Physical Address
304 North Cardinal St.
Dorchester Center, MA 02124
Emerging Gastric Stimulation for Dysmotility Disorder and Obesity
Introduction
Gastrointestinal motility disorders (GMDs) are common along the gut and are one of major causes of functional gastrointestinal (GI) diseases that affect more than 20% of general population and account for more than 40% of patients seen in GI clinic ( ). Typical diseases associated with GMD include gastroesophageal reflux, achalysia, functional dyspepsia, gastroparesis, intestinal pseudo-obstruction, postoperative ileus, irritable bowel syndrome, fecal incontinence, and constipation.
The normal physiological function of the stomach is to accommodate ingested food, store it, and then empty it at an appropriate rate into the duodenum for absorption. There are two major motility actions in the stomach: accommodation reflex action to relax the proximal stomach to accommodate ingested food and antegradely propagated, antral contractions (or peristalsis) to push the ingested food through the pylorus into the duodenum. The relaxation of the proximal stomach is achieved through the activation of the vagus nerve and release of the inhibitory neurotransmitter, nitric oxide. Antral contractions are generated by the activation of the vagal nerve and release of acetylcholine (AcH). The rhythm and propagation of antral contractions are determined by the basic rhythm of the stomach called slow-wave or pace-making activity (3 waves/min in humans).
Currently, treatment options for GMDs have been very limited. Prokinetics were developed to enhance gastric motility, such as cisapride, domperidone, erythromycin, metoclopramide, tegaserod, and prucalopride ( ). However, due to cardiac toxicity or side effects, most of these medications are not available in the United States. Although some of them are available, such as erythromycin, they often do not produce adequate symptom relief that is possibly due to their aggregating effect on gastric accommodation: most of the prokinetic medications impairs gastric accommodation ( ). Accordingly, there is an urgent need for the development of novel therapies for GMDs.
The myoelectrical and neural basis of gastric electrical stimulation (GES) is to modulate the enteric nervous system and/or autonomic functions, or directly modulate myoelectrical rhythm of the stomach. Previous studies have shown that GES can be programmed to alter autonomic functions and thus change gastric motility functions. It is well-known that enhancement or activation of vagal activity improves gastric motility, whereas activation of sympathetic activity inhibits gastric motility. Studies have also been shown that GES with appropriate settings of stimulation parameters is able to alter gastric slow waves or pace-making activities ( ). By normalizing or enhancing gastric slow waves, GES improves gastric motility. Whereas, by impairing gastric slow waves, GES inhibits gastric motility or gastric tone ( ).
In addition to gastric dysmotility, obesity is another disease that is to be addressed with GES in this chapter. Obesity is one of the most prevalent public health problems worldwide. About 1.7 billion individuals in the world are now estimated to be obese (body mass index or BMI ≥ 30 kg/m 2 ) and approximately two-thirds of general population in the United States are overweight and of those, about half are obese. The annual medical cost for the treatment of obesity in the United States is estimated to be $147 billion in 2008 ( ). The analysis of five prospective cohort studies suggested that between 275,000 and 325,000 Americans die each year from obesity-related diseases ( ). Obesity is also associated with an increased prevalence of socioeconomic hardship due to a higher rate of disability, early retirement, and widespread discrimination ( ).
The treatment of obesity can be classified into three categories: general measures (diet and exercise), pharmacotherapy, and surgical treatment. Diet and exercise are the first treatment/preventive option for obesity. Although an acceptable weight loss may be achieved with such measures, maintaining weight loss seems to be more difficult, particularly for patients who were treated with caloric restriction. About 50% of patients regain weight within 1 year after treatment and almost all patients regain weight within 5 years ( ). Pharmacotherapy for obesity has been problematic. Various drugs have been developed for the treatment of obesity. These include amphetamine derivatives such as fenfluramine and dexfenfluramine, sibutramine, diethylpropion, mazindol, phentermine, phenylpropanolamine, orlistat, etc. ( ). However, in general, the outcome of medical treatment has been disappointing due to either adverse effects/events (AEs) or a lack of long-term efficacy. Surgical treatment is typically reserved for patients with morbid obesity (BMI > 40) ( ). A number of surgical procedures have been used clinically, including sleeve gastrectomy that restricts food intake, gastric bypass that promotes maldigestion of ingested nutrients, such as Roux-en-Y and biliopancreatic diversion, duodenal switch and gastric banding (called lap-banding if the procedure is done laparoscopically) or adjustable gastric banding ( ). Among these various procedures, Roux-en-Y gastric bypass is the most effective. However, it should be noted that the gastric bypass procedure as well as other surgical procedures have a number of drawbacks: (1) it alters the anatomy of the gut, is irreversible and therefore poses a significant problem in patients who fail to reduce body weight; (2) it involves morbidity and mortality; the mortality rate is about 0.2%–2% and the rate of serious adverse events (SAEs) is about 5%–8% ( ); (3) it impairs micronutrient absorption and results in metabolic and nutritional complications. Nutrient deficiencies following gastric bypass include protein-calorie malnutrition, fat malabsorption, iron deficiency, vitamin B 12 deficiency, folate deficiency, riboflavin deficiency, and calcium deficiency ( ).
GES, developed for the treatment of obesity, can be classified into three categories based on their effects: neural GES (nGES) is supposed to act on nerves to induce satiety, excitatory GES (eGES) to enhance gastric motility, and inhibitory GES (iGES) to inhibit gastric motility to enhance satiety or reduce food intake. Compared with the surgical therapies, GES is much less invasive and, most importantly, reversible and adjustable over time. During GES clinical studies, patients, physicians, and surgeons have shown great enthusiasm toward GES. However, controlled studies of GES for obesity, using weight loss as their primary endpoint, have failed to reach significance. The aim of this chapter is to critically review various methods of GES that have been applied for treating obesity and provide insight into a viable GES therapy for obesity.
Gastric Motility and Food Intake
Gastric Myoelectrical Activity and Motility
In the stomach, there is myoelectrical activity that is composed of slow waves and spikes ( ). The slow wave is a rhythmic myoelectrical event that controls the frequency and propagation of peristalsis. The gastric slow wave originates in the proximal stomach (about one-third proximal) and propagates toward the pylorus with increasing amplitude and velocity. The frequency of gastric slow waves is about 3 cycles/min (cpm) in healthy humans and 5 cpm in dogs. In humans, the gastric slow wave is called tachygastria if its frequency is above 4 cpm and bradygastria if its frequency is below 2 cpm. Spikes are superimposed on slow waves. When a slow wave is superimposed with spikes, a lumen-occluding contraction occurs. Otherwise, the slow wave does not produce a lumen-occluding contraction.
In the postprandial state, every slow wave is superimposed with spikes. That is, the stomach contracts at the frequency of the slow wave, which is 3 cpm in humans. The contraction is antegradely propagated from the proximal stomach to the pylorus. If the pylorus is closed, the peristalsis acts to grind the ingested food. If the pylorus is open, the peristalsis pushes the gastric chyme down to the duodenum, an action called gastric emptying. Typically, the stomach is 50% empty 2 h after a meal and more than 90% empty 4 h after the meal.
In the fasting state (about 4 h after a meal), the gastric contraction has a unique pattern and is called a migrating motor complex (MMC) ( ). The MMC migrates from the distal stomach to the distal small intestine and repeats approximately every 2 h. Each cycle of the MMC is classified into three phases: phase I, with almost no contractions; phase II, with intermittent contractions; and phase III, rhythmic contractions at maximum frequency. The function of the fasting MMC is to clear the gut from the stomach to the ileum of substance, especially substances that are nondigestible.
GES may alter gastric slow waves and therefore change gastric motility. For example, GES with appropriate pulse width (long pulses) at a frequency slightly higher than the frequency of intrinsic slow waves may pace the stomach to electrically oscillate at a higher rhythm and may also normalize dysrhythmic slow waves and thus improve gastric motility ( ); this could be a method for treating gastric dysmotility. On the other hand, GES with appropriate pulse width at a tachygastrial frequency may induce tachygastria and dysrhythmia and thus impair gastric motility ( ); this could be a method for treating obesity by slowing digestive process.
Roles of Gastric Motility in Food Intake and Digestion
The stomach has two major functions: (1) to accommodate ingested food, serving as a reservoir and (2) to propel ingested food into the small intestine, functioning as pump. Upon ingestion of food, the stomach is relaxed to a certain degree to accommodate food, a process called accommodation reflex that is mediated through vagal activation and release of nitric oxide. If the volume of the ingested food is beyond the gastric accommodation, the pressure of the stomach will build up, leading to the sensation of bloating and fullness, and termination of food intake, a process defined as satiation in a recent publication by . A reduced gastric accommodation leads to a reduction in food intake and/or enhanced postprandial fullness/bloating. In patients with functional dyspepsia, impaired (or reduced) gastric accommodation has been reported to be correlated with weight loss ( ). In patients with obesity, one would expect a large stomach or increased gastric accommodation; however, a review of the published studies in the literature does not support such a concept, i.e., statistically there is no difference in the size of the stomach or gastric accommodation between lean and obese subjects ( ). However, a number of studies have demonstrated that gastric distention induced by an intragastric balloon leads to a reduction in food intake or early satiation ( ). Despite the fact that a meta-analysis of 15 published clinical studies concluded that balloon distention is effective in reducing weight within a period of about 6 months, its long-term efficacy could not be established ( ). The long-term failure of this method is attributed to the adaptation of the stomach. After a sufficiently long-term use of the intragastric balloon, the size of the stomach is increased to accommodation the balloon and therefore the intragastric balloon does not help in building up higher gastric pressure upon food intake and its effect on satiation is reduced.
The second function of the stomach is to empty the ingested food to the small intestine, a process called gastric emptying. The speed of gastric emptying is believed to be associated with satiety or appetite that determines the amount of food intake of a subsequent meal ( ). The emptying of the stomach is accomplished by peristaltic contractions of the distal stomach. Impairment in antral contractions delays gastric emptying, leading to a motility disorder called gastroparesis (delayed emptying of solid). In patients with gastroparesis, the aim of GES is to enhance gastric contractions and accelerate gastric emptying. For treating obesity, however, the aim of GES is to appropriately inhibit antral contractions and delay gastric emptying, as a delay in gastric emptying is known to reduce intake of a subsequent meal or postponement of the subsequent meal. A number of studies have investigated the difference in gastric emptying between lean and obese subjects. Controversial results have been reported with some showing rapid emptying, some showing slower emptying and some others showing no changes ( ). However, intervention-induced delay in emptying has been linked to increased satiety, reduced food intake and/or weight loss. One good example of this is the use of antiobesity medications. A number of these drugs have been shown to delay gastric emptying associated with increased satiety or weight loss. These include sibutramine ( ), romonabant ( ) and oleoylethanolamide ( ). Studies performed in our lab have shown the similar link between intervention-induced delay in gastric emptying and increased satiety. GES with appropriate parameters/configurations has been shown to delay gastric emptying in dogs and humans, associated with reduced intake of food or water as well as weight loss ( ).
You're Reading a Preview
Become a Clinical Tree membership for Full access and enjoy Unlimited articles
If you are a member. Log in here