Overview
The primary goal in the management of gastroparesis is to reverse or correct underlying etiologies. If that is not possible, treatment should aim to promote gastric emptying and relieve symptoms. Medications that inhibit or delay gastric emptying should immediately be discontinued, if possible.
Dietary Measures
The prime goal of therapy is to maintain adequate nutrition. For the majority of patients, dietary modifications are an effective means of reducing symptoms while maintaining nutrition. Solid foods should be reduced and replaced by liquids (these empty more readily from the stomach). Patients should eat several smaller meals per day, rather than two or three large meals. Diet should be low in fiber and fat, as both have an inhibitory effect on gastric emptying. Diabetics should avoid hyperglycemia, as it acutely delays gastric emptying.
Medical Therapy Prokinetic Therapy
In most patients, medications that promote gastric emptying have become a cornerstone of disease management. The most commonly used medications worldwide are metoclopramide, cisapride, erythromycin, and domperidone. At present, however, only erythromycin and metoclopramide are FDA approved for use in the United States. Erythromycin: This is a macrolide antibiotic, and an analogue to motilin, the hormone believed to be the regulator of the gastroduodenal migrating motor complex (MMC). Erythromycin is a potent stimulant of gastric emptying and promotes solid and liquid emptying through induction of forceful antral contractions similar to those initiated through the migrating motor complex. Both oral and intravenous routes of administration are effective. A liquid erythromycin formulation helps to titrate. In addition to being useful in improving diabetic gastroparesis, erythromycin has benefited patients after vagotomy, subtotal gastrectomy, and esophagectomy. In addition, it helps relieve radiation- and scleroderma-induced gastroparesis. Unfortunately, erythromycin may adversely interact with a number of medications, and many patients have reportedly become resistant to its effects after several weeks (tachyphylaxis) of use. A variety of doses have been used: oral-dosing ranges from 50-250mg four times daily. The intravenous form of delivery is more efficacious, especially for the acute management of symptoms in hospitalized patients. The recommended intravenous dose is 1-2mg/kg every 8 hours. Abdominal cramps and nausea are common side effects of treatment. Metoclopramide: Metoclopramide belongs to the benzamide class. It is a central dopamine (D2) and serotonin (5-HT3) receptor antagonist, hence its anti-emetic effect. It also promotes prokinetic effects through facilitation of acetylcholine release from enteric neurons (5-HT4), antagonism of myenteric dopamine (D2) receptors, and sensitization of smooth muscle muscarinic receptors. Prokinetic benefits are limited to the proximal gut and result in increased esophageal and antral contractions, decreased pyloric and duodenal tone, and increased gastric emptying and small bowel motility. Metoclopramide is the sole FDA-approved agent for diabetic gastroparesis in the United States. Improvement of gastric tone has also been reported in patients with prior vagotomy and/or gastrectomy, as well as in patients with anorexia nervosa. Prokinetic effects are noted 3 minutes after an intravenous dose, and 60 minutes following an oral dose. The usual adult oral dose is 5-20mg four times a day, taken 30 minutes before meals, and at bedtime. Intravenous dosing (usually in an inpatient setting) is 10mg every 2-3 hours as needed. Subcutaneous injections can also be given (5-10mg three to four times daily). Numerous side effects have been reported, primarily due to the drug’s central nervous system effects. Drowsiness, dystonic reactions, and agitation are the most acute dystonic reactions can occasionally develop, and should be treated with discontinuation, and use of diphenhydramine. Extrapyramidal movements may develop in chronically treated, and may even be irreversible—especially in the elderly. Other adverse effects include depression, hyperprolactinemia, galactorrhea, amenorrhea, and impotence. Other Agents Bethanechol: Bethanechol, a muscarinic agent that causes uncoordinated gastric contractions, is of historical value, but has no current role in the management of gastroparesis. Cisapride: Cisapride is a serotonin (5-HT4) agonist that facilitates acetylcholine release at the level of the Myenteric plexus, and a (5-HT3) receptor antagonist, causing gastric smooth muscle contraction and possibly having an anti-emetic effect. Its prokinetic effects are those of increased lower esophageal sphincter tone, and improved antral, jejunal, and colonic motility. Cisapride provides symptomatic relief for a wide spectrum of patients, and has become the treatment of choice for medium and long-term management of gastroparesis. The routine dose is 10-20mg four times daily (preferably given 30 minutes before meals and at bedtime). The drug’s side effects generally stem from its physiologic properties, in that it may cause abdominal cramping and diarrhea. The major concern, however, are the more than 270 cases of serious cardiac arrhythmias that have been associated with cisapride use. In fact, it is thought that cisapride may prolong the QT interval thus predisposing users to Torsades de Pointes. Although a rare occurrence, this ventricular arrhythmia may result in hypotension, syncope, or even sudden death. Medications that increase cisapride levels should be avoided (viz. macrolide antibiotics -erythromycin, clarithromycin, and azole anti-fungals, nefazodone, and protease inhibitors). Medications that prolong the QT-interval should also obviously be avoided (particularly anti-arrhythmics such as quinidine, amiodarone, procainamide, sotalol). Moreover, patients with personal or family history of QT prolongation, those with history of, and/or at risk for, cardiac arrhythmias/significant cardiac disturbances should not be given Cisapride. Recently, it has been recommended that a baseline electrocardiogram (QTc should be < 450msecs), electrolytes, and serum creatinine be obtained prior to initiating treatment. As a result, cisapride has been withdrawn from the open market, and is only available on special request from the manufacturer. Domperidone: A benzimidazole derivative, Domperidone acts as a peripheral Dopaminergic (D2) receptor antagonist. Its effects are similar to those of metoclopramide. Because it minimally crosses the blood-brain barrier, domperidone is devoid of metoclopramide central nervous system side effects: it very rarely causes hyperprolactinemia, gynecomastia, galactorrhea, impotence, and amenorrhea. Dystonic reactions are extremely rare. It also has no effect on serotonin, as do metoclopramide and cisapride. Domperidone, however, has anti-emetic properties as a result of its action on the chemoreceptor trigger zone. It is generally dosed orally, 10-40mg four times daily. A suppository form is also available. Although widely used for the chronic management of gastroparesis in many countries, domperidone has not been FDA-approved for use in the U.S.
Anti-Emetic Therapy
Prokinetic therapy will, for the most part, offer relief from the nausea and vomiting that accompany gastroparesis—either indirectly by promoting motility, or through the anti-emetic properties of substances such as metoclopramide and domperidone. Occasionally, however, a refractory patient is encountered for whom additional therapy is required. Several options exist for these patients. Phenothiazine derivatives (promethazine and prochlorperazine) act by antagonizing dopamine receptors. Other anti-emetic agents include thiethylperazine and trimethobenzamide, the use of which may be limited by extrapyramidal side effects, especially if used in conjunction with metoclopramide. In addition, the relatively new 5-HT3 antagonists (ondansetron, granisetron, and dolasetron) are potent anti-emetics and have been proven efficacious in treating chemotherapy and radiation-induced nausea and vomiting. They are available as oral or intravenous preparations. Ondansetron is available as a liquid and lingual dissolving tablet, of which both are well tolerated and quickly absorbed. Side effects include constipation, headache, and sedation. Chronic use of these agents may be limited due to excessive cost.
Endoscopic Therapy
Decompressive Gastrostomy: Some patients who are refractory to dietary and medical interventions may benefit from an endoscopically placed gastrostomy tube (surgical or fluoroscopic placement can be undertaken when endoscopic placement is unsuccessful or not feasible) (Figure 11). This device helps drain the stomach, thus aiding in the avoidance of nausea and vomiting flares. Some patients, however, will fail a gastrostomy tube. In such cases, in order to avoid dehydration and malnutrition, a jejunostomy tube may be considered. Complications of percutaneously placed tubes include: 1% procedure death, 25% infectious complications, in addition to peristomal leak, perforation, fistula formation, dislodgement, or tube dysfunction from clogging. Intravenous hydration will occasionally be required in acute flares. Only rarely will parenteral nutrition be required. | | Figure 11.A,B,C, Technique foe the endoscopic placement of a gastrostomy tube. (Click on the blue letters to view the consecutive images.) |
Surgical Therapy
Surgical intervention has not been studied, and thus has no role in the management of gastroparesis.
Novel Therapies Botulinum Toxin
Studies suggest that type I diabetics suffer from poor coordination of antro-pyloro-duodenal contraction and relaxation functions. More importantly, when they do experience contractions, they suffer a failure of pyloric relaxation. Unfortunately, there are no systemic medications to target the pylorus. Botulinum toxin, a product of the bacteria Clostridium botulinum, is a neurotoxin that prevents acetylcholine release from nerve terminals. When locally injected into striated or smooth muscle segments, it prevents muscle contraction. As a result, botulinum toxin has been reported as a therapeutic agent in several spastic muscular conditions, including achalasia, hypertensive lower esophageal sphincter, anismus, sphincter Of Oddi dysfunction (go to the Sphincter of Oddi Dysfunction section), and chronic anal fissure. Similarly, in patients with gastroparesis due to pylorospasm, there is excessive smooth muscle tone with failure to relax. Prolonged pyloric contractions may cause functional resistance to gastric outflow. To date, only a few patients have been treated with pyloric injections of botulinum toxin. Preliminary reports, however, have described good response in decreasing pyloric resistance and improving gastric emptying. Gastric Pacing
There has recently been increasing interest in treating gastroparesis by gastric electric stimulation. Although early tests did not met with success, more recent studies have demonstrated some effect. The concept consists of implanting electrodes on the gastric serosa (through open or laparoscopic approach), thus providing continuous or intermittent (e.g. at meal time) electric stimulation. The expectation is increased contractility, and hence improved gastric emptying. The largest study to date on gastric pacing (WAVESS: Worldwide Anti-Vomiting Electrical Stimulation Study) was an open label study that enrolled 33 patients. Although researchers reported 80% improvement in symptoms, emptying times improved only modestly. Side effects included infection, pacer migration, and stomach wall perforation. A few smaller, later studies have reported some success, such that treated patients no longer needed jejunostomy tube feedings. Novel Potential Agents
There is considerable ongoing research aimed at identifying novel therapies for gastroparesis. Putative agents include: Sildenafil (potentiates nitric oxide) improves pyloric relaxation. Definitive improvement on gastroparesis has not been documented, however. Levosulpiride (Dopamine receptor D2-antagonist) is expected to reverse dopaminergic inhibition on gastric contraction. A randomized trial has demonstrated effectiveness comparable to cisapride. Loxiglumide (CCK-A antagonist) was found to increase antral motility. It remains under investigation. Clonidine (a 2-receptor agonist), a commonly used anti-hypertensive, decreases antro-duodenal contractions. Although in studies clonidine did not alter gastric emptying in healthy adults, it did improve emptying in diabetics. The exact mechanism remains unclear. Further studies are needed. Tegaserod (5-HT4 partial agonist) increased gastric emptying in tested diabetic mice, but not in healthy volunteers. More studies are in progress. Clarithromycin (a newer macrolide) has shown promise in improving gastric emptying. Further studies are awaited.
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