Gastric electrical stimulation for gastroparesis: a goal greatly pursued, but not yet attained

The lack of an effective medical treatment for gastroparesis has pushed the research of new techniques of gastric electrical stimulation (GES) for nearly half a century of experimentation with a large variety of electrical stimuli delivered to the gastric wall of animals and patients with gastroparesis. Three principal methods are currently available: gastric low-frequency/high-energy GES with long pulse stimulation, high-frequency/low-energy GES with short pulse stimulation and neural sequential GES. The f...     

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.     

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.     

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.     

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.     

Postprandial antropyloroduodenal motility and gastric emptying in gastroparesis--effects of cisapride.

There is little information about the organisation of antroduodenal contractions or pyloric motility in patients with gastroparesis. The mechanisms responsible for the acceleration of gastric emptying by cisapride in patients with gastroparesis are also poorly understood. Simultaneous manometric and scintigraphic recordings were performed in 12 patients with gastroparesis and nine healthy volunteers before and after cisapride administration. Antropyloroduodenal pressures were recorded with a sleeve/side hole manometric assembly and gastric emptying with a scintigraphic method. Thirty minutes after the solid component of the test meal had begun to empty from the stomach all subjects received 5 mg cisapride intravenously over 10 minutes and recordings continued for a further 60 minutes. In the 30 minutes before cisapride there was no significant difference in the number of antral pressure waves (median 20 v 33, NS), basal pyloric pressure, or the number of isolated pyloric pressure waves between patients and volunteers, but the number of antral waves of extent > or = 6 cm (median 1 v 5, p < 0.05) was less in the patients, as was gastric emptying (8% v 20%, p < 0.05). In the patients, there was no change in the number of antral waves after cisapride, but there was an increase in the number of antral waves > or = 6 cm in extent (median 7 v 1, p < 0.05) and in the rate of gastric emptying (26% v 8%, p < 0.01). In the healthy subjects, cisapride increased gastric emptying (31% v 20%, p < 0.05), but reduced the number of antral waves (10 v 33, p < 0.05). Cisapride had no significant effect on the number of antral waves of extent more than or equal to 6 cm (11 v 5, NS). The number of isolated pyloric pressure waves decreased after cisapride (4 v 11, p < 0.05). There was a relationship between gastric emptying and the number of antral pressure waves of extent more than or equal to 6 cm in both the patients (r=0.38, p<0.05) and healthy subjects (r=0.05, p<0.01). There was no significant relationship between gastric emptying and the number of antral waves. It is concluded that disturbance of the relationship between antral, pyloric, and duodenal pressure waves is a major abnormality of postprandial gastric motor function in patients with gastroparesis. The stimulation of antral pressure waves of extent more than or equal to 6 cm may contribute to the acceleration of gastric emptying produced by cisapride in patients with gastroparesis and in normal subjects.     

Management of gastroparesis

Gastroparesis presents with nausea, vomiting, early satiety and abdominal discomfort, as well as a range of nongastrointestinal manifestations in association with delays in gastric emptying. The disorder may be a consequence of systemic illnesses, such as diabetes mellitus, occur as a complication of gastroesophageal surgery or develop in an idiopathic fashion and may mimic other disorders with normal gastric emptying. Some cases of idiopathic gastroparesis present after a viral infection. Management relies primarily on therapies that accelerate gastric emptying or reduce vomiting, although endoscopic or surgical options are available for refractory cases. Current research is focusing on the cellular and molecular mechanisms underlying development of delayed gastric emptying, as well as factors unrelated to motor dysfunction that may elicit some symptoms. Future pharmaceuticals will target the contractile and nonmotor defects via novel pathways. Novel electrical stimulation techniques will be employed either alone or in combination with medications.     

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.     

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.     

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.     

Pyloric injection of botulinum toxin for treatment of diabetic gastroparesis

BACKGROUND: Diabetic gastroparesis is a common clinical problem. The pathophysiology includes prolonged pyloric contractions that may cause functional resistance to gastric outflow. Botulinum toxin was injected into the pyloric sphincter in an attempt to decrease pyloric resistance and improve gastric emptying. METHODS: Six patients with diabetic gastroparesis and an abnormal solid phase gastric emptying study underwent upper endoscopy during which 100 units of botulinum toxin were injected into the pyloric sphincter. Gastric emptying studies were obtained at 48 hours and 6 weeks after injection. Patients were questioned about symptoms of gastroparesis, and a symptom score was obtained at baseline and at 2 weeks and 6 weeks after injection. OBSERVATIONS: There was a mean improvement in the subjective symptom score at 2 weeks of 55% (range 14% to 80%). This improvement was maintained at 6 weeks. There was a 52% improvement in gastric emptying at 2 and 6 weeks. CONCLUSION: Pyloric injection of botulinum toxin can improve symptoms and gastric emptying in patients with diabetic gastroparesis. Further evaluation of pyloric injection of botulinum toxin as a treatment for diabetic gastroparesis is warranted.     

Human electrogastrograms

A method to record the gastric basic electrical rhythm (BER) using skin electrodes is described. Correlation is made with mucosal suction electrodes in 20 volunteers. Successful simultaneous recording from surface electrodes and mucosal electrodes is made in 16/20 subjects (80%). An increase in amplitude of the recorded gastric BER with gastric contractions is demonstrated and discussed. Five patients with gastric motility disturbances and chronic nausea are also investigated. Four of these patients had diabetic gastroparesis. Each had preservation of the gastric BER. The rate was usually normal at three per minute, but during acute nausea episodes which occurred in three of the four, an abnormally increased rate of the BER (tachygastria) was seen. This finding was also seen in a subject with atrophic gastritis and delay of gastric emptying. The surface electrogastrogram may prove to be a useful tool for the investigation of patients with suspected gastric arrhythmias.This project received support from a General Research Support Grant to the University of Wisconsin Medical School from the National Institutes of Health, Division of Research Facilities and Resources, Bethesda, Maryland.     

Gastroparesis： Current diagnostic challenges and management considerations

Gastroparesis refers to abnormal gastric motility characterized by delayed gastric emptying in the absence of mechanical obstruction. The most common etiologies include diabetes, post-surgical and idiopathic. The most common symptoms are nausea, vomiting and epigastric pain. Gastroparesis is estimated to affect 4% of the population and symptomatology may range from little effect on daily activity to severe disability and frequent hospitalizations. The gold standard of diagnosis is solid meal gastric scintigraphy. Treatment is multimodal and includes dietary modification, prokinetic and anti-emetic medications, and surgical interventions. New advances in drug therapy, and gastric electrical stimulation techniques have been introduced and might provide new hope to patients with refractory gastroparesis. In this comprehensive review, we discuss gastroparesis with emphasis on the latest developments; from the perspective of the practicing clinician.     

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.     

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.     

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.     

Gastric and esophageal emptying in dystrophia myotonica. Effect of metoclopramide

Gastric and esophageal emptying were measured using scintigraphic techniques in 16 patients with dystrophia myotonica and in 22 normal volunteers. Gastric emptying of a solid meal was slower than the normal range (defined as the mean +/- two standard deviations obtained in the normal volunteers) in 15 of the 16 patients, and gastric emptying of the liquid meal was slower than the normal range in 10 of the patients. Esophageal emptying was also markedly delayed in patients, with 15 of 16 patients having an emptying time longer than the normal range. There was no relationship between gastrointestinal symptoms, or the severity of the peripheral (skeletal) muscle weakness, and either gastric or esophageal emptying. Oral administration of metoclopramide resulted in a significant improvement in gastric emptying of the solid meal and a nonsignificant trend toward more rapid liquid emptying, but no change in esophageal emptying. These results indicate that there is a very high prevalence of gastric and esophageal smooth muscle dysfunction in dystrophia myotonica and that gastroparesis is likely to be a treatable cause of morbidity in this disease.     

Ghrelin enhances gastric motility through direct stimulation of intrinsic neural pathways and capsaicin-sensitive afferent neurones in rats

BACKGROUND: Ghrelin may stimulate gastric motility via the vagal nerve pathway. However, the mechanism of ghrelin-induced changes in gastrointestinal motility has not yet been clearly defined. The present study was designed to investigate whether ghrelin accelerates gastric emptying via capsaicin-sensitive afferent neurones and directly affects the enteric neuromuscular function. METHODS: Gastric emptying of nutrient solids was assessed after intravenous administration of saline or ghrelin in conscious rats. The effects of ghrelin on gastric emptying were also examined in rats pretreated with capsaicin. Gastric emptying and intestinal transit of non-caloric liquids were evaluated using 51Cr solution. The effects of ghrelin on spontaneous contractile activities of isolated strips from stomach and jejunum were also investigated and the influence of ghrelin on motor responses to carbachol and electrical field stimulation was examined. RESULTS: Ghrelin significantly accelerated gastric emptying of both nutrient solids and non-caloric liquids in conscious rats. The intestinal transit of non-caloric liquids was also enhanced by ghrelin. Pretreatment with capsaicin prevented the ghrelin-induced acceleration of gastric emptying of nutrient solids. Ghrelin did not modulate spontaneous and carbachol-induced contractions of strips of gastric body, gastric antrum and jejunum. However, electrical field stimulation-induced contractions were significantly enhanced by ghrelin in the gastric body. CONCLUSIONS: The results suggest that the stimulatory effects of ghrelin on gastric motility are mediated by direct stimulation of the enteric neural pathway and capsaicin-sensitive afferent neurones.     

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。     

Measurement by epigastric impedance of gastric emptying in diabetic autonomic neuropathy

Changes in impedance across the epigastrium form the basis of a new non-invasive method of assessing gastric emptying of liquids. The apparatus is simple to use at the bedside and, in conjunction with conventional investigations, is of value in diagnosing gastroparesis in patients with diabetic autonomic neuropathy and symptoms of recurrent vomiting. We measured gastric emptying of liquids in 22 diabetics aged 33.4 +/- 9 years (mean +/- SD) with severe symptomatic autonomic neuropathy (mean heart rate variability 4.9 +/- 2.2 SD beats/min), and 15 normal controls. Median 'half emptying' time in the diabetics with autonomic neuropathy was prolonged overall but it was not always abnormal (12.25 min, range 6.5-greater than 30 compared to 8.0 min, range 3-17; p less than 0.01). Results in five diabetics with symptoms of recurrent vomiting corresponded with those using conventional radiological methods, confirming gastroparesis in three instances and excluding it in two. The effect of metoclopramide was also studied and was shown to accelerate gastric emptying in some but not all of the patients. Assessment of gastric emptying using the impedance method assists in establishing the diagnosis of gastroparesis and is of value for repeated measurements.