Gastric electrical stimulation (GES) is a therapy providing neurostimulation via two electrodes implanted in the gastric smooth muscle.
The predominant mechanism of action of GES is by central control of nausea and vomiting by affecting the chemoreceptor trigger zone, and it also enhances vagal nerve function.
The most important effect of GES is its powerful antiemetic mechanism, which is beneficial when utilized as therapy for drug-refractory gastroparetic patients.
GES does not address, nor is it indicated for the reduction of abdominal pain or discomfort in gastroparetic (GP) patients.
GES in some patients improves gastric emptying, but its mechanism of action is not explained by improving gastric emptying or affecting the gastric electrical rhythm of gastroparetic patients, regardless of GP etiology.
In the clinical world of treating severe symptoms of drug-refractory gastroparesis, there are not many pharmacological 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 problems with tachyphylaxis, provide limited options for the growing number of gastroparetic patients around the world .
There is a need to consider new therapeutic options for the 30% or more of the gastroparetic population, whose symptoms are not addressed by existing drugs or investigational agents. Unfortunately, the unpredictability of drug absorption in gastroparetics who also frequently vomit, poses further challenges. In addition, implementing nutritional support modalities, optimizing diabetic control, as well as improving lifestyle modifications are all required to maximize therapy.
History and progression of the gastric electrical stimulation concept
Searching the internet for the first published papers on electrical pacemakers utilized in gastroenterology uncovered the article published in 1963 when experimental development of gastrointestinal pacing was introduced for the first time as a promising therapeutic option for paralytic ileus . Only 18 papers were included as references, and all of them were crucial in building a foundation for the hypothesis to suggest a role for electrical stimulation in the GI tract . This body of work encouraged others to examine this innovative approach to control symptoms of dysmotility disorders. Kelly and Laforce at Mayo Clinic induced anterograde and retrograde conduction of slow waves in canines with gastric stimulation in 1972 . Therefore, Keith Kelly, the distinguished Mayo Clinic surgeon is often recognized as the “Father of the clinical application of gastric pacing,” and deserves recognition and acknowledgment for his early initiatives towards electrical activities of the gut and his contributions to establishing a great interest in GI electrophysiology . The next reasonable step was to investigate the relationship of myoelectrical activity to gastric contractility in order to establish feasible parameters of electrical stimulation of the gastrointestinal tract in humans. This challenge of understanding how gastric peristalsis was propagated – and how it was possible to regulate an electrical rhythm while recreating a physiological gastric rate of 3 cycles/minute of slow waves – became the major focus of clinical investigations to control symptoms in gastroparetic patients ( Figs. 30.1 and 30.2 ).
Due to increasing knowledge of gastric electrophysiology, some basic science and clinical scientists such as Bellahsene and McCallum in 1992, and Familoni in 1997 reported increased gastric emptying and improved peristalsis in canines treated with gastric pacing .
Temporary external non-implantable devices were used by McCallum and colleagues at the University of Virginia in the early 1990s to “pace” the stomach by entraining the rhythm via utilization of high-energy, long pulse (300 ms) stimulations with the anticipation to induce electromechanical coupling, and in turn to initiate smooth muscle contractions . Results of these studies were very promising with improvement in gastric emptying and symptoms, but due to the possibility to develop infections at the site, the study was limited to 3 months total duration. However, this therapy of “true gastric pacing” pursued by McCallum, Sarosiek, Lin and Chen, provided evidence for converting tachygastrias and irregular electrical rhythms and for entraining the stomach, and improving gastric emptying . ( Figs. 30.3–30.6 ). Long term pacing in dogs was also achieved by Chen and Ross and energy challenges were also overcome .
The ability to commercialize this concept of “true gastric pacing” was not pursued by technology companies who saw this therapy as only helping the small market of gastroparesis patients . Their “business” analysis was that there were approximately 5 million gastroparetics in the country of whom perhaps only 30% would require this “pacing” treatment, and hence it was not a great business investment and so “true gastric pacing” remains not commercially available.
A major contribution in the clinical utilization of temporary and permanent GES systems implanted in humans was introduced by Abell on behalf of the Global Enteric Multicenter Study (GEMS) study group in 1996, when safety and feasibility of GES, as well as improvement of GP symptoms and nutritional parameters were recorded in 12 drug-refractory gastroparetic patients .
Other clinical trials initiated by few major academic centers followed this path, and provided data of their investigations . The Worldwide Anti-Vomiting Electrical Stimulation Study (WAVESS) and the Compassionate Use of Electrical Stimulation Study (CUESS) were conducted under the sponsorship of the Medtronic Corporation, the manufacturer of GES between 1998 and 2000. This investigation provided important scientific data to apply for FDA approval of the system. In a nutshell, refractory diabetic and idiopathic GP patients were randomized to GES ON or OFF at the time of surgery and then crossed over to the other treatment arm after a month. Data analyses showed that with all patients turned ON (first or second month) symptoms significantly improved compared to the sham group. Overall, diabetics were more responsive than idiopathics. After 12 months of all patients being “turned ON,” symptoms were significantly reduced compared to baseline. GES received Humanitarian Use Device (HUD) designation in September of 1999 (HUD#990014). Unfortunately, due to the lack of positive objective measurements, GES marketed as The Enterra Therapy System (Medtronic, Inc., Minneapolis, MN), was only approved in March of 2000 as a Class III medical device under the Humanitarian Device Exemption™ (HDE) application (H990014). www.fda.gov/media/107336/download . It was indicated for treatment of chronic drug-refractory nausea and vomiting symptoms of diabetic and idiopathic gastroparesis. This FDA status of GES by the HDE restricts sales to <4000 devices/year, and it also requires approval of the Institutional Review Board (IRB) from the medical center providing such therapy.
Different methods of stimulation
The principles of cardiac pacing have provided a scientific foundation to translate a similar concept into gastric stimulation in order to increase the energy so that slow waves can be entrained, and thus control gastric dysrhythmias.
Two major approaches of GES have been recognized:
Long-pulse with high energy (milliseconds) and a physiologic frequency of stimulation (3 cycles/min) using single or multichannel electrodes. Such parameters entrain slow waves, control dysrhythmias, and in turn improves the rate of gastric emptying and GP symptoms . Such therapies are recognized as a temporary and external “pacemaker.”
Short-pulse with low energy (microseconds) and frequencies higher than physiologic (12 cycles/min) called “neurostimulation” may improve nausea and vomiting in GP patients without a significant acceleration in gastric emptying, and does not reverse slow wave dysrhythmias .
Therefore, it is accepted that the clinical outcomes and objective results of improved gastric emptying are strictly depended on the electrical parameters programmed as a GES-specific treatment approach ( Fig. 30.7 ).
“Gastric Pacing” in clinical investigations
A long or high energy pulse width of 10–600 ms and maximal frequency of 4.3 cycles per minutes defines “pacing parameters” which have been shown to result in entrainment of gastric slow waves, reduce gastric dysrhythmias, and improve gastric emptying . Besides these objective results initially developed in dog models, utilization of such parameters were able to alleviate symptoms in subsequent gastroparesis in human studies .
A pioneering clinical trial by McCallum et al. reported the use of an external “pacemaker” device, which was introduced during a surgical procedure with implantation of an internal neurostimulation device . More details about that study are included in the Clinical Studies section of this chapter.
Previously published observations presented similar outcomes when multi-channel pacing of the stomach was investigated in dog models .
As formerly summarized, there are number of reasons why there is currently no available FDA-approved long-pulse generating devices on the market ( Fig. 30.8 ).
Utilization of “gastric neurostimulation” in clinical settings
Parameters provided by gastric neurostimulation are based on short pulse stimulation of 330 microseconds, and a frequency 3–4 times higher than the physiologic rate of gastric slow waves. Original reports from canine studies showing reinforcement of gastric contractions and improvement of gastric emptying rates were instrumental in initiating such analyses in humans . Unfortunately, during the design and conduction of numerous clinical trials while introducing GES with high-frequency of 14 Hz and low 330 µsec pulse energy parameters known as Enterra® Therapy, (Medtronic, Inc., Minneapolis, MN) it has been confirmed that Enterra does not affect the basal gastric electrical rhythm and it doesn’t accelerate gastric emptying. GES improves the rate of gastric emptying in a few gastroparetics, but it does not appear to be its mechanism for improving symptoms, as GES does alleviate GP symptoms in most patients, even those who still have delayed emptying of their stomach. Despite trying all possible combinations of the electrical parameters, this is the final conclusion.
Indications for GES
The GES Enterra System was approved in March of 2000 by the FDA as a Humanitarian Use Device for the treatment of patients with chronic, intractable (drug-refractory) nausea and vomiting in idiopathic and diabetic gastroparesis. Based on results of additional studies, it was shown that a post-surgical gastroparetic patients could also benefit from GES if 50% or more of their stomach was still present after a partial gastrectomy . Similarly, post-vagotomy gastroparetics who underwent surgical fundoplication could be considered suitable candidates. The literature also describes symptomatic GP patients who are awaiting or are post-renal or post-pancreatic transplantation as potential candidates to receive GES Enterra therapy. The goal here is to stop the vomiting which will allow them to absorb the antirejection medications and preserve their transplanted organs.
Screening criteria for GES candidates and clinical assessment during the decision-making process include a few major points suggested by the FDA. One recommendation is that GP patients must be presenting with symptoms for more than 1 year and must not have responded to or have been intolerant to prokinetic and antiemetic medications. Patients should also have documented delayed gastric emptying (retention of >60% at 2 hour and/or >10% at 4 hour) based on the “gold standard” nuclear medicine 4 hour scintigraphy imaging test of a technetium-99m–labeled, 255 kcal solid an egg-white meal (Egg Beaters® or generic equivalent) . Additionally, a patient’s nutritional status has to be adequate, sometimes requiring oral caloric supplements, while the more severe subset may need enteral or total parenteral nutrition such as TPN and/or gastro-jejunal tube (J-tube) feeding in the setting of significant weight loss or other consequences of nutritional deficiency. Other important subjective measures that play an important role in patient selection besides nausea and vomiting include impairment of mental and physical aspects of quality of life and social dysfunction .
All surgically and anesthesia relevant criteria, as well as consideration of whether future need for frequent screening with magnetic resonance imaging (MRI) will be clinically necessary must be evaluated and scrutinized in order not to jeopardize patients’ comorbidities.
Patients are not candidates for GES if they are pregnant, undergoing peritoneal dialysis (hemodialysis is acceptable), suffer from chemical dependency (opiate addiction), or if they are diagnosed with rumination syndrome, an eating disorder, or cyclic vomiting syndrome. Patients with a limited lifespan based on a diagnosis of cancer or paraneoplastic syndrome should also be excluded from the list of suitable candidates for implantation of GES. On rare occasions, occupations requiring physical contact and combat where the pulse generator will be traumatized is another contraindication.
The evaluation process and all logistic preparations for GES therapy can be time-consuming and requires a multidisciplinary team approach with outstanding cooperation and understanding by all team members – including patients and family members. Such a well-established and functioning team should involve not only a GI motility clinician but also research personnel, a surgeon and an endocrinologist. The best outcomes, however, are achieved when dietitians, psychologists or psychiatrists, pain specialists, diabetic educators, Medtronic’s representatives, social workers and hospital administration all work collectively in a “team” fashion. The best scenario is when such a team is headed up by a gastroenterologist with expertise in gastroparesis committed to the long-term follow up of the patient.
Components of the Enterra therapy system
The implantable, programmable and permanent GES System includes 3 major components: a small battery-powered (non-rechargeable) Neurostimulator which serves as a pulse generator (Medtronic Enterra Therapy Model 3116 – in the past) and Model 37800 Implantable Neurostimulator (INS) (currently used device), and two intramuscular 35 cm long leads (Medtronic Model 4351) with a 1-cm long electrode on the end of the wire ( Fig. 30.9 ).
The size of the GES pulse generator is: Height 2.2” (55 mm); Width 2.4” (60 mm); Depth 0.4” (10 mm), and weight 45 g (1.6 oz).
This System is interrogated with a handheld external programmer (N’Vision Clinician Programmer Medtronic Model 8840) – by either a physician or designated healthcare provider – to noninvasively adjust parameters identified during examination of the integrity of Enterra Therapy specific to each patient and based on the patient’s clinical presentation. This programmer also assesses the neurostimulator’s battery status and troubleshooting’s the device during any follow up clinic visits and/or future surgeries ( Fig. 30.10 ).
Enterra II contains an accurate End-of-Service battery capacity indicator, which transfers such information to the programmer, and is available for the clinician to assess the current use of the battery. It also shows how long the therapy could last without jeopardizing loss of energy from the battery, and in turn to be able to schedule surgical procedures for replacement of the device. In cases where the patient lives in a town without a physician with Enterra expertise, then a Medtronic representative may be available to assist a local doctor with such function during visit of the patient.
Surgical implantation of gastric electrical stimulation
The device is placed surgically by either robotic-assisted laparoscopy or through an open laparotomy approach. Two permanent electrodes are placed on the greater curvature of the stomach, 9 and 10 cm proximal to the pylorus. The electrodes are secured into the muscularis propria layer of the stomach. Intra-operative upper endoscopy is performed to ensure that there is no penetration of the electrodes into the lumen. The other ends of the electrodes are connected to the pulse generator, which is then placed and secured by sutures in a subcutaneous pocket above the abdominal wall fascia in either the right or left upper mid-quadrants of the abdomen. The pocket is generously irrigated with an antibiotic-containing solution and the patient receives intravenous antibiotics, both before and two days post-surgery. GES therapy could be preferably initiated in the operating room or later on, when the patient, is able to tolerate a soft food diet but before discharge from the hospital ( Fig. 30.11 ).
More information related to the surgical implantation of GES system are included in chapter 31 of this book.
Interrogation of the GES system
The load impedance is tested during surgery using the programmer to verify electrical integrity of the implanted system, both with an open and closed neurostimulator pocket. The pulse generator is initially programmed to standardized/default parameters: pulse width, 330 μs (microseconds); (current) amplitude, 5 mA; rate 14 Hz; cycle ON: 0.1 s; cycle OFF: 5.0 s. It is usually activated in the operating room or within 48 hours after surgery. At various intervals of outpatient follow-up after implantation, the pulse generating device can be interrogated. We typically see the following ranges: impedance or resistance between 2 electrodes is from 200 to 800 ohms, voltage (amplitude) between 1.0 and 4.0 volts. A post-operative abdominal x-ray (both AP and lateral) should be performed to document the original location of the electrodes. Such documentation in the record is necessary and helpful in the future when identifying possible repositioning (dislodgment) of the electrode(s). If the impedance exceeds 800 ohms on interrogation, this may suggest either possible dislodgement or erosion of one of the electrodes into the gastric lumen ( Figs. 30.12 and 30.13 ).