Anesthetic Routines: The Anesthesiologist's Role in GI Recovery and Postoperative Ileus

All patients undergoing bowel resection experience postoperative ileus, a transient cessation of bowel motility that prevents effective transit of intestinal contents or tolerance of oral intake, to varying degrees. An anesthesiologist plays a critical role, not only in the initiation of surgical anesthesia, but also with the selection and transition to effective postoperative analgesia regimens. Attempts to reduce the duration of postoperative ileus have prompted the study of various preoperative, perioperative, and postoperative regimens to facilitate gastrointestinal recovery. These include modifiable variables such as epidural anesthesia and analgesia, opioid-sparing anesthesia and analgesia, fluid restriction, colloid versus crystalloid combinations, prokinetic drugs, and use of the new peripherally acting mu-opioid receptor (PAM-OR) antagonists. Review and appropriate adaptation of these multiple modifiable interventions by anesthesiologists and their surgical colleagues will facilitate implementation of a best-practice management routine for bowel resection procedures that will benefit the patient and the healthcare system.

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title: Clinical perspective on postoperative ileus and the effect of opiates
abstract: Postoperative ileus (POI) is a mandatory period of cessation of intestinal function, after abdominal surgery. Over the last decade research has continued into this field, and while we continue to learn about pathogenesis, few controlled data are available for management. The clinical manifestations of POI are reviewed. Management techniques are also reviewed, including the use of postoperative care plans with early ambulation and diet, the effects of epidural anaesthesia, benefits of laparoscopic approaches for intestinal resection, and potential avenues for prevention using novel medications.

title: Neuroimmune mechanisms in postoperative ileus
abstract: Postoperative ileus (POI) is a common clinical condition arising after almost every abdominal surgical procedure, leading to increased patient morbidity and prolonged hospitalisation. Recent advances in insight into the underlying pathophysiology have identified intestinal inflammation triggered by handling of the intestine as the main mechanism. Not only does the local inflammatory process compromise the contractile activity of the handled intestine, but it also activates inhibitory neural pathways and possibly triggers inflammation at distant untouched areas, leading to a generalised impairment of gastrointestinal motility. Macrophages residing in the muscularis externa and mast cells are the key players in this inflammatory cascade. Pharmacological interventions preventing the activation of these immune cells reduce the influx of leucocytes into the intestine, an effect associated with a reduction of the duration of POI. New potential therapeutic strategies to shorten POI based on these new insights will undoubtedly enter the clinical arena soon.

title: Review of postoperative ileus.
abstract: Postoperative ileus (POI) is an inevitable adverse consequence of surgical procedures. In fact, prolonged POI can lead to patient discomfort, decreased mobility, delayed enteral feeding, and ultimately, prolonged hospitalizations and increased costs. It is believed that POI occurs as a result of inhibitory neural reflexes and inflammatory processes. The use of postoperative opioids also appears to contribute to ileus. Recently, the potential influence of endogenous opioids, in addition to exogenous opioids, on the pathogenesis of ileus has come to light and spurred investigations into new treatment strategies. Over the years, several treatment modalities have become accepted management options for POI; chief among these are nasogastric suction and prokinetic agents. However, data demonstrating that these agents reduce the duration of POI are limited. Of current treatment modalities, use of epidural local anesthetics appears to be the most effective means of reducing POI. Other potentially effective treatments include early enteral feeding and less invasive surgical procedures. Together, these techniques have reduced the length of stay after colonic surgery to 2 to 3 days. Future studies, including those incorporating investigational agents, such as kappa-opioid agonists and peripheral mu-opioid antagonists, into a multimodal regimen, may offer new treatment options to further impact POI duration.

title: Surgical manipulation of the gut elicits an intestinal muscularis inflammatory response resulting in postsurgical ileus.
abstract: To investigate the pathophysiologic mechanisms that lead to ileus after abdominal surgery.



The common supposition is that more invasive operations are associated with a more extensive ileus. The cellular mechanisms of postsurgical ileus remain elusive, and few studies have addressed the mechanisms.



Rats were subjected to incremental degrees of surgical manipulation: laparotomy, eventration, "running," and compression of the bowel. On postsurgical days 1 and 7, muscularis infiltrates were characterized immunohistochemically. Circular muscle activity was assessed using mechanical and intracellular recording techniques in vitro.



Surgical manipulation caused an increase in resident phagocytes that stained for the activation marker lymphocyte function-associated antigen (LFA-1). Incremental degrees of manipulation also caused a progressive increase in neutrophil infiltration and a decrease in bethanechol-stimulated contractions. Compression also caused an increase in other leukocytes: macrophages, monocytes, dendritic cells, T cells, natural killer cells, and mast cells.



The data support the hypothesis that the degree of gut paralysis to cholinergic stimulation is directly proportional to the degree of trauma, the activation of resident gut muscularis phagocytes, and the extent of cellular infiltration. Therefore, postsurgical ileus may be a result of an inflammatory response to minimal trauma in which the resident macrophages, activated by physical forces, set an inflammatory response into motion, leading to muscle dysfunction.

title: Alvimopan for the Management of Postoperative Ileus
abstract: To review the pharmacology, pharmacokinetics, clinical efficacy, safety, dosage, and administration of alvimopan, a peripherally acting μ-opioid receptor antagonist, in the management of postoperative ileus (POI).  A literature search (1980–October 2004%) applying the terms alvimopan, ADL 8–2698, and LY246736 was conducted using MEDLINE. Information was also obtained from scientific congress abstracts and data on file with the manufacturer.  Studies and abstracts investigating alvimopan and POI were considered for inclusion; however, they were restricted to English-language articles.  Alvimopan is a novel, peripherally acting μ-opioid receptor antagonist that is currently under evaluation for the management of POI. POI presents significant clinical challenges that can delay patient recovery and contribute to increased morbidity and prolonged hospitalization after surgery. Clinical trials have demonstrated that alvimopan, at oral doses of 6 and 12 mg, can accelerate time to recovery of gastrointestinal (GI) function and time to hospital discharge following abdominal surgery. The incidence of adverse events with alvimopan therapy was shown to be similar to that of placebo.  Alvimopan is well tolerated and effective at accelerating GI recovery and time to discharge in patients who have undergone bowel resection or hysterectomy when administered prior to surgery and twice daily thereafter until discharge or for up to 7 days. Alvimopan potentially offers significant benefits for patients with POI over currently available treatments.

title: Sympathetic input into the enteric nervous system
abstract: The basic concepts of the autonomic nervous system of organs and tissues were formulated around the turn of the century and summarised in a classical monograph by Langley (1921).1 The detailed distribution of the sympathetic nerves was, however, not elucidated until it became possible to stain sympathetic neurones specifically using the Falck-Hillarp technique. When this technique was applied to the gastrointestinal tract the picture seen was in some respects surprising. At the time it was generally believed that most organs and tissues had a dual innervation (sympathetic and parasympathetic) with opposite effects on function. It seemed, therefore, puzzling when the Falck-Hillarp technique revealed that innervation of a major part of the gastrointestinal wall, the smooth muscle layers, was very scarce. Instead it was found that most adrenergic fibres make contact with one of the two major plexuses in the alimentary canal. Adrenergic innervation is seen in the mucosa, in particular around the crypt epithelium.2 The functional consequences of this distribution are discussed below.

This brief review of the interplay between the sympathetic and enteric nervous systems will discuss the control of blood vessels, epithelial transport, motility, and endocrine cells (the enterochromaffin cells in particular).

There is dense adrenergic innervation of both precapillary and postcapillary vessels in the digestive tract. Stimulating the sympathetic nerves to the gut elicits a blood flow response which is very characteristic. Immediately on electrically stimulating the splanchnic nerves, pronounced vasoconstriction is observed which, however, subsides within a few minutes to reach a steady state level of blood flow. It seems probable that flow during steady state represents the “physiological” response to nerve activation. Intestinal flow resistance is thus only moderately increased (2–3 times) even when stimulating the sympathetic vasoconstrictor nerves at high rates (8–16 Hz). When investigating blood flow distribution within the intestinal wall …

title: Postoperative ileus: a preventable event
abstract: Postoperative ileus has traditionally been accepted as a normal response to tissue injury. No data support any beneficial effect of ileus and indeed it may contribute to delayed recovery and prolonged hospital stay. Efforts should, therefore, be made to reduce such ileus.

title: Opioid-Induced Bowel Dysfunction
abstract: Opioid treatment for postoperative or chronic pain is frequently associated with adverse effects, the most common being dose-limiting and debilitating bowel dysfunction. Postoperative ileus, although attributable to surgical procedures, is often exacerbated by opioid use during and following surgery. Postoperative ileus is marked by increased inhibitory neural input, heightened inflammatory responses, decreased propulsive movements and increased fluid absorption in the gastrointestinal tract. The use of opioids for chronic pain is characterised by a constellation of symptoms including hard dry stools, straining, incomplete evacuation, bloating, abdominal distension and increased gastroesophageal reflux.The current management of opioid-induced bowel dysfunction among patients receiving opioid analgesics consists primarily of nonspecific ameliorative measures. Intensive investigations into the mode of action of opioids have characterised three opioid receptor classes — μ, δ and κ — that mediate the myriad of peripheral and central actions of opioids. Activation of μ-opioid receptors in the gastrointestinal tract is responsible for inhibition of gut motility, whereas receptors in the central nervous system mediate the analgesic actions of opioids. Blocking peripheral opioid receptors in the gut is therefore a logical therapeutic target for managing opioid-induced bowel dysfunction.Available opioid antagonists such as naloxone are of limited use because they are readily absorbed, cross the blood-brain barrier, and act at central opioid receptors to reverse analgesia and elicit opioid withdrawal. Methylnaltrexone and alvimopan are recently developed opioid antagonists with activity that is restricted to peripheral receptors. Both have recently shown the ability to reverse opioid-induced bowel dysfunction without reversing analgesia or precipitating central nervous system withdrawal signs in non-surgical patients receiving opioids for chronic pain. In addition, recent clinical studies with alvimopan suggest that it may normalise bowel function without blocking opioid analgesia in abdominal laparotomy patients with opioid-related postoperative ileus.

title: The Role of Epidural Anesthesia and Analgesia in Surgical Practice
abstract: To review the potential and proven benefits and complications of epidural anesthesia/analgesia.  Advances in analgesia/anesthesia have improved patient satisfaction and perioperative outcomes. Epidural anesthesia/analgesia is one of these advances that is gaining rapid acceptance due to a perceived reduction in morbidity and overall patient satisfaction.  A MEDLINE search was conducted for all pertinent articles on epidural anesthesia/analgesia.  Retrospective, prospective, and meta-analysis studies have demonstrated an improvement in surgical outcome through beneficial effects on perioperative pulmonary function, blunting the surgical stress response and improved analgesia. In particular, significant reduction in perioperative cardiac morbidity (∼30%), pulmonary infections (∼40%), pulmonary embolism (∼50%), ileus (∼2 days), acute renal failure (∼30%), and blood loss (∼30%) were noted in our review of the literature. Potential complications related to epidural anesthesia/analgesia range from transient paresthesias (<10%) to potentially devastating epidural hematomas (0.0006%).  Epidural anesthesia/analgesia has been demonstrated to improve postoperative outcome and attenuate the physiologic response to surgery.

title: Epidural Anesthesia and Gastrointestinal Motility
abstract: P ostoperative ileus, a temporary inhibition of gastrointestinal function, is a universal complication after major abdominal surgery. Treatment for ileus is supportive and has changed little since Wangensteen’s 1932 report (1) that nasogastric suction could delay or replace operative management of bowel obstruction, thereby reducing mortality. Gastric decompression, together with IV hydration and electrolyte replacement, remains the only proven therapy for ileus (2,3). Liu et al. (4) suggest that epidural analgesia may significantly shorten the duration of postoperative ileus. The benefits of a reduction in ileus include decreased patient morbidity and potentially substantial cost-savings, as prolongation of hospitalization in the United States due to ileus has been estimated to cost $1,500 per patient or $750,000,000 annually (3). Nevertheless, clinical guidelines currently promulgated by some consulting firms continue to state that “while epidural analgesia is effective for thoracic surgery and certain major musculoskeletal procedures, it has often been associated with prolonged ileus, delayed oral nutrition, and discharge in patients with gastrointestinal surgery” (Milliman and Robertson, Inc, Actuaries and Consultants, Seattle, WA, written communication, 1996). In this article, the pathophysiology of postoperative ileus is reviewed, and a framework for appreciating the theoretical basis for an effect of epidural anesthesia, especially thoracic epidural anesthesia, on ileus is provided. Potential risks and benefits of epidural anesthesia for bowel surgery are considered, including an examination of relevant animal studies. The major focus of this article is to review recent clinical studies comparing epidural analgesia with systemic analgesia, as well as to review studies comparing epidural narcotics with epidural local anesthetics with regard to postoperative ileus. Catheter location is discussed as a particularly important factor in determining the effects of epidural blockade on gastrointestinal motility. Finally, suggestions for future research are offered.

title: Opioids and opioid receptors in the enteric nervous system: from a problem in opioid analgesia to a possible new prokinetic therapy in humans
abstract: The gut is a neurological organ, which implies that many neuroactive drugs such as opioid analgesics can seriously disturb gastrointestinal function, because many of the transmitters and transmitter receptors present in the brain are also found in the enteric nervous system. One of the most common manifestations of opioid-induced bowel dysfunction is constipation which results from blockade of peristalsis and intestinal fluid secretion. The discovery of opioid receptor antagonists with a peripherally restricted site of action, such as N-methylnaltrexone and alvimopan, makes it possible to normalize bowel function in opiate-treated patients without compromising central opioid analgesia. There is emerging evidence that opioid receptor antagonists may also have prokinetic actions, reversing pathological states of gastrointestinal hypomotility that are due to overactivity of the enteric opioid system.

title: The effect of bupivacaine and morphine on pain and bowel function after colonic surgery
abstract: Sixty patients scheduled for colonic surgery were randomly allocated to four groups according to postoperative pain medication: I. Control group, the patients received oxycodone intramuscularly (0.15 mg kg1) on request. II. Epidural bupivacaine (0.25%) continuously administered by infusion pump, 66 ml h‐1, for 48 h. III. Epidural morphine, 2–6 mg, at the end of operation and repeated on the first and second postoperative mornings. IV. Epidural morphine, 2–6 mg per die, administered for 48 h continuously by infusion pump. All patients received a balanced anaesthesia with enflurane, fentanyl and vecuronium. Postoperatively, intramuscular oxycodone was given on request. There were no significant differences between the groups in changes in peak flow, spirometry and blood‐gas analyses postoperatively. Pain intensity (visual analogue scale) was lower in Groups II and III at 3 h and in Group IV at 24 h compared to the control Group I. All the epidurally treated groups needed less additional analgesics than the control Group I. Postoperatively bowel movements occurred on the second day in Group II (bupivacaine) as compared to the fourth day in all other groups (P < 0.05).

title: Effect of continuous postoperative epidural analgesia on intestinal motility
abstract: The effect of postoperative epidural bupivacaine on intestinal motility was studied by measuring the transit time of barium contrast through the intestines in 16 patients after resection of the left colon and/or rectum. Fourteen patients served as controls and received postoperative injections of pentazocine. Mean transit time through the intestinal tract was 35 h in the epidural group and 150 h in the control group, a difference that is significant at the 0·1 per cent level. The average time before passage of flatus and faeces was different between the two groups at the 0·1 per cent level. We conclude that postoperative epidural bupivacaine constitutes an effective means of analgesia after colorectal surgery and is associated with a short duration of intestinal paralysis.

title: Effects of Perioperative Analgesic Technique on Rate of Recovery after Colon Surgery
abstract: Choice of perioperative analgesia may affect the rate of recovery of gastrointestinal function and thus duration and cost of hospitalization after colonic surgery.

title: Epidural anaesthesia and analgesia - effects on surgical stress responses and implications for postoperative nutrition.
abstract: Surgical injury leads to an endocrine-metabolic and inflammatory response with protein catabolism, increased cardiovascular demands, impaired pulmonary function and paralytic ileus, the most important release mechanisms being afferent neural stimuli and inflammatory mediators.



Epidural local anaesthetic blockade of afferent stimuli reduces endocrine metabolic responses, and improve postoperative catabolism. Furthermore, dynamic pain relief is achieved with improved pulmonary function and a pronounced reduction of postoperative ileus, thereby providing optimal conditions for improved mobilization and oral nutrition, and preservation of body composition and muscle function. Studies integrating continuous epidural local anaesthetics with enforced early nutrition and mobilization uniformly suggest an improved recovery, decreased hospital stay and convalescence.



Epidural local anaesthetics should be included in a multi-modal rehabilitation programme after major surgical procedures in order to facilitate oral nutrition, improve recovery and reduce morbidity.

title: Continuous epidural infusion of bupivacaine and morphine for postoperative analgesia after hysterectomy
abstract: The analgesic efficacy and side‐effects of combined epidural infusion of bupivacaine and morphine, in comparison with these drugs alone, for postoperative analgesia after hysterectomy (60 patients) were evaluated. Before general anaesthesia, all patients had an epidural catheter placed (Th11‐12) and 20 ml of 0.5% bupivacaine was injected. In random order, epidural infusion was continued for 24 h with either 0.25% bupivacaine 4 ml‐ h‐1 (BUPI‐group), a bolus of 2 mg of morphine followed by morphine 0.2 mg‐ h‐1 (MO‐group), or a combination of the two drugs (COMB‐group). A urinary bladder catheter was kept for 24 h. Supplementary postoperative pain medications were i.m. morphine 0.1 mg‐ kg‐1 or rectal indomethacin 50 mg, on request. Immediately after awakening from general anaesthesia and transfer to the recovery room, 18/20 of the BUPI‐group patients, 17/20 of the MO‐group patients and 19/20 of the COMB‐group patients were pain‐free. In the postoperative evening and the first postoperative morning, the corresponding figures were 7/20 and 10/20 in the BUPI‐group, 15/20 and 15/20 in the MO‐group, and 18/20 and 15/20 in the COMB‐group (postop. evening; P<0.01 BUPI vs. others). The number of patients requiring supplementary analgesics (morphine and indomethacin) during the first 24 h was greatest in the BUPI‐group (P<0.01). The number of patients who vomited during the 24‐h period was 3 in the BUPI‐group, 9 in the MO‐group and 5 in the COMB‐group. Postoperatively, normal bowel function was restored after 1.9 days in the BUPI‐group, 2.2 days in the MO‐group and 2.6 days in the COMB‐group, on average (P<0.01 BUPI vs. COMB). Recatheterization of the urinary bladder (once) was required in 4 patients in the MO‐group and 2 in the COMB‐group, but in none of the BUPI‐group. It is concluded that although the morphine‐containing epidural infusions (6.8 mg 24 h‐1) were superior to that containing bupivacaine alone with respect to postoperative analgesia after hysterectomy, the occurrence of disturbing emetic and urinary side‐effects made the therapy not totally satisfactory.

title: Effect of epidural bupivacaine vs combined epidural bupivacaine and morphine on gastrointestinal function and pain after major gynaecological surgery.
abstract: In a double-blind study, we investigated the effects of postoperative epidural local anaesthetic, with or without addition of epidural morphine, on postoperative pain and gastrointestinal function in patients scheduled for radical hysterectomy and pelvic lymphadenectomy. Forty patients were randomized into two study groups: 48-h postoperative epidural 0.2% bupivacaine 8 ml h(-1) (bupi group) or 48-h postoperative epidural 0.2% bupivacaine/morphine 50 microg at 4 ml h(-1) (bupi/morph group). Patients were observed for at least 96 h after surgery. No differences in pain at rest, during cough or mobilization were observed. Patients in the bupi group requested a significant greater amount of supplementary analgesics, but times to first flatus and defaecation were reduced compared with patients in the bupi/morph group. Itching was a significant problem in patients in the bupi/morph group. No differences in postoperative nausea and vomiting, mobilization or time to discharge from hospital were observed between groups. The addition of morphine to postoperative epidural bupivacaine has only limited effect on pain relief and increases time to normalization of gastrointestinal function.

title: Randomized controlled trial comparing the controlled rehabilitation with early ambulation and diet pathway versus the controlled rehabilitation with early ambulation and diet with preemptive epidural anesthesia/analgesia after laparotomy and intestinal resection.
abstract: Multimodal postoperative care regimens accelerate recovery after abdominal surgery. The benefit of thoracic epidural (TE) analgesia over patient-controlled analgesia (PCA) remains unproven when used with a fast-track postoperative care plan.



Fifty-six patients undergoing major intestinal resection, and on a fast-track postoperative care plan, were randomized to preemptive TE or PCA. Patients were evaluated at standard time points for pain score, quality of life (Short Form-36), and complications. Oral analgesia was substituted for TE and PCA on the second postoperative day. Discharge criteria were identical for both groups.



Six patients (20.6%) had a failed epidural. There was no difference in length of stay (5.8 versus 6.2 days, TE versus PCA, P = .55), total length of stay (including readmissions), pain scores, quality of life, complications, or hospital costs at any time point.



TE offers no advantage over PCA for patients undergoing major intestinal resections who are on a fast-track postoperative care plan using PCA.

title: Effect of adding ketorolac to intravenous morphine patient‐controlled analgesia on bowel function in colorectal surgery patients – a prospective, randomized, double‐blind study
abstract: Postoperative ileus (PI) is the transient impairment of bowel motility due to surgical trauma and the associated physiological responses. Postoperative ileus results in patient discomfort, increases gastrointestinal risks, prolongs hospital stay and increases medical expenses. In this study, we investigated the effect of patient‐controlled analgesia (PCA) morphine with or without ketorolac on bowel functions in patients after colorectal surgeries.

title: Opioid-sparing Effects of Ketorolac and Its Correlation With the Recovery of Postoperative Bowel Function in Colorectal Surgery Patients: A Prospective Randomized Double-blinded Study
abstract: ObjectivesPostoperative ileus (PI) is one of many common complications in major abdominal surgery. PI results in patient discomfort, increased gastrointestinal leakage, prolonged hospital stay, and increased medical expenses. In this study, we have investigated the morphine-sparing effects of ketorolac and its correlation with the duration of PI in patients with colorectal surgeries. MethodsWe collected data from 102 patients who had received elective colorectal resection. The patients were randomly allocated into 2 groups and received intravenous patient-controlled analgesia (IVPCA) morphine (M group) or IVPCA morphine plus ketorolac (M+K group). Time-scale morphine consumption (per 12 h), recovery of bowel functions (the first bowel movement and passage of flatus), pain scores, and opioid-related side effects were then recorded. ResultsPatients in the M+K group received 18.3% less morphine than those in the M group within 72 postoperative hours. The maximal opioid-sparing effects of ketorolac appeared in 12 to 24 postoperative hours. The onset of the first bowel movement and passage of flatus was significantly less in the M+K group than in the M group. The M group showed a 5.25 times greater risk of inducing PI, a result comparable with the M+K group in colorectal surgery patients. DiscussionThe addition of ketorolac to IVPCA morphine has demonstrated a clear opioid-sparing effect and benefits in regards to the shortening of the duration of bowel immobility. We suggest that adding ketorolac to morphine IVPCA be included in the multimodal postoperative rehabilitation program for the early restoration of normal bowel function.

title: Meta‐analysis of intravenous lidocaine and postoperative recovery after abdominal surgery
abstract: Continuous intravenous administration of lidocaine may decrease the duration of ileus and pain after abdominal surgery.

title: The Analgesic Effects of Gabapentin After Total Abdominal Hysterectomy
abstract: We investigated, in a randomized, placebo-controlled, double-blind study, the efficacy and safety of gabapentin on pain after abdominal hysterectomy and on tramadol consumption in patients. The 50 patients were randomized to receive either oral placebo or gabapentin 1200 mg 1 h before surgery. Anesthesia was induced with propofol and maintained with sevoflurane in 50% N2O/O2 with a fresh gas flow of 2 L/min (50% N2O in O2) and fentanyl (2 μg/kg). All patients received patient-controlled analgesia with tramadol with a 50 mg initial loading dose, 20 mg incremental dose, 10-min lockout interval, and 4-h limit of 300 mg. The incremental dose was increased to 30 mg if analgesia was inadequate after 1 h. Patients were studied at 4, 8, 12, 16, 20, and 24 h for visual analog (VAS) pain scores, heart rate, peripheral oxygen saturation, mean arterial blood pressure, respiratory rate, sedation, and tramadol consumption. The VAS scores in the sitting and supine position at 1, 4, 8, 12, 16, and 20 h were significantly lower in the gabapentin group when compared with the placebo group up to 20 h after surgery. The tramadol consumption at 12, 16, 20, and 24 h and total tramadol consumption were significantly less in the gabapentin group when compared with placebo group. Sedation scores were similar at all the measured times. There were no differences between groups in adverse effects. Preoperative oral gabapentin decreased pain scores and postoperative tramadol consumption in patients after abdominal hysterectomy.

title: Preemptive use of gabapentin significantly decreases postoperative pain and rescue analgesic requirements in laparoscopic cholecystectomy
abstract: PurposeTo evaluate the comparative preemptive effects of gabapentin and tramadol on postoperative pain and fentanyl requirement in laparoscopic cholecystectomy.MethodsFour hundred fifty-nine ASA I and II patients were randomly assigned to receive 300 mg gabapentin, 100 mg tramadol or placebo in a double-blind manner two hours before laparoscopic cholecystectomy under general anesthesia. Postoperatively, patients’ pain scores were recorded on a visual analogue scale every two hours for the initial 12 hr and thereafter every three hours for the next 12 hr. Patients received fentanyl 2μg·kg−1 intravenously on demand. The total fentanyl consumption for each patient was recorded.ResultsPatients in the gabapentin group had significantly lower pain scores at all time intervals (2.65 ± 3.00, 1.99 ± 1.48, 1.40 ± 0.95, 0.65 ± 0.61) in comparison to tramadol (2.97 ± 2.35, 2.37 ± 1.45, 1.89 ± 1.16, 0.87 ± 0.50) and placebo (5.53 ± 2.22, 3.33 ± 1.37, 2.41 ± 1.19, 1.19 ± 0.56). Significantly less fentanyl was consumed in the gabapentin group (221.16 ± 52.39 μg) than in the tramadol (269.60 ± 44.17 μg) and placebo groups (355.86 ± 42.04 μg;P < 0.05). Sedation (33.98%), nausea/retching/vomiting (24.8%) were the commonest side effects in the gabapentin group whereas respiratory depression (3.9%) was the commonest in the tramadol group and vertigo (7.8%) in the placebo group.ConclusionPreemptive use of gabapentin significantly decreases postoperative pain and rescue analgesic requirement in laparoscopic cholecystectomy.RésuméObjectifÉvaluer et comparer les effets préventifs de la gabapentine et du tramadol sur la douleur postopératoire et les besoins de fentanyl lors d’une cholécystectomie laparoscopique.MéthodeQuatre cent cinquante-neuf patients d’état physique ASA I et II ont été répartis au hasard et ont reçu 300 mg de gabapentine, 100 mg de tramadol ou un placebo, en double aveugle, deux heures avant la cholécystectomie laparoscopique sous anesthésie générale. Après l’opération, les scores de douleur ont été notés sur l’échelle visuelle analogique toutes les deux heures pendant les 12 premières heures et toutes les trois heures pendant les 12 h suivantes. Les patients ont reçu 2 μg·kg−1 de fentanyl intraveineux sur demande et la consommation totale a été notée pour chacun.RésultatsLes patients du groupe gabapentine ont présenté des scores de douleur significativement plus bas pour tous les intervalles de mesures (2,65 ± 3,00; 1,99 ± 1,48; 1,40 ± 0,95; 0,65 ± 0,61) que ceux du groupe tramadol (2,97 ± 2,35; 2,37 ± 1,45; 1,89 ± 1,16; 0,87 ± 0,50) ou placebo (5,53 ± 2,22; 3,33 ± 1,37; 2,41 ± 1,19; 1,19 ± 0,56). La demande de fentanyl a été significativement plus basse avec la gabapentine (221,16 ± 52,39 μg) qu’avec le tramadol (269,60 ± 44,17 μg) ou le placebo (355,86 ± 42,04 μg; P < 0,05). La sédation (33,98 %), les nausées/haut-lec∁ur/vomissements (24,8 %) ont été les effets négatifs les plus fréquents avec la gabapentine tandis que la dépression respiratoire (3,9 %) a été plus fréquente avec le tramadol et le vertige (7,8 %) avec le placebo.ConclusionL’usage préventif de gabapentine diminue significativement la douleur postopératoire et la demande d’analgésique de secours lors de la cholécystectomie laparoscopique.

title: (–)-(1R,2R)-3-(3-Dimethylamino-1-ethyl-2-methyl-propyl)-phenol Hydrochloride (Tapentadol HCl): a Novel μ-Opioid Receptor Agonist/Norepinephrine Reuptake Inhibitor with Broad-Spectrum Analgesic Properties
abstract: (–)-(1R,2R)-3-(3-Dimethylamino-1-ethyl-2-methyl-propyl)-phenol hydrochloride (tapentadol HCl) is a novel μ-opioid receptor (MOR) agonist (Ki = 0.1 μM; relative efficacy compared with morphine 88% in a [35S]guanosine 5′-3-O-(thio)triphosphate binding assay) and NE reuptake inhibitor (Ki = 0.5 μM for synaptosomal reuptake inhibition). In vivo intracerebral microdialysis showed that tapentadol, in contrast to morphine, produces large increases in extracellular levels of NE (+450% at 10 mg/kg i.p.). Tapentadol exhibited analgesic effects in a wide range of animal models of acute and chronic pain [hot plate, tail-flick, writhing, Randall-Selitto, mustard oil colitis, chronic constriction injury (CCI), and spinal nerve ligation (SNL)], with ED50 values ranging from 8.2 to 13 mg/kg after i.p. administration in rats. Despite a 50-fold lower binding affinity to MOR, the analgesic potency of tapentadol was only two to three times lower than that of morphine, suggesting that the dual mode of action of tapentadol may result in an opiate-sparing effect. A role of NE in the analgesic efficacy of tapentadol was directly demonstrated in the SNL model, where the analgesic effect of tapentadol was strongly reduced by the α2-adrenoceptor antagonist yohimbine but only moderately attenuated by the MOR antagonist naloxone, whereas the opposite was seen for morphine. Tolerance development to the analgesic effect of tapentadol in the CCI model was twice as slow as that of morphine. It is suggested that the broad analgesic profile of tapentadol and its relative resistance to tolerance development may be due to a dual mode of action consisting of both MOR activation and NE reuptake inhibition.

title: A randomized, double-blind, placebo-controlled phase 3 study of the relative efficacy and tolerability of tapentadol IR and oxycodone IR for acute pain
abstract: To evaluate the relative efficacy and tolerability of tapentadol immediate release (IR) and oxycodone IR for management of moderate to severe pain following orthopedic surgery (bunionectomy).  Randomized patients (N = 901) received oral tapentadol IR 50 or 75 mg, oxycodone HCl IR 10 mg, or placebo every 4–6 h over a 72-h period following surgery. Acetaminophen (≤2 g) was allowed in the first 12 h after the first dose of study drug. In the primary analysis, tapentadol IR (50 and 75 mg) was evaluated for efficacy superior to placebo and non-inferior to oxycodone HCl IR 10 mg (using sum of pain intensity difference [SPID] over 48 h), and tolerability superior to oxycodone IR (using incidence of treatment-emergent adverse events [TEAEs] of nausea and/or vomiting).  Statistically significantly higher mean SPID48 values were observed with tapentadol IR (50 and 75 mg) and oxycodone HCl IR 10 mg than placebo (all p < 0.001). The efficacy of tapentadol IR 50 mg and 75 mg was non-inferior to oxycodone HCl IR 10 mg. The incidence of TEAEs of nausea and/or vomiting was statistically significantly lower with tapentadol IR 50 mg versus oxycodone IR 10 mg (35 vs. 59%; p < 0.001). No statistically significant difference in the incidence of nausea and/or vomiting was observed between tapentadol IR 75 mg and oxycodone IR 10 mg (51 vs. 59%; p = 0.057). A possible limitation of this study was that the intense dose and patient monitoring may not represent real-world situations and may result in higher incidences of TEAEs than expected in a practice setting; this bias would be similar for all treatment groups.  Clinically meaningful and statistically significant improvements were observed with tapentadol IR 50 mg and 75 mg compared with placebo for the relief of moderate-to-severe acute pain after orthopedic surgery. Tapentadol IR 50 mg and 75 mg were non-inferior to oxycodone HCl IR 10 mg for the treatment of acute pain based on the primary efficacy endpoint of SPID48 and the pre-specified margin of 48 points. The incidence of nausea and/or vomiting was statistically significantly lower for tapentadol IR 50 mg and numerically lower for tapentadol IR 75 mg than for oxycodone HCl IR 10 mg.

title: The gastrointestinal tract after anaesthesia.
abstract: Gastrointestinal tract motility may be reduced markedly after surgery with delay in gastric emptying. these alterations are induced partly by surgery, partly by the residual effects of anaesthetic agents, and particularly by opioids administered for post-operative pain relief. These changes may be antagonized to a certain extent by administration of prokinetic agents such as cisapride. Post-operative ileus reduces the rate of mobilization and may also reduce or delay absorption of drugs administered by the gastrointestinal tract. Furthermore, post-operative nausea and vomiting, multi-factorial in aetiology, may ensue and also be responsible for delayed mobilization, subjective discomfort and delay in administration of oral agents post-operatively. A serious problem may be leakage from bowel anastomoses. Although the causes are primarily surgical, an increase in bowel contractility may be deleterious and it has been suggested that neostigmine and morphine may be implicated in anastomotic dehiscence.

title: Anaesthesia, surgery, and challenges in postoperative recovery
abstract: Surgical injury can be followed by pain, nausea, vomiting and ileus, stress-induced catabolism, impaired pulmonary function, increased cardiac demands, and risk of thromboembolism. These problems can lead to complications, need for treatment in hospital, postoperative fatigue, and delayed convalescence. Development of safe and short-acting anaesthetics, improved pain relief by early intervention with multimodal analgesia, and stress reduction by regional anaesthetic techniques, beta-blockade, or glucocorticoids have provided important possibilities for enhanced recovery. When these techniques are combined with a change in perioperative care a pronounced enhancement of recovery and decrease in hospital stay can be achieved, even in major operations. The anaesthetist has an important role in facilitating early postoperative recovery by provision of minimally-invasive anaesthesia and pain relief, and by collaborating with surgeons, surgical nurses, and physiotherapists to reduce risk and pain.

title: Failure of Epidural Anesthesia to Prevent Postoperative Paralytic Ileus
abstract: &NA; This study used radiopaque markers and serial abdominal radiographs to assess the effect of epidural anesthesia on postoperative colonic ileus. Epidural anesthesia did not result in significantly faster return of propulsive motility in the colon after surgery as compared with control (P > 0.05). In addition, no significant difference was seen between the groups in colonic transit time and time for the first passage of gas and feces. The level of inhibition of sympathetic efferent nerves to the abdominal cavity was assessed by repeated measurements of blood glucose levels during the first postoperative day. Blood glucose levels were found to be significantly lower in the epidural group, demonstrating an inhibition of efferent sympathetic nerves below the level of T‐5. Results show lack of effect of continuous epidural anesthesia in the prevention of postoperative paralytic ileus and suggest that mechanisms other than spinal reflexes play a major part in the development and maintenance of intestinal paralysis.

title: Randomized controlled trial to examine the influence of thoracic epidural analgesia on postoperative ileus after laparoscopic sigmoid resection
abstract: The aim of the study was to evaluate whether perioperative epidural analgesia had any effect on the duration of postoperative ileus after laparoscopic sigmoid resection.

title: Allergen-induced increase of eosinophil cationic protein in nasal lavage fluid: effect of the glucocorticoid budesonide.
abstract: It was our aim to study the effect of nasal allergen provocation on the concentration of eosinophil cationic protein (ECP) in nasal lavage fluid, with and without glucocorticoid pretreatment. Twenty grass-pollen sensitive volunteers were provoked outside the pollen season on 2 consecutive days after pretreatment for 2 weeks with the glucocorticoid, budesonide, as a nasal spray (400 micrograms/day) and with placebo with a double-blind, crossover design. Nasal lavage fluid was repeatedly collected during a 10-hour period to study both early and late-phase responses. 99mTechnetium-albumin was added to the lavage fluid, making it possible to calculate the amount of secretion and the degree of dilution. The results were as follows: (1) There was no correlation between ECP concentration and dilution factor in the individual samples. (2) The mean concentration of ECP in lavage fluid from untreated, prechallenge noses was 400 micrograms/L. (3) The ECP level did not increase during the early phase response. (4) There was a late occurring increase in the ECP concentration (6 to 24 hours). (5) This increase was completely inhibited by budesonide pretreatment. (6) The glucocorticoid therapy also reduced the prechallenge ECP concentration. In conclusion, allergen provocation in the nose results in a late occurring increase of ECP in nasal lavage fluid, and one of the therapeutic effects of topical glucocorticoid therapy may be an inhibition of the allergen-induced increase of this cytotoxic molecule.

title: Pathophysiology and clinical implications of perioperative fluid excess.
abstract: The practice of perioperative fluid therapy is variable, ranging from ‘high volume’ to ‘dry’ regimen. A review of the data on the effect of ‘high volume’ perioperative fluid therapy suggests that the resulting overhydration may have deleterious effects on cardiac and pulmonary function, and on recovery of gastrointestinal motility (postoperative ileus), tissue oxygenation, wound healing and coagulation. These observations call for randomized studies of the effects of ‘high’ vs ‘low’ volume replacement therapy on postoperative morbidity, in order to establish evidence-based guidelines for perioperative fluid management. Perioperative fluid replacement has been, and still is, the focus of much debate. This debate has primarily focused on the various types of fluid components available for replacement therapy, and not on the actual amount of fluid administered.

title: Effect of salt and water balance on recovery of gastrointestinal function after elective colonic resection: a randomised controlled trial
abstract: Low concentrations of albumin in serum and long gastric emptying times have been returned to normal in dogs by salt and water restriction, or a high protein intake. We aimed to determine the effect of salt and water balance on recovery of gastrointestinal function after elective colonic resection in human beings.



We randomly allocated ten patients to receive postoperative intravenous fluids in accordance present hospital practice (> or = 3 L water and 154 mmol sodium per day) and ten to receive a restricted intake (< or = 2 L water and 77 mmol sodium per day). All patients had no disease other than colonic cancer. The primary endpoint was solid and liquid-phase gastric emptying time, measured by dual isotope radionuclide scintigraphy on the fourth postoperative day. Secondary endpoints included time to first bowel movement and length of postoperative hospital stay. Analysis was by intention to treat.



Median solid and liquid phase gastric emptying times (T(50)) on the fourth postoperative day were significantly longer in the standard group than in the restricted group (175 vs 72.5 min, difference 56 [95% CI 12-132], p=0.028; and 110 vs 73.5 min, 52 [9-95], p=0.017, respectively). Median passage of flatus was 1 day later (4 vs 3 days, 2 [1-2], p=0.001); median passage of stool 2.5 days later (6.5 vs 4 days, 3 [2-4], p=0.001); and median postoperative hospital stay 3 days longer (9 vs 6 days, 3 [1-8], p=0.001) in the standard group than in the restricted group. One patient in the restricted group developed hypokalaemia, whereas seven patients in the standard group had side-effects or complications (p=0.01).



Positive salt and water balance sufficient to cause a 3 kg weight gain after surgery delays return of gastrointestinal function and prolongs hospital stay in patients undergoing elective colonic resection.

title: Effect of Intraoperative Fluid Management on Outcome after Intraabdominal Surgery
abstract: The debate over the correct perioperative fluid management is unresolved. The impact of two intraoperative fluid regimes on postoperative outcome was prospectively evaluated in 152 patients with an American Society of Anesthesiologists physical status of I–III who were undergoing elective intraabdominal surgery. Patients were randomly assigned to receive intraoperatively either liberal (liberal protocol group [LPG], n = 75; bolus of 10 ml/kg followed by 12 ml · kg−1 · h−1) or restrictive (restrictive protocol group [RPG], n = 77; 4 ml · kg−1 · h−1) amounts of lactated Ringer's solution. The primary endpoint was the number of patients who died or experienced complications. The secondary endpoints included time to initial passage of flatus and feces, duration of hospital stay, and changes in body weight, hematocrit, and albumin serum concentration in the first 3 postoperative days. The number of patients with complications was lower in the RPG (P = 0.046). Patients in the LPG passed flatus and feces significantly later (flatus, median [range]: 4 [3–7] days in the LPG vs. 3 [2–7] days in the RPG; P < 0.001; feces: 6 [4–9] days in the LPG vs. 4 [3–9] days in the RPG; P < 0.001), and their postoperative hospital stay was significantly longer (9 [7–24] days in the LPG vs. 8 [6–21] days in the RPG; P = 0.01). Significantly larger increases in body weight were observed in the LPG compared with the RPG (P < 0.01). In the first 3 postoperative days, hematocrit and albumin concentrations were significantly higher in the RPG compared with the LPG. In patients undergoing elective intraabdominal surgery, intraoperative use of restrictive fluid management may be advantageous because it reduces postoperative morbidity and shortens hospital stay.

title: Effect of intraoperative fluid administration and colloid osmotic pressure on the formation of intestinal edema during gastrointestinal surgery.
abstract: The effects of intraoperative changes in plasma colloid osmotic pressure (COP) on the formation of intestinal edema were studied in patients during modified Whipple's operation (hemipancreato-duodenectomy). Eighteen patients (ASA physical status I or II) were randomly assigned to one of three groups. They received either lactated Ringer's (RL group, n = 6), 10% hydroxyethyl starch (HES group, n = 6), or 20% human albumin (HA group, n = 6) as a volume replacement solution, which was given to maintain central venous pressure (CVP) at the preoperative level. Jejunal specimens were obtained after the first transsection of the jejunum and prior to the jejuno-jejunostomy. Their water fraction (g H2O/g tissue dry weight) was measured gravimetrically. COP was determined prior to induction of anesthesia and upon removal of the second jejunal sample. In the RL group, 3,850 +/- 584 ml (data are means +/- SEM) of volume replacement solution were infused from induction of anesthesia to removal of the second jejunal sample. In the HES group, 1,358 +/- 45 ml were infused, and in the HA group, 463 +/- 49 ml were infused. During this time, COP decreased from 20.3 +/- 0.5 mmHg to 14.1 +/- 0.6 mmHg in the RL group, remained at 22.0 +/- 0.9 mmHg in the HES group, and increased from 20.7 +/- 0.9 mmHg to 28.1 +/- 0.9 mmHg in the HA group.(ABSTRACT TRUNCATED AT 250 WORDS)

title: Basic and clinical pharmacology of new motility promoting agents
abstract: Recent research has provided new information about drugs that could be used to treat functional motility disorders. Promotility drugs accelerate gastric emptying or colonic transit and these properties may contribute to their efficacy in treating symptoms associated with gastroparesis, functional dyspepsia or constipation. 5‐Hydroxytryptamine4 receptors are targets for drugs (tegaserod, renzapride) that treat symptoms in constipated irritable bowel syndrome patients and in gastroparesis. Drugs acting at motilin (erythromycin) and cholecystokinin‐1 (dexloxiglumide) receptors accelerate gastric emptying. Dexloxiglumide might be useful in the treatment of functional dyspepsia particularly that associated with lipid intake. Alvimopan is a μ‐opioid receptor antagonist that does not cross the blood brain barrier. Alvimopan is effective in treating postsurgical ileus and perhaps opiate‐induced bowel dysfunction. Successes and failures of recent efforts to develop promotility agents revealed opportunities and challenges for developing new promotility drugs. The pharmacological properties of partial agonists might be exploited to develop effective promotility drugs. However, opposing actions of promotility agents on motility (increased contraction vs decreased accommodation) limit the clinical efficacy of drugs with these opposing actions. Selection of appropriate patient populations for evaluation of new drugs is also critical.

title: Prokinetic Agents for the Treatment of Postoperative Ileus in Adults: A Review of the Literature
abstract: Metoclopramide, cisapride, and erythromycin are commonly administered to reduce the duration of postoperative ileus (POI). As these agents are not without potential adverse effects, their efficacy in shortening the duration of POI should be evaluated. The etiology of POI is not well understood and therefore the precise treatment is unclear. Nasogastric suction is the mainstay of therapy, and management of fluid and electrolyte imbalances is crucial. The role of prokinetic agents is less understood. Available literature evaluating these drugs specifically for POI were reviewed, but results are confounded by issues such as sample size, variability in types of operations performed, and insensitive end points (flatus, bowel sounds). No literature supports reducing the duration of POI with metoclopramide, and limited data show benefit with cisapride. Data evaluating erythromycin are sparse, and the drug is believed to be ineffective. Domperidone, a prokinetic agent not available in the United States, has not been evaluated in POI. Due to these limitations, treatment remains largely supportive with a limited role for prokinetic agents.

title: Neostigmine increases postoperative colonic motility in patients undergoing colorectal surgery.
abstract: Gastrointestinal motility is frequently impaired after abdominal surgery. We investigated the effects of neostigmine on colonic motility in patients after colorectal surgery and in healthy volunteers.



Colonic motility was recorded by a manometry/barostat system in 12 patients after left colonic or rectal resection during baseline and after the intravenous administration of increasing doses of neostigmine on postoperative days 1, 2, and 3. In addition, colonic motility was recorded in 7 healthy volunteers.



Neostigmine increased the colonic motility index. This increase was from 135 +/- 28 mm Hg/min at baseline to 574 +/- 219 mm Hg/min after administration of 5 microg/kg neostigmine on day 3 after surgery (mean +/- SEM, P <.05). In healthy volunteers, neostigmine at a dose of 5 microg/kg increased the colonic motility index from 184 +/- 73 to 446 +/- 114 mm Hg/min (P <.05). Barostat bag volumes decreased dose-dependently after neostigmine administration in patients as well as in volunteers, indicating an increase in colonic tone.



Colonic motility and tone increased after neostigmine administration at a dose of 5 microg/kg in postoperative patients and in healthy volunteers. Neostigmine can be used to stimulate colonic motility after colorectal surgery and has a similar effect postoperatively as in healthy volunteers.

title: Amelioration of intestinal dysmotility and stasis by octreotide early after small-bowel autotransplantation in dogs.
abstract: Intestinal dysmotility and stasis after intestinal transplantation are considered to promote bacterial overgrowth and translocation. Two prokinetic agents, KW5139 (13-leu-motilin) and the somatostatin analogue octreotide acetate, were studied to determine whether they can ameliorate intestinal dysmotility during the early postoperative period.



Motility was recorded by multiple extraluminal strain-gauge transducers in 6 dogs on postoperative days 1, 3, 7, and 14. A barium meal study was performed with a separate group of 8 dogs on postoperative days 3 and 7.



The agent KW5139 induced brief, weak contractions in the graft and had little effect on the dilated bowel; however, octreotide induced motor activity that propelled accumulated intestinal contents into the colon and reduced dilation of the transplanted bowel.



Octreotide, but not KW5139, ameliorates intestinal dysmotility associated with bowel autotransplantation during the early postoperative period. Short-term administration of octreotide may be useful for the treatment of dysmotility following intestinal transplantation.

title: Postoperative Ileus
abstract: The pathogenesis of postoperative ileus (PI) is multifactorial, and includes activation of inhibitory reflexes, inflammatory mediators and opioids (endogenous and exogenous). Accordingly, various strategies have been employed to prevent PI. As single-modality treatment, continuous postoperative epidural analgesia including local anaesthetics has been most effective in the prevention of PI. Choice of anaesthetic technique has no major impact on PI. Minimally invasive surgery reduces PI, in accordance with the sustained reduction in the inflammatory responses, while the effects of early institution of oral nutrition on PI per se are minor. Several pharmacological agents have been employed to resolve PI (propranolol, dihydroergotamine, neostigmine, erythromycin, cisapride, meto-clopramide, cholecystokinin, ceruletide and vasopressin), most with either limited effect or limited applicability because of adverse effects. The development of new peripheral selective opioid antagonists is promising and has been demonstrated to shorten PI significantly. A multi-modal rehabilitation programme including continuous epidural analgesia with local anaesthetics, enforced nutrition and mobilisation may reduce PI to 1–2 days after colonic surgery.

title: Gastrointestinal prokinetic drugs have different affinity for the human cardiac human ether-à-gogo K(+) channel.
abstract: Agonists of the serotonin 5-hydroxytryptamine 4 (5-HT4) receptor are widely used to activate motility in the gastrointestinal tract. Among these, cisapride was recently withdrawn from the U.S. market because of its proarrhythmic effects. Cisapride is a potent blocker of human ether-à-gogo (HERG) K(+) channels and prolongs the cardiac action potential in a reverse use dependence manner. We compared the effects of four different 5-HT4 receptor agonists (cisapride, prucalopride, renzapride and mosapride) on cloned HERG channels with the objective to evaluate and compare their proarrhythmic potential. K(+) currents from HERG-transfected COS-7 cells were recorded under physiological conditions using the whole cell configuration of the patch-clamp technique. Short (500 ms) depolarizing prepulses were used and following deactivating HERG currents were measured. Cisapride inhibited the HERG channels in a concentration-dependent manner with an IC(50) of 2.4 10(-7) M. The IC(50) value for prucalopride to block HERG (5.7 10(-6) M) was 20-fold higher than that of cisapride. Renzapride was slightly more potent than prucalopride (IC(50) = 1.8 10(-6) M). Mosapride produced no significant effects on the recombinant HERG current. The voltage dependence of HERG block was also investigated. The block mediated by cisapride or renzapride was voltage-dependent whereas that produced by prucalopride was not. We conclude that the rank order of potency of 5-HT4 agonists to block HERG is cisapride > renzapride > prucalopride > mosapride. We also conclude that 5-HT4 agonists devoid of side effects on the HERG current such as mosapride can be found as a safe alternative to cisapride.

title: Use of novel prokinetic agents to facilitate return of gastrointestinal motility in adult critically ill patients
abstract: feeding due to impaired gastrointestinal motility is common in critically ill patients. Strategies to prevent or treat gastrointestinal hypomotility include the use of prokinetic agents. Many currently employed prokinetic agents are associated with serious adverse drug reactions. The novel prokinetic agents – alvimopan, tegaserod, and dexloxiglumide – are reviewed. Recent findingsAlvimopan exerts mixed, but generally favorable, effects on restoration of gastrointestinal motility in patients with postoperative ileus. The observation of increased opioid requirements (without increased pain scores) and associated clinical ramifications requires further study. Tegaserod stimulates the peristaltic reflex and improves motility in multiple sites along the gastrointestinal tract. Its efficacy in improving gastrointestinal hypomotility in the critically ill population has not yet been determined. Furthermore, its use has been associated with the development of ischemic colitis and increased requirement for abdominal/pelvic surgery. Dexloxiglumide may be beneficial for improving gastric emptying in critically ill patients, especially those receiving lipid-enriched enteral feeds. SummaryNovel prokinetic agents show promise for management of gastrointestinal hypomotility in the critically ill population. However, further study is required before these agents can be recommended for use.

title: Effect of erythromycin on gastric motility in controls and in diabetic gastroparesis.
abstract: The effect of three doses of erythromycin on interdigestive gastrointestinal motility and on plasma motilin levels was studied in healthy volunteers and patients with diabetic gastroparesis. Abnormalities of interdigestive motility were observed in 40% of the patients. In healthy volunteers, 40 mg erythromycin elicited a premature phase 3 that started in the stomach. In contrast to the spontaneous gastric phase 3, this erythromycin-induced phase 3 was not accompanied by a motilin peak. In patients with diabetic gastroparesis, 40 mg erythromycin induced a premature phase 3 in three patients, no response in one patient, and a burst of antral contractions in another patient. Doses of 200 and 350 mg erythromycin elicited a burst of antral phase-3-like contractions in both volunteers and patients, which was not accompanied by a motilin peak. This phase-3-like activity did not migrate to the small intestine and was not followed by a phase 1, but by a prolonged period of antral contractile activity. The number and amplitude of antral contractions after 200 or 350 mg erythromycin were significantly higher than after 40 mg. The motor patterns induced by different doses of erythromycin offer potential therapeutic applications.

title: Motilin and Clinical Application
abstract: Motilin is a regulatory polypeptide of 22 amino acid residues and orginates in motilin cells scattered in the duodenal epithelium of most mammals and chickens. Motilin is released into the general circulation at about 100-min intervals during the interdigestive state and is the most important factor in controlling the interdigestive migrating contractions. Recent studies have revealed that motilin stimulates endogenous release of the endocrine pancreas. Clinical application of motilin as a prokinetic has become possible since erythromycin and its derivatives were proved to be nonpeptide motilin agonists.

title: Effect of intravenous erythromycin on postoperative ileus.
abstract: We attempted to determine whether the administration of erythromycin shortens the period of postoperative ileus by a prospective, double-blind, placebo-controlled study. Seventy-seven patients were randomized and included in the statistical calculations. The patients were stratified according to the operation performed (cholecystectomy, celiotomy, or other major abdominal operations). Forty-one patients (group 1) received 250 mg erythromycin intravenously every 8 h for nine doses upon admission to the recovery room. Thirty-six patients (group 2) received placebo. The time (in hours) to first passage of flatus, first liquid meal, first bowel movement, and total length of hospital stay was recorded. There was no significant difference between group 1 and group 2 in time to first flatus (54.9 +/- 29 vs. 53.9 +/- 27 h, respectively), first meal (70.4 +/- 44 vs. 71.7 +/- 65), first bowel movement (81.8 +/- 32 vs. 80.1 +/- 28), or length of hospital stay (185.2 +/- 183 vs. 182.1 +/- 163). Erythromycin, in the dosage tested in this study, does not seem to alter clinical parameters of gastrointestinal motility after an abdominal operation. New prokinetic agents may deserve further studies.

title: Prokinetic effect of erythromycin after colorectal surgery
abstract: Nausea and vomiting three to seven days after an elective operation on the colon and rectum remain a persistent clinical problem. Erythromycin, a safe, inexpensive drug that stimulates intestinal motilin receptors, has previously been shown to accelerate gastric emptying significantly after upper gastrointestinal surgery. We aimed to evaluate the effect of postoperative intravenous erythromycin on postoperative ileus in patients undergoing elective surgery for primary colorectal cancer.  Between May 1998 and April 1999, 150 patients undergoing primary resection of colon or rectal cancer were enrolled in this prospective, randomized, placebo-controlled trial. One hundred thirty-four patients completed the study. Patients were excluded if they had extensive metastatic disease, were taking medications known to interact with erythromycin, or if they required an ileostomy. Patients received either 200 mg of intravenous erythromycin or placebo every six hours. Clinical endpoints were recorded and continuous endpoints are presented as mean ± standard deviation.  There were no significant complications related to erythromycin. The erythromycin (n=65) and placebo (n=69) groups were comparable regarding demographic and operative factors. The erythromycin group had a slightly shorter length of time to passage of flatus (4.1 ± 1.3vs. 4.4 ± 1.1 days;P=0.03). There was no significant difference between erythromycin and placebo in time to first solid food (5.6 ± 1.9vs. 5.4 ± 1.8 days), time to first bowel movement (5.2 ± 1.9vs. 5.4 ± 1.3 days), or time to discharge from hospital (7.5 ± 2.0vs. 7.6 ± 2.8 days). There was no difference in the rate of clinically significant nausea (26vs. 26 percent;P=0.99), vomiting (17vs. 16 percent;P=0.88), or nasogastric tube placement (9vs. 7 ).  Erythromycin does not seem to alter clinically important outcomes related to postoperative ileus in patients undergoing resection for colorectal cancer.

title: Negative effect of Metoclopramide in postoperative adynamic ileus. A prospective, randomized, double blind study
abstract: In a double blind controlled study including 60 patients it was found that Metoclopramide has a negative effect upon the resolution of postoperative adynamic ileus. Metoclopramide causes a delay in the time from operation to the first passage of flatus.

title: The Effects of Metoclopramide on Postoperative Ileus A Randomized Double‐blind Study
abstract: Metoclopramide or placebo was administered postoperativcly in a randomized, double-blind fashion to 115 patients undergoing laparotomy. The effect of metoclopramide on postoperative adynamic ileus (PAI) was evaluated. The patients were stratified into two groups: Group A—those with laparotomy without a gastrointestinal anastomosis or ostomy procedure, and group B—those with laparotomy undergoing an anastomosis or ostomy procedure. Metoclopramide reduced nausea and emesis postoperatively. However, the only significant effect on postoperative adynamic ileus was an earlier return to tolerance of solid foods in the patients in Group A.

title: Does metoclopramide reduce the length of ileus after colorectal surgery?
abstract: Between August 1988 and September 1989, 100 consecutive patients who underwent elective abdominal colorectal surgical procedures were prospectively randomized to receive or not to receive metoclopramide. Metoclopramide was intravenously administered every 8 hours from the completion of surgery until a solid food diet was able to be tolerated. Seven patients were not included in the final tabulations because of one death, one small bowel obstruction requiring laparotomy, one anastomotic leak requiring laparotomy, and four protocol violations. Ninety-three patients, 37 men and 56 women (mean age, 59.5; range, 14–89 years) underwent 40 segmental colectomies, 13 total abdominal colectomies, 8 abdominoperineal resections, 8 ileoanal pouch procedures, 7 small bowel resections, and 17 other colorectal procedures. The 40 patients who received postoperative metoclopramide were in Group 1, and the 53 who did not were in Group 2. The mean length of time between laparotomy and commencement of oral fluid and oral solid intake in Groups 1 and 2 were 3.5 and 4.8 days, and 3.5 and 5.0 days, respectively. These differences were not statistically significant (P>0.05). Prolonged ileus was seen in seven patients in Group 1 and in eight patients in Group 2. These differences were also not statistically significant (P>0.05). Prolonged ileus was defined as the need for nasogastric tube reinsertion or discontinuation of oral intake. We conclude that metoclopramide does not significantly alter the course of postoperative ileus.

title: Effect of surgical stress on endogenous morphine and cytokine levels in the plasma after laparoscopoic or open cholecystectomy
abstract: Endogenous morphine in the brain leads to various biological responses after surgery. The aim of this study was to determine whether morphine levels in the plasma would be enhanced by open laparotomy rather than by laparoscopic procedures.
 Methods: We compared 19 patients who underwent laparoscopic cholecystectomy with five patients who underwent resection of the gallbladder by open laparotomy. Morphine levels in the plasma were measured by an electrochemical detection system.
  Postoperative endogenous morphine levels were higher with open laparotomy than with the laparoscopic technique (three h after surgery: open, 200 ± 52.6 fmol/ml vs laparoscopy, 17.6 ± 3.7, p < 0.01). This morphine elevation accounted for higher levels of cytokine, greater pain scores, and longer duration of fasting in open laparotomized patients than in laparoscopic cholecystectomy patients. Stress hormone levels in the plasma were also higher with open laparotomy than with laparoscopy.
  Morphine synthesis was enhanced by open laparotomy, resulting in greater biological response postoperatively than that seen with laparoscopic cholecystectomy.

title: Analgesic agents for the postoperative period. Opioids.
abstract: Opioids are the most commonly used medication for patients with acute pain. Morphine is the prototype with which all other opioids are compared. Synthetic and semisynthetic derivatives of morphine have unique properties, allowing for the use of a larger selection of medication. An understanding of the mechanisms of action, adverse effects, and routes of administration of the various potent opioids is important for good postoperative pain management.

title: ADL 8‐2698, a trans‐3,4‐dimethyl‐4‐ (3‐hydroxyphenyl) piperidine, prevents gastrointestinal effects of intravenous morphine without affecting analgesia
abstract: ADL‐8–2698 is a novel peripherally restricted opioid antagonist that may selectively prevent opioid‐induced gastrointestinal effects without reversing analgesia. Gastrointestinal transit time (lactulose hydrogen breath test) was measured in 14 volunteers with oral and intravenous placebo, oral placebo and intravenous morphine (0.05 mg · kg−1), and oral ADL 8–2698 (4 mg) and intravenous morphine (0.05 mg · kg−1) in a double blind, cross‐over study. Morphine prolonged gastrointestinal transit time from 69 to 103 minutes (P = .005); this was prevented by ADL 8–2698 (P = .004). Postoperatively, 45 patients were randomly assigned in a double‐blind fashion to receive ADL 8–2698 (4 mg) or placebo and intravenous morphine (0.15 mg/kg) or to receive oral and intravenous placebo. Analgesia and pupil constriction were measured. Morphine analgesia and pupil constriction were unaffected by ADL 8–2698 and differed from placebo (P < .002). We conclude that ADL 8–2698 prevents morphine‐induced increases in gastrointestinal transit time by means of selective peripheral opioid antagonism without affecting central opioid analgesia.

title: Effects of enteric‐coated methylnaltrexone in preventing opioid‐induced delay in oral‐cecal transit time
abstract: Methylnaltrexone is the first peripheral opioid receptor antagonist. It has the potential to prevent or reverse the peripherally mediated gastrointestinal effects of opioids. In previous human volunteer trials, we demonstrated that oral uncoated methylnaltrexone prevented morphine‐induced delay in gastrointestinal transit time.

title: Antagonism of Gastrointestinal Opioid Effects
abstract: The opium poppy has been used for several thousand years to control diarrhea and relieve pain. In 1803, Sertürner reported the isolation of a pure active alkaline substance from opium, and named it “morphine,” after Morpheus, the Greek god of dreams. Today, morphine and other opioids are widely used in clinical settings, especially as analgesics to treat moderate to severe pain. Opioids are also frequently used as premedicant drugs before anesthesia and surgery because of their sedative, anxiolytic, and analgesic properties. A common side effect of opioids as pain medications is constipation. Constipation is a significant problem in 40% to 45% of patients with metastatic malignancy1,2 and in 90% of patients treated with opioids.3 Data from animal experiments show that the gastrointestinal (GI) tract is very sensitive to opioids, even at very low doses. The ratio between subcutaneous analgesic and constipating doses of morphine in the rat is approximately 4 to 1, i.e., 4 times more morphine needed for analgesia than slowing of motility.4 Another report indicated that approximately 20 times less oral morphine is needed to antagonize castor oil diarrhea than to produce analgesia in mice.5 This gut sensitivity to opioids is probably caused by relatively poor penetration of morphine into the brain and, thus, partly explains why constipation is a severe problem in those patients receiving opioids. In addition, it is well known that tolerance develops with repeated use of opioids to relieve pain, but tolerance does not appear to extend to GI motility and transit. Opioid receptors and endorphins are widely distributed in the central nervous system (CNS) and throughout the GI tract. However, the site of action of exogenous opioid-induced constipation is somewhat controversial. Data from animal experiments show that morphine can act within the CNS to alter autonomic outflow to the gut.6 However, opioids may also affect intestinal motility by a direct effect on the bowel. Manara et al.7 have shown that the inhibition of gastric transit by morphine results primarily from direct drug action on gut opioid sites with no significant contribution from a centrally elicited effect. Loperamide, an opioid receptor agonist with limited ability to access the CNS, is used clinically to treat diarrhea, suggesting that direct, local gut action is present in the opioid-constipating effect in humans. Using human small intestine muscle-strip preparation, we showed that morphine-induced inhibition of muscle-strip contraction elicited by electrical stimulation can be blocked by opioid antagonists.8 We also observed that after opioid antagonists, the force produced by muscle contraction was enhanced up to 27% compared with control levels, suggesting an inhibitory gut modulation by endogenous opioids in humans. The GI effects of morphine are primarily mediated by and -opioid receptors in the bowel. Morphine inhibits gastric emptying and reduces propulsive peristalsis of the intestine, thereby decreasing the rate of intestinal transit and producing constipation. Reduction in gut secretion and increases in intestinal fluid absorption also contribute to morphine’s constipating effect. In palliative care, the management of chronic opioid-induced constipation sometimes is a more difficult issue than the control of pain. Therefore, it is desirable to maintain the central analgesic effect of morphine while preventing or reducing its peripheral gut effects. Nonselective opioid receptor antagonists (e.g., naloxone, naltrexone, and nalmefene) cross the blood-brain barrier and, thus, block both the benFrom the Department of Anesthesia & Critical Care and Committee on Clinical Pharmacology, The Pritzker School of Medicine, The University of Chicago, Chicago, Illinois. Accepted for publication April 13, 2000. Supported in part by a grant from the International Anesthesia Research Society, National Institutes of Health Grant No. R01 CA79042, and Grant No. M01 RR00055 from the US Public Health Service General Clinical Research Center. Methylnaltrexone was originally formulated and subsequently modified by faculty at the University of Chicago. The University of Chicago and Drs. Yuan and Foss stand to benefit financially from the further development of methylnaltrexone.  Chun-Su Yuan, M.D., Ph.D., Department of Anesthesia & Critical Care, The University of Chicago, 5841 S Maryland Ave, MC 4028, Chicago, IL 60637.

title: Phase III Trial of Alvimopan, a Novel, Peripherally Acting, Mu Opioid Antagonist, for Postoperative Ileus After Major Abdominal Surgery
abstract: PURPOSEPostoperative ileus presents significant clinical challenges that potentially prolong hospital stay, contribute to readmission, and increase morbidity. There is no approved treatment for postoperative ileus. Alvimopan is a novel, peripherally acting, mu opioid receptor antagonist currently in development for the management of postoperative ileus.METHODSPatients undergoing partial colectomy or simple or radical hysterectomy were randomized to receive alvimopan 6 mg (n = 152), alvimopan 12 mg (n = 146), or placebo (n = 153) orally 2 hours before surgery and twice daily thereafter until discharge or for up to seven days. The primary efficacy end point, time to return of gastrointestinal function, was a composite measure of passage of flatus or stool and tolerating solid food. Secondary end points included time to the hospital discharge order written. Adverse events were monitored throughout the study.RESULTSMean time to gastrointestinal recovery was significantly reduced in patients treated with alvimopan 6 mg vs. placebo (hazard ratio = 1.45; P = 0.003), with a smaller reduction seen with alvimopan 12 mg (hazard ratio = 1.28; P = 0.059). Mean time to the hospital discharge order written was significantly accelerated in patients treated with alvimopan 6 mg (hazard ratio = 1.50; P < 0.001). The most common treatment-emergent adverse events across all treatment groups were nausea, vomiting, and hypotension; the incidence of nausea and vomiting was reduced by 53 percent in the alvimopan 12-mg group.CONCLUSIONSIn patients undergoing major abdominal surgery, alvimopan accelerated gastrointestinal recovery and time to the hospital discharge order written compared with placebo and was well tolerated.

title: Alvimopan, a Novel, Peripherally Acting μ Opioid Antagonist: Results of a Multicenter, Randomized, Double-Blind, Placebo-Controlled, Phase III Trial of Major Abdominal Surgery and Postoperative Ileus
abstract: To demonstrate that alvimopan (6 or 12 mg) accelerates recovery of gastrointestinal (GI) function in patients undergoing laparotomy for bowel resection or radical hysterectomy. Postoperative ileus (POI) following laparotomy may increase morbidity and extend hospitalization. Opioids can contribute to the duration of POI. Alvimopan is a novel opioid receptor antagonist in development for the management of POI. A total of 510 patients scheduled for bowel resection or radical hysterectomy were randomized (1:1:1) to receive alvimopan 6 mg, alvimopan 12 mg, or placebo orally ≥2 hours before surgery, then twice a day (b.i.d.) until hospital discharge or for up to 7 days. The primary efficacy end point was a composite of time to recovery of upper and lower GI function. An associated secondary end point was time to hospital discharge order written. The modified intent-to-treat population included 469 patients (451 bowel resection and 18 radical hysterectomy patients). Time to recovery of GI function was accelerated for the alvimopan 6 mg (hazard ratio [HR] = 1.28; P < 0.05) and 12 mg (HR = 1.54; P < 0.001) groups with a mean difference of 15 and 22 hours, respectively, compared with placebo. The time to hospital discharge order written was also accelerated in the alvimopan 12 mg group (HR = 1.42; P = 0.003) with a mean difference of 20 hours compared with placebo. The incidence of adverse events was similar among treatment groups. Alvimopan accelerated GI recovery and time to hospital discharge order written compared with placebo in patients undergoing laparotomy and was well tolerated.

title: Peripherally Acting Mu-Opioid Receptor Antagonists and Postoperative Ileus: Mechanisms of Action and Clinical Applicability
abstract: Postoperative ileus (POI), a transient cessation of coordinated bowel function after surgery, is an important health care problem. The etiology of POI is multifactorial and related to both the surgical and anesthetic pathways chosen. Opioids used to manage surgical pain can exacerbate POI, delaying gastrointestinal (GI) recovery. Peripherally acting mu-opioid receptor (PAM-OR) antagonists are designed to mitigate the deleterious effects of opioids on GI motility. This new class is investigational for POI management with the goal of accelerating the recovery of upper and lower GI tract function after bowel resection. In this review, we summarize the mechanisms by which POI occurs and the role of opioids and opioid receptors in the enteric nervous system, discuss the mechanism of action of PAM-OR antagonists, and review clinical pharmacology and Phase II/III POI trial results of methylnaltrexone and alvimopan. Finally, the role of anesthesiologists in managing POI in the context of a multimodal approach is discussed.

title: Clinical trial: alvimopan for the management of post‐operative ileus after abdominal surgery: results of an international randomized, double‐blind, multicentre, placebo‐controlled clinical study
abstract: Aliment Pharmacol Ther 28,

title: Gastrointestinal tract recovery in patients undergoing bowel resection: results of a randomized trial of alvimopan and placebo with a standardized accelerated postoperative care pathway.
abstract: To investigate the efficacy and safety of alvimopan, 12 mg, administered orally 30 to 90 minutes preoperatively and twice daily postoperatively in conjunction with a standardized accelerated postoperative care pathway for managing postoperative ileus after bowel resection.



This multicenter, randomized, placebo-controlled, double-blind, phase 3 trial enrolled adult patients undergoing partial bowel resection with primary anastomosis by laparotomy and scheduled to receive intravenous, opioid-based, patient-controlled analgesia. A standardized accelerated postoperative care pathway including early ambulation, oral feeding, and postoperative nasogastric tube removal was used to facilitate gastrointestinal (GI) tract recovery in all of the patients.



The primary end point was time to GI-2 recovery (toleration of solid food and first bowel movement). Secondary end points included time to GI-3 recovery (toleration of solid food and first flatus or bowel movement), hospital discharge order written, and actual hospital discharge. Postoperative length of hospital stay based on calendar day of hospital discharge order written, opioid consumption, and overall postoperative ileus-related morbidity were recorded.



Alvimopan, 12 mg, was well tolerated and significantly accelerated GI-2 recovery, GI-3 recovery, and actual hospital discharge compared with a standardized accelerated postoperative care pathway alone (hazard ratio = 1.5, 1.5, and 1.4, respectively; P < .001 for all). Time to hospital discharge order written as measured by hazard ratio (1.4) and by postoperative calendar days (mean for alvimopan, 5.2 days; mean for placebo, 6.2 days) was also accelerated. Opioid consumption was comparable between groups, and alvimopan was associated with reduced postoperative ileus-related morbidity compared with placebo.



Alvimopan, 12 mg, administered 30 to 90 minutes before and twice daily after bowel resection is well tolerated, accelerates GI tract recovery, and reduces postoperative ileus-related morbidity without compromising opioid analgesia.

title: Preoperative Intensive, Community-Based vs. Traditional Stoma Education: A Randomized, Controlled Trial
abstract: PURPOSEConventional practice in colorectal surgery involves stoma education being imparted postoperatively. Proficiency in stoma management often delays patients’ discharge following colorectal surgery. The aim of this randomized, controlled trial was to compare preoperative intensive, community-based stoma education with conventional postoperative stoma education after elective colorectal surgery.METHODSForty-two elective colorectal patients requiring a stoma were randomized into an intensive preoperative teaching (study) or postoperative (control) group. Intervention for the study group included two preoperative visits in the community during which patients were taught with audiovisual aids to use and change the stoma pouching system. Goal-directed postoperative stoma education was standardized for both groups. Outcomes measured included time to stoma proficiency, postoperative hospital stay, unplanned stoma-related interventions in the community within six weeks of discharge, and preoperative and postoperative hospital anxiety and depression scores. Cost-effectiveness of the intervention was also evaluated.RESULTSAll outcomes measured were improved in the study group, including time to stoma proficiency(5.5 vs. 9 days; P = 0.0005), hospital stay (8 vs. 10 days; P
 = 0.029), and unplanned stoma-related community interventions per patient (median 0 vs. 0.5; P = 0.0309). No adverse effects of the intervention were noted. The average cost saving per patient was £1,119 ($2,104) for the study group compared with the control group.CONCLUSIONSStoma education is more effective if undertaken in the preoperative setting. It results in shorter times to stoma proficiency and earlier discharge from the hospital. It also reduces stoma-related interventions in the community and has no adverse effects on patient well-being.

title: An expert opinion on postoperative pain management, with special reference to new developments
abstract: Importance of the field: Recently, much attention has been directed towards the effect of opioid-sparing strategies on postoperative morbidity and hospitalization, and on different nociceptive mechanisms involved in various postoperative pain states and surgical procedures. This has resulted in an increased interest in secondary, or adjunct, analgesics and procedure-specific analgesic methods. Areas covered in this review: The present paper aims to review and discuss recent developments within the field of various adjunct, systemic analgesics and local/regional anesthetic methods for management of postoperative pain, based on evidence from randomized, clinical trials published within the last 5 years. What the reader will gain: The reader will gain insight into the current role of pregabalin, glucocorticoids and systemic lidocaine for the management of postoperative pain. In addition, the current status of local infiltration analgesia for hip and knee arthroplasty, transversus abdominis plane block for abdominal operations, and the analgesic effect of wound instillation of capsaicin are reviewed. Take home message: The evidence of a substantial analgesic effect of pregabalin on acute postoperative pain is questionable, and more convincing evidence of the role of glucocorticoids and systemic lidocaine is needed before they should be recommended as analgesics in daily clinical practice. Local infiltration analgesia after hip and knee arthroplasty, transversus abdominis plane block after abdominal operations and local application of capsaicin lend some promise, but there is still a lack of well-performed RCTs to draw any firm conclusions. Procedure-specific analgesic combinations within well-defined rehabilitation paradigms should be explored further to reduce adverse effects associated with the use of conventional analgesic treatment protocols, and to improve postoperative outcome.

title: Acute pain management for opioid dependent patients
abstract: Patients requiring acute pain management may be opioid dependent as a result of either recreational or therapeutic opioid use, including those in opioid addiction programmes. Pain in these patients is often under‐estimated and under‐treated. In addiction, drug‐seeking behaviour differentiates it from simple dependence. With few randomised controlled trials, current evidence predominantly consists of guidelines based on case reports, retrospective studies and expert opinion. Consensus recommendations include maintaining regular provision of the patient's pre‐existing opioid requirement, with additional analgesia, ideally multimodal, in appropriate combinations of short‐acting opioid (as required), local anaesthesia, and adjuvant anti‐inflammatory analgesics and paracetamol. Patient controlled analgesia with higher bolus doses and shorter lock‐out intervals is a recommended strategy. Transdermal opioid patches and implantable pumps will continue to deliver opioid, to which non‐opioid and short‐acting opioids may be added. Re‐exposure to opioid is ideally avoided in previously addicted patients, but if not feasible, opioid therapy should be prescribed.

title: Opioid consumption in total intravenous anesthesia is reduced with dexmedetomidine: a comparative study with remifentanil in gynecologic videolaparoscopic surgery.
abstract: To evaluate the capacity of dexmedetomidine (DEX), an alpha(2) adrenergic agonist drug, as a substitute for remifentanil (REM), a potent opioid, in total intravenous anesthesia (TIVA), in patient undergoing gynecologic videolaparoscopy.



Randomized, single-blinded study.



University-affiliated hospital.



30 ASA physical status I and II women, patients (22-56 yrs), scheduled for gynecologic videolaparoscopy.



Patients were anesthetized with DEX or REM in continuous venous infusion, associated with propofol, in a target-controlled infusion.



Heart rate, mean blood pressure (MBP), systolic blood pressure (SBP), diastolic blood pressure (DBP), plasma glucose, and cortisol were determined before anesthetic induction, 5 minutes after tracheal intubations and 30 minutes after initial surgical incision. Extubation and orientation times, and postanesthesia care unit (PACU) discharge times were noted.



Blood cortisol levels were higher in the DEX group than in the REM group at 30minutes after surgical incision. Cortisol levels decreased as a function of time in the REM group, whereas intheDEX group they decreased in the second sample and returned to basal levels at 30 minutes. Hyperglycemia was higher in DEX than in REM during the second and third sample collection. However, glucose increased as a function of time in both groups. Analysis of MBP and DBP indicated adecrease in blood pressure at 5 minutes after tracheal intubations in both groups. At 30 minutes afterincision, MBP and DBP returned to basal levels in the DEX group, whereas the variables were significantly lower in the REM group. There were significant differences between groups for systolic blood pressure and heart rate at 5 and 30 minutes after incision with a greater decrease in REM. The extubation and orientation times were significantly increased in the DEX group, when compared with those of the REM group. There were no differences in postanesthesia care unit discharge times between groups.



Dexmedetomidine was a clinically effective drug as a REM substitute in TIVA, during minimally invasive video gynecologic surgical procedures; however, patients anesthetized with DEX showed a more prolonged recovery time for some parameters such as orientation and extubation times.

title: A systematic review of COX‐2 inhibitors compared with traditional NSAIDs, or different COX‐2 inhibitors for post‐operative pain
abstract: We have reviewed the analgesic efficacy of cyclooxygenase‐2 (COX‐2) inhibitors compared with traditional non‐steroidal anti‐inflammatory drugs (NSAIDs), different COX‐2 inhibitors, and placebo in post‐operative pain.

title: Intravenous Lidocaine Speeds the Return of Bowel Function, Decreases Postoperative Pain, and Shortens Hospital Stay in Patients Undergoing Radical Retropubic Prostatectomy
abstract: Postoperative ileus is a concern among surgical patients. Epidural anesthesia nd analgesia with local anesthetics can decrease the duration of ileus. Significant systemic absorption of local anesthesia occurs during epidural use. ln this study, we examined whether many of the beneficial effects on bowel function seen with epidural lidocaine are also present when the drug is given parenterally. Forty patients undergoing radical retropubic prostatectomy were studied with one half of the patients receiving a lidoCaine bolus (1.5 mg/kg) and infusion (3 mg/min, unless weight <70 kg, then 2 mg/min); the other half received a saline infusion. A blind observer recorded the patient’s daily pain score, the time the patient first experienced flatulence and had the first bowel movement, and the total use of analgesics. Lidocaine-treated patients first experienced flatulence in a significantly shorter time (P < 0.01) than control patients. Lidocaine patients’ hospital stay was also significantly shorter (P < 0.05); on average, they spent 1.1 fewer days in the hospital. Iv lidocaine initiated before anesthesia nd continued 1 h postoperatively significantly sped up the return of bowel function. Lidocaine patients were also more comfortable postoperatively. Many of the bowel function benefits attributed to epidural lidocaine are also present when the drug is administered parenterally. Additionally, the length of hospital stay was reduced in lidocaine-treated patients.  This study prospectively examined whether lV lidocaine could affect the return of bowel function after radical prostate surgery. Lidocaine-treated patients had shorter hospita1 stays, less pain, and faster return of bowel function. In this population, lidocaine infusion can be a useful adjunct in anesthetic management.

title: Acid suppression in the perioperative period.
abstract: Aspiration of oropharyngeal and gastric contents during surgery, although infrequent, is a recognized complication of general anesthesia that carries significant risk for serious complications. Complications of aspiration have been reported to cause 10% to 30% of anesthesia-related deaths. Unconsciousness interferes with multiple biologic mechanisms that guard the airway against aspiration, and this is compounded in surgery by anesthesia-induced neurologic impairment and the risks related to placement of nasogastric and endotracheal tubes. Consequences of anesthesia-related aspiration include aspiration pneumonia, acute respiratory distress syndrome, pulmonary edema, and long-term complications such as laryngotracheal damage and decreased lung compliance. Therefore, averting aspiration, particularly in the elderly and other high-risk patients, should be part of the perioperative plan. Although antacids and histamine 2-receptor antagonists have been used perioperatively with some success, they are limited by short duration of action and systemic side effects, among other factors. Proton pump inhibitors are currently being investigated in surgical patients at risk for aspiration or stress ulcers and seem to be potent, extremely effective, and well tolerated. This article reviews the risks for, and potential outcomes of, anesthesia-related aspiration, identifies high-risk populations, and outlines the experience to date with available preventive treatments.

title: Effect of Dexamethasone on Postoperative Symptoms in Patients Undergoing Elective Laparoscopic Cholecystectomy: Randomized Clinical Trial
abstract: BackgroundDexamethasone has been reported to reduce postoperative nausea and vomiting (PONV) after laparoscopic cholecystectomy (LC). However, its effects on other surgical outcomes, such as pain and fatigue, have been unclear. We evaluated the efficacy of preoperative dexamethasone for ameliorating postoperative symptoms after LC.MethodsIn this prospective, double-blind, placebo-controlled study, 210 patients scheduled for elective LC were analyzed after randomization to intravenous dexamethasone (8 mg) or a placebo. All patients underwent standardized procedures for general anesthesia and surgery. Episodes of PONV and the pain and fatigue scores were recorded on a visual analog scale. Analgesic and antiemetic requirements were also recorded.ResultsThere were no significant differences between groups with regard to medical or demographic variables. Significantly fewer patients experienced PONV in the dexamethasone group immediately after LC and at 6 and 12 h. The need for ondansetron to relieve PONV was higher in the placebo group (P = 0.001). Patients in the study group reported less postoperative pain during the first 24 h and less fatigue after 6, 12, and 24 h. The need for buprenorphine to relieve intolerable pain was also less in this group (P = 0.009). There were no side effects, and the morbidity was similar in the two groups (6.7 vs. 7.6%).ConclusionsThe regimen we employed is safe and without apparent side effects. Thus, preoperative dexamethasone can significantly reduce the incidence of PONV, pain and fatigue after elective LC.

title: Systematic review on the short‐term outcome of laparoscopic resection for colon and rectosigmoid cancer
abstract: Several large randomized controlled trials on laparoscopic resection for colon and rectosigmoid cancer have recently been published. There is a need to provide an up‐to‐date systematic review in this subject.

title: Systematic review of prophylactic nasogastric decompression after abdominal operations
abstract: Routine use of nasogastric tubes after abdominal operations is intended to hasten the return of bowel function, prevent pulmonary complications, diminish the risk of anastomotic leakage, increase patient comfort and shorten hospital stay. This meta‐analysis of published studies examines the efficacy of this practice after abdominal surgery in achieving each of these goals.

title: Pharmacologic Options to Prevent Postoperative Ileus
abstract: To summarize the evidence on pharmacologic options in preventing postoperative ileus (POI).  The Cochrane Database of Reviews and OVID databases and Food and Drug Administration (FDA) Web site were searched (1950–April 2009) using the term postoperative ileus. Study Selection and Data Extraction: Meta-analyses and randomized controlled trials were included for review. The FDA Web site was searched for clinical reviews and label information for drugs indicated for the prevention of POI.  Three meta-analyses, 2 on gum-chewing and 1 on alvimopan, and 18 clinical trials were identified. Only gum chewing and alvimopan were effective in preventing POI. Gum chewing reduced the time to first flatus and bowel movement (weighted mean difference 21h, p = 0.0006 and 33h; p = 0.0002, respectively). In one meta-analysis, gum chewing significantly reduced length of stay (LOS) by 2.4 days (p < 0.00001) but this was not replicated in the second meta-analysis. Alvimopan shortened the time to reach a composite endpoint of solid food intake, plus/minus flatus, and bowel movement (93 vs 105 h; p < 0.001). A higher incidence of myocardial infarction was observed in a 12-month study of alvimopan for the treatment of opioid-induced bowel dysfunction, but not in studies in patients undergoing bowel resection. Alvimopan decreased the time to written hospital discharge order (hazard ratio 1.35; p<0.01), while the significance of a reduction in LOS (0.2–1.3 days) was not reported.  Gum chewing and alvimopan are effective in preventing POI, but given safety concerns and higher cost with alvimopan, gum chewing may be preferred.

title: Colonic Surgery With Accelerated Rehabilitation or Conventional Care
abstract: BACKGROUNDFor patients undergoing colonic surgery, the postoperative hospital stay is usually 6 to 10 days, and the morbidity rate is 15 to 20 percent. Fast-track rehabilitation programs have reduced the hospital stay to 2 to 3 days. The aim of this study was to evaluate the postoperative outcome after colonic resection with conventional care compared with fast-track multimodal rehabilitation.METHODSOne hundred thirty consecutive patients receiving conventional care (group 1) in one hospital were compared with 130 consecutive patients receiving multimodal, fast-track rehabilitation (group 2) in another hospital. Outcomes were time to first defecation after surgery, postoperative hospital stay, and morbidity during the first postoperative month.RESULTSMedian age was 74 years (group 1) and 72 years (group 2). American Society of Anesthesiologists (ASA) score was significantly higher in group 2 (P < 0.05). Defecation occurred on day 4.5 in group 1 and day 2 in group 2 (P < 0.05). Median hospital stay was 8 days in group 1 and 2 days in group 2 (P < 0.05). The use of a nasogastric tube was longer in group 1 (P < 0.05). The overall complication rate (35 patients) was lower in group 2 (P < 0.05), especially cardiopulmonary complications (5 patients; P < 0.01). Readmission was necessary in 12 percent of cases for group 1 and 20 percent in group 2 (P > 0.05).CONCLUSIONSTime to first defecation, hospital stay, and morbidity may be reduced after colonic resection with fast-track multimodal rehabilitation.

title: A clinical pathway to accelerate recovery after colonic resection.
abstract: To investigate the feasibility of a 48-hour postoperative stay program after colonic resection.



Postoperative hospital stay after colonic resection is usually 6 to 12 days, with a complication rate of 10% to 20%. Limiting factors for early recovery include stress-induced organ dysfunction, paralytic ileus, pain, and fatigue. It has been hypothesized that an accelerated multimodal rehabilitation program with optimal pain relief, stress reduction with regional anesthesia, early enteral nutrition, and early mobilization may enhance recovery and reduce the complication rate.



Sixty consecutive patients undergoing elective colonic resection were prospectively studied using a well-defined postoperative care program including continuous thoracic epidural analgesia and enforced early mobilization and enteral nutrition, and a planned 48-hour postoperative hospital stay. Postoperative follow-up was scheduled at 8 and 30 days.



Median age was 74 years, with 20 patients in ASA group III-IV. Normal gastrointestinal function (defecation) occurred within 48 hours in 57 patients, and the median hospital stay was 2 days, with 32 patients staying 2 days after surgery. There were no cardiopulmonary complications. The readmission rate was 15%, including two patients with anastomotic dehiscence (one treated conservatively, one with colostomy); other readmissions required only short-term observation.



A multimodal rehabilitation program may significantly reduce the postoperative hospital stay in high-risk patients undergoing colonic resection. Such a program may also reduce postoperative ileus and cardiopulmonary complications. These results may have important implications for the care of patients after colonic surgery and in the future assessment of open versus laparoscopic colonic resection.

title: Effect of bisacodyl on postoperative bowel motility in elective colorectal surgery: a prospective, randomized trial
abstract: BackgroundPostoperative ileus is a common condition after abdominal surgery. Many prokinetic drugs have been evaluated including osmotic laxatives. The data on colon-stimulating laxatives are scarce. This prospective, randomized, double-blind trial investigates the effect of the colon-stimulating laxative bisacodyl on postoperative ileus in elective colorectal resections. Secondary endpoints were incidence and duration of nasogastric tube reinsertion, incidence of vomiting, length of hospital stay, and visual analogue scores for pain, cramps, and nausea.ResultsOne hundred sixty-nine patients were analyzed, and 31 patients discontinued the study. Groups were comparable in baseline demographics. Time to GI-3 was significantly shorter in the bisacodyl group (3.0 versus 3.7 days, P = 0.007). Of the single parameters defining GI-3, there was a 1-day difference in time to defecation in favor to the bisacodyl group (3.0 versus 4.0 days, P = 0.001), whereas no significant difference in time to first flatus or tolerance of solid food was seen. No significant difference in the secondary endpoints was seen. Morbidity and mortality did not differ between groups.ConclusionBisacodyl accelerated gastrointestinal recovery and might be considered as part of multimodal recovery programs after colorectal surgery.

title: Multimodal strategies to improve surgical outcome.
abstract: To evaluate the effect of modifying perioperative care in noncardiac surgical patients on morbidity, mortality, and other outcome measures.



New approaches in pain control, introduction of techniques that reduce the perioperative stress response, and the more frequent use of minimal invasive surgical access have been introduced over the past decade. The impact of these interventions, either alone or in combination, on perioperative outcome was evaluated.



We searched Medline for the period of 1980 to the present using the key terms fast track surgery, accelerated care programs, postoperative complications and preoperative patient preparation; and we examined and discussed the articles that were identified to include in this review. This information was supplemented with our own research on the mediators of the stress response in surgical patients, the use of epidural anesthesia in elective operations, and pilot studies of fast track surgical procedures using the multimodality approach.



The introduction of newer approaches to perioperative care has reduced both morbidity and mortality in surgical patients. In the future, most elective operations will become day surgical procedures or require only 1 to 2 days of postoperative hospitalization. Reorganization of the perioperative team (anesthesiologists, surgeons, nurses, and physical therapists) will be essential to achieve successful fast track surgical programs.



Understanding perioperative pathophysiology and implementation of care regimes to reduce the stress of an operation, will continue to accelerate rehabilitation associated with decreased hospitalization and increased satisfaction and safety after discharge. Developments and improvements of multimodal interventions within the context of "fast track" surgery programs represents the major challenge for the medical professionals working to achieve a "pain and risk free" perioperative course.

title: Consensus review of optimal perioperative care in colorectal surgery: Enhanced Recovery After Surgery (ERAS) Group recommendations.
abstract: To describe a consensus review of optimal perioperative care in colorectal surgery and to provide consensus recommendations for each item of an evidence-based protocol for optimal perioperative care.



For every item of the perioperative treatment pathway, available English-language literature has been examined.



Particular attention was paid to meta-analyses, randomized controlled trials, and systematic reviews.



A consensus recommendation for each protocol item was reached after critical appraisal of the literature by the group.



For most protocol items, recommendations are based on good-quality trials or meta-analyses of such trials.



The Enhanced Recovery After Surgery (ERAS) Group presents a comprehensive evidence-based consensus review of perioperative care for colorectal surgery. It is based on the evidence available for each element of the multimodal perioperative care pathway.

title: Postoperative ileus-related morbidity profile in patients treated with alvimopan after bowel resection.
abstract: Postoperative ileus (POI), an interruption of coordinated bowel motility after operation, is exacerbated by opioids used to manage pain. Alvimopan, a peripherally acting mu-opioid receptor antagonist, accelerated gastrointestinal (GI) recovery after bowel resection in randomized, double-blind, placebo-controlled, multicenter phase III POI trials. The effect of alvimopan on POI-related morbidity for patients who underwent bowel resection was evaluated in a post-hoc analysis.



Incidence of POI-related postoperative morbidity (postoperative nasogastric tube insertion or POI-related prolonged hospital stay or readmission) was analyzed in four North American trials for placebo or alvimopan 12 mg administered 30 minutes or more preoperatively and twice daily postoperatively until hospital discharge (7 or fewer postoperative days). GI-related adverse events and opioid consumption were summarized for each treatment. Estimations of odds ratios of alvimopan to placebo and number needed to treat (NNT) to prevent one patient from experiencing an event of POI-related morbidity were derived from the analysis.



Patients receiving alvimopan 12 mg were less likely to experience POI-related morbidity than patients receiving placebo (odds ratio = 0.44, p < 0.001). Fewer patients receiving alvimopan (alvimopan, 7.6%; placebo, 15.8%; NNT = 12) experienced POI-related morbidity. There was a lower incidence of postoperative nasogastric tube insertion, and other GI-related adverse events on postoperative days 3 to 6 in the alvimopan group than the placebo group. Opioid consumption was comparable between groups.



Alvimopan 12 mg was associated with reduced POI-related morbidity compared with placebo, without compromising opioid-based analgesia in patients undergoing bowel resection. Relatively low NNTs are clinically meaningful and reinforce the potential benefits of alvimopan for the patient and health care system.

title: Economic analysis of alvimopan in North American Phase III efficacy trials.
abstract: The economic effect of the use of alvimopan in four randomized, double-blind, placebo-controlled, Phase III, North American efficacy trials was analyzed.



Patients were eligible for the study if they were 18 years or older, were undergoing laparotomy for partial small or large bowel resection with primary anastomosis, and were scheduled for postoperative pain management with opioid-based i.v. patient-controlled analgesia. Patients analyzed in the North American Phase III trials received placebo or alvimopan 12 mg orally before surgery. Doses were administered twice daily beginning the day after surgery until hospital discharge or for a maximum of 15 doses.



Compared with placebo, alvimopan was associated with a significantly shorter mean time to gastrointestinal (GI) recovery and a significantly shorter mean time to a written discharge order. Alvimopan was also associated with a mean hospital length of stay (LOS) of one full day less than placebo. The mean cost of alvimopan based on a mean of 8.9 12-mg doses was $558.00; the alvimopan cost at the upper limit of allowed dosing was $937.50. Combining the alvimopan and hospital costs for each patient, total costs for the alvimopan group were estimated to be lower than for the placebo group.



In a post hoc analysis, alvimopan was associated with significantly faster upper and lower GI recovery after bowel resection and a mean LOS reduction of one day compared with placebo. The mean estimated hospital cost was $879-$977 less for patients who received alvimopan compared with placebo. The base-case and sensitivity analyses suggest that, on average, the use of alvimopan compared with placebo may have a cost-saving effect in the hospital setting.

title: ‘Fast-track’ multimodal rehabilitation program improves outcome after laparoscopic sigmoidectomy: a controlled prospective evaluation
abstract: BackgroundLaparoscopic colorectal resection improves patient outcome by reducing pain, postoperative pulmonary dysfunction, gastrointestinal paralysis, and fatigue. A multimodal rehabilitation program (“fast-track”) with epidural analgesia, early oral feeding, and enforced mobilization may further improve the excellent results of laparoscopic colorectal resection, enabling early ambulation of these patients.MethodsFifty two consecutive patients underwent laparoscopic sigmoidectomy with standardized regular perioperative treatment (standard) or multimodal rehabilitation program (“fast-track”). Outcome measures included pulmonary function, duration of postoperative ileus, pain perception, fatigue, morbidity, and mortality.ResultsTwenty nine standard-care patients (19 men and 10 women) and 23 fast-track patients (15 men and eight women) were evaluated. Demographic and operative data were similar for the two groups. On the 1st postoperative day, pulmonary function was improved (p = 0.01) in fast-track patients. Oral feeding was achieved earlier (p < 0.01) and defecation occurred earlier (p < 0.01) in the fast-track group. Visual analogue scale scores for pain were similar for the two groups (p > 0.05), but fatigue was increased in the standard-care group on the 1st (p = 0.06) and 2nd (p < 0.05) postoperative days. Morbidity was not different for the two groups. Fast-track patients were discharged on day 4 (range, 3–6) and standard-care patients on day 7 (range, 4–14) (p < 0.001).ConclusionMultimodal rehabiliation can improve further on the excellent results of laparoscopic sigmoidectomy and decrease the postoperative hospital stay.

title: ‘Fast track’ postoperative management protocol for patients with high co‐morbidity undergoing complex abdominal and pelvic colorectal surgery
abstract: A combination of factors has emphasized the need to reduce postoperative stay after surgery. Multimodal care plans may shorten hospital stay, but have been associated with high readmission rates and are generally reserved for straightforward, non‐complicated colonic (not rectal) resections. This study evaluated a ‘fast track’ protocol in patients undergoing major colonic and rectal surgery.

title: Convalescence after Colonic Resection with Fast-Track versus Conventional Care
abstract: Multi-modal rehabilitation programmes may improve early postoperative body composition, pulmonary function, exercise capacity, and reduce hospital stay. So far, no data are available on convalescence after discharge.  The objectives where to compare convalescence data (fatigue, sleep, time to resume normal activities, and functional capabilities) and need for nursing care and contact to general practitioner with fast-track multi-modal rehabilitation compared with conventional care after colonic surgery.  Non-randomised, prospective controlled study in 30 consecutive patients undergoing fast-track rehabilitation with continuous epidural analgesia, enforced oral nutrition, mobilisation, planned early discharge, and 30 consecutive patients undergoing conventional care. Patients were interviewed preoperatively and 14 and 30 days postoperatively.  Median hospital stay was 2 vs. 8 days in the fast-track vs. conventional care group, respectively (p < 0.01). Fourteen days postoperatively, total and mid-day sleep were increased in the conventional care group when compared with the fast-track group (p < 0.01). Fatigue was increased significantly at 14 days (p < 0.05) and throughout the study period compared with the fast-track group (p < 0.01). Similarly, ability to walking stairs, cooking, house keeping, shopping and walking outdoor was significantly less reduced at 14 days in the fast-track group, who also regained leisure activities earlier (p < 0.05). There was no significant difference between groups at 30 days or between need for nursing care and visits to general practitioners. Readmission for surgery-related events occurred more frequently (5 vs 1 patient) in the fast-track group.  Fast-track rehabilitation with early discharge after colonic surgery results in earlier resumption of normal activities with reduced fatigue and need for sleep postoperatively compared to conventional care, and without increased need for nursing care or visits to general practitioners. However, readmissions may occur more frequently.

title: Fast-track colonic surgery: status and perspectives.
abstract: Multi-modal rehabilitation with an emphasis on preoperative information, reduction of surgical stress responses, optimized dynamic pain relief with continuous epidural analgesia and early mobilization and oral nutrition may reduce hospital stay, morbidity, convalescence, and costs (fast-track surgery). Current results from fast-track colonic surgery suggest that postoperative pulmonary, cardiovascular, and muscle function are improved and body composition preserved as well as a normal oral intake of energy and protein can be achieved. Consequently, hospital stay is reduced to about 2-4 days, with decreased fatigue and need for sleep in the convalescence period. Despite a higher risk for readmissions, overall costs and morbidity seem to be reduced. Existing data from several institutions support the concept of fast-track colonic surgery to improve postoperative organ functions, thereby allowing for early rehabilitation with decreased hospital stay, convalescence, and costs. Further data are needed from multi-national institutions on morbidity, safety, and costs.

title: Gum chewing enhances early recovery from postoperative ileus after laparoscopic colectomy.
abstract: Postoperative ileus limits early hospital discharge for patients who have undergone laparoscopic procedures. Sham feeding has been reported to enhance bowel motility. Here, the effect of gum chewing is evaluated as a convenient method to enhance postoperative recovery from ileus after laparoscopic colectomy.



A total of 19 patients who underwent elective laparoscopic colectomy for colorectal cancer participated in the study. Each patient was randomly assigned to one of two groups: a gum-chewing group (n = 10, mean age 58.6 years, range 50 to 71 years) or a control group (n = 9, mean age 60.6 years, range 45 to 80 years). The patients in the gum-chewing group chewed gum three times a day from the first postoperative AM until oral intake. The times of the first passage of flatus and defecation were recorded precisely.



The first passage of flatus was seen, on average, on postoperative day 2.1 in the gum-chewing group and on day 3.2 in the control group (p < 0.01). The first defecation was 2.7 days sooner in the gum-chewing group (postoperative day 3.1) than in the control group (5.8 days; p< 0.01). All patients tolerated gum chewing on the first operative AM. The postoperative hospital stays for the gum-chewing and control groups were 13.5+/-3.0 days and 14.5+/-6.1 days, respectively.



Gum chewing aids early recovery from postoperative ileus and is an inexpensive and physiologic method for stimulating bowel motility. Gum chewing should be added as an adjunct treatment in postoperative care because it might contribute to shorter hospital stays.

title: Gum chewing stimulates bowel motility in patients undergoing radical cystectomy with urinary diversion.
abstract: Several studies have shown that gum chewing may stimulate bowel motility after gastrointestinal surgery. Because urinary diversion typically uses a segment of bowel, it is conceivable that patients undergoing cystectomy and diversion may benefit from gum chewing. This study aimed to determine whether gum chewing in the immediate postoperative period facilitates a return to bowel function in patients undergoing cystectomy and urinary diversion.



A total of 102 patients underwent radical cystectomy and urinary diversion for clinically localized bladder cancer. Each patient followed our institution's perioperative cystectomy care plan. The first cohort of patients underwent surgery between July 2004 and August 2005 and served as a comparison (control) group in which no gum was dispensed. The second cohort underwent surgery during September 2005 to July 2006. These patients were given chewing gum to begin on postoperative day 1. Outcome measures included time to flatus, time to bowel movement, length of hospital stay, and complications.



The time to flatus was shorter in patients who received gum compared with controls (2.4 versus 2.9 days; P <0.001). Also, time to bowel movement was reduced in patients who received gum (3.2 versus 3.9 days; P <0.001). There was no significant difference in length of hospital stay between gum-chewing patients and controls (4.7 versus 5.1 days, respectively; P = 0.067). Gum chewing was well tolerated in all patients.



Gum chewing may speed the recovery of bowel function after cystectomy and diversion. These findings are consistent with outcomes in the colorectal surgery published data that support the use of chewing gum as an easy and inexpensive way to enhance recovery after surgery.

title: Gum chewing reduces ileus after elective open sigmoid colectomy.
abstract: Gum chewing after elective open colon resection may stimulate bowel motility and decrease duration of postoperative ileus.



Prospective, randomized study in a community-based teaching hospital.



Thirty-four patients undergoing elective open sigmoid resections for recurrent diverticulitis or cancer.



First feelings of hunger, time to first flatus, time to first bowel movement, length of hospital stay, and complications.



A total of 34 patients were randomized into 2 groups: a gum-chewing group (n = 17) or a control group (n = 17). The patients in the gum-chewing group chewed sugarless gum 3 times daily for 1 hour each time until discharge. Patient demographics, intraoperative, and postoperative care were equivalent between the 2 groups. All gum-chewing patients tolerated the gum. The first passage of flatus occurred on postoperative hour 65.4 in the gum-chewing group and on hour 80.2 in the control group (P = .05). The first bowel movement occurred on postoperative hour 63.2 in the gum-chewing group and on hour 89.4 in the control group (P = .04). The first feelings of hunger were felt on postoperative hour 63.5 in the gum-chewing group and on hour 72.8 in the control group (P = .27). There were no major complications in either group. The total length of hospital stay was shorter in the gum-chewing group (day 4.3) than in the control group (day 6.8), (P = .01).



Gum chewing speeds recovery after elective open sigmoid resection by stimulating bowel motility. Gum chewing is an inexpensive and helpful adjunct to postoperative care after colectomy.

title: Does gum chewing ameliorate postoperative ileus? Results of a prospective, randomized, placebo-controlled trial.
abstract: A preliminary report has been interpreted to suggest that gum chewing reduces duration of postcolectomy ileus.



We rigorously tested this hypothesis in a prospective, randomized, placebo-controlled study. Patients undergoing open colectomy (n = 66) were randomized to receive 1 of 3 postoperative regimens beginning on postoperative day 1: sips (control, n = 21); sips and accupressure wrist bracelet (placebo, n = 23); and sips and gum chewing (treatment, n = 22). Patients were unaware of which regimen constituted placebo or treatment; end points were assessed by blinded investigators. Power was set a priori at 85% to detect a 0.75-day difference in time to first postoperative passage of flatus between placebo and treatment groups. Groups were compared using the log-rank test.



Groups were equivalent with respect to demographic and surgical characteristics. Median times to first postoperative passage of flatus were as follows: sips, 67 hours; bracelet and sips, 72 hours; gum and sips, 60 hours (p = 0.384). There were no significant differences in time to passage of first bowel movement, time until patients were ready for discharge, or time until actual discharge among the three groups. Inpatient and 30-day followup demonstrated no difference in frequency or distribution of postoperative complications.



In contrast to findings of a preliminary study, our clinical trial suggests that gum chewing, although safe, does not reduce duration of postcolectomy ileus.

title: Prospective trial of aggressive postoperative bowel stimulation following radical hysterectomy.
abstract: Postoperative traditional feeding protocols are not based on scientific studies, but rather on anecdotal evidence. We present the first prospective trial of aggressive postoperative bowel stimulation following radical hysterectomy in an attempt to determine its effect on the length of hospital stay.



Twenty consecutive patients undergoing radical hysterectomy were entered onto a prospective trial of aggressive postoperative bowel stimulation, which consisted of 30 cc milk of magnesia p.o. b.i.d. starting on postoperative day 1 and biscolic suppositories q.d. starting on day 2. A clear liquid diet was begun following flatus or bowel movement and patients were discharged 12 h after tolerating a clear liquid diet. Diet was slowly advanced at home.



Median time to flatus was 3 days, bowel movement 3 days, and clear liquid diet 3 days. Median time to discharge was 4 days. No patients developed ileus or bowel obstructions and there were no readmissions for bowel complications. Our median time to discharge of 4 days represents a 50% reduction in hospital stay compared to our previous prospective study using traditional postoperative bowel management (8 days), which was statistically significant at P = 0.001.



Aggressive bowel stimulation with milk of magnesia and biscolic suppositories resulted in early return of bowel function and early discharge with no noticeable complications.

title: Prospective trial of early feeding and bowel stimulation after radical hysterectomy.
abstract: In an attempt to decrease hospital stay we performed a prospective trial of aggressive bowel stimulation and early postoperative feeding after radical hysterectomy.



In a prospective trial of 20 consecutive patients undergoing class 3 radical hysterectomy, feeding of a clear liquid diet and bowel stimulation with oral 66% sodium phosphate solution  were instituted on postoperative day 1. Patients were discharged after passage of flatus or stool.



Median time to discharge was 3.5 days. No patient had emesis, ileus, or bowel obstruction. The decrease in hospital stay with respect to those in our previous trial with traditional postoperative feeding and our original study on postoperative bowel stimulation was statistically significant.



Aggressive bowel stimulation with Fleet Phospho-Soda and early feeding after radical hysterectomy resulted in early return of bowel function and early discharge without significant intestinal complication.

title: Normal gastrointestinal transit after colonic resection using epidural analgesia, enforced oral nutrition and laxative
abstract: Postoperative ileus usually lasts for 2–5 days after colonic surgery and may contribute to discomfort and pulmonary complications. With multimodal rehabilitation (epidural analgesia, early oral nutrition and mobilization, and laxative) defaecation occurs 1–2 days after colonic surgery. The aim of this study was to assess the transit rate of the entire gastrointestinal tract after colonic resection with multimodal rehabilitation.

title: Alvimopan, a selective peripherally acting μ‐opioid antagonist *
abstract: Alvimopan is a novel, peripherally acting μ‐opioid antagonist that is being developed for the management of acute postoperative ileus and for the reversal of the delayed gastrointestinal and colonic transit that result in symptoms such as constipation, nausea and motility disorders in patients treated with opiate analgesics. There is a clinical need for effective medications for the treatment of postoperative ileus and opiate‐induced constipation and other motility disorders. This review addresses the basic and applied pharmacology and current evidence for the use of the medication, alvimopan, in clinical gastroenterology.

title: Causes of increased hospital stay after radical cystectomy in a clinical pathway setting.
abstract: Our institution targets postoperative days 6 to 8 for discharge home after radical cystectomy. We examined this population to determine the causes of increased hospital stay and risk factors that may predict prolonged hospitalization.



We reviewed the records of 304 consecutive patients who underwent radical cystectomy from October 1995 to July 2000. The variables examined included age, gender, race, American Society of Anesthesiologists score, urinary diversion type, smoking history, estimated blood loss, transfusion requirement, operative time, hospital stay, perioperative minor and major complications, and the mortality rate.



Of the 304 patients 144 (47.4%) underwent ileal conduit diversion and 145 (47.7%) underwent orthotopic bladder substitution. Median hospital stay was 7 days (range 4 to 48). Of 302 patients 225 (74%) were discharged home by postoperative day 8, while 52 of the remaining 77 (67.5%) with increased hospital stay were discharged home by day 12. Postoperative ileus was the most common cause of increased hospitalization (53 of 77 cases or 68.8%). Major complications developed in 15 patients (4.9%), of whom 66% required a hospital stay of greater than 12 days. There was a single perioperative death (0.3%). No preoperative variables other than race predicted increased hospitalization. Of the clinical variables increased estimated blood loss, transfusion and minor or major complications correlated with an increased stay (p <0.05). However, on multivariate analysis only complications were associated with prolonged hospitalization.



Our cystectomy clinical care pathway targets a hospital discharge date that is safely achieved in the majority of patients. Postoperative ileus is the most common cause of prolonged hospitalization. Age, gender, American Society of Anesthesiologists score, urinary diversion type and pathological stage did not correlate with increased hospital stay.

title: Methods for decreasing postoperative gut dysmotility.
abstract: Postoperative disturbances of gastrointestinal function (postoperative ileus) are among the most significant side-effects of abdominal surgery for cancer. Without specific treatment, major abdominal surgery causes a predictable gastrointestinal dysfunction which endures for 4-5 days and results in an average hospital stay of 7-8 days. Ileus occurs because of initially absent and subsequently abnormal motor function of the stomach, small bowel, and colon. This disruption results in delayed transit of gastrointestinal content, intolerance of food, and gas retention. The aetiology of ileus is multifactorial, and includes autonomic neural dysfunction, inflammatory mediators, narcotics, gastrointestinal hormone disruptions, and anaesthetics. In the past, treatment has consisted of nasogastric suction, intravenous fluids, correction of electrolyte abnormalities, and observation. Currently, the most effective treatment is a multimodal approach. Median stays of 2-3 days after removal of all or part of the colon (colectomy) are now achievable. Recent discoveries have the potential to significantly reduce postoperative ileus in patients with cancer who have had abdominal surgery.

title: Postoperative morbidity and mortality following resection of the colon and rectum for cancer
abstract: The aim of this study was to report the prevalence of postoperative complications and mortality of patients with colorectal cancer when treated by conventional surgery.  Morbidity and mortality following open resection for colorectal cancer were analyzed in 1,846 patients whose clinical, operative, and pathology data were prospectively documented over a 20-year period.  Mortality following elective resection of the left and right colon was low, whereas overall morbidity was high (37.2 percent). Respiratory and cardiac complications were especially common. Incidence of clinically significant leakage was similar following right (0.5 percent) or left (1.1 percent) hemicolectomy. Incidence of anastomotic leakage was significantly higher after emergency right hemicolectomy (4.3 percent). Overall morbidity following excision of the rectum was high (40.2 percent). Respiratory and cardiac complications predominated. Incidence of clinically significant anastomotic leakage following anterior resection was low (2.9 percent). Over the years, there has been a decline in the number of patients with tumor demonstrated histologically in a line of resection, suggesting an improved local surgical clearance.  These results following conventional surgery may be useful when evaluating new techniques.

title: Implementation of a clinical pathway decreases length of stay and cost for bowel resection.
abstract: To examine the effect of a clinical pathway for small and large bowel resection on cost and length of hospital stay.



Clinical pathways are designed to streamline patient care delivery and maximize efficiency while minimizing cost. Theoretically, they should be most effective in commonly performed procedures, in which volume and familiarity are high.



A clinical pathway to assist in the management of patients undergoing bowel resection was developed by a multidisciplinary team and implemented. Data about length of stay and cost was collected for all patients undergoing bowel resection 1 year before and 1 year after pathway implementation. Three groups were compared: patients undergoing bowel resection in the year prior to pathway implementation (prepathway), patients in the year after pathway implementation but not included on the pathway (nonpathway), and patients included in the pathway (pathway).



The mean cost per hospital stay was $19,997.35 +/- 1244.61 for patients in the prepathway group, $20,835.28 +/- 2286.26 for those in the nonpathway group, and $13,908.53 +/- 1113.01 for those in the pathway group (p < 0.05 vs. other groups). Mean postoperative length of stay was 9.98 +/- 0.62 days (prepathway), 9.68 +/- 0.88 days for (nonpathway), and 7.71 +/- 0.37 days (pathway) (p < 0.05 vs. other groups).



Implementation of the pathway produced significant decreases in length of stay and cost in the pathway group as compared to the prepathway group. These results support the further development of clinical pathways for general surgical procedures.

title: Patient preferences for acute pain treatment.
abstract: Optimal treatment for acute pain is a function of an individual's willingness to make trade-offs between treatment side effects and pain control. The objective was to investigate the degree to which patients are willing to make these trade-offs.



Fifty patients undergoing major abdominal surgery were enrolled and completed interviews before and after surgery. Measures included an experience with pain questionnaire and an adaptive conjoint analysis (ACA) interview.



Percentage of pain relief obtained post-surgery was between 70 and 80%. Eight-two per cent reported at least one moderate or severe side effect. ACA results demonstrated that pain efficacy and side effect type/severity have almost equal 'importance' scores. Patients varied in their willingness to trade-off pain efficacy for different or milder side effects.



We conclude that people have different relative preferences for different side effects and are willing to trade-off pain relief for less upsetting and/or less severe side effects but to different degrees. Thus, physicians should consider offering pain medications with fewer side effects than narcotics as a first choice. Our study indicates the need to balance analgesia and side effects in order for patients to achieve optimal pain control.