EDUCATION PRACTICE. Management of Delayed Gastric Emptying. Clinical Scenario. The Problem. Management Strategies and Supporting Evidence

Transcription

1 CLINICAL GASTROENTEROLOGY AND HEPATOLOGY 2005;3: EDUCATION PRACTICE Management of Delayed Gastric Emptying FRANK K. FRIEDENBERG and HENRY P. PARKMAN Temple University Hospital, Philadelphia, Pennsylvania Clinical Scenario A 31-year-old woman with a 20-year history of insulin-dependent diabetes mellitus presents for the evaluation of nausea, vomiting, postprandial fullness, and discomfort for 6 months. There has been a loss of approximately 10% of her body weight during the same time period. On examination she has a body mass index of 20 (normal, kg/m 2 ). Orthostatic hypotension is present on standing. The abdomen is mildly tender in the epigastric region without distention. Stool is negative for occult blood. Fasting blood glucose is 160 mg/dl, and the hemoglobin A 1C value is 8.9%. Abdominal ultrasound, complete blood count, thyroid function tests, aminotransferases, and lipase are normal. Upper endoscopy after an overnight fast demonstrates a small amount of retained solid food; however, the mucosa appears normal, and a rapid urease test for Helicobacter pylori is negative. A gastric emptying test with a meal consisting of scrambled eggs radiolabeled with 99m Tc sulfur colloid demonstrates 64% retention at 2 hours (normal, 50%) and 26% retention at 4 hours (normal, 10%). How should this patient with delayed gastric emptying be managed? The Problem Gastroparesis, or delayed gastric emptying, is a common cause of chronic nausea and vomiting. In referral clinics, up to 40% of patients with long-standing type 1 diabetes have delayed gastric emptying primarily as a complication of vagal nerve dysfunction. Symptom exacerbation is frequently associated with poor glycemic control. Acute hyperglycemia may impair gastric emptying. In addition to nausea and vomiting, symptoms of gastroparesis might include early satiety and postprandial fullness. Postprandial and nocturnal abdominal pain can be particularly bothersome in up to 60% of patients and is often recalcitrant to treatment. However, in contrast to functional dyspepsia, pain is usually not the predominant complaint in patients with diabetic gastroparesis. Patients with diabetic gastroparesis frequently have evidence of autonomic neuropathy involving other portions of the gastrointestinal tract including dysphagia, diarrhea, and constipation. Orthostatic hypotension and tachycardia might also be present. Physiologic changes that might explain symptoms in patients with diabetic gastroparesis include impaired fundic relaxation in response to a meal, abnormal antral contractile activity during phase III of the migratory motor complex, gastric dysrhythmias, and pylorospasm. All of these abnormalities might improve with control of hyperglycemia. In patients with gastroparesis, liquid emptying remains relatively normal until the late stages of disease. Delayed gastric emptying of solids is commonly documented scintigraphically by using a radioisotope-labeled meal (Figure 1). Most centers use a 99m Tc sulfur colloid labeled egg sandwich as a test meal. Scintigraphic images are obtained at baseline, 30 minutes, and then 1 and 2 hours after ingestion, and the results are expressed as percent gastric retention. It has been proposed that extension of the test to 4 hours improves accuracy, but this is not commonly done at most centers. It might be useful to know how much is retained at 4 hours to plan the frequency, consistency, and size of meals. Management Strategies and Supporting Evidence The treatment of diabetic gastroparesis centers on the regulation of serum glucose levels, control of symptoms, maintenance of nutrition, and improvement in quality of life. Diet and Diabetes Control Regulation of blood glucose while maintaining adequate caloric intake can represent a considerable chal- Abbreviations used in this paper: FDA, Food and Drug Administration; 5-HT, 5-hydroxytryptamine by the American Gastroenterological Association /05/$30.00 PII: /S (05)00371-X

2 July 2005 MANAGEMENT OF DELAYED GASTRIC EMPTYING 643 Figure 1. Results of a 4-hour gastric emptying study demonstrating gastroparesis. After an overnight fast, the patient consumed a meal consisting of scrambled eggs labeled with.5 mci 99m Tc sulfur colloid and 300 ml of water. Scintigraphic images were obtained at 0, 30, 60, 120, 180, and 240 minutes after meal ingestion. A region of interest was drawn around the entire stomach for all images acquired (shown here at T 0). The geometric mean of gastric counts was determined at each imaging time. After correction for radionuclide decay, mean gastric counts at each imaging time were expressed as a percent of the maximal geometric mean counts at time 0. The percent retention at 2 and 4 hours after meal ingestion for solids was calculated to be 45% at 2 hours and 31% at 4 hours. Normal gastric emptying with this meal is 50% retention at 2 hours and 10% at 4 hours. lenge in the management of patients with diabetic gastroparesis. Nausea and vomiting from delayed gastric emptying might lead to episodes of hypoglycemia resulting in substantial morbidity. Excessive carbohydrate intake can induce hyperglycemia, whereas a solid meal containing fat as a significant calorie source can further impair gastric emptying as a result of the release of CCK. Interestingly, some patients with gastroparesis can tolerate fat in liquid form. Small, frequent meals are preferred, although most patients have adapted their eating habits to this pattern before evaluation. Diabetes should be managed with agents that have a short duration of action and preferably insulin. Long-acting preparations of insulin (eg, zinc preparations) and long-acting sulfonylurea medications (eg, glyburide) should be avoided. Patients should use short-acting insulin on an adjusted dose regimen with consideration for the size of the meal, preprandial glucose value, and severity of symptoms of gastroparesis. Large portions of insoluble fiber can delay gastric emptying and should be avoided. Excessive fiber intake can theoretically lead to the formation of bezoars, although these rarely develop. Pharmacologic Therapy (Table 1) Promotility agents. There are few large studies that have evaluated prokinetic agents in the management of diabetic gastroparesis. Metoclopramide. Metoclopramide, the only Food and Drug Administration (FDA) approved drug for the treatment of gastroparesis, works not only as a peripheral cholinergic prokinetic but also has central and peripheral dopamine receptor antagonism. The antagonism of central dopamine receptors might lead to both therapeutic as well as adverse (extrapyramidal dystonic reactions, especially tardive dyskinesia) effects. The largest controlled study evaluated metoclopramide 10 mg 4 times Table 1. Commonly Used Medications for Diabetic Gastroparesis Therapy Prokinetic Antiemetic Mechanism of action Metoclopramide (Reglan) Peripheral cholinergic prokinetic (5-HT 4 receptor mediated); central and peripheral dopamine receptor antagonism Erythromycin Motilin receptor agonism Tegaserod (Zelnorm) 5-HT 4 agonism Domperidone (Motilium) Selective peripheral dopamine antagonism Prochlorperazine (Compazine) Phenothiazine potent antidopaminergic, weak antihistaminic, weak anticholinergic agent Meclizine (Antivert) Potent antihistaminic, anticholinergic Promethazine (Phenergan) Potent anticholinergic, antihistaminic, weak antidopaminergic agent Trimethobenzamide (Tigan) Unknown Ondansetron (Zofran) 5-HT 3 receptor antagonism Granisetron (Kytril) 5-HT 3 receptor antagonism Dolasetron (Anzemet) 5-HT 3 receptor antagonism Palonosetron (Aloxi) 5-HT 3 receptor antagonism

3 644 FRIEDENBERG AND PARKMAN CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 3, No. 7 daily in 45 patients with diabetic gastroparesis. After 3 weeks of treatment, metoclopramide improved nausea and postprandial fullness to a greater extent than placebo. Patients who received metoclopramide exhibited improved gastric emptying. Interestingly, there was a relatively poor correlation between the magnitude of gastric emptying improvement and changes in symptom scores. Long-term administration of metoclopramide can be problematic because efficacy declines over time, and side effects such as sedation and fatigue can be significant. Domperidone. Domperidone is a selective peripheral dopamine antagonist. In 3 separate placebo-controlled studies involving only 31 patients, domperidone was found to be effective in reducing the symptoms of nausea and vomiting. Other symptoms such as abdominal pain and bloating were shown to decrease by nearly 70% in one study. Domperidone has been shown to accelerate gastric emptying by 21% 37%. The usual dose is 20 mg before meals and at bedtime. Side effects are uncommon and are principally related to hyperprolactinemia (the pituitary lies outside of the blood-brain barrier), which can lead to gynecomastia and excessive lactation. Erythromycin. Erythromycin, a motilin receptor agonist, is used for diabetic gastroparesis often as a second-line agent after metoclopramide. Intravenous infusions can provide acute relief for hospitalized patients. Chronic oral therapy with 125 mg 3 or 4 times daily might be tried, although tachyphylaxis and side effects including nausea and abdominal pain limit the usefulness of this therapy. In the only randomized, double-blind study involving 12 patients with diabetic gastroparesis the superiority of erythromycin over placebo could not be demonstrated. Antiemetic agents. Prochlorperazine and promethazine. These agents can be used orally, parenterally, or per rectum to control nausea, but side effects limit their utility. At high doses promethazine may cause sedation, blurring of vision, dry mouth, and urinary retention, whereas prochlorperazine is associated with restlessness, stiffness in the legs and arms, and tremors of the hands and fingers. The adult dose of promethazine is mg every 4 6 hours. Prochlorperazine might be given as 5 10 mg every 6 8 hours or 25 mg per rectum every 12 hours. A sustained release formulation is available in a dose of 15 mg by mouth daily or 10 mg twice daily. Meclizine, a related medication with primarily antihistaminic properties, may also be used. 5-Hydroxytryptamine 3 receptor antagonists. This category includes 4 FDA-approved medications: ondansetron, granisetron, dolasetron, and palonosetron, which are principally used for the prevention of nausea and vomiting caused by radiation and chemotherapy for cancer. They are useful agents for patients who fail or cannot tolerate promethazine or prochlorperazine, although no controlled data for gastroparesis are available. Our preference is to use ondansetron, which might be administered as a liquid, tablet, orally disintegrating tablet, or intravenously. For patients with severe nausea mg daily in 3 4 divided doses is sufficient. The cost of this class of medications is considerable in comparison to other agents. Enteral Tube Feeding Enteral feeding is preferred over total parenteral nutrition if the chronic symptoms of gastroparesis lead to malnutrition. In these rare instances, patients with gastroparesis might require long-term feeding through a jejunostomy tube usually without venting gastrostomy. Feeding tubes might be inserted endoscopically, laparoscopically, or fluoroscopically, depending on local expertise. We prefer a gastrostomy and jejunostomy tube to be inserted at separate sites if both are needed rather than combined tubes, because proximal migration of combined tubes can interrupt feeding and require repositioning. It is important to demonstrate with a nasojejunal tube that jejunal feeding will be tolerated before a feeding jejunostomy is placed. Areas of Uncertainty General measures. It is unknown whether agents that increase sensitivity to insulin such as the thiazolidinedione class of medications might be beneficial in treating patients with diabetic gastroparesis. Likewise, no controlled studies have examined whether pancreatic islet cell transplantation improves gastric emptying or symptoms of gastroparesis. Diagnostic tests. Additional methods for assessing gastric emptying that remain primarily research tools include duplex ultrasonography of the antropyloric region and magnetic resonance imaging assessment of gastric emptying. Magnetic resonance imaging evaluation has the additional benefit of providing a measurement of gastric volume. Antroduodenal manometry and multichannel electrogastrography provide insight as to whether the etiology of gastroparesis is neuropathic (diabetes) or myopathic (connective tissue disorder), but they are not performed routinely

4 July 2005 MANAGEMENT OF DELAYED GASTRIC EMPTYING 645 Figure 2. Management algorithm for treatment of diabetic gastroparesis. CT, computed tomography; PRN, as circumstances may require. at most gastrointestinal centers and are rarely indicated in patients with known diabetes and symptoms of gastroparesis. A breath test with a 13 C-labeled meal (eg, octanoate muffin or egg containing Spirulina platensis) isconvenient and correlates with gastric emptying by scintigraphy. Breath CO 2 rises after the meal is absorbed in the small intestine, thus indirectly measuring solid emptying of the stomach. The advantage of the breath test is that it does not use ionizing radiation. Breath testing to measure gastric emptying is performed in Europe but much less often in the United States. Motility agents. Combination therapy. There are no controlled trials that examine combining prokinetic agents for the treatment of diabetic gastroparesis. A logical option would be to combine metoclopramide with erythromycin, because they do not have overlapping mechanisms of action. Because each agent appears to lose efficacy over time, another area that should be investigated is scheduled rotation of prokinetic drugs such as every 6 weeks. Tegaserod. Tegaserod, a 5-hydroxytryptamine 4 (5- HT 4 ) agonist, is currently available for the treatment of constipation-predominant irritable bowel syndrome and

5 646 FRIEDENBERG AND PARKMAN CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 3, No. 7 chronic constipation. Tegaserod was shown to accelerate gastric emptying in healthy volunteers and in patients with gastroparesis. There appears to be a dose-response relationship with tegaserod for gastroparesis as opposed to functional constipation. It is not known whether tegaserod improves symptoms of gastroparesis. Botulinum toxin. Normal gastric emptying depends on the interplay of fundic tone, antral contractile activity, and pyloric relaxation. Several small, open-label studies have demonstrated symptom improvement and acceleration of gastric emptying with injection of botulinum toxin into the pyloric sphincter. The procedure is performed during endoscopy by using a sclerotherapy needle to inject IU of medication circumferentially. Repeat injection might be required every 4 6 months. Controlled data are needed before this expensive therapy can be recommended. Surgery. Gastric electrical stimulation. Gastric electrical stimulation with the use of a high-frequency (12 cpm), low-energy signal might hold promise for patients with gastroparesis not responsive to medical therapy. Stimulator wire placement requires a laparotomy or laparoscopy with suturing into the muscularis propria along the greater curve. The pulse generator is placed in a pocket within the anterior abdominal wall. In a double-blind, multicenter study involving 33 patients with both idiopathic (n 16) and diabetic gastroparesis (n 17) there was a 50% reduction in the frequency of weekly vomiting; however, total gastroparesis symptom scores improved only modestly. Several complications were noted including pocket infection, pulse generator erosion through the skin, and lead perforation of the stomach. Published Guidelines An American Gastroenterological Association technical review on the diagnosis and treatment of gastroparesis recommends dietary manipulation along with the administration of antiemetic and prokinetic agents as primary therapy. Recommendations in the Management of This Patient Figure 2 provides an algorithm for the treatment of diabetic gastroparesis. The aims of treatment should be to control symptoms of delayed gastric emptying while maintaining adequate nutritional support. This patient should be advised to increase her caloric intake in the form of liquids. She should be advised to eat relatively small meals and to limit the intake of fat and fiber, both of which can delay gastric emptying. If the patient is unable to meet her caloric needs by oral intake despite medical treatment, the next step would be the placement of a nasoenteric feeding tube. Placement of a jejunostomy feeding tube is to be considered if nasoenteric feeding is tolerated well. Attention to glucose control is important. The patient should be advised to check her glucose level before each meal and to use short-acting insulin dosed on the basis of glucose level, anticipated meal size, and severity of symptoms. Metoclopramide should be started at a dose of 10 mg 1 half hour before meals, with a bedtime dose added if she experiences nocturnal symptoms that interfere with sleep. Metoclopramide can be increased to 20 mg, although side effects, particularly drowsiness, might limit the use of this dose. If this regimen is unsuccessful, then the substitution of erythromycin 125 mg before meals should be tried. An antiemetic such as prochlorperazine 5 10 mg orally or 25 mg by suppository or promethazine 25 mg orally or by suppository should be added on an as needed basis every 4 6 hours to control nausea. If these medications are not effective or significant side effects develop, substitution with orally dissolving ondansetron 8 mg every 8 12 hours can be tried. For cases refractory to the above treatment, referral to a center with both FDA and local institutional review board permission to use domperidone should be considered. Other options would be the injection of IU of botulinum toxin into the pylorus or initiation of treatment with tegaserod 6 mg orally 3 times per day. Patients in whom all therapy fails might be referred to a center experienced in the placement of a gastric electrical stimulator, preferably in the setting of a controlled trial, or they can be considered for placement of a jejunal tube to facilitate enteral feeding. Suggested Reading 1. Parkman HP, Harris AD, Krevsky B, et al. Gastroduodenal motility and dysmotility: update on techniques available for evaluation. Am J Gastroenterol 1995;90: Takahashi T, Nakamura K, Itoh H, et al. Impaired expression of nitric oxide synthase in gastric myenteric plexus of spontaneously diabetic rats. Gastroenterology 1997;113: Parkman HP, Hasler WL, Fisher RS. American Gastroenterology Association technical review on the diagnosis and treatment of gastroparesis. Gastroenterology 2004;127: Maganti K, Onyemere K, Jones MP. Oral erythromycin and symptomatic relief of gastroparesis: a systematic review. Am J Gastroenterol 2003;98: Patterson D, Abell T, Rothstein R, et al. A double-blind multicenter comparison of domperidone and metoclopramide in the treatment of diabetic patients with symptoms of gastroparesis. Am J Gastroenterol 1999;94: Abell T, McCallum R, Hocking M, et al. Gastric electrical stimulation for medically refractory gastroparesis. Gastroenterology 2003;125: Address requests for reprints to: Frank Friedenberg, MD, Temple University Hospital, 8th Floor Parkinson Pavilion GI, 3401 N Broad St, Philadelphia, PA frank.friedenberg@temple.edu.