Gastric Electrical Stimulation: A Useful Option for Gastroparesis
By R.W. McCallum, MD
Professor, Department of Medicine, University of Kansas, Kansas City
Gastroparesis is a disorder of gastric motility that typically requires prokinetics combined with antiemetic agents. Prokinetic agents stimulate gastric motility and coordinate gastric-duodenal motor activity. They include metoclopramide, erythromycin, cisapride, domperidone and tegaserod. However, several issues have curtailed the already limited medical therapy menu including: (i) removal of cisapride from the U.S. market in 2000; (ii) restricted availability of domperidone in the U.S.; (iii) side effects related to metoclopramide and; (iv) a recent article indicating that erythromycin prolongs cardiac depolarization and is associated with torsades de pointes and possible sudden death (1, 2). For patients who are refractory to available medications or need consideration for enteral/parenteral feeding, gastric electrical stimulation (GES) has shown its advantages over medications in decreasing GI symptoms and enhancing health-related quality of life (2, 3).
Gastric Electrical Stimulation (GES) for Treatment of Gastroparesis
What is GES?
GES consists of a series of electric pulses, usually in a rectangular shape, with a constant current or a constant voltage. To date, there have been basically two methods of GES for treatment of gastroparesis: (i) high energy/low frequency stimulation, known as gastric pacing, which utilizes long pulse width in the order of milliseconds (ms) and stimulation frequency in the vicinity of the physiologic frequency of the gastric slow wave; or (ii) low energy/high frequency stimulation, known as neurostimulation, which uses short pulse width in the order of a few hundred microseconds (ms) or trains of short pulses and stimulation frequency much higher than the physiologic frequency of the gastric slow wave. Both methods have benefited the symptoms of gastroparesis (3). Improvements in gastric emptying as well as symptoms have only been achieved by pacing the stomach at its intrinsic slow wave frequency with long pulses (300 ms) (4). However, there are no implantable devices available in the market capable of generating long pulses. On the other hand, high frequency and low energy stimulation (short pulse of 330 µs) is employed by the FDA approved device (Enterra TM Therapy, Medtronic, Minneapolis) under Humanitarian Device Exemption (HDE) (5) and provided as a Human Use Device (HUD), thus requiring an institutional Review Board (IRB) approval, with financial coverage provided by Medicare and all insurance carriers (6). The following discussion will focus on Enterra Therapy.
Enterra TherapyTM
The implantable GES system for Enterra Therapy consists of a pair of electrodes sutured to the muscular layer of the greater curvature of the stomach and connected to a pulse generator, called the neurostimulator, implanted in a subcutaneous pocket in the abdominal wall. The pulse generator can be activated and programmed externally. It is a permanently implantable device with a battery life expectation of six to eight years and the system can be implanted by laparotomy or laparoscopy. The pulse-generator contains an electronic circuit that controls the stimulation frequency and strength. There are situations where those parameters can be adjusted to fit a patient’s individual needs, such as increasing voltage if resistance or impedance increases, or increasing current if the patient is not sustaining an overall improvement of symptoms. This technique of interrogation involves placing the programmer on the skin over the implant site and, in seconds, the investigator can identify the strength and timing of the stimulation pulse and continue the program or alter it.
How does GES work?
The operation of the device is based on the following theories:
1. Activation of the central mechanisms for nausea and vomiting control related to afferent nerves being stimulated by the constant high frequency current in the stomach wall.
2. Enhanced relaxation of the fundus of the stomach by this current thus providing better accommodation and decreased sensitivity to distention.
3. Augmentation of the amplitude of gastric slow wave after eating.
4. Increase in cholinergic function and decreased sympathetic function.
5. Small and unpredictable improvements in gastric emptying (13-15).
Who are the best candidates?
Candidates for Enterra Therapy include patients with documented gastroparesis, diabetic or idiopathic, chronic, not responding to available drug therapy (5). Particular consideration should be given to patients who are being evaluated for enteral/parenteral nutrition because of the risk and expense associated with these types of nutrition support, and the possibility that GES might preclude the need for such intervention.
The patient-selection criteria currently adopted at our center have evolved since initial FDA approval for Enterra (7). For example, patients with a gastric resection of less than 50 percent or post-vagotomy (typically occurring during fundoplication) are included. Also, post-renal or -pancreas transplants are accepted. Gastric retention criteria are now ≥50 percent at two hours and ≥6 percent at four hours utilizing the four-hour egg beater meal as the gold standard. Symptom severity, quality of life, level of function and family assessment are some of the important subjective measures that may play a role in patient-selection criteria. Objective measures include weight loss, requirements for nutritional support, TPN and G-j tubes, as well as the number of ER visits and hospitalizations. Patients are excluded if they are pregnant, suffering from chemical dependency, undergoing peritoneal dialysis or have a limited life-span based on diagnosis of cancer.
The goals of GES include a significant improvement in nausea and vomiting within six months of device placement and elimination of other nutritional support, such as j-tube feeding and TPN, as well as significant decreases in medical costs related to hospitalizations and ER visits. In addition, patients with diabetic gastroparesis should experience a decrease in HbA1c, with an ability to tolerate oral medications, and can become candidates for renal and pancreas transplants. Clinically relevant symptom improvement has been defined as >50 percent improvement after GES. Published data indicates that approximately 75 percent of patients achieve this (3, 7-9). Of the remaining 25 percent, a subpopulation has no improvement in symptoms or the number of the hospitalization days. This subgroup, which is approximately 5 percent of all implanted patients in our series, ultimately requires total gastrectomy.
Predictors for Post-gastric Electrical Stimulation Outcome
Based on a retrospective analysis of 87 gastroparetic patients, the best symptom improvement achieved by GES therapy in refractory gastroparesis is in diabetics (21 percent treatment failure rate, i.e. <25 percent symptom improvement) and postsurgical patients (16 percent failure), while the worst results are in idiopathics (35 percent failure rate) (10). Negative indicators include the pre-operative role and dose level of the narcotics, the relationship of abdominal pain as a preceding event before vomiting, a history of migraine headaches and lack of appreciation of another explanation for the vomiting, such as the role of the menstrual cycle, in worsening symptoms, anorexia nervosa, rumination syndrome and cyclic vomiting syndrome. Also, marked gastric slow wave dysrythmias as measured by the electrogastrogram are present in up to one-third of patients and are a marker for depletion of interstitial cells of Cajal, the blue print for gastric motor function (11).
What are some complications?
It has been shown that 4 percent of the implanted devices required removal due to infection at the pulse generator pocket site, pain, battery dysfunction or inability to interrogate, and finally, detachment and/or displacement of the device or penetration of an electrode through the stomach wall into the lumen (6-9). Both x-ray findings and/or increase in the impedance above 1,000 ohms may indicate these types of complications. If the patient’s symptom response is not being sustained, we recommend considering ruling out any technical complications. The usual precautions, which patients are informed about, include turning off the device during an MRI study and cardioversion, the use of cautery and, of course, informing security at airport screening.
Future Directions
As previously mentioned, up to 35 percent of the recipients of the GES device (depending on etiology) may have limited or no clinical response and continue to present a clinical challenge. Therefore, it is imperative to explore this technology further. One goal is multi-point electrical stimulation, which will integrate and synchronize both low and high energy stimulation from electrodes at two or more sites located from the proximal to distal stomach. The goal is to achieve acceleration in gastric emptying as well as symptom control. Battery life is going to be a challenge for such a device so perhaps the high energy stimulation would be reserved for pre- and post-prandial periods and low energy for prolonged fasting and at night.
References
1. Ray WA, Murray KT, Meredith S, Narasimhulu SS, Hall K, Stein C. Oral erythromycin and the risk of sudden death from cardiac causes. N Engl J Med 2004;351(11):1089-96.
2. Lin Z, Forster J, Sariosek I, McCallum RW. Treatment of Gastroparesis with Electrical Stimulation. Dig Dis Sci 2003;48(5):837-48.
3. Cutts TF, Luo J, Starkebaum W, Rashed H, Abell TL. Is gastric electrical stimulation superior to standard pharmacologic therapy in improving GI symptoms, healthcare resources, and long-term healthcare benefits? Neuogastroenterol Motil 2005;17:35-43.
4. McCallum RW, Chen JDZ, Lin ZY, Schirmer BD, Williams RD, Ross RA. Gastric pacing improves emptying and symptoms in patients with gastroparesis. Gastroenterology 1998;114: 456-61.
5. US Food and Drug Administration. H990014 - EnterraTM Therapy System (formerly named Gastric Electrical Stimulation (GES) system). Issued March 31, 2000. Available at: http://www.fda.gov/cdrh/ode/H990014sum.html.
6. Namin F, Lin Z, Sarosiek I, McCallum RW. Gastric electrical stimulation: Who are the best candidates and what are the results? Practical Gastroenterology Sept. 2005:23-38.
7. McCallum RW, Lin ZY, Sarosiek I and Forster J. Clinical response to gastric electrical stimulation in patients with postsurgical gastroparesis. Clinical Gastroenterology and Hepatology 2005;3:49-54.
8. Abell T, McCallum RW, Hocking M, Koch K, Abrahamssion H, LeBlang I, Lindberg G, Konturek J, Nowak T, Quigley EMM, Tougas G, Starkebaum W. Gastric electrical stimulation for medically refractory gastroparesis. Gastroenterology 2003;125:421-8.
9. Lin Z, Sarosiek, Forster J and McCallum RW. Symptom response, long-term outcomes and adverse events beyond three years of high-frequency gastric electrical stimulation for gastroparesis. Neurogastroenterol Motil 2006;18:18-27.
10. Lin Z, Sarosiek I, Forster J, McCallum. Predictors of symptom non-responders to high-frequency gastric electrical stimulation for refractory gastroparesis (abstract). Gastroenterology 2006;130(4, Suppl 2):A-601.
11. Forster J, Damjanov I, Lin Z, Sarosiek I, Wetzel P, McCallum RW. Absence of interstitial cells of Cajal in patients with gastroparesis and correlation with clinical findings. J Gastrointestinal Surgery 2005;9:102-8.
12. McCallum RW, Lin Z, Sarosiek I, Forster J. Is high-frequency electrical stimulation effective in patients with chronic functional nausea and vomiting and a normal gastric emptying. Gastroenterology 2006;130(4, Suppl 2):A-511.
13. Luo J, Rashed H, Eaton P et al. Long-term treatment of gastric electrical stimulation is associated with autonomic and enteric nervous system changes (abstract). Dig Dis Sci 2000; 45:1244.
14. Tach J, Coulie B, Van Cutsem E, Ryden J, Janssens KU. The influence of gastric electrical stimulation on proximal gastric motor and sensory function in severe idiopathic gastroparesis (abstract). Gastroenterology 1999; 116:G4733.
15. Lin Z, Dusing RW, Collins ZS, McMillin C, Cocjin J, Sarosiek I, McCallum RW. Mechanisms of high-frequency electrical stimulation of the stomach in gastroparesis patients (abstract). Neurogastroenterol Motil 2005;17(4):626.