C l i n i c a l C o n s e n s u s U p d at e in G e n e r a l S u r g e ry

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1 C l i n i c a l C o n s e n s u s U p d at e in G e n e r a l S u r g e ry e x p e r t - g e n e r a t e d & e v i d e n c e - b a s e d r e v i e w s o f i m p o r t a n t d e v e l o p m e n t s i n c l i n i c a l m e d i c i n e Postoperative Ileus: Profiles, Risk Factors, and Definitions A Framework for Optimizing Surgical Outcomes in Patients Undergoing Major Abdominal and Colorectal Surgery Findings, Definitions, and Analysis of The Postoperative Ileus Management Council (PIMC) National Experts Clinical Consensus Panel Applying Landmark Evidence to Surgical Principles and Practice: Focus on the Natural History of Postoperative Ileus Editor s Note Postoperative ileus (POI) has emerged as a perioperative event of considerable interest to surgeons, hospital executives, and patients, who (independently and as a group) have become increasingly focused on identifying strategies that can reduce complications, costs, morbidity, and prolonged hospital length of stay (LOS) or readmissions associated with major abdominal surgery. Historically, POI has been characterized by abdominal pain, nausea, vomiting, inability to progress to an oral diet, abdominal distension and bloating, and delayed passage of flatus and stool. 1-4 In addition to its adverse clinical consequences, POI may be the single most important contributor to increased LOS and consumption of health care system resources associated with major abdominal surgery. It has been estimated that shortening the mean LOS by as little as 1 day has the potential for reducing the US annual health care system costs by approximately $1 billion. 5 In view of the formidable medical and economic burdens associated with POI, a search for efficient ways to reduce duration and severity of this condition has been ongoing for decades, with substantial progress having been made in the past few years. Although postoperative gastrointestinal (GI) recovery protocols are not standardized, some centers have reported more rapid GI recovery time by implementing aggressive multimodal postoperative care pathways involving early ambulation and nutrition, opioid-sparing analgesia, and standardized general anesthesia. 6-9 Although these strategies may not be uniformly adaptable to all surgical centers, investigators continue to evaluate protocols, methods, and pharmacologic agents that have the potential to accelerate GI recovery, enhance patient comfort, and reduce the LOS in at-risk populations. The economic implications and concerns associated with prolonged LOS following surgery have become more significant in the current era of declining health care resources. Medicare data from the Federal Register indicate that between October 1999 and September 2000 there were 161,000 patients who underwent abdominal surgery. 10 These patients stayed approximately 1.8 million days in the hospital (11.3 days per patient) and consumed $1.75 bil- PIMC National Experts Clinical Consensus Panel and Scientific Roundtable: Cochairs, PIMC: Conor Delaney, MD, PhD, FRCSI, Professor and Chief, Division of Colorectal Surgery, Vice-Chair, Department of Surgery, Case Western Reserve University, University Hospitals of Cleveland, Cleveland, Ohio. Henrik Kehlet, MD, PhD, Professor, Section for Surgical Pathophysiology, The Juliane Marie Centre, Rigshospitalet, Copenhagen, Denmark. Anthony J. Senagore, MD, Professor and Chair, Department of Surgery, Medical University of Ohio, Toledo. Distinguished Members, PIMC National Experts Clinical Consensus Panel: Anthony J. Bauer, PhD, Associate Professor of Medicine, Department of Medicine/Gastroenterology, University of Pittsburgh, Pittsburgh, PA. Robert Beart, MD, Professor of Colorectal Surgery, Keck School of Medicine, University of Southern California, Los Angeles. Richard Billingham, MD, Clinical Professor of Surgery, Department of Surgery, University of Washington School of Medicine, Seattle. Robert L. Coleman, MD, Director, Clinical Research, Department of Gynecologic Oncology, University of Texas, M. D. Anderson Cancer Center, Houston. Eric J. Dozois, MD, Assistant Professor of Surgery, Program Director, Division of Colon and Rectal Surgery, Mayo Clinic, Rochester, Minn. John B. Leslie, MD, MBA, Professor, Anesthesiology, Mayo Clinic College of Medicine, Consultant in Anesthesiology, Mayo Clinic Arizona, Scottsdale. John Marks, MD, Chief of Colorectal Surgery, Main Line Health System, Senior Investigator, Lankenau Institute for Medical Research, Philadelphia, PA. Alec J. Megibow, MD, MPH, FACR, Professor of Radiology, Department of Radiology, NYU School of Medicine, New York, NY. Fabrizio Michelassi, MD, Lewis Atterbury Stimson, Professor of Surgery, Chairman, Department of Surgery, Weill Medical College, Cornell University, New York, NY. Richard A. Steinbrook, MD, Associate Professor of Anesthesia, Harvard Medical School, Director, Clinical Research, Department of Anesthesia, Critical Care, and Pain Medicine, Beth Israel Deaconess Medical Center, Boston, Mass. Jointly Sponsored by the University of Massachusetts Medical School Office of Continuing Education. Supported by an Unrestricted Educational Grant from Adolor Corporation and GlaxoSmithKline

2 is published by Pharmatecture, LLC, 885 Woodstock Road, Suite 430 #145, Roswell, GA Editor-in-Chief: Gideon Bosker, MD Copyright 2006 by Pharmatecture, LLC. All rights reserved. Reproduction, distribution, or translation without express written permission is strictly prohibited Program Audience: This program is intended for colorectal surgeons, general surgeons, anesthesiologists, and other surgical specialties. OBJECTIVES Physicians will learn how to identify gastrointestinal, pain-associated, and other clinical findings characteristic and/or diagnostic of postoperative ileus (POI) Physicians will learn the pharmacological, mechanical, procedural, disease-specific, and inflammation-related risk factors for POI Physicians will learn objective measurements, clinical features, and prognostic factors that can be used to define POI, and how to stratify patients at risk for acquiring POI Physicians will learn the pharmacoeconomic and resource utilization consequences of POI, as well as the importance of postoperative recovery of gastrointestinal function and resumption of oral intake as critical determinants of the length of hospital stay Physicians will learn the role of pharmacotherapeutic interventions, as part of a multimodal approach, to reducing incidence and severity of POI NEEDS ASSESSMENT The rationale for producing this CME-certified clinical monograph focusing on postoperative ileus management is based on the results of a needs assessment survey conducted in Results of this clinical needs assessment survey indicated an interest on the part of specialists in topics related to detection, screening, risk stratification, patient selection, monitoring, and management of patients with postoperative ileus. Among the specific topic areas survey respondents indicated practitioners wished to be covered within the framework of evidence-based, CME programming were the following: (1) How to identify gastrointestinal, pain-associated, and other clinical findings characteristic and/or diagnostic of postoperative ileus (POI); (2) Objective measurements, clinical features, and prognostic factors that can be used to define POI; (3) Postoperative complications associated with POI; (4) Pharmacoeconomic and resource utilization consequences of POI; (5) The role of pharmacotherapeutic interventions, as part of a multimodal approach, to reducing incidence and severity of POI; (6) Patient selection and identification for pharmacologic approaches to reducing severity and duration of POI; and (7) Strategies for improving the management of postoperative ileus (POI) using risk stratification criteria predicting patients at risk for POI DESIGNATION OF CREDIT This activity has been planned and implemented in accordance with the Essentials and Standards of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of the University of Massachusetts Medical School (UMMS). The UMMS is accredited by ACCME to provide continuing medical education for physicians. The UMMS designates this continuing medical education activity for up to 4 credit hours in Category 1 toward the Physicians Recognition Award of the American Medical Association. Each physician should claim only those hours of credit that he/she actually spent in the educational activity. Effective Dates: This material is authorized for CME credits beginning May 1, 2006, and expiring May 1, To Receive Complimentary CME Credit: 1. Participants may complete an online evaluation form to receive up to 4 credits of Category 1 CME. 2. Go to to access the CME test for this program. 3. Complete the online evaluation form and submit. You will receive your certificate from the University of Massachusetts Medical School within 2-4 weeks. In accordance with the Standards of the Accreditation Council for Continuing Medical Education (ACCME) and the guidelines of the Association of American Medical Colleges (AAMC), it is the policy of the University of Massachusetts Medical School to disclose whatever interest or affiliation a speaker might have with any commercial organization whose products or services are related to the subject matter being presented. Conor Delaney, MD, PhD, FRCSI (Professor and Chief, Division of Colorectal Surgery, Vice-Chair, Department of Surgery, Case Western Reserve University, University Hospitals of Cleveland, Cleveland, Ohio) discloses he has received grant or research support from Adolor, U.S. Surgical, and Gore. He is a consultant for Adolor, Gore, U.S. Surgical, and Ethicon. He is on the Speaker s Bureau of Adolor, Ethicon, and U.S. Surgical. John B. Leslie, MD, MBA, (Professor, Anesthesiology, Mayo Clinic College of Medicine, Consultant in Anesthesiology, Mayo Clinic Arizona, Scottsdale) discloses that he has received grant or research support from GlaxoSmithKline, Progenics, Baxter Pharma. Richard Steinbrook, MD discloses past research support from Adolor Corporation, and past healthcare spokesperson for Adolor/ GlaxoSmithKline. John Marks, MD (Chief of Colorectal Surgery, Main Line Health System, Senior Investigator, Lankenau Institute for Medical Research, Philadelphia, PA), discloses honorarium and education grant support from U.S. Surgical, and having received speaker honoraria from Ethicon, Wolf, Stryker, and GlaxoSmithKline. Richard A. Steinbrook, MD (Associate Professor of Anesthesia, Harvard Medical School, Director, Clinical Research, Department of Anesthesia, Critical Care, and Pain Medicine, Beth Israel Deaconess Medical Center, Boston, Mass.), has received research support from Adolor and been on speaker s bureau for Adolor/GlaxoSmithKline. Henrik Kehlet, MD, PhD (Professor, Section for Surgical Pathophysiology, The Juliane Marie Centre, Rigshospitalet, Copenhagen, Denmark) discloses no conflicts. Anthony J. Senagore, MD (Professor and Chair, Department of Surgery, Medical University of Ohio, Toledo), discloses no conflicts. Anthony J. Bauer, PhD (Associate Professor of Medicine, Department of Medicine/ Gastroenterology, University of Pittsburgh, Pittsburgh, PA) discloses no conflicts. Robert Beart, MD (Professor of Colorectal Surgery, Keck School of Medicine, University of Southern California, Los Angeles) discloses no conflicts. Richard Billingham, MD (Clinical Professor of Surgery, Department of Surgery, University of Washington School of Medicine, Seattle) discloses no conflicts. Robert L. Coleman, MD, Director, Clinical Research, Department of Gynecologic Oncology, University of Texas, M. D. Anderson Cancer Center, Houston. Eric J. Dozois, MD, Assistant Professor of Surgery, Program Director, Division of Colon and Rectal Surgery, Mayo Clinic, Rochester, Minn. Alec J. Megibow, MD, MPH, FACR (Professor of Radiology, Department of Radiology, NYU School of Medicine, New York, NY) discloses no conflicts. Fabrizio Michelassi, MD (Lewis Atterbury Stimson, Professor of Surgery, Chairman, Department of Surgery, Weill Medical College, Cornell University, New York) discloses no conflicts. NOTE: This Consensus Update reflects the opinions, output, and analyses of a panel of experts, investigators, educators, and clinicians whose activities for this document, while independent, was commercially supported by the sponsor noted on the front page of this publication. It is not meant to be, nor substitute for national guidelines or recommendations generated by professional, academic societies, colleges, or associations.

3 lion in health care. Although historical rates for postoperative stay after abdominal surgery have been between 6 and 10 days for most surgical practices, recent studies 11,12 and the evolution of laparoscopic bowel surgery have challenged these numbers and have introduced protocols to shorten the LOS to 3 to 5 days. Clearly, reducing the LOS associated with POI has become a health care priority for the surgical community. With the introduction of fast-track protocols and multimodal management strategies, expectations about appropriate LOS are changing, and it is expected that the time may come when the current accepted durations of POI will no longer be considered an inevitable consequence of abdominal surgery. Against this backdrop, the Postoperative Ileus Management Council (PIMC)-a multidisciplinary group of experts from the fields of general surgery, colorectal surgery, anesthesiology, and radiology-convened to evaluate the medical and surgical literature on POI and to develop a consensus-based, Continuing Medical Education-accredited document that would illuminate important issues related to its etiology, natural history, and management. The National Experts Clinical Consensus Panel members of the PIMC (hereafter referred to as the Panel) were selected based on their analytical, editorial, clinical, and academic abilities. Participants also were identified as being leaders in colorectal surgery, general surgery, or anesthesiology, as well as for their technical, procedural, and investigational excellence in general and colorectal surgery, with special expertise in POI. Using fair balance and drawing on landmark clinical trials and peer-reviewed publications, the Panel was charged with providing unbiased analysis, recommendations, and guidelines for surgical practice issues related to POI. Recognizing that POI is a broad topic that includes multiple diagnostic and therapeutic dimensions, the specific mission statement for this roundtable was to articulate and to characterize risk factors, precipitants, findings, and definitions useful for identifying, risk stratifying, and signaling the resolution of symptoms in patients with POI. The Panel reviewed and cited a significant body of the available medical and surgical literature, and according to a consensus-based analysis, it generated a working definition for POI, characterized the natural history of this condition, and categorized its associated complications. Specifically, the Panel sought to define salient clinical features of this condition, including the type and expected duration of postoperative findings, severity of symptoms, temporal parameters for resolution, triggers for more intensive evaluation, discharge criteria, differential diagnosis, and possible strategies for prevention. It was the Panel s proposition that a more rigorous delineation of the natural history, precipitating factors, and time course of POI would facilitate the development of successful approaches to evidence-based management for this patient population, including fast-track strategies based on multimodal approaches. In particular, reducing the time spent in the hospital after major abdominal surgery was identified as a rational goal, as this should have a beneficial effect by increasing the availability of hospital beds and by reducing the overall cost of the hospital stay, while offering more rapid recovery for the patient. Moreover, it was the position of the Panel that the development of a standardized definition for POI will permit comparison of outcomes among institutions and regions and will allow evaluation of new therapeutic techniques, in the expectation of improving outcomes after major abdominal surgery. The processes, critical analyses, and scientific output of the Panel were formulated to produce evidence-based educational information and to outline surgical principles for the explicit objective of improving patient care in the setting of major abdominal and colorectal surgery. A MEDLINE search was conducted to retrieve peer-reviewed publications-including clinical trials, epidemiological databases, and expert reviews-focusing on POI, common complications of colorectal and abdominal surgery, economic costs associated with POI, therapeutic modalities for management of POI, and related issues. Specific MEDLINE terms that were used were the general term postoperative ileus and postoperative ileus with the following modifiers: colorectal surgery, gynecological surgery, review, pharmacologic therapy, and fast-track. To ensure scientific rigor, a database of approximately 80 articles was provided for review by all PIMC members 3 weeks before the roundtable. To stimulate discussion for the 2-day meeting, the Panel chairs presented summaries of the surgical literature pertaining to the topic. These oral presentations were followed by in-depth discussions and then by formulation of definitions and critical analysis of the disease process, including its natural history, risk factors, differential diagnosis, and complications. A predetermined question-andanswer grid was used to guide the consensus process. The final manuscript was prepared in close collaboration with the Panel cochairs and was then distributed to all members for their critical review, comments, and revisions. The primary educational objective of this PIMC National Experts Clinical Consensus Panel Update is to assist clinicians managing postoperative patients in accomplishing and Legal Disclaimer and Practice Application Caution Clinical Consensus Update is publication intended for educational value only,. Its contents, analyses, and any recommendation made herein are intended to make scientific information and opinion available to health professionals, to stimulate thought, and further investigation. This publication is not designed nor is any aspect of the contents here intended to provide advice regarding medical diagnosis or treatment for any individual case. Any decisions regarding diagnosis and/or management of any individual patient or group of patients should be made on individual basis after having consulted appropriate sources, whether they be appropriate consultants and/or guidelines and recommendations issued by national organizations, professional societies, governmental health organizations, or similar bodies. This publication is not intended for use by the layman. Opinions expressed herein are not necessarily those of this publication, but reflect the opinions and analyses of the experts who have authored the material. Mention of products or services does not constitute endorsement. Clinical, legal, financial, and other comments are offered for general guidance only; and professional counsel should be sought for all specific situations.

4 understanding the following: (1) identify GI, pain-associated, and other clinical findings characteristic or diagnostic of POI; (2) characterize the pharmacologic, mechanical, procedural, disease-specific, and inflammation-related risk factors for POI; (3) implement and assess objective measurements, clinical findings, and prognostic factors that can be used to define POI; (4) use predictive factors that can be used to risk stratify patients likely to acquire POI; (5) identify and recognize postoperative complications associated with POI; and (6) assess and reduce the pharmacoeconomic and resource utilization consequences of POI. To accomplish these objectives, the Panel sought to characterize, in evidence-based detail, the multiple precipitants of POI, including risk profiles, drug-specific factors, and strategies for ameliorating the symptoms and duration of POI. Special emphasis was placed on the importance of postoperative recovery of GI function and resumption of oral intake as critical determinants of the LOS and adverse economic consequences associated with POI. Patient selection and identification, as well as approaches to reducing the severity and duration of POI, were discussed. Furthermore, the Panel emphasized the need for developing a team approach to managing POI in the setting of general and colorectal surgery. Finally, the relationship between postoperative GI function and LOS, as well as the clinical implications of protracted symptoms, was analyzed in detail to formulate a possible framework for evaluating multimodal strategies for this patient population. It is anticipated that issues related to patient management, pharmacologic treatment, and multimodal therapy will be the focus of a subsequent consensus panel. OVERVIEW OF POI Postoperative ileus is a potentially serious condition that occurs after almost all types of GI surgery. 13 The duration of POI has been reported to correlate with the degree of surgical trauma and is most extensive after colonic surgery. 2,13 Postoperative ileus may also occur after extraperitoneal surgery, although it is less commonly associated with these procedures. The key pathophysiologic feature of POI is inhibition of coordinated bowel activity, which leads to accumulation of GI secretions and gas. Clinical symptoms typically include abdominal pain, nausea and vomiting, distension and bloating, delayed passage of flatus and stool, and inability to progress to an oral diet. 2,13,14 The course of POI is variable; in some cases it resolves quickly, while in other cases resolution may take days or weeks. 2 Surgeons, hospital administrators, and quality assurance directors-as well as patients-have identified POI as a significant health care problem. Associated symptoms cause significant patient distress, discomfort, and morbidity. Moreover, in patients with postoperative pain, uncontrolled symptoms of POI can exacerbate discomfort and may be a barrier to effective pain management. 15 Physicians traditionally wait for return of GI function before sending patients home following abdominal surgery. Consequently, POI is the most common reason for delayed hospital discharge after abdominal surgery. It is also associated with an increased risk for readmission to the hospital and may significantly increase the costs of postoperative care. 2,13,14 Experts have emphasized that the etiology of POI is multifactorial and that it is most effectively treated with a multimodal approach that may include limitation of narcotics, alternative pain medications such as nonsteroidal anti-inflammatory drugs, and use of a thoracic epidural with local anesthetics when clinically indicated. 2,14 Findings suggest that implementation of postoperative clinical pathways that incorporate a multimodal combination of approaches may produce more prompt return of GI function and shorter LOS. In addition, promising new therapies are being investigated, including those based upon the use of peripheral μ-opioid receptor antagonists, which have been evaluated for their capacity to reduce clinical manifestations of POI and the LOS in patients undergoing abdominal surgery. 16 BEST SURGICAL PRACTICE AND INVESTIGATIONAL FRAMEWORK FOR POI Surgical experts concur that gastrointestinal (GI) tract surgery is associated with a mandatory period of cessation of coordinated bowel motility. Characterized as postoperative ileus (POI), this lasts for a variable length of time, generally several days. The resolution times of the small bowel, stomach, and colon may vary. POI may also be associated with non-gi abdominal surgery, or even surgery that is not performed intra-abdominally, such as major orthopedic or cardiac surgery. Although this is a common condition, it is curious that a precise consistent definition of POI has been lacking. In fact, the definition of POI has varied in different publications, with toleration of diet and return or passage of flatus or stool having varied importance to different authors. In addition, despite numerous laboratory research studies, controversy remains about the normal duration of POI. To permit more rigorous characterization of the disease process, the Panel proposed a standardized definition for POI. The Panel acknowledged that, while experts have convened previously to generate a consensus opinion outlining definitions and classification of POI, the PIMC was charged with refining and crystallizing these findings. The proposed definitions presented herein, while representing the outcomes of a consensus-based group of experts, await endorsement and acceptance from national surgical associations and from colleges. Nevertheless, the proposed definitions (Table 1) were developed to establish acceptable normal limits for the duration of this condition and to provide a classification of its different clinical manifestations. By standardizing such parameters, it is anticipated that surgeons will be better able to identify patients at risk for POI, to evaluate the safety and efficacy of different interventions, and to optimize patient care. The pathogenesis of POI is attributed to a complex set of

5 relationships and interactions among inhibitory neural reflexes, release of neurotransmitters, inflammatory mediators, and endogenous and exogenous opioids. 17 Animal and human models have suggested that inflammation in the intestinal wall may be directly involved. 18 A consensus conference has reviewed and reported the basic science and some clinical aspects of POI. 19 More details about postulated mechanisms of action and the pathophysiology of POI are presented in subsequent sections. DEFINITIONS The Panel defined POI as transient cessation of coordinated bowel motility after surgical intervention, which prevents effective transit of intestinal contents or tolerance of oral intake. Primary POI was defined as such cessation occurring in the absence of any precipitating complication, whereas secondary POI was defined as that occurring in the presence of a precipitating complication (infection, anastomotic leak, etc) (Table 1). There are no standard definitions for the duration of POI, and authors historically have variably selected tolerance of diet or passage of flatus or stool as their benchmark criteria for recovery of bowel function. The data available for the time of return of each of these intestinal functions are based on multiple small series of patients. In general, recovery of small bowel function returns first, typically within the first 24 hours. Peristalsis generally returns within 48 hours in the stomach and within 48 to 72 hours in the colon. Many patients may not be offered food because of the type of surgery they have undergone, such as duodenal surgery or a high jejunostomy, or because of such complications as enterocutaneous fistula or mechanical ventilation after surgery. In an attempt to synthesize the current body of evidence, to account for these qualifiers, and to incorporate data from different trials, the Panel defined the duration of POI as the time from surgical intervention until passage of flatus or stool and until initiation of adequate oral intake that is tolerated and maintains hydration during 24 hours. This definition is supported by several recent publications assessing the efficacy of fast-track protocols after colorectal surgery. 8,20 The early introduction of diet is a component of all multimodal and fast-track care pathways, although there is no proof that this is the factor that accelerates recovery. 8,21 Indeed, in a recent randomized controlled trial evaluating the effect of the early introduction of diet, this did not shorten the time to passage of flatus or stool. 22 It may be that offering early diet simply saves patients from having to wait the extra day or 2 for bowel function before starting to eat, thereby having them ready for discharge at an earlier time point. 19,22 These patients, experiencing a routine recovery from POI, usually have minimal symptoms of distension but may have mild crampy abdominal pain as GI function returns. Recurrence of POI usually is signaled by cessation of passage of flatus or stool, with bloating and nausea or vomiting, requiring a change of in-hospital management or readmission to the hospital. This is a particularly important problem because the economic costs and management of complications associated with recurrence can be significant, especially in cases of ileus where the POI initially resolves but recurs 1 or more days later, not infrequently after the patient has been discharged from the hospital. Readmission occurs in approximately 10% of patients undergoing major abdominal surgery, and about half of these patients are readmitted for GI failure or some measure of recurrence of their POI. 23 Experts have been challenged with establishing an acceptable duration of POI after abdominal surgery (open and laparoscopic). Generally, normal POI should resolve by the fifth postoperative day (POD) after open abdominal surgery and by the third POD after laparoscopic abdominal surgery (Table 2) (See Page 6). To account for the variability in presentations and multiple recovery curves reported in the literature, the Panel defined recurrence of primary POI as cessation of passage of flatus or stool, with bloating and nausea or vomiting after a period of apparent resolution. It is unusual for POI to occur after thoracic or orthopedic Table 1. Summary of Proposed Postoperative surgery. Ileus Management On the other Council hand, after National abdominal Experts surgery Clinical there is Consensus Panel Def initions of Postoperative Ileus and Pivotal Aspects of Its Natural Histor Transient cessation of coordinated bowel motility after surgical intervention, which prevents effective transit of intestinal contents or tolerance of oral intake Primary POI occurs in the absence of any precipitating complication. Secondary POI occurs in the presence of a precipitating complication (infection, anastomotic leak, etc). Duration of POI is defined as the time from surgical inter vention until passage of flatus or stool and until initiation of adequate oral intake that is tolerated and maintains hydration during 24 hours. Tolerance of oral intake is defined as adequate oral intake to maintain hydration during 24 hours. Recurrence of primary POI is defined as the cessation of passage of flatus or stool, with bloating and nausea or vomiting after a period of apparent resolution. Type I comprises panintestinal ileus (no flatus or bowel movement, presence of nausea or vomiting). Type II comprises upper GI symptoms (nausea, vomiting, and flatus present). Type III comprises lower GI ileus (no flatus or bowel movement, tolerance of diet).

6 a normal period of cessation of coordinated bowel motility, and the different stages of recovery of each section of the GI tract after surgery have been demonstrated. Although normal and clearly representing a physiologic response to surgery, there are no data suggesting that POI is beneficial for postoperative recovery. PROLONGED POI It is important to be able to identify patients who have prolonged POI (ie, those individuals whose symptoms endure long enough to become potentially problematic). Recent evidence obtained from series of patients assessing the effectiveness of fast-track postoperative protocols has shown that bowel function returns in about 65% of patients undergoing open abdominal surgery by the fifth POD (Table 2). Similarly, data from 234 consecutive patients who underwent laparoscopic colon surgery at the Cleveland Clinic have shown POI resolution by the third POD in about 70% of patients. 8,13,19,20,26,27 Patients who have no bowel function after these time points may be entering the phase of clinically relevant prolonged POI. Distinguishing between a prolonged course of POI and small bowel obstruction is mandatory for ensuring appropriate patient evaluation and postoperative management. Unlike primary POI, small bowel obstruction frequently is a manifestation of postoperative complications necessitating prompt intervention. Computed tomography is considered the dominant radiographic modality for evaluating patients with suspected small bowel obstruction. Triggers identified by the Panel as prompting need for radiological investigation include presence of fever, elevated white blood cell count, prolonged POI, tachycardia, abdominal distension, abdominal pain and tenderness, crampy or colicky pain, and persistent vomiting. Different recovery curves for POI have been reported, and resolution rates have varied according to various factors, including surgical characteristics and methods, anesthesia, patient profiles, medication use, and other parameters. Consequently, defining prolonged POI may be problematic, and uniform time limits may be difficult to apply to individual patients. Finally, discharge criteria for patients recovering from major abdominal or colorectal surgery vary among centers. The Panel proposed that discharge after major abdominal or colorectal surgery was warranted in patients who were passing flatus or stool, who were maintaining adequate oral intake Table 2. Recovery of Intestinal Function After Laparoscopic or Open Abdominal Surgery* Source No. of Patients Laparoscopic Sugery Open Sugery Braga et al, ± ±0.6 Chen et al, ± ±1.8 Delaney et al, ; Delaney et al, ; Delaney ; Delaney et al, ; Delaney et al, ; Delaney et al, ±1.6 Delaney et al, ; Delaney et al, ; Delaney ; Delaney et al, ; Delaney et al, ; Delaney et al, Kehlet and Holte, ; Kehlet and Mogensen, ; Kehlet (range, 2-6) Lacy et al, ± ±2.7 Lumley et al, (range, 1-7) Steed et al, Young-Fadok et al, (range, 1-6) 5 (range, 3-12) *Data are given as mean±sd number of days unless otherwise indicated.

7 (as defined in Table 1), and who had adequate oral analgesia and pain control, provided that there were no other indications for prolonging the hospitalization. CLASSIFICATION OF POI Patients with clinically problematic POI can present in a number of ways. As previously mentioned, all patients undergoing major abdominal surgery must negotiate an obligatory period of ileus. This resolves in a mean of 5 days, although in some cases resolution may be observed within 2 days. Most patients with POI have minimal symptoms and await the passage of flatus or stool to signal recovery so that they may be discharged from the hospital. While in most cases surgeons will initiate food intake for their patients after resolution of POI, an increasing number of surgeons will offer their patients liquids or a diet by mouth without waiting for flatus or stools. 21 Whether oral intake should be reserved until the GI tract has fully recovered is a matter of debate among academic surgeons. The following classification scheme for POI was endorsed by the PIMC. This classification scheme assigns patients to different categories according to specific clinical manifestations of POI. Type I (Panintestinal) The finding of panintestinal POI may occur in the early postoperative setting. This subset of patients may manifest early and persistent nausea and vomiting, without passage of flatus or stool. Patients with symptomatic panintestinal POI often require nasogastric tube (NGT) placement. This is consistent with the early phase of POI before return of any intestinal function, before toleration of food, and before return of bowel function. Type II (Upper GI) Some patients with POI have significant upper GI symptoms with persistent nausea and vomiting, with or without distension. There may be multiple causes for these findings, some of them independent of primary POI. This subgroup accounts for most of the approximately 5% of patients who require insertion of an NGT. These patients may start passing small amounts of flatus or stool while having persistent upper GI symptoms. In these patients, symptoms typically resolve sufficiently to warrant discharge from the hospital, but they may subsequently require readmission with persistent upper GI symptoms. At this point in their time course, this cohort is difficult to distinguish from those with early (particularly partial) postoperative small bowel obstruction, as the symptoms are essentially identical, with vomiting, distension, and crampy abdominal pain-with or without the passage of variable amounts of flatus, stool, or diarrhea-dominating the clinical picture. Type III (Lower GI) In a significant minority of cases, patients may fail to pass flatus or stool, but symptoms of distension, nausea, or vomiting are minimal or absent. These patients often tolerate liquids and a diet for several extra days and seem to be waiting solely for return of colonic function before leaving the hospital. INCIDENCE OF POI Based on data reported by the Health Care Financing Administration (HCFA) that included more than 161,000 major intestinal surgical procedures performed in 150 US hospitals, the overall incidence of POI that was diagnostically coded in the medical records was 8.5% (Table 3). The incidence of POI varied based on the type of procedure and ranged from 4.1% for abdominal hysterectomy to 19.2% for small bowel resection. (See Table 3) Because these data include only POI that was documented and coded in the medical record, they likely underestimate the true incidence of clinically significant POI. Clearly, POI is a common postoperative condition that has a profound ef- Table 3. Incidence of POI for the Most Common Abdominal Surgeries in the US (From Health Care Financing Administration, , Federal Register 10 ) Procedure Description Abdominal hysterectomy Large bowel resection Small bowel resection Appendectomy Cholecstectomy Nephroureterectomy Other precedures Total Procedures Procedures, N 456, ,336 48, ,964 81,013 44, ,492 1,661,729 Coded POI cases, N (%) 18,796 (4.1%) 38,243 (14.9%) 8,364 (19.2%) 10,936 (6.2%) 6,893 (8.5%) 3,979 (8.9%) 53,814 (9.0%) 142,026 (8.5%) HCFA Data (Medicare, ). Evaluating 161,000 major intestinal/colorectal resections from 150 US hospitals.

8 fect on the course of postoperative recovery for a significant percentage of surgical patients. Fortunately, our understanding of the pathogenesis of POI is evolving, allowing for the development of effective and safe therapeutic approaches to decrease its incidence and duration. PATHOGENESIS OF POI Normal bowel function requires the coordination of GI motility, mucosal transport, and defecation reflexes. Gastrointestinal motility is dependent on the electrophysiologic activity of smooth muscle cells, neural input from the intrinsic and autonomic nervous systems, hormonal interactions, and coordinated smooth muscle contraction. 32 As would be expected, the pathogenesis of POI is multifactorial and involves many of these normal mechanisms. Surgical stress leads to complex physiologic responses that alter normal neurohormonal signaling and intestinal motility. In addition, anesthetics and analgesics administered during the perioperative period can play a key role in development or prolongation of POI. Based on data from animal and human studies, 3 major mechanisms-neurogenic, inflammatory, and pharmacologichave been identified as major precipitating factors for POI. In one study, 17 the duration of POI was shown to be directly related to the degree of surgical manipulation and the magnitude of the inflammatory response. These mechanisms are not independent of each other but together lead to POI. The importance of each of these contributing mechanisms may vary during the time course of POI, although there is considerable overlap. 33 Neuronal mechanisms appear to play the most significant role early after abdominal surgery. However, there are clearly other important mechanisms because POI often does not resolve for several days. 33 Neurogenic Mechanisms The smooth muscles of the GI tract display continuous electrical activity characterized by slow waves and spikes. Slow waves represent muscular contraction in the stomach. Spikes, which vary by location in the GI tract, occur automatically when the resting membrane potential of GI smooth muscle exceeds a given threshold resting membrane potential. Spikes represent superimposed action potentials that cause most contractions of the GI tract. The resting membrane potential, and therefore GI smooth muscle motility, is modulated by neurotransmitters, hormones, pharmacologic agents, and parasympathetic and sympathetic activity. Normal functioning of the GI tract depends on a coordinated functioning of these various stimuli. In general, the stomach and small intestine exhibit well-coordinated electrical activity because they have numerous gap junctions between myocytes that allow current to pass from cell to cell, resulting in regular well-ordered contractions. In contrast, the colon has few gap junctions and does not function as an organized unit. Therefore, contraction and motility in the colon are more dependent on extrinsic neural input to integrate the smooth muscle activity. 32 In the normally functioning GI tract, sympathetic stimulation is generally inhibitory, whereas parasympathetic activity stimulates gut motility. GI Excitatory Stimuli Excitatory stimuli to the GI tract include stretching of the muscles, acetylcholine, and parasympathetic activity. Parasympathetic input to the esophagus, stomach, small intestine, and proximal half of the large intestine is via the vagus nerve. The distal part of the colon receives its innervation by means of the pelvic nerves via the sacral parasympathetic nerves. Stimulation of these parasympathetic neurons causes a general increase in activity of the enteric nervous system and an increase in GI motility. 32 Acetylcholine is a major excitatory neurotransmitter in the GI tract, and administration of atropine, which blocks the effects of acetylcholine, blocks colonic contractions. 32 Gastrin, cholecystokinin, motilin, and substance P also increase GI motility. 32 GI Inhibitory Activity Sympathetic nerve fibers located in the thoracic and lumbar regions of the spinal cord (between T5 and L2) reach the GI tract through the splanchnic nerves. Sympathetic nerve endings release norepinephrine, which exerts an inhibitory motor effect in the GI tract. Norepinephrine exerts its major inhibitory action on enteric neurons and, to a lesser degree, on smooth muscle cells. 32 Nitric oxide, somatostatin, glucacon, and gastric inhibitory peptide also have inhibitory effects on GI motility. 32 The primary factor, among many precipitating factors leading to POI, is hyperactivity of the autonomic nervous system. In the postoperative period, the sympathetic system exerts more effect than the parasympathetic system, leading to decreased motility and ileus. 6 During abdominal surgery, activation of inhibitory reflexes originates from the incision (somatic fibers) and from manipulation of the intestines (visceral fibers). 17,33 The activation of neural pathways during abdominal surgery depends on the intensity of the nociceptive stimulus applied and the part of the intestine evaluated. Skin incision and laparotomy briefly inhibit motility, mainly by activation of a low-threshold adrenergic inhibitory pathway. 3,33 More intense stimuli, such as handling of the intestine, trigger an additional high-threshold supraspinal (autonomic) pathway. 33 Catecholamines play an important role in the early phases of POI; however, plasma and tissue levels normalize long before the return of bowel activity. This indicates that, although sympathetic hyperactivity is an important mechanism leading to POI, it is clear that this is not the only mechanism leading to POI because it may take several days or weeks for normal bowel function to resume. 34 These reflexes may be inhibited by the use of epidural local anesthetics, which have been shown to result in reduction of POI. 17

9 There are other factors that lead to activation of inhibitory pathways during abdominal surgery. Taché and colleagues 35 showed that cecal manipulation results in the central release of corticotropin-releasing factor in the hypothalamus and the dorsal vagal complex. This central neural activity is thought to stimulate an efferent inhibitory motor pathway that produces activation of adrenergic and nonadrenergic noncholinergic motor neurons via vagal and splanchnic pathways. Nitric oxide appears to play a key inhibitory role, as does the inhibitory neurotransmitter vasoactive intestinal peptide. 36 Corticotrophin-releasing factor also seems to play a central role in this pathway. Intracisternal injection of a corticotrophin-releasing factor antagonist prevents gastric ileus. 33,37 Blockade of the calcitonin gene-related peptide resulted in a similar effect. 33 Most studies investigating these neurogenic mechanisms were performed in animals early in the postoperative period, so these data primarily support the involvement of neuronal mechanisms early after surgery. In addition, they focused mainly on proximal bowel motility, and the effective duration of ileus may be dependent primarily on the return of colonic motility. 36 Therefore, it is important to consider the effect of other mechanistic pathways, such as inflammation and pharmacologic mechanisms. Inflammatory Mechanisms It appears that there is a significant local inflammatory response following abdominal surgery that contributes to the development of POI by impairing smooth muscle function. 33 The degree of ileus appears to correspond directly to the magnitude of the intestinal inflammatory response. 14,33 Surgical manipulation of the intestine leads to activation of normally quiescent macrophages. When activated, these cells release kinetically active substances such as nitric oxide and prostaglandins through inducible nitric oxide synthase and cyclooxygenase-2 (COX-2) pathways. 33 Intestinal manipulation also causes secretion of proinflammatory cytokines, including tissue necrosis factor α, interleukin 1β (IL-1β), and IL-6. These cytokines cause up-regulation of adhesion molecules, such as intercellular adhesion molecule 1, on the vascular endothelium, which leads to further activation of leukocytes and to their transmigration into the tissues. In the tissues, leukocytes release additional nitric oxide, prostanoids, cytokines, reactive oxygen intermediates, and proteases that may lead to tissue damage. 33 Investigations have found a causative link between migration of leukocytes into the intestinal mucosa and gut paralysis. A causal link was established between bowel manipulation, leukocyte infiltration of the muscularis, and impaired GI contractility. 32,38 Increasing the intensity of surgical manipulation has been shown to increase the accumulation of several populations, including neutrophils, macrophages, mast cells, T cells, natural killer cells, and dendritic cells. 32,39 At the same time, smooth muscle contraction is attenuated, and this correlates with the intensity of inflammation. The GI paralytic response has been shown to be biphasic and consists of a short temporary initial paralysis, followed by a longer-lasting impairment of muscle activity that correlates with activation and infiltration of inflammatory cells. 40 The precise target of action is still unknown, but the neutrophilderived inflammatory mediators may directly interfere with local neurotransmission or smooth muscle contractility. 32,34 Attenuation of this leukocyte recruitment prevents surgically induced suppression in muscle function. 33,40 While the inflammatory mechanisms previously described contribute to impaired intestinal transit, gastric emptying is delayed for up to 24 hours after surgery. This suggests that other mechanisms affecting motility distal from the site of inflammation are likely to be involved. 33 One possible mechanism is an interaction between these inflammatory mediators and primary afferent neuronal activity, triggering the neural inhibitory pathways already described. This is supported by data from a mouse model that showed that GI manipulation generated infiltrates that delayed gastric emptying through an adrenergic pathway; the pathway was blocked by pretreatment with guanethidine. 33,41 Other inflammatory mechanisms have an effect on neuronal pathways. Prostaglandins secreted through the up-regulation (eg, an increase in the number of receptors for a drug on cell surfaces so that the cells are more reactive to the effects of the agent) of COX-2 are involved in the pathogenesis of inflammatory POI by sensitizing primary afferent nerves. 33,42 In an animal model, there was increased COX-2 expression, resulting in elevated levels of prostaglandins in the peritoneal cavity and circulation and in decreased jejunal circular muscle contractility in the perioperative setting of abdominal surgery. In vitro findings demonstrated that this effect was lessened with the administration of COX-2 inhibitors. 43 In investigations using a mouse model, pretreatment with a selective COX-2 inhibitor decreased leukocyte infiltration by 40% and prevented dilation of an ileus. 33,44 Mast cells appear to play a crucial role in the inflammatory response that leads to POI. Intestinal manipulation activates mast cells, and once activated, they release potent proinflammatory mediators (such as tissue necrosis factor α, histamine, and proteases) and produce newly synthesized mediators and cytokines that contribute to the inflammatory response. In a mouse model, after intestinal manipulation, mast cell protease 1 levels were increased, and induced gastric emptying was delayed after 24 hours. Both of these indicators, as well as inflammation, were prevented by pretreatment with the mast cell stabilizer ketotifen fumarate. 33,41 The clinical relevance of many of these findings in rodent models has been confirmed recently in surgical specimens obtained from patients undergoing intestinal resection. As in the rodent models, the levels of inflammatory inducible nitric oxide synthase, COX-2, and IL-6 messenger RNA were significantly induced during surgery within the muscularis of patients undergoing intestinal surgery. 33,38,45,46

10 Pharmacologic Mechanisms In the postoperative period, endogenous opioids are released as part of the stress response, and exogenous opioids are the most potent and commonly used analgesics for postoperative pain control. Both activate the same receptor sites and contribute to decreasing GI motor activity. 34 Opioids affect a variety of GI functions, including motility, secretion, and transport of electrolytes and fluids. They have been shown to profoundly inhibit peristaltic activity; moreover, they delay gastric emptying and intestinal transit and play an important role in precipitating prolonged POI. 33 Opioid effects are complex to decipher because they are mediated by different classes of cell-surface receptors and are dependent on species and on different sites of action, including those the brain, spinal cord, peripheral nervous system, and GI region. 47 There are 3 distinct types of opioid receptors: δ, μ, and κ receptors. The GI effects of opioids are mediated primarily by μ-opioid receptors within the bowel, whereas spinal or cerebral opioid receptors play a minor role. 17 When bipolar electrodes were placed in the ascending colon and descending colon during laparotomy in 25 patients, 18 of whom received morphine sulfate, it was found that intravenous and intramuscular morphine induced short nonpropulsive colonic spike bursts. However, there was no colonic response in any patient who was given epidural morphine, suggesting a direct effect on the colon. 48 The effects of opioids on the GI tract are receptor specific, and this must be kept in mind when evaluating the potential therapeutic role of pharmacologic agents that work through opioid pathways. 33 The ratio between the analgesic and constipating effect of morphine is approximately 4:1 (ie, 4 times more morphine is needed to obtain analgesic effect than to slow GI motility). 17,47 With repeated opioid administration for pain relief, tolerance to the analgesic effect develops, but tolerance to the adverse GI effects does not. 17 It has been proposed that narcotic use may be proportional to the length of the abdominal incision. To investigate this hypothesis, Cali and colleagues 49 performed a prospective evaluation of 40 patients who underwent uncomplicated predominantly left colon and rectal resection to determine whether return of bowel function after colectomy is directly related to narcotic use and to evaluate the effect of incision length on POI. Patient-controlled morphine administration was the only postoperative analgesic used. 49 There were significant correlations between time to return of bowel sounds (r=0.74; P=.001), time to report of first flatus (r=0.47; P=.003), and time to bowel movement (r=0.48; P=.002) with the amount of morphine administered. There was no significant correlation between incision length and morphine dose or incision length and return of bowel function. These results suggest that total morphine dose directly adversely affects motility of the small intestine and colon after colectomy. Therefore, it may appear to be more beneficial to target therapy at the opioid pathways than to focus on altering surgical techniques. 49 Opioids may also affect GI motility via effects on the immune system by binding to specific opioid receptors on leukocytes. 33 These effects differ based on the type of opioid receptor; μ-opioid agonists are primarily immunosuppressive, while δ-opioid agonists appear to enhance immune function. 33,50 Opioids have also been shown to potentiate inducible nitric oxide synthase induction, and nitric oxide release from phagocytes is of particular importance to the pathophysiology of POI. However, other investigations have shown that endogenous and exogenous opioids act through δ- and μ-receptors to decrease the release of nitric oxide and nonadrenergic noncholinergic inhibitory neurotransmitters. 33 Treatment with the κ-opioid receptor agonist fedotozine reverses ileus induced by surgery or peritonitis, possibly by a peripheral action on nonvagal sensory afferent pathways. 33 Administration of the nonselective opioid antagonist naloxone hydrochloride reverses gut paralysis, but it is systemically absorbed and enters the central nervous system, leading to loss of analgesia. Selective inhibition of GI opioid receptors by peripherally acting antagonists with limited oral absorption and poor ability to cross the blood-brain barrier has been shown to reduce the severity and duration of POI and to improve GI transit in patients with opioid bowel dysfunction. 47 Therefore, opioid antagonists that target pathways specific to POI are preferred. Other Mechanisms Gastrointestinal tract permeability may also be increased following the trauma of surgery, which allows enhanced uptake of luminal bacterial products. This may contribute to the development of POI. Enteral feeding may maintain the integrity of the GI mucosa and may reduce POI. Fluid overload that may occur in the perioperative period may contribute to POI, possibly due to edema in the intestinal wall impairing GI motility. 17 Fluid shifts among the cellular, interstitial, and vascular compartments may also lead to electrolyte abnormalities involving potassium and magnesium; such alterations have correlated with altered GI neuromuscular function and with prolongation of POI. 34 An overview of the mechanisms of POI is given in Table 4 (See Page 10). CLINICAL ISSUES AND THE EFFECT OF POI Postoperative ileus is an important medical problem that results in significant clinical and financial effects on patients and the health care system. It is the most common reason for delayed hospital discharge after abdominal surgery, and it leads to increased health care costs. This section will present an overview of POI and address key clinical and economic issues and questions related to POI. 10

11 Table 4. Possible Mechanisms of Postoperative Ileus Mechanisms Autonomic nervous system Enteric nervous system Hormones & neuropeptides Inflammation Anesthesia Narcotics Factors Involved Sympathetic inhibitory pathways Substance P, nitric oxide Vasoactive intestinal peptide; corticotropin-releasing factor ligands; calcitonin gene-related peptide ligands Macrophage & neutrophil infiltration; cytokines, other inflammatory mediatiors General anesthetics Opiates Question 1: When Does a Normal Poi Become a Prolonged POI? As a general proposition, the duration of POI correlates with the degree of surgical trauma and is most extensive after colonic surgery. 2,14 Recovery of intestinal motility after surgery usually follows a predictable course characterized by the following sequence of events: (1) small intestinal motor activity returns within 5 to 10 hours after surgery; (2) gastric motor activity recovers more slowly, in approximately 24 to 48 hours; and (3) resumption of colonic motility occurs on PODs 3 through 5 and typically is the rate-limiting factor for the resolution of ileus. Risk profiling of patients for POI is an imperfect science. While associations between POI severity and types of surgery, preexisting comorbidity, and pharmacologic therapy have been reported, a fully developed risk equation has not yet been evaluated or confirmed in clinical studies. Nevertheless, there appears to be a relationship between the duration of POI and the anatomical location of the surgery, with the most prolonged natural history noted after procedures that involve the colon. Although not substantiated, some experts have suggested that there may also be a difference in the duration of POI based on right-sided vs left-sided colonic procedures. 17 Further trials are necessary to confirm this hypothesis. A transperitoneal procedure will generally lead to ileus of longer duration than that caused by a retroperitoneal approach. 6 The extent of surgery also affects the duration of postoperative symptoms. A direct correlation between duration of ileus and operation time or blood loss has also been reported. 6 There is significant interpatient variability in the duration of POI (ie, some individuals recover quickly after extensive procedures, whereas other patients who undergo rapid, uncomplicated, and straightforward procedures develop prolonged ileus). This may be due to several factors known to affect GI motility. The general health of the patient may be an important factor in the return of GI motility, especially in patients with significant and coexisting conditions. Patients with systemic infections may experience ileus that lasts for weeks, presumably as a result of the release of cytokines. Patients with congestive heart failure or obstructive pulmonary disease may also have longer-term GI motility problems due to decreased cardiac output or hypoxia. 6 Unfortunately, few studies are available that have evaluated the effect of GI recovery (eg, POI, cost, readmissions, and LOS) following open laparotomy, and most include only a small number of patients or patients who were treated using a diverse range of postoperative protocols. Investigators evaluated patients from the placebo arms of 3 phase III trials assessing the efficacy of an oral peripherally acting μ-opioid receptor antagonist for the management of POI. 5,13,16,51 Their findings represent an important source of postoperative recovery data from a controlled setting and a homogeneous patient population. The analysis of postoperative GI recovery and LOS patterns provides important insights into upper and lower GI recovery, symptoms, morbidity and mortality, LOS, and readmission after bowel resection (BR) in a large group of patients (n=383) receiving a standardized multimodal postoperative management protocol. 13 Question 2: What Is the Effect of POI on Patient Morbidity? As noted, POI is an important contributor to patient discomfort and postoperative morbidity, which can range from cramping and abdominal pain to nausea and vomiting. 4 In investigations by Delaney and colleagues, 13 persistent and refractory postoperative nausea and vomiting led to postoperative NGT insertion. Nasogastric tube insertion is associated with considerable discomfort to patients and is most likely unnecessary, as data show that it does not predictably decrease the duration of POI across a broad population of surgical patients. On the contrary, it may actually increase postoperative morbidity, including pulmonary complications. 13,52,53 Nelson and colleagues 53 performed a meta-analysis of 28 studies that included 2108 patients randomized to routine NGT placement and 2087 patients randomized to selective or no NGT placement. Those not having an NGT routinely inserted experienced an earlier return of bowel function (P<.001), a marginal decrease in pulmonary complications (P=.07), and marginal increases in wound infection (P=.08) and ventral hernia (P=.09). Anastomotic leakage was similar in the 2 groups (P=.70). The authors concluded that routine nasogastric decompression does not accomplish any of its intended goals and so should be abandoned in favor of selective use of the NGT. 53 Another important consideration is that patients are usually required to fast for 12 to 24 hours before surgery, and this compromised metabolic state may continue until the resolution of POI, resulting in catabolism, fatigue, and decreased immunity. Fatigue may in turn lead to decreased mobility and delayed functional recovery. Therefore, the ability to take oral nutrition as soon as possible after surgery is a desirable 11

12 clinical end point for patients. 2,13 Table 5 (See Page 13) summarizes the adverse consequences of POI. Nausea and vomiting are common symptoms of POI and often lead to delayed tolerance of oral nutrition. In the evaluation by Delaney and colleagues, 13 nausea and vomiting were the most common GI adverse events. The incidence of nausea was highest on the day of surgery (16.4%) and decreased on each day thereafter (Figure 1). The incidence of vomiting was 1% on the day of surgery but increased to 2% to 3% on PODs 1 through 6. Not surprisingly, the patterns of nausea and vomiting in this analysis correlate with the timing and distribution of postoperative NGT insertion and upper and lower GI recovery (Figure 2) (See Page 13). Question 3: What is the Effect of POI on LOS? The usual LOS after major abdominal surgery reported in clinical trials is 5 to 10 days; in some cases, the LOS exceeds this period. Postoperative ileus can significantly prolong the duration of hospital admission following abdominal surgery. 11,12 As published in the Federal Register, Medicare data based on 161,000 major intestinal resection operations showed a mean LOS of 11.5 days in patients with diagnostic coding for POI compared with only 6.5 days in those without coding for POI (Figure 3) (See Page 14). 10 The increased LOS was related to pain, nausea and vomiting, fatigue, placement of devices such as drains or NGTs, and organ dysfunction that may by induced by stress (Table 6) (See Page 13). 11,12 Recent studies have helped elucidate the relationship between POI and LOS. Chang and colleagues 54 evaluated the records of 304 consecutive patients who underwent radical cystectomy; 144 patients (47.4%) underwent ileal conduit diversion, and 145 patients (47.7%) underwent orthotopic bladder substitution. The median LOS was 7 days (range, 4-48 days). Of 302 patients, 225 were discharged home by POD 8, while 52 of the remaining 77 with increased LOS were discharged home by POD 12. Postoperative ileus was the most common cause of prolonged hospitalization (53 [68.8%] of 77 patients). In the recent investigation reported by Delaney and colleagues, 13 it was shown that recovery of upper and lower GI function was closely associated with LOS. Hospital discharge was most common on the day after the mean time to upper and lower GI recovery (Figure 4) (See Page 14). The mean LOS in their analysis (6.1 days) was similar to the LOS results of 9.9 to 13.7 days reported among a national database for patients who underwent BR (based on the hospital discharge order written). 13 The reported differences may be attributed to patient inclusion criteria used in the trials. Results suggest that GI recovery can be accelerated and that LOS can be decreased with a consistent up-to-date postoperative care pathway. However, despite these interventions, prolonged LOS and patient morbidity still occur, and further effective therapeutic interventions are needed. Figure 1. Incidence of Nasea & Vomiting by Postoperative Day Patients, % Nausea (only) Vomiting (only) Noth nausea and vomiting Postoperative Day *Modified intent-to-treat population, placebo arm HCFA Data (Medicare, ). Evaluating 161,000 major intestinal/colorectal resections from 150 Postoperative upper and lower gastrointestinal recovery and gastrointestinal morbidity in patients undergoing bowel resection pooled analysis US hospitals. of placebo data from three randomized controlled trials. Delaney CP, Senagore AJ, Viscusi ER, Wolff BG, Fort J, Du W, Techner L, Wallin B, for the Alvimopan Postoperative Ileus Study Group. Am J Surgery. 2006; 191(3):