Gastric electrical stimulation (GES) is neurostimulation; its mechanism of action is affecting central control of nausea and vomiting and enhancing vagal function. GES is a powerful antiemetic available for patients with refractory symptoms of nausea and vomiting from gastroparesis of idiopathic and diabetic causes. GES is not indicated as a way of reducing abdominal pain in gastroparetic patients. The need for introducing a jejunal feeding tube means intensive medical therapies are failing, and is an indication for the implantation of the GES system, which should always be accompanied by a pyloroplasty to guarantee accelerated gastric emptying.
Key points
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Gastric electrical stimulation (GES) is neurostimulation; its mechanism of action is affecting central control of nausea and vomiting and enhancing vagal function.
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GES is a powerful antiemetic available for patients with refractory symptoms of nausea and vomiting from gastroparesis of idiopathic and diabetic causes.
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The need for introducing a feeding tube means that intensive medical therapies are failing, and the implantation of the GES system may be indicated at the time of surgical placement of a feeding tube.
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Because there is no acceleration of gastric emptying with GES neurostimulation by itself, a surgical pyloroplasty should accompany GES surgery to help improve the rate of gastric emptying.
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Total gastrectomy is indicated in that small subset of gastroparetic patients (<5%) when vomiting does not respond to GES in order to prevent hospitalizations and improve quality of life.
History of gastric electrical stimulation
In the clinical world of treatment of severe symptoms of drug-refractory GP, there are not many pharmacologic or surgical options. The list of available prokinetic and antiemetic agents has changed very little in the last 30 years. The same medications with their sometimes-severe side effects as well as tachyphylaxis problems provide limited choices for the growing number of gastroparetic patients around the world.
There is a need to consider new therapeutic approaches for the 20% to 25% of the gastroparetic population, whose symptoms are not addressed by existing drugs, investigational agents, nutrition support modalities, better diabetic control, as well as lifestyle modifications.
Therefore, the pioneering thinking of surgeon Ayden Bilgutay, MD and his colleagues in the early 1960s provided a new approach. The concept of gastrointestinal pacing by using intraluminal electrical stimulation was first studied in the setting of postoperative ileus. This innovating theory led to more research in a canine model in 1970, laying the foundation to investigate myoelectrical activities, contractility, and finally electrical stimulation of the gastrointestinal tract in humans. The challenge of understanding how gastric peristalsis was regulated by an electrical rhythm led to identifying the pacemaker site located in the corpus along the great curvature 5 to 7 cm from the cardia. The interstitial cells of Cajal were also identified as a network controlling the direction, velocity (rate), and frequency of gastric waves and, thus, the frequency and coordination of muscle contractions. This increasing knowledge of gastric electrophysiology inspired, in the late 1990s, a group of scientists and clinicians, such as Qian, Kelly, McCallum, Morison and Familoni, to pursue the potential therapeutic role of gastric pacing and normalization of myoelectrical dysrhythmia.
Different methods of stimulation
The original concept of gastric pacing was based on similar principals to cardiac pacing, namely, strengthening of gastric slow waves and also overcoming electrical dysrhythmias. Two GES parameters have been established: (1) Long-pulse with high energy and a physiologic frequency of stimulation using single or multichannel electrodes. These parameters can entrain slow waves, reverse dysrhythmias, and, hence, accelerate gastric emptying. (2) On the other hand, short-pulse low-energy GES at frequencies higher than physiologic is termed neurostimulation, and may alleviate gastroparetic symptoms, specifically nausea and vomiting, without a meaningful improvement in gastric emptying or changing the underlying slow-wave rhythm pattern. Hence, the predicted outcome or goals of GES depend on the parameters of the applied stimulation ( Fig. 1 ).
Gastric Pacing
Pioneering studies using antegrade stimulation with a long duration or high-energy pulse width of 10 to 600 milliseconds and maximal frequency of 4.3 cpm, thus achieving pacing parameters, have shown a complete entrainment of gastric slow waves, normalization of gastric dysrhythmia, acceleration of gastric emptying, and better control of GP symptoms in initially a dog model and now in humans.
A clinical trial was reported whereby an external low-frequency and high-energy stimulation device was tested against an implantable high-frequency and low-energy gastric stimulation device. The primary goals were to investigate the effects of 2-channel gastric pacing on gastric myoelectrical activity and energy consumption with the secondary intent to monitor gastric emptying and symptoms in patients with severe diabetic GP. Four pairs of temporary pacing wires were secured on the serosa of the stomach at the time of laparotomy to place the Enterra System (Medtronic, Inc, Minneapolis, MN) in 19 patients with severe GP who were not responding to standard medical therapies. Two of the pairs were for electrical stimulation and the other two for recording. Five days after surgery, the optimal pacing parameters for the entrainment of gastric slow waves in each patient were identified by serosal recordings. Two-channel gastric pacing was then initiated for 6 weeks using a newly developed external multichannel pulse generator. Key results showed that 2-channel gastric pacing at 1.1 times the intrinsic frequency entrained gastric slow waves and normalized gastric dysrhythmia by decreasing tachygastria in the fasting and postprandial state, significantly reducing GP symptoms and improving mean 4-hour gastric retention in patients with diabetic GP with an excellent safety profile. This observation was also in agreement with the results on multichannel gastric pacing previously published in both healthy and diseased canine models.
One of the major drawbacks for single-channel gastric pacing with long pulses is that it needs high stimulation energy to entrain gastric slow waves and normalize dysrhythmias. This is explained by the fact that the stimulating electrode has to be placed in the proximal stomach to avoid reverse pacing. To entrain gastric slow waves, the stimulation energy for the single-channel gastric pacing has to be high enough to ensure the stimulation pulses are propagated a distance of 20 cm or greater from the proximal stomach to the distal antrum. Therefore, multichannel GES was designed to mimic the natural propagation and characteristics of the gastric slow waves. For 2-channel gastric pacing with long pulses used in this study, each stimulation channel was responsible to entrain slow waves at a distance of 8 cm. As a result, the consumption of stimulation energy with 2-channel gastric pacing was much less than that with single-channel gastric pacing and, hence, saving battery life. This concept had already been proposed and studied in a dog model, and research in this area is continuing. Currently, there are no US Food and Drug Administration (FDA)–approved long-pulse–generating implantable devices available on the market ( Fig. 2 ).
Neurostimulation
The pulse width in short-pulse stimulation is a few hundred microseconds, and the frequency is 3 to 4 times higher than the physiologic rate of gastric slow waves. Reports in dogs had shown strengthening of gastric contractions and acceleration of gastric emptying. These findings set the stage for studies GES in humans, although these observations have not been reproducible with subsequent experiments. Investigating gastric stimulation with high-frequency/low-energy parameters, known as Enterra therapy (Medtronic, Inc, Minneapolis, MN), led to many clinical trials. The net result indicates that GES by the Enterra device does produce a significant and sustained improvement in symptoms and nutritional status in the majority of patients with intractable symptomatic GP. These results were initially based on open-label studies and in subgroups of patients with diabetic and idiopathic GP (ID-GP). The World Anti-Vomiting Electrical Stimulation Study (WAVESS) was a double-blind crossover study whereby the Enterra system was activated or shammed starting at the time of surgery. Based on the positive results of this trial, in March of 2000, this therapy was approved by the US FDA as a humanitarian device exemption (HDE) and it is commercially available as the implantable pulse generator to treat drug-refractory nausea and vomiting secondary to diabetic or ID-GP. As of December 2014, there are more than 8,000 patients implanted worldwide with Enterra therapy.
Because of the paucity of double-blind placebo-controlled data focused on Enterra therapy (GES therapy), in diabetic (DM) and ID-GP, further prospective clinical trials were conducted to evaluate the efficacy and safety of gastric neurostimulation therapy. The primary objectives were to demonstrate an improvement in weekly vomiting frequency (WVF) when the device was turned ON, relative to when the device was turned OFF, during a blinded 3-month crossover phase. The secondary goals were to demonstrate a reduction in symptom scores and to assess changes in quality of life, gastric emptying, number of days in the hospital, and body mass index in the ID-GP cohort when receiving active stimulation for up to 12 months. Unlike the WAVESS design, the double-blind randomization began after 6 weeks of open-labeled Enterra therapy ( Figs. 3 and 4 ).
The first message from these trials was that the initiation of GES for 6 weeks caused a rapid and significant reduction of symptoms, which was able to be sustained despite a period of up to 3 months with the device OFF. The second important point was related to the observation that even though the double-blind 3-month crossover period showed a nonsignificant reduction in vomiting in the ON versus OFF period, at 12 months with ON stimulation continuing, there was a significant decrease in vomiting symptoms and days of hospitalizations and improvement of quality of life in patients diagnosed with severe medication-unresponsive GP of DM and ID causes.
Since the HDE approval of Enterra therapy for diabetic and ID causes of GP, postsurgical patients with GP were subsequently added to the clinical cohort investigated and a trial of gastric stimulation trial was successful. This condition occurs in up to 10% of patients who undergo vagotomy, either intentional or inadvertent, mostly related to Nissen fundoplications. It has also been reported in up to 50% of patients undergoing intentional vagotomy in the setting of Billroth I and II, antral resection, and Roux-en-Y surgeries.
Many investigators made serious attempts to look for any differences in the way diabetic, ID, and postvagotomy patients will respond to the gastric stimulation therapy. The longest and largest single-center report in the world to date reviewed prospectively generated data based on 10 years of experience, whereby 188 patients with GP were followed up for a mean of 56 months. Overall, the clinical outcomes observed by the investigators were consistent with previous shorter-term studies reported from many centers indicating that there was a >50% symptomatic improvement that can be sustained with GES therapy for as long as 10 years ( Table 1 ).
| GP Symptoms | Diabetic Gastroparetic Patients (n = 111) | Idiopathic Gastroparetic Patients (n = 41) | Postsurgical GP (n = 30) |
|---|---|---|---|
| Baseline | 19.8 ± 5.0 | 18.6 ± 5.8 | 19.1 ± 3.4 |
| Follow-up | 8.7 ± 6.04* | 9.7 ± 6.2* | 10.9 ± 7.6* |
| Improvement (%) | 55 | 47 | 48 |
| >50% reduction (%) | 60 | 49 | 59 |
| Follow-up time (mo) | 54 | 57 | 63 |
| Results of Gastric Emptying | |||
|---|---|---|---|
| Gastric Retention (%) | Diabetic Gastroparetic Patients (n = 75) | Idiopathic Gastroparetic Patients (n = 20) | Postsurgical GP (n = 24) |
| Baseline at 2 h | 70.5 (53.0–86.0)! | 63.0 (43.0–71.0) | 80.5 (68.0–92.0)! |
| Follow-up at 2 h | 68.0 (45.0–84.0) | 60.5 (53.5–78.0) | 65.0 (35.5–86.0)* |
| Baseline at 4 h | 39.5 (21.0–68.0)! | 30.5 (10.0–40.0) | 48.0 (33.0–73.0)! |
| Follow-up at 4 h | 30.0 (9.0–57.0) | 20.5 (6.2–55.5) | 40.0 (4.5–73.0)* |
One of the major findings from that study was that patients with DM and post-surgical GP had a superior (>50%) reduction in their symptom scores than patients with ID-GP (60% vs 59% vs 49%, respectively). In the DM group, the better symptom control was also reflected by a reduction in hemoglobin A1c level from 8.5% to 7.8%, which has implications for overall better morbidity and mortality in patients with DM. The improvement in severity of vomiting makes these patients better candidates for renal and/or pancreas transplant because vomiting prevents reliable absorption of immunosuppressant medications. Most of the studied patients (75%) continued to have similar degrees of delayed GE during the follow-up visits. A comparison of long-term symptom responses among 3 etiologic subgroups (DM, ID, post-vagotomy) showed that the diabetic group responded better than others; hence, the expectation of a therapeutic response based on cause is important for selecting patients to receive GES. One explanation for the limited improvement in patients with ID-GP might be the fact that the ID group consists of a relatively heterogeneous mix of patients and often with more concomitant abdominal pain complaints than seen in other subgroups with GP. It is well known that abdominal pain is the least likely complaint to be improved by GES.
Surgical implantation of gastric electrical stimulation and its parameters
The implantation technique of GES is included in all published manuscripts where patients receive the Enterra therapy system (Model 7425G or Model 3116; Medtronic, Inc Minneapolis, MN) via the surgical, laparotomy, or laparoscopy approach. Two intramuscular leads (Model 4351; Medtronic, Inc) are inserted into the muscularis propria of the stomach using either laparoscopy or laparotomy as previously described. The 2 electrodes are sutured 9 and 10 cm from the pylorus on the greater curvature of the stomach and connected by leads of 35 cm in length to the pulse generator placed subcutaneously in the abdominal wall, usually in the right upper quadrant. The device is programmed to standardized parameters (5 mA, 14 Hz, 330 μs, cycle on 0.1 second, cycle off 5 seconds) using a programmer (Model 7432 or Model 8840, Medtronic, Inc) ( Fig. 5 ).
The programming parameters are usually set as the default at surgery and are reevaluated approximately 3 months after surgery. Also, it is suggested by the manufacturer that the voltage should be adjusted during interrogation of the system, based on impedance (resistance between 2 electrodes) to maintain a 5-mA current. Some investigators proposed specially designed algorhythms ; but because of the lack of any controlled trials, these are presented as suggestions only for clinically nonresponding patients. Over time and specifically during a 10-year observation, the current is increased approximately 20% to 30% during intermittent interrogations based on a perception by the clinician that symptoms are not optimally controlled and more voltage might help. This practice is not based on any supportive evidence.
Adverse Events
Based on the experiences of many investigators, there is a consensus on what adverse events may occur: (1) dislodgement of GES electrodes (trauma, tingling/braiding of the leads), (2) penetration of electrodes through the gastric mucosa, (3) lead insulation damage, (4) lead or neurostimulator erosion or migration, and (5) bowel obstruction. The main complication is the 6% risk of infection at the pulse generator site. This complication is a little more likely to occur in the immediate postoperative setting but can also occur at any time, particularly in patients with diabetes, or secondary to trauma, injuries and falls, or it could be related to systemic infections. The major concern is related to comorbidities, especially in the diabetic group of patients.
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