in the previous section.24,25 Continuous electrical partially reversed the inhibition of transit induced by lap- response activity is the last to return to normal (approxi- arotomy, evisceration, and manipulation. In contrast, N␻- mately 72 hours after surgery) and is associated with the nitro-L-arginine administration had no effect on gas- onset of flatus. Although the electrical activity of the gastrointestinal transit altered by the skin incision or by trointestinal tract is disturbed in patients with paralytic postlaparotomy only and partially reversed the negative ef- operative ileus, the return of normal electrical activity does fects on motility caused by laparotomy, evisceration, and not always coincide with resolution of the ileus. manipulation. Given in combination, these drugs showed no additional effects over reserpine therapy alone in the The Role of the Autonomic Nervous System skin incision and laparotomy-only groups; however, administration of these drugs resulted in a complete rever- A balance exists between excitatory and inhibitory input sal of the inhibition of gastrointestinal motility induced in the regulation of bowel motility. Parasympathetic stimu- by laparotomy, evisceration, and manipulation. These re- lation increases gastrointestinal motility, whereas sympa- sults support the involvement of NO release in postop- thetic stimulation is inhibitory. Sympathetic input serves erative ileus. The role of NO in the pathogenesis of post- as the predominant inhibitory impetus to the bowel and operative ileus in humans remains unclear. Experimental provides the efferent limb of numerous reflex pathways. evidence13,35 has shown that antagonists to vasoactive in- Supporting evidence for this concept is based on animal testinal peptide, substance P, and inhibitors of NO syn- experiments26 that demonstrated the predominance of sym- thesis improve postoperative bowel motility. pathetic inhibition following division of the parasympa- Calcitonin gene–related peptide (CGRP) is present thetic (vagal) and sympathetic (splanchnic) neural in- in visceral afferent neurons in the gastrointestinal tract and put. Previous studies have demonstrated sympathetic acts on peripheral receptors to delay gastric emptying and output as a factor in the pathogenesis of postoperative il- gastrointestinal motility in rats.14,36 It is possible that ab- eus. The mechanism of sympathetic inhibition involves dominal surgical procedures stimulate the release of CGRP preventing the release of acetylcholine from excitatory fi- from these neurons, causing inhibition of bowel motility. bers located in the myenteric plexus. Small-bowel post- The administration of CGRP receptor antagonists or mono- operative ileus and delayed gastric emptying are ablated clonal antibodies to CGRP has been shown36 to partially using chemical sympathectomy with 6-hydroxydopam- prevent postoperative gastric ileus in rats. ine.27,28 In addition, intestinal catecholamine stores are de- Endogenous opioids are released after surgery and pleted more rapidly after laparotomy vs no laparotomy.29 have been suggested as a cause of postoperative il- However, sympathetic blockade is not always suc- eus.37,38 Their effects on gastric emptying and intestinal cessful in reversing the inhibition of gastrointestinal mo- smooth-muscle contraction are mediated by the µ-opioid tility induced by abdominal surgical procedures.30 Thus, receptor. Enkephalin is a potent ␦-opioid receptor ago- other mechanisms, such as nonadrenergic noncholin- nist that has been reported to inhibit gastric motility and ergic nerves, are believed to play a role in inhibiting gut increase pyloric tone in animal experiments.39,40 motility after surgery. Corticotropin-releasing factor (CRF) is instrumen- tal in orchestrating the stress response.41,42 A previous study The Role of Neurotransmitters, by Tache´etal43 has shown that the peripheral adminis- Local Factors, and Hormones tration of CRF and CRF-related peptides induces a delay in gastric emptying and an inhibition of gastric motility A variety of neurotransmitters, local factors, and hor- similar to that seen in postoperative gastric ileus. Periph- mones has been proposed to contribute to postoperative eral CRF decreases gastric emptying of a nonnutrient or ileus, although no single factor has been clearly proven nutrient meal in rats, mice, and dogs when administered to be responsible. Vasoactive intestinal peptide causes an intravenously. Similar effects are seen in rats and mice if increase in inhibitory input to the gastric cholinergic neu- the CRF or CRF-related peptides are injected intraperito- rons, creating a decrease in antral and pyloric activity.31 neally or subcutaneously.10,44-50 Furthermore, peripheral Substance P, which is a neurotransmitter involved in pain, injection of a nonselective CRF receptor antagonist be- has also been hypothesized to have a role in postopera- fore laparotomy and cecal palpation completely allevi- tive ileus.32 ates postoperative gastric ileus assessed during the first 3 Nitric oxide (NO) is believed to be the predominant hours after surgery in rats.47,51 In humans, surgical stress inhibitory nonadrenergic noncholinergic neurotransmit- has been associated with an elevation in circulating levels ter of the gastrointestinal tract. It is thought to act through of CRF.52-54 The source of the CRF is unclear. The pep- its constitutive form of NO synthetase within enteric neu- tide is present in the adrenal medulla, and splanchnic nerves rons.33 Researchers30,34 have examined the role of NO in a and hormonal stimulation can trigger its release.55,56 Spe- rat model of postoperative ileus. Rats were assigned to un- cifically, arginine vasopressin that is released in response dergo a skin incision, laparotomy only, or laparotomy, to surgical stress can trigger CRF release. Studies are on- evisceration, and manipulation of the cecum and small going to elucidate the mechanisms by which CRF inhib- intestine. Reserpine, an inhibitor of adrenergic neurotrans- its gastric emptying.

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©2003 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/30/2021 The Role of Inflammation to that of 48 to 72 hours’ duration, as used in other studies. At least 4 studies67,72,74,75 have compared epidural bupiv- In 1998, Kalff et al57 hypothesized that common surgical acaine with epidural opioid, and 3 of these studies dem- procedures performed on the intestine elicit activation of onstrated a significant reduction in the duration of the macrophage network in the muscularis externa and postoperative ileus in the epidural bupivacaine group com- generate leukocyte recruitment. He further proposed that pared with the epidural opioid group. Of the few prospec- this inflammatory reaction is responsible for a period of tive studies72,74,76 comparing the effects of epidural bupiv- postoperative dysmotility.57 In this study, rats were ex- acaine and combined epidural bupivacaine and morphine posed to varying degrees of “gentle” surgical manipula- on recovery from postoperative ileus, epidural bupiv- tion, ranging from a midline laparotomy to “running” of acaine alone seems to be superior without significantly ad- the bowel. Rats that were not subjected to laparotomy or versely affecting pain relief. The location of the epidural anesthesia served as age-matched controls. The results sup- is important; low-thoracic and lumbar epidural adminis- ported their hypothesis in that a progressive increase in tration has not been shown64,72,73,77,78 to have beneficial ef- neutrophil infiltration was seen with increasing degrees fects on postoperative ileus. of bowel manipulation. The authors concluded that their data support the belief that an inflammatory event initi- POSTOPERATIVE NARCOTIC ANALGESIA ated by abdominal surgical procedures is associated with postoperative ileus. However, they also conceded that extra- Opioids have an inhibitory effect on gastric motility and abdominal, surgically induced postoperative ileus is caused also increase tone in the antrum and the first portion of by another mechanism. the duodenum in healthy individuals.79 The effects of opi- Schwarz et al58 found an induction of cyclooxy- ates on the small intestine are slightly more compli- genase 2 (COX-2) messenger RNA and protein in resi- cated. Morphine sulfate has biphasic properties in hu- dent macrophages and a subpopulation of enteric neu- mans: (1) initial effects on motility are stimulatory via rons after laparotomy and intestinal manipulation in rats. activation of MMC phase III, and (2) this stimulation is The increase in COX-2 expression resulted in elevated followed by atony, which is responsible for the slowing levels of prostaglandins in the peritoneal cavity and the of gastrointestinal transit.79,80 Morphine increases the tone circulation. As a result, decreased jejunal circular muscle and amplitude of nonpropulsive contractions and de- contractility was observed in vitro. This effect could be creases propulsive waves in the colon. The additive ef- reversed with administration of COX-2 inhibitors. Cli- fect of these actions is to decrease colonic motility.79 nicians should be cautious in applying this model to hu- However, treatment with the morphine receptor an- mans. Although in rats the small intestine is said to serve tagonist naloxone hydrochloride has proven ineffective as a good model for postoperative ileus, the same does in the treatment of postoperative ileus.2 New µ-opioid not hold true for humans. It would be worthwhile to in- receptor antagonists are being developed and may have vestigate the effects of COX-2 inhibition on postopera- the potential to alleviate opiate-related adverse effects. tive gastric and colonic motility. Methylnaltrexone bromide, a quaternary derivative of nal- trexone, is one such drug. It is poorly lipid soluble and ANESTHESIA therefore does not cross the blood-brain barrier, but it can inhibit the negative effects of opioids on the gut. As All types of anesthesia have an effect on bowel motil- a result, it does not antagonize the central analgesic ef- ity.59 Anesthetic agents exert their strongest effects on the fects of morphine or initiate opioid withdrawl.81 An- region of the bowel that depends most on neural inte- other drug being investigated is the µ-opioid receptor an- gration. Most notably, the large intestine is devoid of in- tagonist ADL-8-2698. Administration of 6 mg of this drug tercellular gap junctions, which makes the colon more shortened the median time to passage of first flatus, the susceptible to the inhibitory actions of anesthetics.2 median time to the first bowel movement, and the length Delayed gastric emptying is observed after expo- of hospital stay in a study82 of 79 patients, of which 15 sure to anesthesia. Atropine, halothane, and enflurane underwent partial colectomy and 63 underwent total ab- all decrease gastric emptying. The consequences of de- dominal hysterectomy. Other experimental studies37 in- layed gastric emptying are possible aspiration, indicate that opioid agonists working at the ␬ receptor may creased risk of postoperative nausea and vomiting, and be beneficial by serving as an analgesic and decreasing delayed absorption of medications.60-62 postoperative ileus. Questions remain about the role of In theory, epidurals with local anesthetics can block these agents in patients not treated with opioids for post- afferent and efferent inhibitory reflexes, increase splanch- operative pain and about whether the beneficial effects nic blood flow, and have anti-inflammatory effects.63,64 Epi- of these agents are seen in patients undergoing other sur- dural anesthetics have the added benefit of blocking the gical procedures. afferent stimuli that trigger the endocrine metabolic stress response to surgery and thus inhibit the catabolic activity TREATMENTS of hormones released during this process.65 In most studies,66-76 thoracic epidurals with bupivacaine hydrochlo- Nasogastric Intubation ride significantly reduced ileus vs systemic opioid therapy in patients undergoing abdominal surgical procedures. In For many years, the nasogastric tube has been the one of the statistically nonsignificant studies,64 an epidu- mainstay of treatment; however, recent studies have ral anesthesia of 24-hours’ duration was used as opposed questioned its routine use. These randomized clinical stud-

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©2003 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/30/2021 ies83,84 conclude that nasogastric decompression does not Many clinicians use laxatives as a treatment for para- shorten time to first bowel movement or decrease time lytic postoperative ileus. No randomized trials evaluat- to adequate oral intake. Furthermore, these studies83,84 ing the role of these agents in paralytic postoperative il- report that inappropriate use may contribute to postop- eus have been conducted, to our knowledge. Conducting erative complications such as fever, pneumonia, and a MEDLINE database search for the key words “laxa- atelectasis. Although these studies do not recommend rou- tives” and “postoperative ileus,” only 1 nonrandom- tine use of nasogastric intubation, the clinician may have ized, unblinded trial was found. This trial consisted of selected cases in which the patient benefits from symp- 20 patients who underwent radical hysterectomy and were tomatic relief. postoperatively treated with 30 mL of milk of magnesia by mouth twice daily and biscolic suppositories every Electrical Stimulation day.103 The median time to flatus and bowel movement was 3 days. The authors observed a 50% reduction in the Given the previous descriptions of abnormal gastrointes- length of hospital stay vs a group of patients from a pre- tinal electrical activity, efforts have been made to use elec- viously reported prospective study103 of patients under- trical stimulation as a corrective measure. An attempt has going radical hysterectomy (4 vs 8 days). This study been made to apply electrical stimulation directly to the should be followed by a randomized, prospective, double- bowel wall in dogs, but this procedure was not success- blind, controlled study to determine the benefit, if any, ful.85 Other studies show that using gastrointestinal pac- of using laxatives. ing in humans is largely ineffective.2 Prostaglandins are known to affect bowel motility. The mechanism of prostaglandin E2 and prostaglandin Early Postoperative Feeding F2, although not entirely clear, seems to be the stimulation of acetylcholine release from myenteric plexus neu- 104 Early postoperative enteral feeding via oral or nasoen- rons. In humans, oral prostaglandin E2 is reported to teric administration has been suggested as a way to de- increase small intestine and colonic transit.2 Further stud- crease the duration of postoperative ileus. The logic be- ies are needed to determine whether there is clinical ben- hind early enteral feeding is that food intake can (1) efit from prostaglandins. stimulate a reflex that produces coordinated propulsive Sympathetic inhibitory input is thought to play a role activity and (2) elicit the secretion of gastrointestinal hor- in the pathogenesis of postoperative ileus.27,28 Thus, based mones, causing an overall positive effect on bowel mo- on existing experimental evidence, human studies at- tility.86 The role of early postoperative enteral feeding re- tempting to induce adrenergic inhibition and cholinergic mains unclear because some studies support and others activation were conducted. These studies105 did not dem- refute its benefit on shortening postoperative ileus.87-91 onstrate resolution of postoperative ileus. Studies106,107 using edrophonium chloride and bethanechol chloride have Laparoscopic Procedures reported improvement in postoperative ileus in humans, but the adverse effects of these agents limit their use. Laparoscopic procedures offer the theoretical advan- Acetylcholine is released from the enteric nervous tage of decreased tissue trauma compared with open pro- system and causes increased gut wall contractility.108 cedures. This decrease in tissue trauma may lead to faster Acetylcholine is degraded in the synaptic cleft by acetyl- recovery of postoperative bowel function. Recently, Leung cholinesterase. Neostigmine is a reversible inhibitor of et al92 found lower levels of cytokines (interleukin 1␤ and acetylcholinesterase and as such has been investigated interleukin 6) and C-reactive protein in patients under- as a potential treatment for postoperative ileus. Kreis et going laparoscopic colon resection compared with those al109 recently found that neostigmine therapy signifi- who had open procedures. Animal studies and clinical cantly increased colonic motility in the early postopera- trials93-96 have found statistically significant decreases in tive period in patients undergoing colorectal surgery. These the duration of postoperative ileus after laparoscopic vs results are encouraging, but the “early postoperative pe- open procedures for colon resection. The exact mecha- riod” is most likely a physiologic ileus, and experiments nism responsible for this improvement in postoperative to determine the effect of neostigmine use on paralytic bowel motility remains elusive. Ongoing research may ileus should be performed. answer this question and give insight into the etiology Metoclopramide hydrochloride is a prokinetic agent of paralytic ileus after open procedures. that acts as a cholinergic agonist and a dopamine antagonist. It initiates MMC phase III activity via its antagonis- Pharmacologic Agents tic actions on dopamine. At least 6 controlled clinical tri- als105-111 have investigated the effect of metoclopramide Nonsteroidal anti-inflammatory drug therapy may im- therapy on patients undergoing abdominal surgical pro- prove postoperative ileus by allowing the clinician to re- cedures. Although the end points used in the studies dif- duce the amount of opioid given by 20% to 30%.97 An fered, none of them had a significant benefit in the treat- additional benefit on bowel motility may be derived from ment of postoperative ileus.110-116 the anti-inflammatory properties of nonsteroidal anti- Erythromycin is a 13-carbon antibiotic belonging to inflammatory drugs.98 In most experimental and clini- the macrolide family. The gastrointestinal adverse ef- cal studies,99-102 giving nonsteroidal anti-inflammatory fects induced by this antibiotic include abdominal cramp- drugs resulted in decreased nausea and vomiting and im- ing, nausea, vomiting, and diarrhea. Erythromycin is a proved gastrointestinal transit. motilin receptor agonist that binds to gastrointestinal

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©2003 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/30/2021 smooth-muscle membrane receptors, displacing the en- cer. Their study design randomly assigned patients to re- dogenous ligand motilin. Erythromycin therapy did not ceive a standard postoperative fluid regimen (3 L of water resolve postoperative ileus in patients who underwent and 154 mmol of sodium per day) or a restricted fluid pro- abdominal surgery in the prospective, randomized clini- tocol (Յ2 L of water and 77 mmol of sodium per day). cal trials conducted.117,118 The primary end points of the study included solid- and Cisapride is a serotonin agonist that facilitates liquid-phase gastric emptying as measured by isotope ra- acetylcholine release from the intrinsic plexus. At least dionuclide scintigraph on the fourth postoperative day, with 9 randomized clinical trials119-127 have been performed on first flatus and bowel movement serving as secondary end patients treated with cisapride for postoperative ileus af- points. The results demonstrated significantly longer solid ter undergoing various surgical procedures. However, and liquid gastric emptying for the standard group vs the comparison of these studies is difficult because various restricted fluid group (solid: 175 vs 72 minutes; liquid: 110 end points were used, patients underwent different sur- vs 73 minutes). Patients receiving restricted fluids passed gical procedures, and the doses, durations, and routes were first flatus 1 day earlier, had the first bowel movement 2.5 variable. In 4 studies,119-122 there was a statistically sig- days earlier, and had a 3-day shorter median length of stay nificant reduction in postoperative ileus. Although these in the hospital than patients receiving standard fluid vol- results are encouraging, just as many studies123,126,127 re- umes (P=.001 for all). The authors concluded that a posi- ported no statistically significant effects. The questions tive salt and water balance significant enough to add 3 kg regarding the effectiveness of cisapride will remain as it of body weight after colonic resection delays gastrointes- has been removed from the market for deleterious side tinal transit and prolongs hospital stay. effects. Ceruletide is a synthetic peptide that may enhance The Multimodel Approach to Postoperative Ileus gastrointestinal motility by acting as a cholecystokinin antagonist.1 A slight reduction in ileus was noted in 2 clini- Of all the treatments available (Table 2), which is best? cal placebo-controlled studies.128,129 Ceruletide therapy The best treatment currently available is a multimodal has the adverse effects of nausea and vomiting, which may regimen. Basse et al135 examined a multimodal rehabili- limit its clinical effectiveness. Further investigation is tation regimen for the treatment of postoperative ileus needed before clinical use can be recommended. consisting of continuous epidural analgesia, early oral nu- Octreotide is an analogue of somatostatin that is trition and mobilization, and cisapride and laxative treat- known to inhibit the secretion of many gastrointestinal ment with magnesia. Using this regimen, the authors ob- hormones. Cullen et al130 showed that octreotide therapy served normalization of gastrointestinal transit time within shortens the duration of ileus in the small intestine and 48 hours of colonic resection compared with matched colon of dogs. However, clinical studies are needed to controls. Gastrointestinal transit time was assessed by an prove its efficacy in humans. indium In 111 pentetate scintigraphic method. The rela- tive contribution of each modality is unknown. This par- Other Treatments ticular approach is less than ideal, given that cisapride is no longer available. Also, ambulation has not been Gum chewing may be a simple but effective treatment shown to improve postoperative bowel motility, al- for postoperative ileus. Asao et al131 conducted a ran- though it is beneficial to patients for other reasons.136 domized, prospective, controlled study on gum chew- Another study137 supporting the multimodal ap- ing as a method to stimulate bowel motility after laparo- proach was conducted on patients undergoing segmental scopic colectomy for colorectal cancer. The patients colectomy. The authors used a regimen that included tho- chewed gum 3 times a day starting postoperative day 1 racic epidural anesthesia for 48 hours, omission of a na- until oral intake. The passage of first flatus was on aver- sogastric tube,1Loffluid orally on the day of surgery, mo- age 1.1 days earlier in the gum-chewing group than in bilization within 8 hours of surgery, use of milk of magnesia, controls (day 2.1 vs 3.2). The first defecation also was and an alteration in the incision (curved or transverse) to significantly earlier in the gum-chewing patients (post- minimize pain and pulmonary dysfunction. Ninety-five of operative day 3.1) than in controls (postoperative day 5.8). 100 patients evaluated defecated in 48 to 72 hours. However, the length of hospital stay was not significantly different between the 2 groups (13.5 vs 14.5 days) SUMMARY and overall was somewhat longer than that reported in the literature. The authors hypothesize that the aid in re- Paralytic postoperative ileus continues to be a significant covery from postoperative ileus achieved by gum chew- clinical problem. The etiology of this process can best be ing may be related to the effects of sham feeding. Sham described as multifactorial. These factors act simulta- feeding causes vagal cholinergic stimulation of the gas- neously or at various times during the development of post- trointestinal tract and elicits the release of gastrin, pan- operative ileus. The mechanisms involved in paralytic post- creatic polypeptide, and neurotensin, all of which affect operative ileus include inhibitory sympathetic input; release gastrointestinal motility.132,133 Further prospective, ran- of hormones, neurotransmitters, and other mediators; an domized controlled studies on the effect of gum chew- inflammatory reaction; and the effects of analgesics. Ex- ing on postoperative bowel motility are warranted. perimental studies continue to elucidate the roles and Lobo et al134 wanted to determine the effect of water mechanisms of action of all of these factors. Numerous and salt balance on the recovery of gastrointestinal tran- methods have been used in an attempt to alleviate post- sit in patients undergoing colonic resection for colon can- operative ileus in the clinical setting, without much suc-

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Treatments Benefits Drawbacks Nasogastric tube • Possible relief of vomiting and bloating • Do not shorten duration of ileus • May contribute to fever and atelectasis Early postoperative feeding • Stimulates reflex for propulsive bowel motility • Data not conclusive • Earlier hospital discharge • Patients may not tolerate feeding Laparoscopic procedures • Earlier return of bowel function and earlier hospital • Not all surgical procedures are amenable to the discharge laparoscopic approach Local epidural anesthetic/analgesics • Reduced duration of ileus vs epidural and systemic • Complications associated with epidural catheters morphine • Increases splanchnic blood flow • Blocks afferent and efferent sympathetic inhibitory input • Anti-inflammatory Gum chewing • May shorten the duration of ileus • Only one small trial that was limited to • Simple and inexpensive laparoscopic colectomy Laxatives • May shorten the duration of ileus • Clinical data proving effectiveness/lacking • Inexpensive Nonsteroidal anti-inflammatory • Decreased amount of opioid needed for • Possible increased risk of postoperative bleeding drugs postoperative pain management • Other adverse effects associated with these agents • May increase motility by acting as an anti-inflammatory

cess. At this time, it is best to recommend an approach that 9. Sargrada A, Fargeas MJ, Bueno L. Involvement of alpha-1 and alpha-2 adreno- will decrease factors contributing to paralytic postopera- receptors in the postlaparotomy intestinal motor disturbances in the rat. Gut. 1987;28:955-959. tive ileus. This approach would include limiting the ad- 10. Barquist E, Zinner M, Rivier J, Tache´ Y. Abdominal surgery–induced delayed ministration of narcotics and using alternative analgesics gastric emptying in rats: role of CRF and sensory neurons. Am J Physiol. 1992; such as nonsteroidal anti-inflammatory drugs and plac- 262:G616-G620. ing a thoracic epidural with local anesthetics when pos- 11. Zittel TT, Reddy NS, Plourde V, Raybould HE. Role of spinal afferents and calcitonin gene–related peptide in the postoperative gastric ileus in anesthetized sible. Selective use of nasogastric decompression and the rats. 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