Gastric electrical stimulation for gastroparesis

Key points

• (1)

  Gastric electrical stimulation (GES) is a therapy providing neurostimulation via two electrodes implanted in the gastric smooth muscle.

• (2)

  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.

• (3)

  The most important effect of GES is its powerful antiemetic mechanism, which is beneficial when utilized as therapy for drug-refractory gastroparetic patients.

• (4)

  GES does not address, nor is it indicated for the reduction of abdominal pain or discomfort in gastroparetic (GP) patients.

• (5)

  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.

Introduction

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). https://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:

• 1)

  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.”

• 2)

  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 ).