Richard W. McCallum, MD and Sabu J. George, MD, Division of Gastroenterology and Hepatology, University of Kansas Medical Center
The following article overlaps much of Dr. McCallum’s presentation at the 17th Annual Oley Consumer/Clinician Conference held this summer in Buena Park, CA. A videotape of his full presentation is now available from Oley’s Videotape Library; simply complete the form inserted in this issue. Many thanks to Dr. McCallum for speaking at the conference and authoring this article. For more information on this topic, internet fans may want to visit some websites dedicated to gastroparesis patients; links to these and other helpful sites can be found on Oley’s website at www.oley.org/links.
Gastroparesis is a syndrome characterized by the impaired transit of food from the stomach to the duodenum in the absence of mechanical obstruction. Although several conditions can contribute to impaired gastric motility, diabetes mellitus is the most common cause of gastroparesis. Patients may also have idiopathic gastroparesis with no clearly identifiable cause; up to one-third of these patients have viral-induced gastroparesis. Patients who undergo gastric surgery may develop gastroparesis, especially those who have had preoperative gastric outlet obstruction as a complication of peptic ulcer disease. Other GI surgeries, rheumatologic disorders and neurological disorders, can all contribute to delayed gastric emptying, as can abdominal malignancies. Patients with pseudo-obstruction often have delayed gastric emptying as well.
Symptoms of gastro-paresis may include chronic or intermittent nausea, vomiting, early satiety, abdominal distention after eating, and abdominal pain, which also often follows meals. Acute flares can result in severe vomiting. Morning nausea is an important indicator of gastroparesis. Vomiting may not be a dominant complaint, as the patient may have adjusted his/her diet to include only small amounts of food at a time.
A patient’s medical history may help clarify the cause of gastroparesis. A history of prior ulcer disease or gastric surgery is obviously significant. The patient’s history might also emphasize other medical illnesses and reasons for which the patient may be on medications that contribute to nausea or delayed gastric emptying. These patients are often on numerous medications, and having a physician carefully review the side effects of these drugs can be rewarding.
The details of the nature of the symptoms, particularly the character of the vomitus, associated complaints, the relations to abdominal pain, and the relation to meals, are important. Gastroparesis typically involves vomiting one to three hours after eating, and "old food" from previous meals can even be seen the next morning. The presence of freshly ingested food is suggestive of a mechanical problem, such as a gastric outlet obstruction. Abdominal pain is common in "idiopathic" gastroparesis, and unusual in diabetics.
Patients with viral gastroparesis typically have an abrupt onset of their disease preceded by an acute gastroenteritis-like illness. These patients have a good prognosis, with shorter recovery periods and better quality of life. Patients may be diagnosed with viral gastroparesis when they: are healthy subjects who experienced the acute onset of symptoms typical of a "viral-like" illness; experience persistent symptoms (nausea, vomiting, early satiety, weight loss) for longer than three months; and have no obstruction, metabolic disease, systemic illness, surgery, or use of antimotility medication. Viral serology, can be used too, if it is available.
Gastric Emptying Assessment
Gastric scintigraphy is the best method for diagnosing delayed gastric emptying. A 4-hour test which has the patient eat low-fat egg meals (egg substitute) is standard. Normal ranges for gastric emptying in healthy subjects at 1 hour, 2 hours and 4 hours is 90, 60 and 10 percent, respectively. Gastric retention of greater than 10 percent at 4 hours is indicative of delayed gastric emptying. Unfortunately, many centers use only a 2-hour study to save costs. In a soon-to-be-published multicenter study, we compared 2-hour and 4-hour results in patients suspected of having gastroparesis and showed that limiting the gastric emptying time to 2 hours would have missed 44 percent of patients studied who went on to have delayed gastric emptying at 4 hours (See graph). Thus, while an abnormal result at 2 hours is fairly reliable, and the test may be stopped at that point for patients with abnormal results, the study should be continued for patients with normal results for the full 4 hours.
Management of gastroparesis centers on hydration, dietary manipulation, nutritional supplementation, and pharmacologic therapy after gastroduodenal disease, systemic disease and offending drugs have been excluded. Nutritional support in gastroparesis begins with encouraging smaller-volume, low-fat, low-fiber meals, and if necessary, liquid caloric supplements. Patients are encouraged to drink at least 1 liter of fluids per day in the form of water, fruit juices, or other low-fat drinks. During periods of acute decompensation, intravenous hydration may be necessary. Jejunal feeding tubes may be used at night to supplement daytime feedings and ensure that medications are fully absorbed. These tubes should be placed either by laparoscopy or mini-laparotomy. There is no role for percutaneous endoscopic gastrostomy (PEG) decompression in gastroparesis unless it is accompanied by dilation of the small bowel. Placement of a percutaneous endoscopic jejunostomy (PEJ) is discouraged because in a patient who is frequently vomiting, the PEJ component is consistently regurgitated back into the stomach. Parenteral nutrition should be used only briefly during hospitalization and not encouraged or sustained on an outpatient diagnosed only with gastroparesis, because of the serious complications associated with its use.
Medical therapy has changed in this field because of the withdrawal of cisapride from the US market. With the loss of this agent, metoclopramide has again become the prokinetic of choice. It can coordinate antral duodenal and pyloric muscle function and be a powerful, centrally-acting antiemetic. Approximately 70 percent of patients have no side effects and can tolerate this agent, but its antidopaminergic properties (it may cause Parkinson-like symptoms) remain the major obstacle to its more widespread use. Parenteral, oral and rectal preparations are available; a less appreciated, but very important route of administration, is subcutaneous, to allow for continued absorption despite vomiting, which would lead to unpredictable blood levels if taken orally. Even the most severely symptomatic patients can be stabilized by using a subcutaneous injection of 2 ml, two to four times a day. This can be supplemented orally, until the desired control is achieved. The subcutaneous approach is particularly helpful as an alternative to emergency room visits for hydration and IV metoclopramide, and gives patients the option of fasting or drinking only liquids while gaining symptomatic control with subcutaneous injections. In the IV form, metoclopramide needs to be given every three hours, based on the fact that there is a rapid peak. It is generally well tolerated for two or three days in gastroparetic patients, where there really is no other recourse to break their vomiting cycle. Diphenhydramine hydrochloride (Benadryl) can be used to control side effects.
Erythromycin is the only other prokinetic currently available in the United States. This drug binds to motilin receptors on gastrointestinal tract smooth-muscle membranes, thereby mimicking motilin’s actions. It is more effectively given intravenously than orally, and has decreased efficacy with long-term use. Another potential problem is antimicrobial resistance. Erythromycin is effective in gastroparesis in very low doses of 125-250 mg twice a day, administered in liquid suspension form and can be used in combination with metoclopramide. Reduced dosing lessens the possibility of drug tolerance while maintaining options to increase the dose during symptom exacerbation. Motilin agonists without antimicrobial properties are currently under investigation.
Domperidone is another option that blocks receptors in the central and peripheral nervous systems. The approval of domperidone is not being pursued in the US, but remains the drug of choice in patients who cannot tolerate metoclopramide, and is uniquely suited for patients with Parkinson’s disease who have GI symptoms as a side effect of dopamine-agonist therapy.
Therapy in gastroparesis should be aggressive and extra antiemetic efforts supplied in addition to the prokinetic approach, at least initially, to gain control of symptoms. Nausea is a very severe, debilitating symptom, and antiemetics should be used extensively. Once nausea leads to vomiting, a cycle invariably ensues, resulting in dehydration and hospital admission. Scopolamine patches are often recommended in this situation. Two new drugs, 5-hydroxytryptamine 3 antagonists ondansetron and granisetron, are powerful agents that should be used sparingly because of their cost. The intravenous form is effective when metoclopramide cannot be tolerated.
Another option is the Relief band (Woodside Biomedical, Calsbad, CA), an electronic wrist device that noninvasively stimulates the median nerve by sending electrical impulses of up to 35 mA through two electrodes on the back of the device. The wrist location that the device acts on is coincidentally a well-known acupuncture point referred to as Pericardium 6 or Neiguan point. This device can be a useful adjunct to control nausea when other agents aren’t working or produce undesirable side effects.
Special vigilance should be paid to situations that can thwart medical therapy and result in breakthrough symptoms. For example, hyperglycemic episodes often accompanied by infections, can undermine nausea control. Migraine headaches can provoke symptoms as well, and should be treated with sumatriptan. Cyclic nausea and vomiting occurring abruptly with intervening normal periods can be addressed with combinations of ondansetron, sumatriptan and amitriptyline too. Gastroparesis shows a strong female predominance, and menstrual cycles are important; in the week before menses, when progesterone levels are high, nausea and vomiting can be exacerbated. If this is a predictable event, inhibition of the hormonal milieu by Lupron (TAP Pharmaceuticals, Deerfield, IL) or other gonadotropin-releasing hormones agonists should be considered.
The only data published indicate that over a 5-year-followup, up to 65 percent of gastroparetics required continuous prokinetics therapy, 15 percent were off all prokinetics, and 15 percent required additional nutritional support.
The role of surgery in the treatment of gastroparesis is limited. Surgical jejunostomy tubes can be placed as a definite feeding source past the ligament of Treitz. Total gastrectomy is reserved for intractable weight loss and vomiting in end-stage gastroparesis after all other options have failed. This is usually in the patient who has had a partial gastric resection of either Billroth I or II with or without a Roux-en-Y. Here without an antrum, medical therapies are less successful and bezoar formation is common.
Gastric Electrical Stimulation
Gastric pacing involves using electrical stimulus to activate contraction of smooth muscle, or nausea and vomiting control mechanisms by either: 1) entraining (pacing) at a rate of the intrinsic slow wave by a low-frequency, high-energy method, or 2) using a high-frequency, low-energy stimulation to achieve symptomatic relief. In a study with dogs, gastric emptying increased with low-frequency, high-energy gastric stimulation. Electrical stimulation was also shown to induce gastric emptying and increase the motility index in dogs, if stimulated at frequencies higher than the basal rate.
High Energy; Low Frequency Method
External gastric stimulation with a low-frequency, high-energy method has yielded both significant improvement in symptoms of gastroparesis and acceleration of gastric emptying times of a solid meal into the normal range in nine patients with refractory diabetic or idiopathic gastroparesis. These devices had 4 pairs of pacing wires that were placed on the outer surface of the stomach, along the bottom edge, at an interval of 4 cm., beginning in the midbody. The nearest electrode was used as the pacing electrode. Using neuromuscular stimulation, the stomach was paced at a rhythm of 3 cycles/min., and gastric dysrhythmias were converted to normal rhythm. The patients wore the external stimulator strapped on a belt around the waist. Eight of the nine patients no longer relied on jejunostomy tube feeding. Unfortunately, the external devices were somewhat cumbersome and obtrusive, and required frequent maintenance. Dislodged electrodes were also a common problem. Because these external devices are impractical for long term use, they are available only through an experimental protocol at Kansas University Medical Center.
Low Energy; High Frequency Method
Since then a different type of stimulator has been developed (Enterra, Medtronics, Minneapolis, MN) and is now approved by the US Food and Drug Administration under a Humanitarian Device Exemption. The new gastric neurostimulators are permanently implanted in the patient, and use high-frequency (12 cycles/min.), low energy parameters. The Enterra devices are placed surgically via laparotomy or laparoscopy. The electrodes are placed 9.5 and 10.5 cm from the pylorus on the greater curvature of the antrum of the stomach. The leads connect to the neurostimulator, which is placed in a small pocket incision in the abdominal wall. An upper endoscopy is performed in the operating room to confirm proper lead placement and rule out perforation. In addition, endoscopic ultrasound can be used to confirm placement more accurately. A programmer who communicates with the device via telemetry turns it on just before the patient is discharged from the hospital.
The multicenter Worldwide Anti-Vomiting Electrical Stimulation Study (WAVESS) trial has successfully inserted internal gastric stimulators in 33 patients. The initial design of the WAVESS study was a double-blind crossover (1 month of stimulation and sham) followed by 12 months open label. In the double-blind section of the study, the WAVESS study group showed a significant reduction in vomiting and a clear patient preference for having the device turned on. During the next 12 months, the WAVESS study group reported a greater than 50 percent improvement in vomiting and quality of life. In the majority of these patients, gastric emptying was improved, but still had not returned to normal by one year. Unlike the high-energy, lower frequency method, the Enterra device does not pace or entrain the stomach, nor does it normalize dysrhythmias.
Improvement in patients’ symptoms when using the Enterra device may be explained by a number of theories involving neurostimulation: 1) activation of a central mechanism for nausea and vomiting control related to the constant high-frequency stimulation of the stomach wall, 2) augmentation of the amplitude of the gastric slow wave after eating, 3) enhanced relaxation of the proximal stomach and hence better accommodation, or 4) a modest improvement in gastric emptying.
WAVESS analysis of long-term hospitalization outcomes and economic impact of long-term gastric electrical stimulation indicates a 75 percent reduction in hospital use in the first year after implant for these patients with challenging problems. Average savings in the first year were approximately $65,000 per patient. Analysis of nutritional outcome has shown a significant increase in the body mass index (BMI) and an average 12 to 15 pound weight gain. In addition, 90 percent of patients who required jejunal feedings, had the tubes removed within six months and were eating. Most important to remember is that these are young patients, the majority of whom are women in the prime of their life who can now be restored to a functional life at home, school or work.
Current inclusion criteria for Enterra therapy at our institution are the following: symptoms for more than one year despite standard medical management, over seven episodes of vomiting per week, and abnormal gastric retention (at 2 hours over 60% or at 4 hours over 10%). Exclusion criteria include any patient with an organic obstruction or pseudo-obstruction, a primary eating or swallowing disorder, chemical dependency, or current pregnancy. Surgical complications related to placement of these devices have consisted of lead impedance out of range; infections; and device erosion, migration and stomach wall perforation. Three patients required surgery and device removal.
In the future, multipoint electrical stimulation will integrate stimulation from electrodes in a number of sites, beginning in the stomach and extending into the small bowel and even the colon. Optimally, this technique should be performed with an electrical frequency that is close to the body’s natural frequency and high-energy stimulus, and will help promote and coordinate the signal throughout the upper gastrointestinal tract, thus accelerating gastric emptying and small bowel transit. Patient populations for electrical stimulation are now extending into those who are postvagotomy or post-gastric surgery and those with nausea and vomiting not responding to standard therapy without delayed gastric emptying, small bowel dysmotility, recurrent small bowel bacterial overgrowth, and intestinal pseudo-obstruction.
This article was based on "Gastroparesis" published in the May/June 2001 issue of Clinical Perspectives in Gastroenterology.