Motility Disorders of the Stomach and Small Intestine

Motility Disorders of the Stomach and Small Intestine Justin Barr 

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  Rebekah R. White

GASTRIC MOTILITY ANATOMY AND PHYSIOLOGY The gastric fundus, body, antrum, and pylorus must contract and relax in a coordinated manner to produce satisfactory gastric function and emptying (Figs. 65.1 and 65.2). The thinner fundus receptively relaxes to store food and liquids and then contracts to empty liquids from the stomach. The gastric pacemaker, which is located in the body along the greater curvature, stimulates both the filling and mixing of food in the body and antrum. The antrum strongly and periodically contracts against the closed pylorus to grind solid food particles down to a small size. The antrum peristalses at a frequency of three cycles per minute and propels small particles and liquids into the duodenum as the pylorus opens. Consequently, the stomach has three motile regions that coordinate to empty the stomach. The fundus receptively relaxes and subsequently contracts, and the body then fills and mixes. The antropyloroduodenal complex triturates and then empties into the duodenum as the pyloric sphincter opens. Noncontractile gastric slow waves originate from the gastric pacemaker at a frequency of three waves per minute and propagate in both circumferential and longitudinal directions.1 The network of interstitial cells of Cajal (ICCs) in the myenteric plexus initiates the slow wave and then conducts it to the smooth muscle layer by inducing depolarization. A deeper region of intramuscular ICCs is located in the muscularis propria. These serve to amplify the gastric slow wave signal to reach an action potential level through activation of calcium channels resulting in muscle contractions. Thus the ICCs in the myenteric plexus initiate the slow wave frequency in the smooth muscle, and the intramuscular ICCs propagate the slow wave and permit peristalsis.2 Gastric emptying comes under neural and hormonal control. The enteric nervous system (ENS; the “second brain”) runs along the course of the stomach and intestines, contains over 100 million neurons, and can function independently of the central nervous system (CNS). It consists of two plexuses, submucosal (Meissner) and myenteric (Auerbach), which help direct the smooth muscle. The vagus nerve connects the ENS and the CNS. Several hormones, such as gastrin, cholecystokinin (CCK), glucagon-like peptide (GLP)-1 and GLP-2, peptide YY, and others, also influence gastric motility; a full review of these hormones is beyond the scope of this chapter and is described elsewhere.3

GASTROPARESIS Gastroparesis is objectively delayed gastric emptying in the absence of organic causes such as stricture, ulcer,

tumor, or mechanical obstruction, and in the absence of other causes such as functional dyspepsia, rumination syndrome, cyclic vomiting syndrome, or bulimia/ anorexia nervosa. Official diagnosis requires both objectively confirmed delayed gastric emptying and associated symptoms of nausea, vomiting, bloating, and pain. Mechanisms Recent research has demonstrated the synergistic effect of multiple mechanisms in causing gastroparesis. With gastroparesis, both abnormal peristaltic contractile activity and abnormal electrical slow waves are usually present. Antral hypomotility, likely a neuropathic process reflecting the loss of ICCs, commonly occurs in diabetic patients, with evidence linking it to those with Parkinson disease as well.4 Although the fundus has minimal contractile activity, its normally firm tone facilitates food movement to the body; a lax fundus—shown to result from both vagotomy and diabetes—delays passage of chyme. In contrast, impaired pyloric relaxation, seen primarily in type 1 diabetics, can trap contents in the stomach. The stomach and duodenum must act together, with the pylorus and duodenum relaxing as the antrum contracts. Disruptions in this concert or the various neurohormonal factors that coordinate the process also lead to gastric dysmotility. Epidemiology and Etiology Gastroparesis has an overall prevalence of 24 per 100,000 Americans. The disease affects females more often than males (4 : 1), with the onset of symptoms beginning at an average age of 34 years. There were 16,736 primary hospitalizations for gastroparesis in 2009 (up 18-fold from 1994), at a cost of an average $25,000 per hospitalization.5 The most common etiology of gastroparesis is, unfortunately, idiopathic, representing half of all cases. Diabetes causes about 25% of cases. Gastroparesis typically develops after 10 or more years of diabetes; patients almost always present with various symptoms of autonomic dysfunction as well as increased incidence of microvascular disease.6,7 In the community, around 5% of type 1 diabetics and 1% of type 2 diabetics develop gastroparesis (numbers from patients with more advanced disease receiving care at tertiary centers are much higher: 40% and 15%, respectively).7 Improved glycemic control does not appear to relieve gastroparesis, with symptoms and emptying time unchanged in patients despite better management of blood sugars.8 Gastroparesis does not appear to cause increased mortality in diabetic patients but does serve as a marker for increased morbidity and mortality, likely due to shared effects of microvascular disease.

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Motility Disorders of the Stomach and Small Intestine   CHAPTER 65 

ABSTRACT Gastrointestinal dysmotility represents a severe constellation of symptoms resulting from malfunction of the stomach, small intestine, or large intestine. By definition excluding organic origins of obstruction, the etiologies of the condition range from diabetes to Parkinson’s to more exotic myopathies, although idiopathy remains the most commonly cited cause. Patient presentation typically includes epigastric pain, nausea, vomiting, early satiety, and poor oral intake; constipation characterizes lower GI dysmotility. Severity of the symptoms can range from mildly aggravating to requiring a feeding jejunostomy or even total parental nutrition for survival. CT scan, EGD, and barium swallow are helpful to rule out organic causes, but nuclear medicine emptying studies are required to make diagnosis. Treatment options remain poor. Symptomatic relief with various anti-nausea medications can alleviate minor cases. Metoclopromide remains the only FDA-approved medication for gastroparesis but comes with well-described, severe side effects. Other, more exotic interventions like intrapyloric botulinum injections and implanted gastric pacemakers lack convincing evidence of efficacy. More dramatic, surgical cures like pyloroplasty, jejunostomy feeding tubes, and even small bowel transplant are indicated in particularly severe cases.

KEYWORDS Gastric motility, intestinal motility, gastroparesis, metoclopramide, gastric electric stimulation, dysmotility, ileus, chronic intestinal pseudoobstruction

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SECTION II  Stomach and Small Intestine Serosa Muscularis propria longitudinal circular oblique

Fundus Myenteric plexus Submucosal plexus

Submucosa Muscularis mucosa

Mucosa

Gastric pacemaker

Pylorus

Body

Antrum

FIGURE 65.1  Anatomy and histology of the stomach. (Illustrated by Lauren Halligan, MSMI; copyright Duke University 2016.)

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disease, ~7.5% of cases).9 Specific therapies for these rare etiologies are not addressed in this chapter.

Open pylorus

1

2

Closed pylorus

3

FIGURE 65.2  Peristalsis of the stomach. 1, Fundus relaxes to accept food. 2, Body of stomach fills and mixes the food. 3, Antrum contracts against closed pylorus, aiding the digestive process. 4, Pylorus periodically opens in rhythm with antral contractions to allow contents into the duodenum. (Illustrated by Lauren Halligan, MSMI; copyright Duke University 2016.)

Postsurgical sequelae (especially with intended or inadvertent vagotomy) cause approximately 13% of gastroparesis cases. The remaining patients suffer from a variety of less common causes: radiation, viral disease (e.g., Norwalk), connective tissue disorders (e.g., scleroderma), paraneoplastic syndromes, infiltrative diseases (e.g., amyloidosis), and neurologic disorders (e.g., Parkinson

Clinical Presentation The predominant symptoms are similar regardless of etiology: nausea (80% to 92%) and vomiting (66% to 85%), abdominal bloating (55% to 75%) and early satiety (54% to 60%).10 Previously underestimated, epigastric abdominal pain is present in almost 90% of patients, is worsened by eating (72%), occurs nocturnally (74%), and often disturbs sleep (66%). Abdominal pain is not usually treated satisfactorily by gastric electrical stimulation or by prokinetic drugs.11 Some studies suggest diabetic patients have more vomiting and idiopathic patients have more satiety, but the differences are not significant enough to affect diagnosis or management. Symptoms frequently overlap with functional dyspepsia, a condition that shares similar pathophysiology and presentation and can be difficult to distinguish even with objective testing.12 The Gastroparesis Cardinal Symptom Index (GCSI) is a validated tool used to assess patients’ severity of symptoms.13 Differential diagnoses for these symptoms include gastroparesis, dumping syndrome, functional dyspepsia, ulcer disease, malignancy, gastroesophageal reflux disease, rumination syndrome, cyclic vomiting syndrome, bulimia, and mechanical gastric outlet obstruction. Diagnosis The diagnosis of gastroparesis is usually made after extensive testing to rule out other organic causes. Upper endoscopy with biopsy and an upper gastrointestinal (GI) contrast radiography with or without a small bowel followthrough are usually performed to rule out an organic cause. If these are inconclusive, a gastric emptying scan

Motility Disorders of the Stomach and Small Intestine   CHAPTER 65 

may diagnose gastroparesis. The nuclear medicine solidphase gastric emptying test is the current gold standard for the diagnosis of gastroparesis, in the absence of gastric outlet obstruction. Diagnosis is probable if more than 50% of a solid meal is retained 2 hours after ingestion, or more than 10% of a solid meal is retained at 4 hours. Liquid emptying is less accurate for diagnosis of gastroparesis because liquids may empty normally even with an abnormal solid-emptying scan; recent studies have shown that delayed emptying of liquids relative to solids can increase the sensitivity of the test, especially in nondiabetic patients, although the clinical implications are unclear.14 A radionuclide eggbeater meal (250 kcal and low fat) is used as a test meal for the solid-emptying scan.15 Patients should avoid medicines such as promotility agents, anticholinergics, and opioids 48 hours prior to testing. Diabetic patients should have their blood sugar controlled; blood glucose greater than 275 is a contraindication for proceeding.16 Although not commonly used in clinical settings, breath testing for gastroparesis can be performed with 13C-labeled octanoate or the blue-green algae, Spirulina platensis, in a solid meal, which is absorbed in the small bowel after gastric emptying. It is metabolized to 13CO2, and then removed by respiration and available for breath testing.6,11 Gastric antral, pyloric, and duodenal motility may also be assessed with antroduodenal manometry. This procedure is available at tertiary medical centers, and does require fluoroscopy, catheter placement, and some patient discomfort. The wireless motility capsule has also been used to characterize the number of contractions as well as the motility index in the antrum and the duodenum.6 Diabetic patients with gastroparesis show significantly lower numbers of contractions in both the stomach and small bowel compared with normal patients, whereas idiopathic gastroparetic patients do not show significant differences.17 Pharmacologic Treatment Gastroparesis is initially treated by correcting fluid and electrolyte abnormalities, nutritional deficiencies, identifying and treating underlying causes, and suppressing the symptoms of nausea and vomiting. Diets are changed, using softer solid foods, more liquid supplements, and smaller, more frequent meals. Low-fat and low-fiber diets also help, as does avoidance of carbonated beverages, alcohol, and smoking. 18,19 In a diabetic patient, tight glucose control should be achieved because hyperglycemia has been shown to worsen gastroparetic symptoms, although long-term benefit is controversial and some antidiabetic medications (e.g., GLP-analogs and amylin analogs) can prolong gastric transit time. The mainstay of medical treatment for gastroparesis is the use of both antiemetic and prokinetic medications.11 Regrettably, many of the current recommendations rest on studies performed several decades ago. Symptom management includes controlling nausea, vomiting, and pain. Useful antiemetic agents include prochlorperazine (Compazine) and trimethobenzamide (Tigan), which antagonize dopamine receptors. Antihistamines with histamine (H1)-receptor antagonist properties include diphenhydramine (Benadryl), promethazine, ondansetron (Zofran), granisetron (Kytril), and dolasetron

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(Anzemet). Other agents include scopolamine, an anticholinergic, and aprepitant (Emend), a substance P/ neurokinin-1 receptor antagonist. Dronabinol has also proven effective in subsets of patients.20 Ideally, opioids should be avoided or limited for pain control given their effect on slowing gastrointestinal motility. Selective serotonin reuptake inhibitors (SSRIs) and tricyclic antidepressants (TCAs) have been used with the latter also demonstrating some relief of nausea and vomiting, although amitriptyline has significant anticholinergic side effects that delay gastric emptying.21 All these medications are used empirically with little level I evidence to support one over another. Metoclopramide remains the only US Food and Drug Administration (FDA)-approved medication to treat gastroparesis and should be the first motility agent tried. It functions as a dopamine D2 receptor antagonist and serotonin 5-HT4 receptor agonist, increases gastric motility through acetylcholine release, and relieves nausea via receptors in the brainstem (see later in this chapter for more on dopamine and serotonin). The drug carries a risk of serious side effects, including acute dystonias (incidence 0.2%), of which 1% are tardive dyskinesia. Less severe complications include CNS side effects, such as drowsiness, insomnia, and fatigue, in 20% of patients. Higher doses, longer courses of treatment, and female sex were all associated with increased risk of adverse effects.22–24 Multiple studies over the last few decades, including placebo-controlled randomized clinical trials, have proven the efficacy of metoclopramide.25,26 Resulting papers have consistently demonstrated faster gastric emptying times and improved nausea and vomiting among patients. However, due to the risk of side effects, most studies terminated after 4 weeks, leaving longer-term use under investigated and essentially empirical.27 Recent investigation into nasally administered metoclopramide has shown promise with symptom control and ability to use long-term with diminished risk of side effects.28 Domperidone is another option that also functions as a D2 receptor antagonist. It has similar ability to control symptoms of nausea and vomiting as metoclopramide, demonstrated through placebo-controlled and head-tohead clinical trials.29,30 The starting dose is 10 mg three times per day (TID), increasing to 20 mg TID and at bedtime (qHS). Because domperidone does not cross the blood-brain barrier, patients are not at risk for the CNS side effects that limit metoclopramide use. However, domperidone does prolong the QTc interval and has been associated with sudden cardiac death.31 The drug is not FDA approved and thus not for sale at most US pharmacies; providers may write a prescription for the drug, allowing patients to fill it at a compounding or international pharmacy. Erythromycin works on the motilin receptors located in the gastric antrum and proximal duodenum. Although studies show short-term improvement in gastric motility, no long-term benefit has been demonstrated. The antibacterial properties of the drug potentially alter gut flora, with variable consequences on motility; cardiac side effects (lengthening repolarization time) also complicate the use of the drug.32 Mitemcinal, an erythromycin-derived motilin agonist, has been tested in patients with idiopathic

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SECTION II  Stomach and Small Intestine

and diabetic gastroparesis. Although it did improve gastroparetic symptoms, there was no statistically significant improvement over the prominent placebo effect.33 Ghrelin is expressed primarily by neuroendocrine cells in the gastric fundus and the duodenum. It structurally resembles motilin, and its receptor resembles the motilin receptor. Ghrelin and motilin are coproduced in the same cells in the duodenum and proximal jejunum.34 Basic science investigations have clearly shown its ability, in high doses, to stimulate gastric motility, increase gastric tone, and increase activity of migrating motor complexes (MMCs) in small bowel.35 Ghrelin itself has too short a half-life for clinical utility, leading researchers to create various synthetic analogs. Early randomized double-blinded clinical studies failed to demonstrate superiority over placebos.36 However, new formulations (RM-131) have shown early promise in symptom management, and this remains a very active area of research.37 Intrapyloric Botulinum Injections Pylorospasm has been indicted as a possible cause for delayed gastric emptying. Injected into the pylorus, botulinum toxin works as a neuroinhibitor, preventing muscle contraction. Although nonrandomized trials have reported patient improvement, two prospective, blinded randomized clinical trials demonstrated faster gastric emptying but no relief of symptoms.38 Thus, there is no good evidence to support this practice; the demonstration of benefit in open-label trials suggests a component of placebo effect, recognized as important in functional gastrointestinal illness.39 Gastric Electrical Stimulation Gastric electrical stimulation seeks to induce gastric motility by inducing muscle contraction. The evidence for gastric electrical stimulation has been conflicting. Initial attempts used high-energy, low-frequency electricity to capture and regulate slow waves, normalizing intrinsic gastric electrical and, ideally, motor function. Subsequent studies later demonstrated subjective benefit but no evidence of changes in gastric motor function.40 More recently, technique has shifted to low-energy, high-frequency stimulation, which does not influence slow waves but does appear to modulate gastric nerve activity. In 2000, the FDA approved a Medtronic (Minneapolis, Minnesota) device for treating gastroparesis using these parameters. The stimulator package consists of a Medtronic Enterra stimulator (sized similar to a cardiac pacemaker) and two insulated wire electrodes with an uninsulated metal tip electrode that is connected to a monofilament suture on a straightened needle (Fig. 65.3). The two electrodes are positioned along the anterior greater curvature of the stomach using partial-thickness penetration into the muscularis.41 Placement may be accomplished laparoscopically or via a small upper midline incision. 42 Upper endoscopy is performed at the time of electrode placement to exclude full-thickness gastric wall penetration by the electrode. The stimulator is placed in a subcutaneous pocket on the abdominal wall in a location consistent with the patient’s wishes, previous surgical procedures, and the potential need for future feeding tubes. Both electrodes are then brought through the abdominal wall

FIGURE 65.3  Enterra gastric electric stimulator system, with two Enterra leads, an introducer rod, plastic disks, and Enterra stimulator.

and are connected to the stimulator. Next, the electrical resistance of the circuit through the gastric wall is measured. A typical impedance value of less than 800 ohms is satisfactory. If the impedance is greater, the electrodes may need to be repositioned. Risks associated with the gastric electrical stimulator include full-thickness electrode penetration of the gastric wall at the time of placement or subsequent erosion into the gastric lumen with infection or abscess, for which the electrodes should be removed.43 The presence of two looping wire electrodes within the abdomen can lead to small bowel obstruction, particularly in patients with a history of prior abdominal surgeries. Infection or abscess at the skin pocket stimulator site mandates its removal. Erosion of the stimulator through the skin, even without cellulitis, is also treated by removal. Magnetic resonance imaging (MRI) is not possible after stimulator placement. In hospital, mortality after implantation ranges from 0.8% to 2.4%. Tracked over 10 years, the reoperation rate following stimulator implantation for problems specific to the device is 11.1%, with device removal in 8.4%.44 Evidence regarding efficacy varies. The initial trials underlying FDA approval included an open-label study reporting broad symptomatic improvement and an underpowered double-blind randomized crossover trial (enrolling only 50% of desired participants) that reported some improvement in weekly vomiting frequency, although not in patients with idiopathic disease.41 Most subsequent trials have been open label and/or lacked controls. These have nonetheless demonstrated consistent symptomatic improvement among patients, particularly those with diabetic gastroparesis. Studies have most consistently demonstrated decreased incidence of weekly vomiting. However, a metaanalysis of clinical trials evaluating gastric electrical stimulation did not find any persistent symptom relief.44 Five randomized clinical trials with 185 patients formed the foundation for this analysis, which the authors recognized as differing substantially from conclusions reached in open-label trials. The authors attribute these differences to placebo effect and regression

Motility Disorders of the Stomach and Small Intestine   CHAPTER 65 

to the mean, noting that those with the most severe symptoms reported the most subjective benefit. Other studies have demonstrated surgery exerting a more powerful placebo effect than medications, perhaps partially explaining the reported superiority of gastric electrical stimulation to pharmacologic management.45 Given the 11% risk of reoperation, these results give pause to reflexive implantation. Additional studies are needed. Other Surgical Interventions When prokinetic and antiemetic medications are insufficient to maintain body weight, then venting and feeding tubes are used. A percutaneous gastrostomy tube alone may reduce the incidence of vomiting through intermittent venting or by setting the tube at continuous external drainage. A combination transgastric gastrojejunal tube can vent the stomach and also enable proximal jejunal tube feeding. Placement of a feeding jejunostomy tube allows both adequate nutrition and fluids, and it can reduce the need for hospitalization for intravenous repletion of fluids; it does not improve symptoms. Placement of both a gastrostomy tube for venting and a jejunostomy tube for fluids and nutrition allows some gastroparetics to manage symptoms and improve quality of life. Enteral feeding is preferred over parenteral nutrition, with lower overall cost and avoidance of complications from central intravenous access. Enteral feeding via the jejunostomy tube may be maintained for months or years. Potential complications of a feeding jejunostomy include tube dislodgement with closure of the opening, infection and cellulitis, and leakage from the site as the tract enlarges, which then requires a larger-diameter feeding tube. If small bowel dysmotility accompanies gastroparesis, tube feed rates may need to be limited secondary to nausea, pain, or bloating. If ongoing weight loss then occurs, total parenteral nutrition (TPN) may be required via a percutaneous indwelling central venous catheter line or tunneled central venous catheter. More aggressive surgical interventions have also been studied, including gastrojejunostomy, pyloromyotomy, and completion or subtotal gastrectomy. Drainage procedures include pyloroplasty or pyloromyotomy, and a retrospective review of prospectively collected data on 28 patients demonstrated marked improvement of symptoms ranging from nausea to bloating to pain at 3 months. Gastric transit time decreased from an average of 320 to 112 minutes. Diabetic patients saw less improvement than other patient populations.46 With minimally invasive techniques and shorter lengths of stay minimizing morbidity, this method merits more thorough investigation. Completion or subtotal gastrectomy is most often performed for postsurgical gastroparesis. With a near-total gastrectomy, a small proximal gastric pouch, via a vertical staple line, may be constructed similar to a gastric bypass procedure. A large gastrojejunostomy with a short Roux limb and a feeding jejunostomy should be performed.47

INTESTINAL MOTILITY In the fasting state, small intestinal motility is controlled by the MMC, which exhibits three phases. Phase I is a quiescent period and represents 20% to 30% of the total

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cycle length. Phase II accounts for 40% to 60% of the total cycle length and is characterized by intermittent and irregular contractions. In phase III, intense, rhythmic contractions develop and propagate from the proximal to the distal portion of the intestine over a 5- to 10-minute period. The MMC cycle occurs approximately every 90 minutes during the interdigestive period. However, after a meal, this fasting pattern of intestinal motility is changed to a postprandial pattern, with intermittent phasic contractions of irregular amplitude that are similar to the phase II contractions of the MMC.48 Peristalsis occurs when a segment of circular muscle contracts as a result of excitatory motor neurons while the intestinal segment aboral to the contracted segment is simultaneously relaxed by inhibitory neurons.49 The ICCs are known to be essential regulators of GI motility and seem to serve as pacemaker cells in the GI tract and mediators of neural regulation in GI motility. They lie in close proximity to smooth muscle cells and elements of the ENS. The generation of slow waves occurs within the Auerbach plexus and is an intrinsic property of the ICC network; both circumferential intestinal contractions and longitudinal contractions are produced.49 ICC abnormalities are increasingly being recognized in a number of GI tract disorders, such as chronic intestinal pseudoobstruction, with findings of decreased ICCs or an abnormal ICC network.50,51 Surgical procedures involving the small intestine disrupt ICC networks at the level of the myenteric and deep muscular plexuses, with resultant loss of slow waves and phasic contractions. This loss of intestinal motility, however, partially recovers within 24 hours after surgery.52 Because intestinal motility is controlled by interactions among smooth muscle, enteric nerves, extrinsic nerves, and humoral factors, abnormalities in any of these areas may result in intestinal dysmotility. Small intestinal dysmotility symptoms include abdominal bloating, distention, pain, nausea, and vomiting. Primary disorders causing small intestinal dysmotility include inherited familial visceral myopathies, characterized by smooth muscle degeneration, and familial visceral neuropathies, characterized by the degeneration of enteric nerves. Secondary causes of small intestinal dysmotility include myopathic processes (scleroderma, muscular dystrophies, amyloidosis), neurologic diseases (Parkinson disease, neurofibromatosis, Chagas disease), endocrine disorders (diabetes mellitus, hyperthyroidism, hypothyroidism, hypoparathyroidism), celiac disease, and pharmacologic agents (anti-Parkinson medications, phenothiazines, TCAs, narcotics).53 Smooth muscle disease, such as scleroderma, frequently affects the GI tract, and small intestinal dysmotility develops in approximately 40% of such patients. Proximal involvement leads to megaduodenum or wide-mouth diverticula of the small bowel, with resulting delayed transit, bacterial overgrowth, and malabsorption. Octreotide is useful in treating stasis and the resultant bacterial overgrowth. Muscular dystrophies affect motility of the entire gut; although barium studies may be normal, small intestinal manometry may reveal a myopathic pattern. Amyloidosis produces infiltration of both smooth muscle and the autonomic nerves and affects the motility of the entire GI tract.53

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Neurologic disease is most commonly seen with Parkinson disease, with degeneration of the ENS and inhibition of intestinal motility by anti-Parkinson medications. Neurofibromatosis may produce dysmotility as a result of mechanical obstruction with GI tract tumor formation, but it is also associated with neuronal dysplasia of the ENS. Chagas disease (infection with Trypanosoma cruzi) results in neuronal injury and is manifested as megaduodenum, megajejunum, or pseudoobstruction. 53 Hirschsprung disease or its allied disorders hypoganglionosis and intestinal neuronal dysplasia may produce small intestinal dysmotility.54 Endocrine disorders may also give rise to intestinal dysmotility. Hypothyroidism produces delayed transit, constipation, and pseudoobstruction, which is reversible with thyroid hormone replacement. Hypoparathyroidism may be associated with small intestinal dysmotility and pseudoobstruction, which improve with calcium repletion. Small intestinal complications of diabetes with autonomic neuropathy include delayed transit with bacterial overgrowth and diarrhea. Celiac sprue produces abdominal pain, distention, and malabsorption, with delayed intestinal transit, bacterial overgrowth, and pseudoobstruction.55 Both villous damage and small intestinal dysmotility improve with a gluten-free diet.53 GI motility is enhanced by the stimulation of distinct serotonin (5-hydroxytryptamine [5-HT]) receptors on intestinal sensory nerves. 5-HT is released from mucosal enterochromaffin cells in response to mechanical and chemical stimuli within the intestine. 5-HT activates 5-HT4 receptors on nerves synapsing in the myenteric plexus, which results in motor responses and increased peristalsis and intestinal transit.52 Tegaserod, a selective 5-HT4 partial agonist, significantly accelerates small bowel transit time and gastric emptying.56

DIAGNOSIS OF INTESTINAL DYSMOTILITY After the history, physical examination, and conventional radiographic studies suggest the possibility of intestinal dysmotility, an upper GI study with small bowel followthrough should be performed. This study may demonstrate the possibility of obstructing lesions, such as tumor, stricture, diverticula, or adhesions, and in their absence may identify general small bowel dysmotility. Evaluation of small intestinal transit then may be done by small bowel scintigraphy, with imaging up to 6 hours after ingestion of a radiolabeled meal. Scintigraphy has a specificity of up to 75% for the diagnosis of dysmotility, but it does not differentiate between myopathic and neuropathic causes. Small bowel manometry may be performed if abnormal small bowel transit is found to be present. In the interdigestive period, the MMC is monitored to examine the cycle duration (interval between phase III events), the duration of each phase including the amplitude and propagation velocity of phase III, and the rate of contraction of phase III. A motility disorder is present with abnormal bursts of phasic activity, low-amplitude contractions, poorly coordinated activity, or absent, incomplete, or retrograde phase III activity. With eating, a change in typical postprandial activity is expected, with irregular, phasic contractions of variable amplitude as the intestinal contents are mixed and propelled distally. This postprandial period

lasts for about 4 hours, and then a return to the interdigestive pattern should be noted. Whereas short-duration (2-hour) manometry studies may diagnose abnormalities while a patient is in the fed or postprandial state, longer study periods facilitate study in the interdigestive period as well. This concept has been extended to ambulatory study systems in an attempt to improve diagnostic accuracy. Manometry may also help distinguish myopathic causes of dysmotility from neuropathic causes.

POSTOPERATIVE ILEUS One of the most common etiologies for intestinal dysmotility is postoperative ileus, defined as the lack of intestinal motility after abdominal or pelvic surgery. Ambiguity surrounding the distinction between physiologic postoperative gastrointestinal tract dysfunction and pathologic postoperative ileus problematizes its conception and hampers clinical and epidemiologic investigation of the condition. The precise pathophysiology also remains unclear, and it is thought that inflammatory mediators, interruption of neurotransmitters, and iatrogenic factors, such as anesthesia and opioids, synergistically inhibit bowel peristalsis.57 Increased bowel manipulation and bowel irritation by blood or fecal spillage increase the incidence and severity of the disorder58; incision length does not.59 The small bowel recovers most rapidly after surgery (12–24 hours), followed by the stomach (24–48 hours), and lastly the large bowel (3–5 days). Despite theoretical confusion, most surgeons can readily identify the condition in their patients. Postoperative ileus presents with a lack of bowel function and intolerance to oral intake in the absence of any mechanical obstruction. Clinical presentation varies from asymptomatic dysmotility to crampy pain, nausea, and vomiting. On exam, patients are often distended with tympanic abdomens; bowel sounds, previously heralded as a specific sign of ileus, have recently not demonstrated correlation with the condition or its resolution.60 No objective test can definitively diagnose postoperative ileus. Plain radiographs often show dilated loops of intestine, a nonspecific finding. Computed tomography (CT) scans with contrast can help distinguish between mechanical obstruction and ileus.61 Treatment for postoperative ileus remains limited and essentially unchanged for the last 100 years. Early 20thcentury management involved enterostomies, with high mortality rates around 40%. In the 1930s, Owen Wangensteen advocated using nasogastric tubes to decompress the GI tract and expedite healing, a modality that became increasingly popular and routine.62 Later prospective studies demonstrated the futility of intraoperative placement in preventing ileus, but it remains a common intervention to manage the condition postoperatively in symptomatic patients. Every known promotility drug has been tested with the hope of a pharmaceutical cure, but none consistently demonstrated a more rapid return of bowel function. Recently, several studies have demonstrated the benefit of chewing gum. A Cochrane Review found that chewing gum decreased time to flatus and first bowel movement by about 12 hours, and decreased total length of hospital stay by almost a day, with more dramatic effects seen (and better studied) in colorectal patients.63

Motility Disorders of the Stomach and Small Intestine   CHAPTER 65 

The risk of postoperative ileus has complicated decisions over when to feed patients after surgery. For most of the 20th century, most clinicians waited for bowel function to return in the form of either flatus or stool before advancing the patient’s diet.64 More recently, prospective, randomized clinical trials have demonstrated that early enteral feeding is not only safe but actually hastens return of bowel functions and is associated with a decreased risk in anastomotic leaks, at least in rectal surgery. 65 Early feeding has become the standard of care in colorectal patients through enhanced recovery after surgery (ERAS) pathways and is rapidly extending to other patient populations.

PHARMACOLOGIC TREATMENT Pharmaceutical treatment for intestinal dysmotility largely parallels that for gastric dysmotility. The addition of erythromycin, a motilin agonist, stimulates both gastric emptying and intestinal contractions at low doses. Tegaserod, a 5-HT4 partial agonist, accelerates small bowel transit time and increases both gastric emptying and colonic transit.53,56 Some agents have benefits specifically targeted at pathologies afflicting the small bowel. Octreotide, for example, has been demonstrated as especially effective in scleroderma-induced dysmotility.67 Alvimopan (Entereg) is a novel agent designed to prevent opioidinduced ileus by blocking µ-opioid receptors in the gastrointestinal tract; its limited systemic absorption and inability to cross the blood-brain barrier allow narcotics to continue to treat pain. It must be given to a patient prior to surgery to be effective. Multiple randomized clinical trials have proven that alvimopan reduces time to return of bowel function.68,69 A recent large study demonstrated the clinical utility of the drug in colorectal cases, showing shortened (by 1 day) and cheaper (by approximately $600) postoperative hospital stays.70 Methylnaltrexone (Relistor), which similarly works by blocking peripheral µ receptors, is FDA approved for the treatment of opioid-induced constipation in patients receiving palliative care when other laxatives have failed.71 There does not appear to be any benefit—and there is risk of significant harm—to using alvimopan for opioid-induced constipation in terminal patients or methylnaltrexone to treat acute, postoperative ileus.72

SURGICAL TREATMENT Surgical options for the treatment of nonmechnical small intestine dysmotility are limited. Conversely, mechanical pathologies respond readily to operative intervention. Thus, a thorough investigation for mechanical causes ought to be pursued, including both axial imaging and barium swallow studies as needed. Endoscopy can also be informative while simultaneously harvesting biopsy samples from the gastric, duodenal, and proximal jejunal mucosa for pathological investigation. Small intestinal manometry allows assessment of the MMC. If all the above fail to elicit a diagnosis, surgeons may be asked to perform a diagnostic laparoscopy or, more rarely, laparotomy. The operation must examine the entire course of the bowel. Surgeons can also collect full-thickness jejunal biopsies to assess for visceral myopathy or neurogenic causes of small bowel dysmotility and chronic intestinal pseudoobstruction.73

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Small bowel resection is uncommonly performed, although localized findings may justify segmental resection. Isolated megaduodenum (type I familial visceral myopathy) has been treated by drainage or subtotal duodenal resection, with the posterior biliopancreatic duodenal wall left intact and the proximal jejunum used as an onlay patch.53,74 Primary amyloidosis confined to the small intestine has been reported in the setting of persistent pseudoobstruction and has been treated by partial jejunectomy.75

TRANSPLANTATION In some situations, small intestine transplant is the only curative remedy. Most commonly used in mechanical short-gut patients, transplantation should be considered in any patient permanently dependent on parenteral nutrition for intestinal dysmotility. This includes conditions such as chronic intestinal pseudoobstruction, a heterogeneous group of neuropathic or myopathic pathologies, such as Hirschsprung disease, that result in ineffective smooth muscle contraction and intestinal dysmotility . It most commonly presents in children but can also occur in adults.76 Early referral for transplantation should be considered once permanent TPN has become necessary. About half of such patients require decompressive gastrostomies/ jejunostomies for symptomatic management. Among children with the disorder, over 70% required TPN for more than 5 years, a substantially higher rate than for mechanical short gut. In one series of such patients, none successfully weaned from TPN without transplant.77 In another small series, intestinal transplantation permitted cessation of TPN and increased survival in these patients.78 Adult patients with chronic intestinal pseudoobstruction similarly benefit from small bowel transplantation, often as a part of a multivisceral transplant operation given common involvement of the stomach in adults. In one study, graft and patient survival at 5 years was 60% and 70%, respectively, and at 10 years, 45% and 56% respectively.79

SUMMARY Disorders of gastric and small intestinal motility are challenging for clinicians and particularly for patients. A wide array of conditions with overlapping clinical presentations and few unique objective signs prevents facile diagnosis. The physician must carefully assemble the history, context, and judiciously chosen tests to identify the malady. Once recognized, many of these conditions resist simple treatment. Most pharmacologic interventions date back decades and have either limited efficacy and/or severe side effects, although recent research is identifying novel regimens. Surgical interventions, through implantable devices or alteration of normal anatomy, have limited efficacy in many cases and carry significant risks of their own. Despite these challenges, gastric and intestinal dysmotility affect several thousand patients and carry substantial morbidity. They remain an area of active research.

ACKNOWLEDGMENTS The authors are grateful to John E. Meilahn for his work on a prior version of this chapter that formed the foundation for the current iteration.

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SECTION II  Stomach and Small Intestine

REFERENCES 1. Sanjeevi A. Gastric motility. Curr Opin Gastroenterol. 2007;23(6):625630. 2. Forster J, Damjanov I, Lin Z, Sarosiek I, Wetzel P, McCallum RW. Absence of the interstitial cells of Cajal in patients with gastroparesis and correlation with clinical findings. J Gastrointest Surg. 2005;9(1): 102-108. 3. Khoo J, Rayner CK, Feinle-Bisset C, Jones KL, Horowitz M. Gastrointestinal hormonal dysfunction in gastroparesis and functional dyspepsia. Neurogastroenterol Motil. 2010;22(12):1270-1278. 4. Marrinan S, Emmanuel AV, Burn DJ. Delayed gastric emptying in Parkinson’s disease. Mov Disord. 2014;29(1):23-32. 5. Nusrat S, Bielefeldt K. Gastroparesis on the rise: incidence vs awareness? Neurogastroenterol Motil. 2013;25(1):16-22. 6. Parkman HP, Camilleri M, Farrugia G, et al. Gastroparesis and functional dyspepsia: excerpts from the AGA/ANMS meeting. Neurogastroenterol Motil. 2010;22(2):113-133. 7. Camilleri M, Bharucha AE, Farrugia G. Epidemiology, mechanisms, and management of diabetic gastroparesis. Clin Gastroenterol Hepatol. 2011;9(1):5-12; quiz e7. 8. Jones KL, Russo A, Berry MK, Stevens JE, Wishart JM, Horowitz M. A longitudinal study of gastric emptying and upper gastrointestinal symptoms in patients with diabetes mellitus. Am J Med. 2002; 113(6):449-455. 9. Stein B, Everhart KK, Lacy BE. Gastroparesis: a review of current diagnosis and treatment options. J Clin Gastroenterol. 2015;49(7):550-558. 10. Nguyen LA, Snape WJ Jr. Clinical presentation and pathophysiology of gastroparesis. Gastroenterol Clin North Am. 2015;44(1):21-30. 11. Parkman HP, Hasler WL, Fisher RS. American Gastroenterological Association technical review on the diagnosis and treatment of gastroparesis. Gastroenterology. 2004;127(5):1592-1622. 12. Talley NJ, Ford AC. Functional dyspepsia. N Engl J Med. 2015; 373(19):1853-1863. 13. Revicki DA, Rentz AM, Dubois D, et al. Development and validation of a patient-assessed gastroparesis symptom severity measure: the Gastroparesis Cardinal Symptom Index. Aliment Pharmacol Ther. 2003;18(1):141-150. 14. Sachdeva P, Malhotra N, Pathikonda M, et al. Gastric emptying of solids and liquids for evaluation for gastroparesis. Dig Dis Sci. 2011;56(4):1138-1146. 15. Reddymasu SC, Singh S, Sankula R, Lavenbarg TA, Olyaee M, McCallum RW. Endoscopic pyloric injection of botulinum toxin-A for the treatment of postvagotomy gastroparesis. Am J Med Sci. 2009;337(3):161-164. 16. Camilleri M, Parkman HP, Shafi MA, Abell TL, Gerson L. Clinical guideline: management of gastroparesis. Am J Gastroenterol. 2013; 108(1):18-37; quiz 38. 17. Kloetzer L, Chey WD, McCallum RW, et al. Motility of the antroduodenum in healthy and gastroparetics characterized by wireless motility capsule. Neurogastroenterol Motil. 2010;22(5):527-533, e117. 18. Camilleri M. Appraisal of medium-and long-term treatment of gastro paresis and chronic intestinal dysmotility. Am J Gastroenterol. 1994;89(10):1769-1774. 19. Sanaka M, Anjiki H, Tsutsumi H, et al. Effect of cigarette smoking on gastric emptying of solids in Japanese smokers: a crossover study using the 13C-octanoic acid breath test. J Gastroenterol. 2005;40(6): 578-582. 20. McCallum RW, Sunny J. Status of pharmacologic management of gastroparesis: 2014. Pract Gastroenterol. 2014;38(9):20-42. 21. Sawhney MS, Prakash C, Lustman PJ, Clouse RE. Tricyclic antidepressants for chronic vomiting in diabetic patients. Dig Dis Sci. 2007;52(2):418-424. 22. Bateman DN, Rawlins MD, Simpson JM. Extrapyramidal reactions with metoclopramide. Br Med J (Clin Res Ed). 1985;291(6500):930-932. 23. Heeley E, Riley J, Layton D, Wilton LV, Shakir SA. Prescription-event monitoring and reporting of adverse drug reactions. Lancet. 2001;358(9296):1872-1873. 24. Miller LG, Jankovic J. Metoclopramide-induced movement disorders. Clinical findings with a review of the literature. Arch Intern Med. 1989;149(11):2486-2492. 25. Snape WJ Jr, Battle WM, Schwartz SS, Braunstein SN, Goldstein HA, Alavi A. Metoclopramide to treat gastroparesis due to diabetes mellitus: a double-blind, controlled trial. Ann Intern Med. 1982; 96(4):444-446.

26. Parkman HP, Misra A, Jacobs M, et al. Clinical response and side effects of metoclopramide: associations with clinical, demographic, and pharmacogenetic parameters. J Clin Gastroenterol. 2012;46(6):494-503. 27. Lata PF, Pigarelli DL. Chronic metoclopramide therapy for diabetic gastroparesis. Ann Pharmacother. 2003;37(1):122-126. 28. Parkman HP, Carlson MR, Gonyer D. Metoclopramide nasal spray is effective in symptoms of gastroparesis in diabetics compared to conventional oral tablet. Neurogastroenterol Motil. 2014;26(4):521-528. 29. Patterson D, Abell T, Rothstein R, Koch K, Barnett J. A double-blind multicenter comparison of domperidone and metoclopramide in the treatment of diabetic patients with symptoms of gastroparesis. Am J Gastroenterol. 1999;94(5):1230-1234. 30. Heer M, Müller-Duysing W, Benes I, et al. Diabetic gastroparesis: treatment with domperidone—a double-blind, placebo-controlled trial. Digestion. 1983;27(4):214-217. 31. van Noord C, Dieleman JP, van Herpen G, Verhamme K, Sturkenboom MC. Domperidone and ventricular arrhythmia or sudden cardiac death: a population-based case-control study in the Netherlands. Drug Saf. 2010;33(11):1003-1014. 32. Acosta A, Camilleri M. Prokinetics in gastroparesis. Gastroenterol Clin North Am. 2015;44(1):97-111. 33. McCallum RW, Cynshi O. Clinical trial: effect of mitemcinal (a motilin agonist) on gastric emptying in patients with gastroparesis— a randomized, multicentre, placebo-controlled study. Aliment Pharmacol Ther. 2007;26(8):1121-1130. 34. Wierup N, Bjorkqvist M, Westrom B, Pierzynowski S, Sundler F, Sjolund K. Ghrelin and motilin are cosecreted from a prominent endocrine cell population in the small intestine. J Clin Endocrinol Metab. 2007;92(9):3573-3581. 35. Camilleri M, Papathanasopoulos A, Odunsi ST. Actions and therapeutic pathways of ghrelin for gastrointestinal disorders. Nat Rev Gastroenterol Hepatol. 2009;6(6):343-352. 36. McCallum RW, Lembo A, Esfandyari T, et al. Phase 2b, randomized, double-blind 12-week studies of TZP-102, a ghrelin receptor agonist for diabetic gastroparesis. Neurogastroenterol Motil. 2013;25(11): e705-e717. 37. Shin A, Wo JM. Therapeutic applications of ghrelin agonists in the treatment of gastroparesis. Curr Gastroenterol Rep. 2015;17(2):1-9. 38. Bai Y, Xu MJ, Yang X, et al. A systematic review on intrapyloric botulinum toxin injection for gastroparesis. Digestion. 2010;81(1):27-34. 39. Enck P, Klosterhalfen S. The placebo response in functional bowel disorders: perspectives and putative mechanisms. Neurogastroenterol Motil. 2005;17(3):325-331. 40. Hasler WL. Methods of gastric electrical stimulation and pacing: a review of their benefits and mechanisms of action in gastroparesis and obesity. Neurogastroenterol Motil. 2009;21(3):229-243. 41. Abell T, McCallum R, Hocking M, et al. Gastric electrical stimulation for medically refractory gastroparesis. Gastroenterology. 2003;125(2): 421-428. 42. Mason RJ, Lipham J, Eckerling G, Schwartz A, Demeester TR. Gastric electrical stimulation: an alternative surgical therapy for patients with gastroparesis. Arch Surg. 2005;140(9):841-846; discussion 847–848. 43. Liu RC, Sabnis AA, Chand B. Erosion of gastric electrical stimulator electrodes: evaluation, management, and laparoscopic techniques. Surg Laparosc Endosc Percutan Tech. 2007;17(5):438-441. 44. Levinthal DJ, Bielefeldt K. Systematic review and meta-analysis: gastric electrical stimulation for gastroparesis. Auton Neurosci. 2017;202:45-55. 45. Meissner K, Fässler M, Rücker G, et al. Differential effectiveness of placebo treatments: a systematic review of migraine prophylaxis. JAMA Intern Med. 2013;173(21):1941-1951. 46. Hibbard ML, Dunst CM, Swanström LL. Laparoscopic and endoscopic pyloroplasty for gastroparesis results in sustained symptom improvement. J Gastrointest Surg. 2011;15(9):1513-1519. 47. Hejazi RA, McCallum RW. Treatment of refractory gastroparesis: gastric and jejunal tubes, botox, gastric electrical stimulation, and surgery. Gastrointest Endosc Clin N Am. 2009;19(1):73-82, vi. 48. Xing J, Chen JD. Alterations of gastrointestinal motility in obesity. Obes Res. 2004;12(11):1723-1732. 49. Thomson AB, Drozdowski L, Iordache C, et al. Small bowel review: normal physiology, part 2. Dig Dis Sci. 2003;48(8):1565-1581. 50. Kubota M, Kanda E, Ida K, Sakakihara Y, Hayashi M. Severe gastrointestinal dysmotility in a patient with congenital myopathy: causal relationship to decrease of interstitial cells of Cajal. Brain Dev. 2005;27(6):447-450.

Motility Disorders of the Stomach and Small Intestine   CHAPTER 65  51. Feldstein AE, Miller SM, El-Youssef M, et al. Chronic intestinal pseudoobstruction associated with altered interstitial cells of Cajal networks. J Pediatr Gastroenterol Nutr. 2003;36(4):492-497. 52. Yanagida H, Yanase H, Sanders KM, Ward SM. Intestinal surgical resection disrupts electrical rhythmicity, neural responses, and interstitial cell networks. Gastroenterology. 2004;127(6):1748-1759. 53. Kuemmerle JF. Motility disorders of the small intestine: new insights into old problems. J Clin Gastroenterol. 2000;31(4):276-281. 54. Tomita R, Ikeda T, Fujisaki S, Shibata M, Tanjih K. Upper gut motility of Hirschsprung’s disease and its allied disorders in adults. Hepatogastroenterology. 2003;50(54):1959-1962. 55. Tursi A. Gastrointestinal motility disturbances in celiac disease. J Clin Gastroenterol. 2004;38(8):642-645. 56. Degen L, Petrig C, Studer D, Schroller S, Beglinger C. Effect of tegaserod on gut transit in male and female subjects. Neurogastroenterol Motil. 2005;17(6):821-826. 57. Mattei P, Rombeau JL. Review of the pathophysiology and management of postoperative ileus. World J Surg. 2006;30(8):1382-1391. 58. Doorly MG, Senagore AJ. Pathogenesis and clinical and economic consequences of postoperative ileus. Surg Clin North Am. 2012;92(2): 259-272, viii. 59. Cali RL, Meade PG, Swanson MS, Freeman C. Effect of morphine and incision length on bowel function after colectomy. Dis Colon Rectum. 2000;43(2):163-168. 60. Felder S, Margel D, Murrell Z, Fleshner P. Usefulness of bowel sound auscultation: a prospective evaluation. J Surg Educ. 2014;71(5): 768-773. 61. Vather R, Trivedi S, Bissett I. Defining postoperative ileus: results of a systematic review and global survey. J Gastrointest Surg. 2013;17(5):962-972. 62. Wangensteen OH. The early diagnosis of acute intestinal obstruction with comments on pathology and treatment: with a report on successful decompression of three cases of mechanical small bowel obstruction by nasal catheter siphonage. West J Surg Obstet Gynecol. 1932;40:1-17. 63. Short V, Herbert G, Perry R, et al. Chewing gum for postoperative recovery of gastrointestinal function. Cochrane Database Syst Rev. 2015;(2):CD006506, doi:10.1002/14651858.CD006506.pub3. 64. Livingston EH, Passaro EP Jr. Postoperative ileus. Dig Dis Sci. 1990;35(1):121-132. 65. Boelens PG, Heesakkers FF, Luyer MD, et al. Reduction of postoperative ileus by early enteral nutrition in patients undergoing major rectal surgery: prospective, randomized, controlled trial. Ann Surg. 2014;259(4):649-655.

763

66. Reference deleted in review. 67. Soudah HC, Hasler WL, Owyang C. Effect of octreotide on intestinal motility and bacterial overgrowth in scleroderma. N Engl J Med. 1991;325(21):1461-1467. 68. Wolff BG, Michelassi F, Gerkin TM, et al. Alvimopan, a novel, peripherally acting mu opioid antagonist: results of a multicenter, randomized, double-blind, placebo-controlled, phase III trial of major abdominal surgery and postoperative ileus. Ann Surg. 2004;240(4):728-734; discussion 734–735. 69. Delaney CP, Weese JL, Hyman NH, et al. Phase III trial of alvimopan, a novel, peripherally acting, mu opioid antagonist, for postoperative ileus after major abdominal surgery. Dis Colon Rectum. 2005;48(6): 1114-1125; discussion 1125–1126; author reply 1127–1129. 70. Ehlers AP, Simianu VV, Bastawrous AL, et al. Alvimopan use, outcomes, and costs: a report from the Surgical Care and Outcomes Assessment Program Comparative Effectiveness Research Translation Network Collaborative. J Am Coll Surg. 2016;222(5):870-877. 71. Brenner DM, Chey WD. An evidence-based review of novel and emerging therapies for constipation in patients taking opioid analgesics. Am J Gastroenterol Suppl. 2014;2:38-46. 72. Rodriguez RW. Off-label uses of alvimopan and methylnaltrexone. Am J Health Syst Pharm. 2014;71(17):1450-1455. 73. Arslan M, Bayraktar Y, Oksuzoglu G, et al. Four cases with chronic intestinal pseudo-obstruction due to hollow visceral myopathy. Hepatogastroenterology. 1999;46(25):349-352. 74. Endo M, Ukiyama E, Yokoyama J, Kitajima M. Subtotal duodenectomy with jejunal patch for megaduodenum secondary to congenital duodenal malformation. J Pediatr Surg. 1998;33(11):1636-1640. 75. Deguchi M, Shiraki K, Okano H, et al. Primary localized amyloidosis of the small intestine presenting as an intestinal pseudo-obstruction: report of a case. Surg Today. 2001;31(12):1091-1093. 76. Bond GJ, Reyes JD. Intestinal transplantation for total/near-total aganglionosis and intestinal pseudo-obstruction. Semin Pediatr Surg. 2004;13(4):286-292. 77. Hukkinen M, Merras-Salmio L, Sipponen T, et al. Surgical rehabilitation of short and dysmotile intestine in children and adults. Scand J Gastroenterol. 2015;50(2):153-161. 78. Pakarinen MP, Kurvinen A, Koivusalo AI, et al. Surgical treatment and outcomes of severe pediatric intestinal motility disorders requiring parenteral nutrition. J Pediatr Surg. 2013;48(2):333-338. 79. Lauro A, Zanfi C, Pellegrini S, et al. Isolated intestinal transplant for chronic intestinal pseudo-obstruction in adults: long-term outcome. Transplant Proc. 2013;45(9):3351-3355.