Advances in the management of gastroparesis

Opinion statement The treatment goals for patients with gastroparesis are to control symptoms; to correct fluid, electrolyte, and nutritional deficiencies; and to identify and treat the underlying cause of gastroparesis. For mild symptoms, dietary modifications and a low-dose antiemetic and/or prokinetic agent might provide satisfactory control of symptoms. Dietary treatments include decreasing the solid food component while increasing the liquid nutrient component of meals. Fat and fiber intake should be minimized. Metoclopramide, despite its potential for neurological side effects, remains a prokinetic treatment for symptomatic patients. In patients with diabetic gastroparesis, careful regulation of glycemic control may help to reduce symptoms. Medical management of patients with gastroparesis who do not respond to initial antiemetic or prokinetic therapy or who develop medication-related side effects involves the use of other prokinetic and antiemetic agents with different mechanisms of action. Combinations of prokinetic and antiemetic agents often are tried in patients with persistent symptoms. In some patients with persistent refractory symptoms and failure to maintain adequate fluid and/or nutritional intake, bypassing the stomach with jejunostomy feedings may be necessary. Gastric electrical stimulation is a treatment for refractory gastroparesis. Based on initial studies showing symptom benefit, especially in patients with diabetic gastroparesis, gastric electrical stimulation was granted humanitarian US Food and Drug Administration approval for the treatment of chronic, refractory nausea and vomiting secondary to idiopathic or diabetic gastroparesis. However, which patients are likely to respond, the optimal electrode position, and the optimal stimulation parameters remain areas that need to be addressed.     

Gastric electrical stimulation in gastroparesis: where do we stand?

Gastroparesis is a chronic disabling condition of impaired gastric motility that results in decreased quality of life. Currently available medical therapy consists of prokinetic and/or antiemetic therapy, dietary modifications, and nutritional supplementation. For patients with medication-resistant gastroparesis a non-pharmacological therapy, gastric electric stimulation, has evolved over the last decade. Based on the frequency of the electrical stimulus, gastric electric stimulation can be classified into low- and high-frequency gastric electric stimulation. The first method aims to normalize gastric dysrhythmia and entrain gastric slow waves and accelerates gastric emptying, whereas high-frequency gastric electric stimulation is unable to restore normal gastric emptying, but nevertheless stunningly reduces symptoms, such as nausea and vomiting, re-establishes quality of life, nutritional state in all patients, and metabolic control in patients with diabetic gastroparesis. Gastric electric stimulation presents a new possibility in the treatment of gastroparesis.     

Gastric electrical stimulation for the treatment of diabetic gastroparesis

Diabetic gastroparesis is a component of autonomic neuropathy, and is the most common manifestation of gastrointestinal neuropathy. Diabetes is responsible for about one quarter of gastroparesis. The upper gastrointestinal symptoms are often non-specific and dominated by nausea, vomiting, early satiety, fullness, bloating. We also have to look for diabetic gastroparesis in case of metabolic instability, such as postprandial hypoglycaemia. The pathophysiology of diabetic gastroparesis is complex, partly due to a vagus nerve damage, but also to changes in secretion of hormones such as motilin and ghrelin. A decrease in the stem cell factor (SCF), growth factor for cells of Cajal (gastric pacemaker), was found in subjects with diabetic gastroparesis. These abnormalities lead to an excessive relaxation in the corpus, a hypomotility of antrum, a desynchronization antrum-duodenum-pylorus, and finally an abnormal duodenal motility. The treatment of diabetic gastroparesis is based on diabetes control, and split meals by reducing the fiber content and fat from the diet. The antiemetic and prokinetic agents should be tested primarily in people with nausea and vomiting. Finally, after failure of conventional measures, the use of gastric neuromodulation is an effective alternative, with well-defined indications. Introduced in the 1970s, this technology works by applying electrical stimulation continues at the gastric antrum, particularly in patients whose gastric symptoms are refractory to other therapies. Its efficacy has been recently reported in different causes of gastroparesis, especially in diabetes. Gastric emptying based on gastric scintigraphy, gastrointestinal symptoms, biological markers of glycaemic control and quality of life are partly improved, but not normalized. Finally, a heavy nutritional care is sometimes necessary in the most severe forms. The enteral route should be preferred (nasojejunal and jejunostomy if possible efficiency). However, in case of failure especially in patients with small bowel neuropathy, the long-term parenteral nutrition is sometimes required.     

Clinical application prospects of gastric pacing for treating postoperative gastric motility disorders

Similar to the heartbeat, gastric peristalsis is regulated by an electrical rhythm generated by a pacemaker. Thus, electrical dysrhythmia of gastric slow waves will inevitably affect gastric peristalsis and emptying. The recurrence of postoperative gastroparesis is thereby closely related to the abnormalities of electrical dysrhythmia and ectopic pacemakers, resulting in postoperatively persistent gastric motility disorders in some severe cases, despite the use of prokinetic and antiemetic drugs. Recent studies have demonstrated that gastric pacing, analogous to pacing the human heart, is an attractive and promising therapy that is both feasible and safe. Gastric pacing has been shown to be strikingly effective in normalizing gastric dysrhythmia, increasing the activity of the gastric slow wave and thereby prompting gastric dynamia and emptying. Furthermore, the long-term utilization of gastric pacing can (i) relieve patients from clinical symptoms, such as nausea and vomiting; (ii) release patients with severe postoperative gastroparesis from relying on prokinetic drugs and the jejunal feeding tube; (iii) return patients to normal oral nutritional intake and provide a more satisfactory nutritional status and most importantly; and (iv) give patients a better quality of life. Overall, research focused on gastric pacing has demonstrated excellent prospects for clinical application in the treatment of postoperative gastroparesis disorders, especially for those unresponsive to prokinetic drugs.     

Management of Diabetic Gastroparesis

Symptoms suggestive of gastroparesis occur in 5% to 12% of patients with diabetes. Such a complication can affect both prognosis and management of the diabetes; therefore, practicing clinicians are challenged by the complex management of such cases. Gastroparesis is a disorder characterized by a delay in gastric emptying after a meal in the absence of a mechanical gastric outlet obstruction. This article is an evidence-based overview of current management strategies for diabetic gastroparesis. The cardinal symptoms of diabetic gastroparesis are nausea and vomiting. Gastroesophageal scintiscanning at 15-minute intervals for 4 hours after food intake is considered the gold standard for measuring gastric emptying. Retention of more than 10% of the meal after 4 hours is considered an abnormal result, for which a multidisciplinary management approach is required. Treatment should be tailored according to the severity of gastroparesis, and 25% to 68% of symptoms are controlled by prokinetic agents. Commonly prescribed prokinetics include metoclopramide, domperidone, and erythromycin. In addition, gastric electrical stimulation has been shown to improve symptoms, reduce hospitalizations, reduce the need for nutritional support, and improve quality of life in several open-label studies.     

Diagnostic and therapeutic approach to patients with gastroparesis

Gastroparesis is a chronic alteration of gastric motility characterized by symptoms suggestive of mechanical obstruction and delayed gastric emptying in the absence of obstruction. Gastroparesis can be idiopathic or attributable to neuropathy or myopathy as in diabetes mellitus and scleroderma or can occur after vagotomy. Diagnosis is based on symptoms (nausea, vomiting, abdominal distension and early satiety), physical examination (capotement) and on complementary investigations, the procedure of choice being isotope gastric emptying tests. Treatment depends on the clinical repercussions. In most patients, gastroparesis can be controlled by prokinetic drugs, dietary measures, exclusion of drugs that alter gastric emptying, and exhaustive control of blood glucose levels. In patients with severe gastroparesis, hospital nutritional measures (intravenous and/or enteral), gastric decompression and intravenous antiemetic and prokinetic agents are required. Aggressive nutritional therapies (parenteral or enteral nasojejunal nutrition), intrapyloric injection of botulinum toxin, implantation of a gastric stimulation device, or gastrectomy should only be used in patients unresponsive to conservative treatment or if there is selective alteration of gastric motility.     

Treatment of gastroparesis

Opinion statement Gastroparesis is a condition of impaired gastric motility that can be chronic and result in decreased quality of life and complete disability. Once the diagnosis of gastroparesis is established, the clinician’s attention should immediately focus on restoring nutritional status, providing symptomatic relief from nausea and vomiting, and improving gastric motility. Combination therapy is the rule rather than the exception, and most patients require multiple prokinetic and antiemetic modalities for adequate symptom relief. Currently available medications are often inadequate to achieve therapeutic goals, and newer modalities, such as gastric electrical stimulation, which has been shown to decrease symptoms and improve quality of life, should be employed at a low threshold. Several novel therapeutic options are under investigation and may also become part of the routine treatment of gastroparesis.     

Delayed gastric emptying: Whom to test, how to test, and what to do

Opinion statement Gastroparesis, or delayed gastric emptying, is a common cause of chronic nausea and vomiting as seen in a gastroenterology practice. Diabetic, postsurgical, and idiopathic causes remain the three most common forms of gastroparesis. In addition to nausea and vomiting, symptoms of gastroparesis may include early satiety, postprandial fullness, and abdominal pain. Physiologic changes that may explain symptoms in patients with gastroparesis, in addition to delayed gastric emptying, include impaired fundic accommodation, antral hypomotility, gastric dysrhythmias, pylorospasm, and perhaps visceral hypersensitivity. Diagnosis of gastroparesis is best determined using a radioisotope-labeled solid meal with scintigraphic imaging for at least 2 hours, and preferably 4 hours, postprandially. Most commonly, a 99mTc sulfur colloid-labeled egg sandwich with imaging at 0, 1, 2, and 4 hours is used. Extension of the gastric emptying test to 4 hours improves the accuracy of the test, but unfortunately, this is not commonly performed at many centers. Emptying of liquids remains normal until the late stages of gastroparesis and is less useful. The aims of treatment should be to control symptoms and maintain adequate nutrition and hydration. Patients should be advised to eat small meals and to limit their intake of fat and fiber. Additional dietary recommendations may include increasing caloric intake in the form of liquids. For diabetic patients, control of blood glucose levels is important, as symptom exacerbation is frequently associated with poor glycemic control. Specific treatment often begins with metoclopramide, 10 mg, up to four times daily, after a discussion of possible side effects with the patient. An antiemetic agent, such as prochlorperazine, 5 to 10 mg orally or 25 mg by suppository, can be added on an as-needed basis every 4 to 6 hours to control nausea. If these antiemetic medications are not effective, or if side effects develop, orally dissolving ondansetron, 8 mg every 8 to 12 hours, can be tried on an as-needed basis. If this regimen is unsuccessful, then alternative prokinetic agents—erythromycin, 125 mg, or tegaserod, 6 mg, prior to meals—can be tried. For cases refractory to these treatments, referral to a center with US Food and Drug Administration permission to use domperidone should be considered. Alternatively, symptom modulators such as low-dose tricyclic antidepressants can be tried to reduce symptoms, but these do not improve gastric emptying. In patients for whom all medical therapy fails, other options that are tried at experienced centers include the injection of botulinum toxin into the pylorus, placement of a feeding jejunostomy, and/or placement of a gastric electrical stimulator.     

Gastroparesis: clinical update

Gastroparesis refers to chronically abnormal gastric motility characterized by symptoms suggestive of mechanical obstruction and delayed gastric emptying in the absence of mechanical obstruction. It may be idiopathic or attributable to neuropathic or myopathic abnormalities, such as diabetes mellitus, postvagotomy, postviral infection, and scleroderma. Dietary and behavioral modification, prokinetic drugs, and surgical interventions have been used in managing patients with gastroparesis. Although mild gastroparesis is usually well managed with these treatment options, severe gastroparesis may be very difficult to control and may require referral to a specialist center if symptoms are intractable despite pharmacological therapy and dietetic support. New advances in drug therapy, botulinum toxin injection, and gastric electrical stimulation techniques have been introduced and might provide new hope to patients with refractory gastroparesis. This article critically reviews the advances in the field from the perspective of the clinician.     

The difficult patient with gastroparesis

Gastroparesis is often difficult to manage. First of all, exact criteria for making a diagnosis of gastroparesis have not been established, and merely finding delayed gastric emptying does not justify the label. Furthermore, the relationship between symptoms and gastric emptying rate is poor, and the number of therapies with proven efficacy is extremely limited. A number of technical investigations are helpful to establish the anatomy and motor function of the upper gastrointestinal tract. In most cases where gastroparesis can be presumed or established, prokinetic therapy will be tried. A number of agents are available, with variable efficacy and tolerance. Rarely, in case of debilitating refractory symptoms, experimental or invasive therapies can be tried such as injection of botulinum toxin, enteral feeding tube insertion, gastric electrical stimulation or surgery.     

Gastric electric stimulation for the treatment of gastroparesis

Gastric electric stimulation is an emerging therapy for refractory gastroparesis. Several methods have been used to electrically stimulate the stomach. Initial studies used gastric electrical pacing, which entrains and paces the gastric slow waves at a slightly higher rate than the patient’s normal myoelectric frequency of 3 cycles per minute (cpm). The technique currently practiced uses high-frequency, low-energy stimulation at four times the basal rate (12 cpm). Results from published studies with high-frequency stimulation reveal an improvement in symptoms, primarily of nausea and vomiting, and primarily in patients with diabetic gastroparesis, with only a modest change in gastric emptying. As treatment with gastric electric stimulation evolves, further delineation of its overall effectiveness, the type of patient that will likely respond, optimal electrode placement(s), and stimulus parameters should be explored.     

Nutrition concerns for the patient with gastroparesis

Gastroparesis is a debilitating disease that is the consequence of a variety of conditions resulting in a significant loss of quality of life. Although many cases are mild, some patients have protracted nausea and vomiting, making it difficult, if not impossible, to maintain their hydration and nutritional status. Furthermore, therapeutic levels of medications, such as prokinetic and antiemetic agents, can be difficult to achieve. The intent of this article is to provide the clinician with suggestions to improve the nutritional status of patients with gastroparesis and offer strategies to deal with the nutritional insults that arise in these unfortunate patients.     

The "electrical way" to cure gastroparesis

The treatment of gastroparesis recently received a heavy blow from the restrictions on the use of the prokinetic drug cisapride, but, fortunately, at the same time, a nonpharmacological approach, such as gastric electrical stimulation, came up again with new techniques. After an ultra-decennial experimentation with a large variety of electrical stimuli delivered to the gastric wall of animals and patients with gastroparesis, three principal methods are available at the moment: gastric electrical pacing, high-frequency gastric electrical stimulation, and sequential neural electrical stimulation. The first method aims to reset a regular slow-wave rhythm, but is unable to re-establish efficient contractions and a normal gastric emptying. High-frequency gastric electrical stimulation, although inadequate to restore a normal gastric emptying, nevertheless strikingly improves the dyspeptic symptoms, such as nausea and vomiting, giving the patients a better quality of life and a more satisfactory nutritional status. The last method, neural electrical gastric stimulation, consists of a microprocessor-controlled sequential activation of a series of annular electrodes which encircle the distal two thirds of the stomach and induce propagated contractions causing a forceful emptying of the gastric content. The latter method is the most promising, but it has so far only been tested in animals and would need to be tested in patients with gastroparesis before it can be used as a solution for this disease. All the aforementioned clinical studies, however, are not controlled and nearly all were published in abstract form. Therefore, further controlled trials are needed to establish which of these techniques is more useful for the treatment of gastroparesis.     

Diabetic gastroparesis: An overview of pathogenesis,clinical presentation and novel therapies,with a focus on ghrelin receptor agonists

Diabetic gastroparesis is defined as delayed gastric emptying without mechanical obstruction in the setting of diabetes. Symptoms range from mild bloating to severe vomiting episodes and can result in frequent hospitalizations and poor quality of life. It is suspected that diabetic gastroparesis is underdiagnosed due to its similar presentation to other conditions such as gastroesophageal reflux disease. The pathogenesis of diabetic gastroparesis remains unclear, but proposed mechanisms include vagal dysfunction, hyperglycemia, interstitial cells of Cajal network disturbances, loss of neural nitric oxide synthase expression in the myenteric plexus, and oxidative stress. Current management for diabetic gastroparesis focuses on dietary and lifestyle changes as well as improved glycemic control. Limited options for medical therapies are available that include prokinetic and antiemetic medications. Metoclopramide is the only FDA-approved medication for the treatment of gastroparesis. Metoclopramide improves symptoms of gastroparesis although extended treatment presents challenges such as decreased efficacy over time and increased risks for adverse events. We summarize the current knowledge of the pathophysiology of diabetic gastroparesis and review current and investigational treatments for diabetes gastroparesis.     

Gastric electrical stimulation in intractable symptomatic gastroparesis

BACKGROUND: The treatment of gastroparesis remains unsatisfactory despite prokinetic and anti-emetic drugs. Gastric electrical stimulation has been proposed as a therapeutic option. We have assessed the effect of gastric electrical stimulation on symptoms, medical treatment, body weight and gastric emptying in patients with intractable symptomatic gastroparesis in a non-placebo-controlled study. METHODS: In this multicenter study, 38 highly symptomatic patients with drug-refractory gastroparesis were enrolled. Patients first received temporary electrical stimulation using percutaneous electrodes. The 33 responders to temporary stimulation then underwent surgical implantation of a permanent stimulator. Severity of vomiting and nausea was assessed before and after stimulation. Patients were reassessed 3, 6, and 12 months after permanent implantation. RESULTS: With stimulation, 35/38 patients (97%) experienced >80% reduction in vomiting and nausea. This effect persisted throughout the observation period (2.9-15.6 months, 341 patient-months). Gastric emptying did not initially change, but improved in most patients at 12 months. At 1 year, the average weight gain was 5.5% and 9/14 patients initially receiving enteral or parenteral nutrition were able to discontinue it. CONCLUSION: Electrical stimulation of the stomach has an immediate and potent anti-emetic effect. It offers a safe and effective alternative for patients with intractable symptomatic gastroparesis.     

Diabetische Gastroparese

Symptoms of gastroparesis include nausea and vomiting, early satiety, post-prandial fullness, bloating and abdominal pain, but it is also frequently be asymptomatic. Patients with difficult metabolic control should be considered to have a disordered gastric emptying. Nuclear scintigraphy is the gold standard for quantifying delayed gastric emptying, but noninvasive methods, such as 13C-octanoic acid breath tests, exhibit a highly significant positive correlation to scintigraphy. The main goal of treatment is to minimize the symptoms and accelerate gastric emptying. The basic measures for achieving this are improved glucose control and low fat/low fibre diets that are easy to digest. The prokinetic agents metoclopramide, domperidone and erythromycin are successful in controlling symptoms in the majority of patients with gastroparesis due to diabetes. Patients with persistent symptoms or intermittent but severe symptoms may require surgical techniques such as the gastrostomy and jejunostomy. The significance of gastric pacing devices on gastric emptying and specific symptom controls have to be elucidated in further studies.     

Effect of metoclopramide in diabetic gastroparesis

The aims of our study were to: determine the effect of metoclopramide parenterally and orally on delayed gastric emptying of a radionuclide test meal in symptomatic patients with diabetic gastroparesis not explained by ulceration or other mechanical problems; and evaluate in a double-blind crossover fashion the efficacy of metoclopramide in relieving the symptoms of diabetic gastroparesis. Thirteen patients with subjective evidence of gastric stasis had delayed gastric emptying of an isotope-labeled semisolid meal which was significantly accelerated (p less than 0.05) after 10 mg of metoclopramide parenterally. Patients then received metoclopramide 10 mg and placebo before meals and prior to retiring for 3 weeks in a randomized double-blind crossover design. During metoclopramide therapy nausea, vomiting, anorexia, fullness, and bloating were significantly (p less than 0.05) ameliorated compared to placebo with an overall mean symptom reduction of 52.6%. Gastric emptying studies after completion of the trial is seven patients, subjectively improved and receiving open-labeled metoclopramide, showed significantly less gastric retention. Individual improvements in gastric emptying after parenteral or oral metoclopramide, however, could not be correlated with symptom change during the treatment trial. We conclude that metoclopramide is an important therapeutic adjunct in the management of diabetic gastroparesis and its therapeutic effects are mediated through its prokinetic properties as well as centrally mediated antiemetic actions.     

不同阶段糖尿病胃运动障碍诊治对策

糖尿病患者常见胃运动障碍,表现为上腹胀、早饱、上腹不适、恶心、呕吐等症状以及胃排空延迟,胃排空延迟影响降血糖药的药代动力学,造成餐后血糖升高与降血糖药或胰岛素的血浓度高峰不匹配,进而影响血糖的控制与稳定。糖尿病不同阶段胃运动障碍表现形式不同。核素法是最常用的胃排空诊断方法。糖尿病胃运动障碍的处理包括饮食调节、促动力药以减轻症状、控制血糖,针对胃轻瘫的治疗包括胃电刺激、内镜下幽门注射肉毒杆菌毒素A、内镜下放置鼻胃空肠营养管或经皮内镜下胃（空肠）造瘘、外科手术等。     

Gastroparesis following bone marrow transplantation

Patients often develop nausea, vomiting and bloating after bone marrow transplantation (BMT). These symptoms may interfere with nutrition and the ability to take oral medications. Gastroparesis is a recognized cause of these symptoms in non-transplant patients but less is known about patients who undergo BMT. Between January 1996 and March 1997, a total of 151 patients underwent BMT. Eighteen patients (12%) developed persistent symptoms suggestive of gastroparesis (persistent nausea, vomiting or bloating). Scintigraphic gastric emptying studies were performed to assess for gastroparesis. Prokinetic agents were administered at the time of study. The records on these patients were compared with those of all other patients undergoing BMT during the same time period without these symptoms. Nine patients who demonstrated delayed gastric emptying were further evaluated with esophagastroduodenoscopy and biopsy. Biopsy samples were reviewed for evidence of graft-versus-host disease (GVHD). Fourteen of 18 patients demonstrated delayed gastric emptying and most responded to prokinetic agents given at the time of study. Age, conditioning regimen, cytomegalovirus antigenemia and acute GVHD did not appear to be associated with the development of gastroparesis. Allogeneic BMT recipients were at higher risk than autologous BMT patients (26% vs 0%, P < 0.0001). of allogeneic bmt recipients, there was a nonsignificant trend of patients receiving tacrolimus to be less likely to experience gastroparesis than those receiving cyclosporine (27% vs 48%, P = 0.08). For the nine patients undergoing upper endoscopy, GVHD on gastric biopsy was an uncommon finding and was mild when present. Gastroparesis appears to be a common cause of nausea, vomiting and bloating following allogeneic BMT. This may occur less often with tacrolimus than cyclosporine because of the former agent's prokinetic properties. Patients usually respond to prokinetic drugs at the time of scintigraphy. GVHD and CMV infection do not appear to be major contributing factors.     

Idiopathic and diabetic gastroparesis

Opinion statement The management of both diabetic and idiopathic gastroparesis often represents a substantial clinical challenge. In formulating recommendations for therapy, it should be recognized that these are based on less than optimal evidence; in particular, there are substantial deficiencies in current knowledge relating to the pathophysiology of gastroparesis, as well as the natural history of gastrointestinal symptoms, and the majority of pharmacologic trials have been short term and associated with methodologic limitations. Although the etiologic factors differ, the overall management principles are similar in the two conditions. Maintenance of adequate nutrition is pivotal, and parenteral nutrition may be required in severe cases associated with malnutrition. In patients with diabetes, rigorous attempts should be made to optimize glycemic control —hyperglycemia slows gastric emptying and may exacerbate symptoms and attenuate the effects of prokinetic drugs. Despite the relatively poor predictive value of symptoms, it is reasonable to suggest a trial of prokinetic therapy for about 4 weeks, rather than initially establishing the diagnosis by measurement of gastric emptying. However, it should be recognized that there is a substantial placebo response, a lack of evidence to support the cost effectiveness of such an approach, and that most patients will require prolonged therapy. In type 1 diabetic patients, prokinetic therapy may potentially benefit glycemic control, and this forms an additional rationale (albeit not established) for therapy. Some patients with diabetes and idiopathic gastroparesis with severe vomiting are unable to tolerate oral medication; in such cases subcutaneous metoclopramide may prove useful. Patients with intractable symptoms should be hospitalized and given intravenous erythromycin. The repertoire of prokinetic agents available in the United States is limited and includes metoclopramide, erythromycin, and cisapride (available by special program from its manufacturer); all of these drugs are associated with side effects. The use of metoclopramide may represent the first choice for chronic oral therapy, although it has been studied less comprehensively than cisapride. Combination therapy may be potentially more efficacious than the use of single agents. Dehydration and metabolic derangements should be corrected. The choice of chronic medical therapy should be individualized, taking factors such as age, presence of diabetes, concurrent medications, and comorbidities into account. In a small number of patients in whom medical treatment fails, surgery should be considered, and, if performed, done in a specialized center. A number of novel therapies, including gastric electrical stimulation, are currently being evaluated.