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Postoperative ileus is a clinical problem that has been viewed traditionally as inevitable after major abdominal surgery, and to a much lesser extent after extra-abdominal procedures. There is no precise medical definition of postoperative ileus, but it is generally referred to as the period of impaired gastrointestinal motility that occurs after operation and characterized clinically by abdominal distention, delayed passage of gas and stool, lack of bowel sounds, and accumulation of gas and fluid in the bowel with ensuing nausea and vomiting. Ileus usually resolves in 4 to 5 days but may last from less than 2 days to more than 1 week. The duration of postoperative ileus is perhaps the most important factor that influences the length of hospitalization, which translates to increased costs; since there is no evidence that postoperative ileus has any beneficial effect, efforts to find ways to minimize it are constantly sought. There are currently sufficient data to show that at least 3 mechanisms are involved in the pathogenesis of postoperative ileus: increased inhibitory sympathetic activity, intensified inflammatory response, and utilization of pharmacologic agents that impair gastrointestinal motility, especially opiates.

For more than a century it has been well known that gastrointestinal motility is impaired after abdominal surgery. Scientists also noticed that transection of the spinal cord or splanchnic nerves resulted in a significant increase in spontaneous gastrointestinal contractions. This finding led to the conclusion that normal bowel motility is somehow inhibited by certain input from the nervous system. The fact that this inhibition increases after surgery implies that the input must be sympathetic, which also increases after surgery. Further observations showed that spontaneous contractions occurred even in isolated bowel segments; scientists began to realize that the gut must have an intrinsic nervous network that controls the basic gastrointestinal function, with regulatory input from the central nervous system (CNS), through the action of numerous neurotransmitters.

The enteric nervous system (ENS) and its function were extensively investigated. It was soon realized that the same neurotransmitters that are present in the CNS also function in the ENS; investigators discovered that sympathetic input inhibits bowel motility and parasympathetic stimulation increases it. Additional transmitters were subsequently found to have a variety of influences on bowel motility.

After surgery, the intestinal myoelectrical activity is disorganized with a net hypomotility. This state—postoperative ileus—usually resolves within a few days; it is commonly believed that the stomach regains normal function within 24 to 48 hours following surgery, the small intestine within 24 hours, and the colon within 3 to 4 days. The resolution of postoperative ileus is also difficult to define; some investigators consider hearing normal bowel sounds as a sign of resolving ileus, whereas others believe that the passage of gas or stool is that sign.

Traditionally, it was believed that the increase in the sympathetic activity that occurred after surgery was the major factor that caused ileus. Numerous animal studies proved this theory; transecting the spinal cord, performing abdominal sympathectomies, or using other means to block sympathetic input, consistently resulted in improved intestinal motility. Clearly, epinephrine had an inhibitory influence on bowel motility. Pain stimuli, both from the skin incision and peritoneum, can also induce an inhibitory reflex that is mediated by a variety of other substances including substance P, vasoactive intestinal polypeptide (VIP), nitric oxide (NO), and calcitonin gene-related peptide (CGRP). The specific role of each of these mediators is unknown, and investigational treatment with specific blockers had inconclusive outcomes. Adrenergic blockers also had very limited efficacy in alleviating postoperative ileus, with considerable side effects, and are therefore not routinely used for this indication. However, medical manipulation of the sympathetic nervous system by epidural blockade is 1 of the most elegant methods to reduce the magnitude of postoperative ileus.

Manual manipulation of the intestines induces an inflammatory response in the bowel wall that includes a cell-mediated response with a massive influx of circulating leukocytes and a humoral response with an upregulation and increased levels of prostaglandins and various inflammatory cytokines. Animal and human investigational trials showed that the intensity of the inflammatory response correlated with the duration of postoperative ileus. These trials also showed that treatment with anti-inflammatory agents could significantly reduce inflammation and shorten the duration of ileus.

For decades it has been a well-known fact that opiates inhibit intestinal motility. However, because opiates were, and still are considered by most surgeons as the ultimate analgesics, their side effects were considered inevitable, and therefore accepted and dealt with accordingly with laxatives and stool softeners. The inhibitory effect of opioids on gut motility is achieved by activation of a specific opioid μ receptor, which causes presynaptic blockage of excitatory neurons that innervate the intestinal smooth muscle. Numerous attempts to reverse the effect of opioids with nonspecific antagonists such as naloxone resulted in reversal of the analgesic effect as well, and this approach was also abandoned.

For many years the treatment of postoperative ileus was supportive with routine nasogastric decompression, intravenous fluids, and observation. The normal length of stay following major laparotomies with bowel resection was traditionally between 6 and 10 days, depending on the resolution of postoperative ileus, resumption of oral intake, and passage of gas and stool. Gradually it was demonstrated that nasogastric tubes (NGTs) in fact prolong the duration of postoperative ileus, increase the incidence of pulmonary complications, and significantly delay the resumption of oral intake. Some investigators took a bold step and allowed their patients to resume oral intake even before the clinical resolution of ileus. This maneuver proved to be beneficial, too. Patients were being discharged earlier, usually after tolerating oral intake and not waiting for the first passage of gas or stool in-hospital; several prospective, randomized trials confirmed this finding. Sham feeding can also promote motility. In a single interesting trial, gum chewing has been shown to reduce the duration of postoperative ileus significantly. This method may prove to be both simple and cost-effective.

Patients are usually encouraged to ambulate as early as possible after operation because ambulation is felt to reduce the incidence of pulmonary and thromboembolic complications. Most surgeons speculated that ambulation may contribute to restoration of intestinal motility as well, an idea that was refuted in several trials. In fact, some investigators suggested that physical activity would divert some of the blood flow away from the splanchnic circulation, an effect that would be detrimental to anastomotic healing and normal bowel function. Nevertheless, since normal surgical patients do not practice such vigorous physical activity as to cause these massive shifts in blood flow, early ambulation is, and should continue to be, encouraged to prevent other complications.

The introduction of minimally invasive techniques such as laparoscopy produced significant advantages in patient recovery. Postoperative pain was significantly reduced, which translated to earlier ambulation and better well-being. Despite the fact that the intestinal procedures were the same as in open surgery, patients who underwent laparoscopic surgery were sometimes subjected to an unintentional treatment bias toward a more liberal approach that included earlier oral feeding, less narcotic analgesics, and earlier discharge from hospital. Some clinicians later tried the same approach in open cases with promising outcomes.

Epidural analgesia as a form of sympathectomy usually reduces the duration of postoperative ileus and length of hospital stay. Unlike most other treatment options for postoperative ileus, it is an invasive modality, with a learning curve and potentially serious complications. For an epidural to achieve a maximal effect, it must be administered in the mid-thoracic level or above. Proponents of epidural anesthesia demonstrated impressive reductions in ileus and length of stay, but opponents claim to achieve the same results without epidurals.

A variety of medications have also been tried as potential treatments for postoperative ileus. Adrenergic blockers were modestly effective in animals but were accompanied by serious side effects in humans; parasympathetic agonists such as neostigmine have been used as potential stimulators for the gastrointestinal tract. Initial results were impressive but so were the side effects; currently, parasympathomimetic agents are not used as treatment for postoperative ileus. Several antiemetics and laxatives have also been used for treating postoperative ileus; none of them has any proven efficacy. Cisapride was probably the most successful agent in showing significant efficacy in shortening postoperative ileus, but reports of life-threatening complications resulted in its removal from the market. Nonsteroidal anti-inflammatory drugs (NSAIDs) have been used both as alternative analgesics and anti-inflammatory agents. Increased incidence of postoperative bleeding due to the antiplatelet effect prompted the introduction of more selective NSAIDs that lacked the antiplatelet characteristics, but had the same efficacy. Cyclooxygenase-2 (COX-2) inhibitors are currently almost routinely used as adjuncts to postoperative pain control regimens with impressive results.

Blocking the peripheral effects of opiates without reducing analgesia was an attractive idea. Alvimopan (Entereg; Adolor Corporation, Exton, PA, and GlaxoSmithKline, Pharmaceutical Development, Collegeville, PA) is a novel, selective, peripheral μ₂-opioid receptor antagonist, which recently has been shown to be extremely effective in reversing the intestinal inhibitory effects of opiates. It is indicated for use only when the pain-control regimen includes opiates, and should not be used whenever opiates are excluded. Early trials with other agents such as the peripheral opioid antagonist methylnaltrexone (MNTX; Progenics Pharmaceuticals Inc, Tarrytown, NY) and the new motilin analogue atilmotin (SK-896; Baxter Healthcare Corporation, Deerfield, IL) have revealed similar advantages.

Several trials have investigated the efficacy of various nonconventional treatment modalities for postoperative ileus. Electrical stimulation, guided imagery, psychological suggestion, mechanical massage, and even acupuncture have been tried with surprisingly favorable outcomes. However, randomized clinical trials are required for these methods to be clinically accepted as standard procedures.

Combining the beneficial effects of several treatment modalities is the next logical step. The concept of multimodal approach to the perioperative management of patients undergoing abdominal surgery evolved a decade ago. In the initial reports the investigators combined minimally invasive techniques with perioperative epidural analgesia, avoided NGTs and opiates, encouraged early oral intake and ambulation, and also used cisapride. With this regimen patients were discharged 2 days after operation. Gradually more patients and indications were deemed suitable for the multimodal approach; patients underwent a wide variety of procedures with similar success rates. Other multimodal programs that excluded epidurals from their “fast track” protocols demonstrated excellent results as well.

Although there is no panacea for postoperative ileus, substantial progress has been made toward effective reduction of its duration. Hopefully, with new advances in surgical techniques and medical treatment options, postoperative ileus will be a much less significant problem in the near future.