TY - JOUR
AU - Gannon, Richard, H.
AB - Purpose. Internal and external factors that contribute to postoperative ileus (POI), the efficacy and safety of various nonpharmacologic and pharmacologic interventions that have been evaluated for the prevention or amelioration of POI, and the current multimodal approach used in patients undergoing major abdominal surgery are described. Summary. Catecholamine and cytokine release associated with the stress response to surgery and the use of certain antiemetic medications, opioid analgesics, and inhaled anesthetics are among the factors that contribute to POI. Early ambulation does not affect the duration of POI, although it has other benefits for patients undergoing abdominal surgery. Clinical experience supports the use of laparoscopy instead of laparotomy if possible, removal of nasogastric tubes shortly after surgery, restriction of intravenous fluids, and initiation of clear oral liquids and ambulation on the first postoperative day. The recommended therapeutic approach for patients undergoing major abdominal surgery involves thoracic epidural analgesia using a local anesthetic with or without an epidural opioid analgesic, and systemic nonsteroidal anti-inflammatory drugs for their opioid-sparing effect if systemic opioid analgesics are used. Buprenorphine may be preferred if a systemic opioid analgesic is used, because it has little effect on gastrointestinal smooth muscle. Metoclopramide, erythromycin, beta blockers, laxatives, neostigmine, naloxone, and gum chewing are not useful for treating POI. Conclusion. Most pharmacologic interventions that have been tried in an effort to prevent or ameliorate POI are ineffective or cause intolerable adverse effects. Research is needed to identify and develop new drug therapies for POI. Anesthetics, Antiemetics, Antiinflammatory agents, Buprenorphine, Ileus, Opiates, Postoperative complications, Toxicity Postoperative ileus (POI), an unavoidable complication of surgery, has been attributed in part to a stress response accompanied by increases in the release of catecholamines (e.g., norepinephrine) and cytokines that inhibit colonic motility.1 The cytokines also mediate inflammation, edema, and pain. Nitric oxide, interleukins, prostaglandins, substance P, vasoactive intestinal peptide, and calcitonin gene-related peptide are among the cytokines released as part of the surgical stress response. Various external factors may contribute to POI. These factors include the use of certain antiemetic medications to prevent postoperative nausea and vomiting—transdermal scopolamine (anticholinergic effects), the 5-HT3 antagonists (constipation); opioid analgesics; inhaled anesthetics; and intravenous fluids, which can cause water and electrolyte imbalances (e.g., hypokalemia, hypomagnesemia).1 The strategies used to prevent or ameliorate POI include nonpharmacologic and pharmacologic interventions. Nasogastric tube removal In the past, nasogastric (NG) tubes routinely were inserted shortly before abdominal surgery and kept in place until normal bowel function returned. However, this practice was associated with throat pain, atelectasis (collapse of a portion of the lung), and aspiration pneumonia.2 In a prospective randomized study of the postoperative use of NG tubes in 535 patients who underwent elective colon or rectal surgery, there was no difference in the time to resumption of normal bowel function (94 hours) between patients whose NG tubes were removed in the recovery room and those whose NG tubes remained in place.3 The frequency of abdominal distention, nausea, and vomiting was significantly greater in patients whose NG tubes were removed in the recovery room (28%, 27%, and 19%, respectively) than in patients with postoperative NG tubes (16%, 17%, and 11%, respectively, p < 0.05 for all).3 However, the discomfort of NG tubes and the risk for pulmonary complications are great enough and the frequency of vomiting in patients without NG tubes is low enough that NG tubes are no longer routinely used postoperatively in abdominal surgical patients. Early ambulation Early ambulation after surgery has been encouraged to prevent atelectasis, deep vein thrombosis, and other complications.4,5 However, in a study of 34 patients who underwent abdominal surgery by laparotomy, ambulation on the first postoperative day versus the fourth postoperative day did not shorten the time to recovery of normal bowel function.6 Although it has other benefits, early ambulation does not appear to prevent or ameliorate POI. Early oral intake Conventional wisdom restricted oral intake of fluids and food after abdominal surgery until the resumption of normal bowel function because of concerns that earlier oral intake would increase the risk for nausea, vomiting, and dehiscence of the surgical anastomosis. Anastomotic dehiscence can lead to peritonitis. In four small studies of patients who underwent colon resection, early oral intake of clear liquids on the first postoperative day was compared with delay of oral intake until normal bowel function resumed.7,–10 In one study of 64 patients, vomiting occurred in 44% of patients whose oral intake began on the first postoperative morning and 25% of those who delayed oral intake until normal bowel function resumed.7 There was no difference between the two groups in the duration of POI.7 In the other three studies, there were no differences between early oral intake and later oral intake in the frequency of complications or the time to POI resolution. In two studies, early oral intake was associated with earlier hospital discharge than later oral intake.7,8 Restricting intravenous fluids Restricting i.v. fluid intake after colon surgery has been advocated because fluids administered during surgery are thought to cause bowel edema and slow return of bowel function. Postoperative i.v. fluid restriction (2 L/day) was compared with standard fluid administration (3 L/day) in 20 patients who underwent hemicolectomy by laparotomy and received opioid analgesics by patient-controlled analgesia (PCA).11 The restricted fluid group experienced nearly normal gastric emptying, with the first stool and first solid food on postoperative day 4. By contrast, the standard fluid group experienced delayed gastric emptying, with the first stool and first solid food on postoperative day 6.5. The median time to hospital discharge was significantly longer in the standard fluid group (9 days) than in the restricted fluid group (6 days, p < 0.001). These findings suggest that restricting postoperative i.v. fluids after colon surgery is beneficial. Use of laparoscopy Abdominal laparotomy involves a long incision through the peritoneum and abdominal muscles, resulting in considerable postoperative pain. Usually four to five one-inch incisions are made in the abdomen for a laparoscopic colectomy. Sometimes, one of the incisions needs to be enlarged (by one to two inches) to remove the resected colon. Because the incisions are small, there is usually less abdominal pain. The abdomen is filled with carbon dioxide gas during laparoscopies to optimize the visual field for the surgeon. Most of the gas is removed at the end of the procedure, but residual gas and distention of the peritoneum during the procedure often causes postoperative chest pain and abdominal discomfort for the first 24 hours after surgery. The use of laparoscopy instead of laparotomy for colorectal surgery has been shown to shorten the duration of POI and reduce hospital length of stay (LOS).12,13 With laparoscopy, shorter incisions and less handling of the bowel mean less pain and reduced opioid analgesic requirements, which may allow earlier ambulation and oral intake.14 Thoracic epidural analgesia A meta-analysis revealed that the time to return of gastrointestinal (GI) function after abdominal laparotomy was 24 hours in patients receiving a local anesthetic by the epidural route compared with 37 hours in patients receiving epidural or systemic opioid analgesics.15 However, the use of a local anesthetic alone for thoracic epidural analgesia instead of an opioid PCA after laparotomy and intestinal resection in 56 patients did not affect hospital LOS.16 If thoracic epidural analgesia is to be successful after abdominal surgery, the catheter should be inserted at the T8–10 level of the spinal cord because analgesia is provided only from the site of insertion down (i.e., toward the feet). Insertion of the catheter further down in the lumbar spine will not provide adequate analgesia after abdominal surgery.17 Thoracic epidural analgesia often is used for two days. Technical failures occur in about 20% of patients, usually because of mechanical problems (e.g., catheter dislodgement).16 Thoracic epidural administration of local anesthetics blunts the surgical stress response. Less cytokine production, greater pain relief, lower opioid analgesic requirements, and earlier return of normal bowel function were associated with thoracic epidural administration of the local anesthetic lidocaine than with i.v. administration of the same local anesthetic in 60 patients who underwent colon surgery.18 Neither epidural nor systemic administration of opioid analgesics blunts the surgical stress response.19 Thoracic epidural local anesthetics alone may not provide adequate analgesia. A combination of an epidural opioid with an epidural local anesthetic or a combination of a systemic opioid with the epidural local anesthetic may be required for satisfactory analgesia. Epidural administration of an opioid analgesic plus a local anesthetic provides greater analgesia and less pruritus and hypotension than either epidural opioids or epidural local anesthetics alone.15,20 Morphine, fentanyl, and hydromorphone are commonly used for thoracic epidural analgesia. Morphine is hydrophilic and tends to cause less nausea, vomiting, pruritus, and urinary retention than fentanyl.21 Epidural hydromorphone causes less pruritus than epidural morphine.22 Fentanyl is lipophilic, and its analgesic effect after epidural administration is thought to be mediated in part by therapeutic blood levels achieved after systemic absorption and distribution (i.e., activity at supraspinal opioid receptors), not solely the result of a local effect at spinal opioid receptors.23 Bupivacaine 0.1% is used with or without hydromorphone 10 μg for thoracic epidural analgesia at Hartford Hospital because hydromorphone is neither highly lipophilic nor highly hydrophilic. Promotility agents The promotility agent metoclopramide has been used postoperatively, but it does not shorten the duration of POI after abdominal surgery.24,25 Metoclopramide accelerates gastric emptying and stimulates gastric, pyloric, and small bowel motor activity, but it has little or no effect on the colon.26 Moreover, the drug can cause sedation, akathisia (feelings of motor restlessness), and other extra-pyramidal reactions.26 Erythromycin has agonist activity at receptors for motilin, a GI peptide that stimulates smooth muscle contraction.27 However, erythromycin lacks activity in the colon, and tachyphylaxis (a decrease in response to the drug with repeated doses) is associated with its use.28,29 In a prospective, double-blind, placebo-controlled study of 77 patients who underwent major abdominal surgery, erythromycin 250 mg i.v. every eight hours beginning in the recovery room had no effect on the duration of POI or on LOS, compared with placebo.30 The use of beta blockers to counteract the catecholamines associated with the surgical stress response has been suggested. In a randomized, double-blind, placebo-controlled study of 39 patients who underwent elective colon surgery, the time to first stool was significantly shorter in patients treated with propranolol 4 mg i.v. twice daily (82 hours) or propranolol 10 mg i.v. twice daily (79 hours) than in patients treated with placebo (110 hours, both p < 0.01).31 A greater effect from propranolol was observed in patients more than 60 years of age than in younger patients. Respiratory and cardiovascular adverse effects were not reported, but bronchospasm in patients with pulmonary disease, hypotension, bradycardia, and other adverse effects limit the use of beta blockers for the treatment of POI. Neostigmine is an anticholinesterase agent that inhibits the hydrolysis of acetylcholine and causes cholinergic effects, including increased GI motility.32 However, the cholinergic effects of neostigmine are not selective for muscarinic receptors, which mediate increased GI motility. Cholinergic activity at nicotinic receptors associated with neostigmine use can cause muscle fasciculations. The muscarinic cholinergic effects of neostigmine also can cause bradycardia and increase bronchial secretions. In a controlled, double-blind study of 90 patients who underwent laparotomy, intramuscular (i.m.) administration of up to three 0.5-mg doses of neostigmine every three hours on the third postoperative day did not affect the duration of POI.33 Laxatives have been considered for patients with POI. In a nonrandomized study, 20 women who underwent radical hysterectomy were given milk of magnesia 30 mL orally twice daily beginning on the first postoperative day and bisacodyl suppositories rectally once daily beginning on the second postoperative day.34 Patients were not discharged until 12 hours after tolerating a clear liquid diet, which was begun after flatus or a bowel movement. The median time to flatus, bowel movement, and a clear liquid diet was three days, and the median time to hospital discharge was four days. A historic control group that received traditional postoperative bowel management had a median time to hospital discharge of eight days. The difference in hospital discharge days was significant (p < 0.001); however, this study included a small number of subjects, did not include a comparative placebo group, and used historical controls. Well-designed studies of traditional and laxative-based approaches are needed to assess the true efficacy of laxative therapy. Miscellaneous approaches The possibility that small doses of the opioid antagonist naloxone might be used for patients with POI without reversing analgesia has been considered. The drug would need to be given by the enteral route (i.e., NG tube) because it is unpalatable. In a double-blind, randomized, placebo-controlled study, nine patients with constipation due to opioid analgesic use for chronic pain received naloxone 2 mg or 4 mg or placebo orally three times daily for three weeks.35 All six naloxone-treated patients experienced some improvement in bowel movement frequency, but three of these patients also experienced reversal of analgesia, including one patient with complete reversal of analgesia. Thus, naloxone at these doses is not useful for treating POI because of the potential for reversal of anesthesia. Nonsteroidal anti-inflammatory drugs (NSAIDs) have an opioid-sparing effect (i.e., they reduce opioid analgesic dosage requirements) that may minimize POI.36 These agents may be given orally or parenterally. Buprenorphine is a partial agonist with activity at μ-opioid receptors that causes analgesia but has little effect on GI smooth muscle.37,38 Buprenorphine exhibits a ceiling effect whereby the opioid agonist effect diminishes and opioid antagonist activity predominates when the i.m. dose is increased beyond 0.8 mg.37 The drug should be used with caution in patients who are physically dependent on opioid analgesics (e.g., patients in methadone maintenance programs) because it can precipitate withdrawal. The impact of gum chewing on recovery from POI was evaluated in a randomized, controlled study of 19 patients who underwent elective laparoscopic colectomy.39 Chewing gum three times a day from the first postoperative morning until resumption of oral intake led to a significantly earlier average time of first passage of flatus (postoperative day 2.1 in the gum-chewing group and postoperative day 3.2 in the control group who did not chew gum, p < 0.01) and a significantly earlier first defecation (postoperative day 3.1 in the gum-chewing group and postoperative day 5.8 in the control group, p < 0.01). The average postoperative hospital stay for the gum-chewing group and the control group was 13.5 days and 14.5 days, respectively. The efficacy of gum chewing in a laparoscopic colectomy population needs further research as the number of patients in this study was small and there was no placebo group. These findings generated considerable excitement about the prospect of using gum chewing as a convenient mode of treatment for POI. However, in a subsequent randomized, double-blind, placebo-controlled study, 66 patients undergoing open colectomy were randomly assigned to one of three regimens beginning on the first postoperative day: (1) sips of clear liquids plus gum chewing, (2) sips plus wearing an acupressure bracelet, and (3) sips alone (the control group).40 The median time to first postoperative passage of flatus was 60 hours with sips plus gum chewing, 72 hours with acupressure plus sips, and 67 hours in the control group. The differences between groups were not significant. There were no significant differences among the three groups in the time to the first bowel movement or hospital discharge. Thus, gum chewing does not appear useful for treating POI in an open colectomy patient population. Multimodal therapy Clinical experience supports the use of laparoscopy instead of laparotomy if possible, removal of NG tubes after surgery (i.e., in the recovery room), restriction of i.v. fluids, and initiation of clear oral liquids and ambulation on the first postoperative day in patients undergoing major abdominal surgery. A multimodal therapeutic approach is recommended, involving thoracic epidural analgesia using a local anesthetic with or without an epidural opioid analgesic, and systemic NSAIDs for their analgesic effect as well as their opioid-sparing effect if systemic opioid analgesics are used. In opioid naïve patients, buprenorphine may be preferred if a systemic opioid analgesic is used, because of its minimal effect on the GI tract. Peripherally selective μ-opioid receptor antagonists (e.g., methylnaltrexone, alvimopan) may be an option for treating POI in the near future. Conclusion Most of the pharmacologic interventions that have been evaluated in patients with POI have been abandoned because of a lack of efficacy, intolerable adverse effects, or both. New drug therapies that shorten the duration of POI and can be incorporated into the current multimodal approach are needed to improve outcomes in patients undergoing major abdominal surgery. Footnotes Based on the proceedings of a symposium held December 5, 2006, during the ASHP Midyear Clinical Meeting in Anaheim, CA, and supported by an educational grant from Adolor Corporation and GlaxoSmithKline. Dr. Gannon received an honorarium for his participation in the symposium and for the preparation of this article. Dr. Gannon reports that he has served as a consultant and speaker for Adolor Corporation and GlaxoSmithKline. References 1 Steinbrook RA. Postoperative ileus: why we should treat. Contemp Surg. 2005 ; March suppl: 4 –7. 2 Racette DL, Chang FC, Trekell ME et al. 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TI - Current strategies for preventing or ameliorating postoperative ileus: A multimodal approach
JF - American Journal of Health-System Pharmacy
DO - 10.2146/ajhp070429
DA - 2007-10-15
UR - https://www.deepdyve.com/lp/oxford-university-press/current-strategies-for-preventing-or-ameliorating-postoperative-ileus-x8fZiBCk1v
SP - S8
VL - 64
IS - 20_Supplement_13
DP - DeepDyve
ER -