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.     

Human gastric myoelectric activity and gastric emptying following gastric surgery and with pacing.

Postoperative gastric myoelectric activity, gastric emptying, and clinical course were correlated in 17 patients at high risk of developing gastroparesis after gastric surgery. In addition, an attempt was made to pace the stomach with an electrical stimulus and determine the effect of pacing on early postoperative gastric emptying. Gastric dysrhythmias (bradygastria, slow wave frequency < 2 cycles/min; tachygastria, slow wave frequency > 4 cycles/min) persisted beyond the first postoperative day in 6 patients (35%). Delayed gastric emptying was identified by a radionuclide meal in 15 patients (88%), but symptoms of gastroparesis developed in only 6 of 15 (40%). Patients with postoperative gastroparesis had more frequent dysrhythmias than asymptomatic patients (67% vs. 18%), but these differences were not significant, although we cannot exclude a type II statistical error. Gastric rhythm was entrained in 10 of 16 patients (63%). Pacing increased the gastric slow wave frequency (3.1 vs. 4.1 cycles/min; P < 0.01) but did not improve gastric emptying (gastric retention at 60 minutes, 86% +/- 6% for control and 90% +/- 2% for paced). In conclusion, gastric dysrhythmias do not appear to play a major role in the development of postsurgical gastroparesis. Although gastric rhythm could be entrained in the majority of patients, pacing did not improve gastric emptying overall.     

Abnormal gastric myoelectrical activity and delayed gastric emptying in patients with symptoms suggestive of gastroparesis

Gastric myoelectrical activity modulates gastric motor activity. Abnormalities in gastric myoelectrical activity may be associated with gastric motility disorders. The aim of this study was to investigate the correlation of gastric myoelectrical activity with gastric emptying in symptomatic patients with and without gastroparesis. Ninety-seven patients with symptoms suggestive of gastroparesis participated in the study. Gastric myoelectrical activity was recorded using surface electrogastrography. The electrogastrogram (EGG) was recorded for 30 min in the fasting state and for 120 min after a solid test meal. Gastric emptying of the solid meal was simultaneously monitored for 120 min. Patients with delayed gastric emptying showed a significantly lower percentage of normal gastric slow waves (P<0.03) and a significantly reduced increase of the dominant power in the postprandial EGG (P<0.02). Postprandial EGG parameters were found to be able to predict delayed emptying of the stomach. Postprandial gastric dysrhythmia predicts delayed gastric emptying with an accuracy of 78%, while the abnormality in postprandial EGG power predicts delayed gastric emptying with an accuracy of 75%. All patients with abnormalities in both the rhythmicity and the power had delayed gastric emptying. Patients with delayed gastric emptying have a lower percentage of normal gastric slow waves in the EGG and a lower postprandial increase in the dominant power. Abnormalities in the postprandial EGG seem to be able to predict delayed emptying of the stomach. However, a normal EGG does not seem to guarantee normal emptying of the stomach.     

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 with electrical stimulation

Electrically stimulating the stomach to treat gastroparesis has been proposed by investigators for decades. With the development of techniques of implantable pacing devices and electrodes and promising preliminary results in chronic pacing studies, gastric electrical stimulation (GES) has received increasing attention recently among researchers and clinicians. A number of studies have been performed to investigate the effects of GES on gastric motility, gastric emptying, and gastrointestinal symptoms in both dogs and humans. Based on the frequency of the electrical stimulus used for chronic treatment of gastroparesis, gastric electrical stimulation can be classified into low-frequency stimulation (LFS) and high-frequency stimulation (HFS). Although some of the results are still controversial, the majority of these studies seem to indicate that LFS is able to normalize gastric dysrhythmias and entrain gastric slow waves and accelerate gastric emptying. On the other hand, HFS has no effect on gastric emptying but is able to significantly reduce symptoms of nausea and vomiting in gastroparetic patients. GES has provided an exciting new advance in the treatment of gastroparesis and management of upper gastrointestinal symptoms. This paper will review the available studies of GES in the treatment of gastroparesis and current status of this field.     

Novel insights into the effects of diabetes on gastric motility

Recent data from the Diabetes Control and Complications Trial/Epidemiology of Diabetic Interventions and Complications cohort indicate that the disease burden of gastroparesis in diabetes remains high, consistent with the outcome of cross-sectional studies in type 1 and 2 diabetes. An improved understanding of the pathogenesis of diabetic gastroparesis at the cellular level has emerged in the last decade, particularly as a result of initiatives such as the National Institute of Health funded Gastroparesis Clinical Research Consortium in the US. Management of diabetic gastroparesis involves dietary and psychological support, attention to glycaemic control, and the use of prokinetic agents. Given that the relationship between upper gastrointestinal symptoms and the rate of gastric emptying is weak, therapies targeted specifically at symptoms, such as nausea or pain, are important. The relationship between gastric emptying and postprandial glycaemia is complex and inter-dependent. Short-acting glucagon-like peptide-1 agonists, that slow gastric emptying, can be used to reduce postprandial glycaemic excursions and, in combination with basal insulin, result in substantial reductions in glycated haemoglobin in type 2 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.     

Gastroparesis: prevalence, clinical significance and treatment.

The application of novel techniques to quantify gastric motor function and gastric emptying has yielded important insights into the prevalence, pathogenesis and clinical sequelae of gastroparesis. Both acute and chronic gastroparesis occur frequently; gastric emptying of solids is delayed in 30% to 50% of patients with diabetes mellitus, functional dyspepsia and gastroesophageal reflux disease. While many patients with gastroparesis experience upper gastrointestinal symptoms that adversely affect quality of life, the concept that symptoms are inevitably the direct outcome of delay in gastric emptying is now recognized to be overly simplistic. In contrast, the potential impact of gastroparesis on oral drug absorption and blood glucose control in patients with diabetes mellitus has probably been underestimated. While the use of prokinetic drugs (cisapride, domperidone, metoclopramide and erythromycin) forms the mainstay of therapy in symptomatic patients with gastroparesis, a number of novel pharmacological therapies are being evaluated, and preliminary studies using gastric pacing show promise.     

The use of SmartPill for gastric monitoring

Testing to define delayed gastric emptying is required to diagnose gastroparesis; rapid emptying is found in other patients. Commonly performed methods of gastric emptying testing include scintigraphy and breath testing. The SmartPill wireless motility capsule (WMC) system is US FDA-approved for evaluating suspected delayed emptying in gastroparesis and functional dyspepsia. The device measures transit in the stomach, small intestine, and colon by detecting characteristic pH transitions; and quantifies pressure waves in each gut region. WMC gastric emptying times correlate with scintigraphic measures. Incremental benefits of WMC testing in patients with suspected gastroparesis include delineation of pressure abnormalities and small intestinal and colonic transit delays. Acceptance of trial data confirming usefulness of WMC testing in suspected gastric motor disorders has been hampered by small sample sizes and design limitations. Ongoing multicenter studies will validate the utility of WMC methods in patients with suspected gastroparesis and other upper gastrointestinal motor disorders.     

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.     

Gastric Emptying in Human Disease States

The application of new radioisotope methods in external in vivo scanning has increased our knowledge of how disease and treatment can effect gastric emptying (GE). Solids leave the stomach more slowly than liquids, and conditions causing gastroparesis affect solids before liquids. Gastric mucosal abnormalities and their treatment can affect GE. Diseases of the gastric musculature, including the inflammatory and endocrine myopathies, muscular dystrophies, and infiltrative disorders, can result in significant gastroparesis. Acute and chronic neuropathy may both affect gastric emptying. The latter neuropathies are now the subject of intense investigation with new prokinetic drugs. Finally, abnormal GE may be a major clinical feature of certain severe psychiatric disorders.     

Objective and subjective results of a randomized,double-blind,placebo-controlled trial using cisapride to treat gastroparesis

Cisapride, a relatively new gastrointestinal prokinetic agent, has been reported to increase gastric emptying and improve symptoms of gastroparesis. We investigated these effects of cisapride in patients with severe idiopathic and diabetic gastroparesis during an eight-week trial. The study design was a two-week single-blind placebo run in period to exclude placebo responders, followed by a six-week randomized, double-blind, placebo-controlled treatment phase. Delayed gastric emptying of solids on radionuclide scan and a minimum symptom intensity score were inclusion criteria. Forty-three patients were entered: four placebo responders and one other patient were excluded, leaving 19 patients randomized to cisapride (20 mg per os three times a day before meals), and 19 patients to placebo. Seven individual symptoms of gastroparesis were scored in a daily diary and reviewed at two-week visits. Sixteen patients in the cisapride group were able to complete the trial compared to 12 on placebo. The gastric emptying study was repeated at the end of treatment or at the time of withdrawal for those who dropped out. Cisapride significantly increased solid gastric emptying relative to baseline (P=0.005) whereas placebo did not (P>0.10). Cisapride did not significantly improve any symptom of gastroparesis relative to baseline or to placebo. We conclude that in a population of severe, refractory gastroparetic patients cisapride significantly accelerates gastric emptying of a solid meal without significantly reducing symptoms during a short-term treatment trial compared to placebo. Further trials of cisapride in less advanced and end-stage gastroparetics than studied here or combining cisapride with other prokinetic agents or antiemetics, are warranted.Financial support was provided by Janssen Pharmaceutica. This study took place in the General Clinical Research Center of the University of Virginia Medical Center and was supported by NIH grant M01-RR 00847.     

Pacing the gut in motility disorders

Opinion statement Similar to cardiac pacing, gastrointestinal (GI) pacing is an attractive idea and may become a promising therapy, as the GI organs, like the heart, have their own natural pacemakers. Over the past 10 years, electrical stimulation of the gut has received increasing attention among researchers and clinicians. Several clinical studies have shown that gastric electrical stimulation (GES) with short pulses is able to reduce nausea and vomiting in patients with gastroparesis and that GES with long pulses is able to pace the intrinsic gastric slow waves and thus normalize gastric dysrhythmia. However, possible placebo effects cannot be ruled out, although recent animal studies have revealed various peripheral and central mechanisms involved with GES. Electrical stimulation of the small intestine, colon, or anal sphincter also has been reported for the treatment of dumping syndrome, constipation, and fecal incontinency. Similarly, there is a lack of placebo-controlled studies. In our opinion, pacing of the gut has great potential for the treatment of various GI motor disorders. However, none of the commercially available devices is designed for pacing the gut. The lack of well-suited devices and the invasive nature of gut pacing slow down the progress and clinical applications of gut pacing.     

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.     

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.     

Treatment of high-frequency gastric electrical stimulation for gastroparesis

Background and Aims: The aim of this study was to assess the effects of gastric electrical stimulation (GES) on symptoms and gastric emptying in patients with gastroparesis, and the effects of GES on the three subgroups of gastroparesis. Methods: A literature search of clinical trials using high‐frequency GES to treat patients with gastroparesis from January 1995 to January 2011 was performed. Data on the total symptom severity score (TSS), nausea severity score, vomiting severity score, and gastric emptying were extracted and analyzed. The statistic effect index was weighted mean differences. Results: Ten studies (n = 601) were included in this study. In the comparison to baseline, there was significant improvement of symptoms and gastric emptying (P < 0.00001). It was noted that GES significantly improved both TSS (P < 0.00001) and gastric retention at 2 h (P = 0.003) and 4 h (P < 0.0001) in patients with diabetic gastroparesis (DG), while gastric retention at 2 h (P = 0.18) in idiopathic gastroparesis (IG) patients, and gastric retention at 4 h (P = 0.23) in postsurgical gastroparesis (PSG) patients, did not reach significance. Conclusions: Based on this meta‐analysis, the substantial and significant improvement of symptoms and gastric emptying, and the good safety we observed, indicate that high‐frequency GES is an effective and safe method for treating refractory gastroparesis. DG patients seem the most responsive to GES, both subjectively and objectively, while the IG and PSG subgroups are less responsive and need further research.     

Ghrelin enhances gastric emptying in diabetic gastroparesis: a double blind, placebo controlled, crossover study

BACKGROUND: Diabetic gastroparesis is a disabling condition with no consistently effective treatment. In animals, ghrelin increases gastric emptying and reverses postoperative ileus. We present the results of a double blind, placebo controlled, crossover study of ghrelin in gastric emptying in patients with diabetic gastroparesis. METHODS: Ten insulin requiring diabetic patients (five men, six type I) referred with symptoms indicative of gastroparesis received a two hour infusion of either ghrelin (5 pmol/kg/min) or saline on two occasions. Blood glucose was controlled by euglycaemic clamp. Gastric emptying rate (GER) was calculated by real time ultrasound following a test meal. Blood was sampled for ghrelin, growth hormone (GH), and pancreatic polypeptide (PP) levels. Cardiovagal neuropathy was assessed using the Mayo Clinic composite autonomic severity score (range 0 (normal)-3). RESULTS: Baseline ghrelin levels were mean 445 (SEM 36) pmol/l. Ghrelin infusion achieved a peak plasma level of 2786 (188) pmol/l at 90 minutes, corresponding to a peak GH of 70.9 (19.8) pmol/l. Ghrelin increased gastric emptying in seven of 10 patients (30 (6)% to 43 (5)%; p = 0.04). Impaired cardiovagal tone correlated inversely with peak postprandial PP values (p < 0.05) but did not correlate with GER. CONCLUSIONS: Ghrelin increases gastric emptying in patients with diabetic gastroparesis. This is independent of vagal tone. We propose that analogues of ghrelin may represent a new class of prokinetic agents.     

Disordered gastric motor function in diabetes mellitus

Summary The application of novel investigative techniques has demonstrated that disordered gastric motility occurs frequently in diabetes mellitus. Gastric emptying is abnormal in about 50% of diabetic patients and delay in gastric emptying of nutrient-containing meals is more common than rapid emptying. The blood glucose concentration influences gastric motility in diabetes. In IDDM patients, gastric emptying is retarded during hyperglycaemia and may be accelerated by hypoglycaemia. Gastroparesis therefore does not necessarily reflect irreversible autonomic neuropathy and blood glucose concentrations must be monitored when gastric motility is evaluated in diabetic patients. There is a poor relationship between gastric emptying and gastrointestinal symptoms and the mechanisms by which abnormal motility causes symptoms are unclear. The introduction of new gastrokinetic drugs has improved therapeutic options for the management of symptomatic patients with gastroparesis considerably. The contribution of disordered gastric emptying to poor glycaemic control is unclear, but the demonstration that the rate of gastric emptying is a major factor in normal blood glucose homeostasis suggests that this is likely to be significant.Abbreviations IDDM insulin-dependent diabetes mellitus - NIDDM non-insulin-dependent diabetes mellitus     

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.     

Botulinum toxin for the treatment of gastroparesis: a preliminary report

Gastroparesis is a disorder of gastric motility that results in delayed gastric emptying. Common symptoms include early satiety, postprandial fullness, epigastric pain, nausea, vomiting, and weight loss. The underlying etiologies of gastroparesis are many and include diabetes, prior gastric surgery, collagen vascular disorders, and a previous viral illness. Up to one third of cases are classified as idiopathic. Treatment typically consists of a change in diet to small volume, frequent meals and the use of the prokinetic agents metoclopramide, cisapride, erythromycin, or domperidone. Botulinum toxin has recently been shown to be effective in treating disorders of smooth muscle hypertonicity in the GI tract. This case report describes three patients with severe gastroparesis whose symptoms persisted despite dietary changes and the use of high dose prokinetic agents. All three were treated with intrasphincteric injection of the pylorus with botulinum toxin and all had significant symptomatic improvement afterwards. Possible mechanisms of action of botulinum toxin on the pylorus and its effects in patients with gastroparesis are discussed.