Severe Gastroparesis: Medical Therapy or Gastric Electrical Stimulation

Transcription

1 CLINICAL GASTROENTEROLOGY AND HEPATOLOGY 2010;8: EDUCATION PRACTICE Severe Gastroparesis: Medical Therapy or Gastric Electrical Stimulation SAVIO C. REDDYMASU, IRENE SAROSIEK, and RICHARD W. McCALLUM Center for the Gastrointestinal Nerve and Muscle Function, Division of Gastrointestinal Motility, Department of Medicine, University of Kansas Medical Center, Kansas City, Kansas A Clinical Scenario 33-year-old woman is referred for evaluation of refractory nausea and vomiting of 8 months duration. She has a 20-year history of type I diabetes mellitus complicated by retinopathy and peripheral neuropathy. Her glycemic control is suboptimal and occasionally blood sugars are in the 20-mmol/L (360 mg/dl) range and the recent hemoglobin A1c level is 9.8%. Her symptoms occur postprandially about 30 minutes after a meal and are characterized by nausea, epigastric fullness, bloating, and pain. Vomiting is less frequent (2 3 days/wk); however, when it does occur, it is usually 2 to 4 hours after eating and on several occasions she has identified food in the vomitus that she consumed the previous day. Her severe nausea and vomiting have led to 12 emergency department visits and 4 hospitalizations in the past year. She is not able to work and take care of her family because of those symptoms. She spends most of her day lying in bed or sitting in a chair. She also lost 9 kg in this time frame. She weighs about 50 kg and is 158 cm tall (body mass index: 20 kg/m 2 ). Her abdominal examination reveals epigastric fullness and tenderness. No focal neurologic deficits were elicited. Initial investigations including complete blood count, comprehensive metabolic panel, thyroid function tests (thyroid stimulating hormone, 2 miu/l; free T4, 6 mg/dl), and random cortisol levels (18 mcg/dl) were normal. Further testing that included Helicobacter pylori and celiac sprue serology were negative; an abdominal ultrasound, small-bowel series, and upper gastrointestinal endoscopy did not show any abnormalities. Later, a 90-minute scintigraphic test to measure gastric emptying was performed with a radiolabeled egg meal and was consistent with the diagnosis of gastroparesis (t1/2, 180 min; normal, 100 min). Management recommendations for diabetic gastroparesis by her gastroenterology consultant included dietary modification (small frequent meals and a low-roughage diet), starting metoclopramide orally at 10 mg 4 times/day and promethazine at 25 mg orally every 4 hours as needed. Recommendations also were made to control her blood sugars aggressively. Although she noticed some improvement in symptoms initially with these therapeutic measures, the response seemed to wane over the next few months. Because the patient had a less-than-desired clinical response to the earlier-described measures and she was failing to thrive, her gastroenterologist has referred her to a tertiary care medical center for further evaluation. The patient wants relief from nausea, which she regards as the most disabling symptom, and seeks an opinion regarding gastric electric stimulation versus other potential therapeutic agents for gastroparesis. Problem Clinical Presentation The clinical scenario presented earlier is most consistent with diabetic gastroparesis. This condition is regarded as the end stage in the spectrum of gastric neuromuscular and sensory impairments caused by diabetes. The generic term that is favored is diabetic gastropathy, characterized by recurrent episodes of postprandial nausea, vomiting, epigastric pain and fullness, early satiety, and bloating in the absence of mechanical obstruction of the gastric outlet or the proximal small bowel. These symptoms typically are driven by meal intake but also can be present continuously at varying degrees of intensity. Occasionally, the vomiting episodes do not stop and the patient seeks emergency room care for dehydration, Mallory Weiss tears, and diabetic ketoacidosis. These severe sustained vomiting events sometimes can be explained by hyperglycemia, infections, migraine headache, menstrual cycles, stress, and use of narcotics, but at other times there is no apparent reason for symptom breakthrough despite being on a stable dose of antiemetics and prokinetics. The common etiologies for delayed gastric emptying include diabetes mellitus (as in the patient presented earlier); postsurgical, often as a result of damage of the vagus nerve; and idiopathic (including those thought to have delayed gastric emptying as a result of a viral illness). Other less frequent causes include collagen vascular disease, neurologic problems such as Parkinson disease and multiple sclerosis, intestinal pseudoobstruction, miscellaneous categories including endocrinopathies, medication-related, and as a manifestation of the paraneoplastic syndrome. Important clues pointing to gastroparesis as the probable diagnosis lie in the clinical history and include the following: (1) chronicity of symptoms that differentiate gastroparesis from an acute cause of nausea and vomiting, such as viral gastroenteritis, or acute but recurrent events, such as cyclic vomiting syndrome, in which patients typically have symptom-free intervals in between attacks of nausea, vomiting, and abdominal Abbreviations used in this paper: GES, gastric electric stimulation; ICC, interstitial cells of Cajal by the AGA Institute /10/$36.00 doi: /j.cgh

2 118 REDDYMASU ET AL CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 8, No. 2 pain; (2) timing of symptoms with relation to a meal; gastroparesis patients typically have worsening of nausea and onset of postprandial distress symptoms soon after eating whereas vomiting usually occurs 1 to 4 hours after a meal, at night, or in the morning before breakfast when old food from previous meals can be identified in the vomitus, whereas the rumination syndrome or conditioned vomiting involves effortless regurgitation of liquids and/or solids within 1 to 20 minutes of ingestion and typically not at night; (3) no evidence of gastric outlet obstruction on endoscopy and upper gastrointestinal series that exclude other entities, such as superior mesenteric artery syndrome and small-bowel obstruction; and (4) symptoms not explained by transabdominal imaging studies, which also could include a magnetic resonance angiogram to exclude median arcuate ligament syndrome. Functional dyspepsia is always in the differential diagnosis for gastroparesis. Epigastric discomfort, postprandial fullness, early satiety, and nausea are the dominant symptoms in patients with functional dyspepsia, and unlike patients with gastroparesis, severe vomiting, dehydration, and hospitalizations are not the norm. Interestingly, it has been reported that 30% to 40% of patients with functional dyspepsia have varying degrees of delayed gastric emptying and are sometimes regarded to be in the spectrum of idiopathic gastroparesis. In patients with diabetes, it also would be prudent to rule out celiac sprue by serology or duodenal biopsy. It is not uncommon to see patients with diabetic gastroparesis have co-existing morbidities, such as peripheral neuropathy, retinopathy, nephropathy, or vascular disease. The main complications related to severe gastroparesis include weight loss and malnutrition, poor quality of life, inability to maintain employment, poor glycemic control, inability to absorb oral medications required for other conditions, and the economic burden and morbidity related to repeated emergency room visits and hospitalizations. Pathophysiology Normal gastric function is regulated by a complex interaction between the neurohormonal, myoelectric, and contractile properties of the stomach (Figure 1). Receiving ingested food, successfully triturating, and emptying nutrients into the small bowel are the most essential motor functions of the stomach. Gastric contractility is controlled by the gastric slow waves that originate from the interstitial cells of Cajal (ICC). The electric activity generated by the ICCs begins at the junction of the fundus and the body of the stomach at a rate of approximately 3 cycles per minute (range, 2 4 cycles/min) and Figure 1. Summarizes normal gastric motor function (upper panel) and pathophysiologic changes present in diabetic gastroparesis (lower panel). Produced with help from Sarah Williamson, MA, of the AGA Institute.

3 February 2010 SEVERE GASTROPARESIS 119 is conducted circumferentially and distally toward the pylorus. ICCs entrain the gastric smooth muscle cells, which also are innervated through the enteric nervous system. Whenever there is postprandial stimulation of the stomach, smooth muscle cells can achieve the level of depolarization for electromechanical coupling to occur and generate an action potential leading to gastric contractility up to a rate of 3 times per minute, which eventually results in gastric emptying of nutrients. This response also is modulated by intestinal peptides, such as motilin, ghrelin, cholecystokinin, as well as the vagus nerve. Any process that disrupts the timing or strength of normal gastric contractility can result in gastroparesis (Figure 1). Gastroparesis in diabetic patients is thought to be a manifestation of diabetic autonomic neuropathy. Full-thickness deep muscle biopsies with special staining show depletion of sympathetic fibers and evidence of increased cholinergic function as an overcompensation process. Autonomic neuropathy affecting the vagus nerve results in decreased frequency of antral contractions, reduction in gastric tone, impaired antroduodenal incoordination, antral hypomotility, and pylorospasm leading to delayed emptying of solids. There also is evidence suggesting that gastric electric dysrhythmias occur owing to disruption of the ICC network, which eventually can result in loss of electromechanical coupling. Other factors that predispose diabetic patients to gastroparesis include chronic effects of glucose toxicity on myoinositol metabolism and sorbitol pathways that affect gastric neuromuscular function. Impaired postprandial release of gastrointestinal hormones, such as pancreatic polypeptide, motilin, and ghrelin, also may play a role in the pathogenesis of gastroparesis (Figure 1). The role of the vagus nerve in normal gastric emptying is emphasized by the fact that inadvertent vagal nerve injury during procedures such as fundoplication or from demyelinating disorders such as multiple sclerosis that affect vagal nerve nuclei can cause gastroparesis. Acute hyperglycemia delays gastric emptying and causes gastric electric dysrhythmias that lead to dyspeptic symptoms in diabetic patients. Management Strategies Diagnosis and Assessment of Severity Before formulating a management plan for patients with suspected gastroparesis, it is crucial to establish the diagnosis of delayed gastric emptying. The current gold standard is the gastric emptying scintigraphy test. The American Neurogastroenterology and Motility society as well as the Society of Nuclear Medicine recommend a 4-hour gastric emptying assessment using radiolabeled low-fat (2%), Egg Beaters (Conagra Foods, Omaha, NE) meal with anterior and posterior imaging of the stomach every hour with the patient standing, walking, or sitting between images. Retention of more than 10% at the end of 4 hours is the diagnostic criterion for gastroparesis, with more than 60% retention at the end of 2 hours providing additional support. We invariably see patients referred to us labeled as delayed gastric emptying based on the 90-minute gastric emptying study performed with varying meal compositions who are in turn shown to have a normal 4-hour gastric emptying scintigraphy test using the standardized meal described earlier. We therefore endorse and re-emphasize that performing a 4-hour standardized gastric emptying study is the current standard of care to make the diagnosis of gastroparesis. The gastric emptying study sometimes reveals rapid gastric emptying or dumping syndrome (criteria ranging from 50% to 35% retention of isotope at the end of 1 hour), which is another cause of postprandial symptoms. A normal gastric emptying time should raise suspicion for other etiologies of nausea and vomiting (including cyclic vomiting syndrome and central nervous system related) or also could be interpreted as recovering after viral gastroparesis. Prokinetic medications (accelerate emptying) and proton pump inhibitors (slow emptying) should be held for at least 72 hours and narcotic analgesics (slow emptying) for more than 12 hours before the test. Blood sugar levels before and during the test should be less than 250 mg/dl to avoid the inhibitory effects of hyperglycemia on gastric motility. Once the diagnosis of delayed gastric emptying is established, the next step is to assess the severity of gastroparesis. Revicki et al have proposed the use of the Gastroparesis Cardinal Symptom Index as a validated method to assess symptom severity in patients with gastroparesis and is a 9-item questionnaire based on postprandial fullness, early satiety, nausea, vomiting, and bloating. The Patient Assessment of Upper Gastrointestinal Symptom Severity Index Questionnaire (Revicki et al) is a 20-item questionnaire measuring common gastrointestinal symptoms including heartburn/regurgitation, fullness/early satiety, nausea/vomiting, bloating, and upper and lower abdominal pain. Quality of life can be measured using the short form-36 assessment, which contains physical as well as mental composite scores. Hopefully these or other methodologies will be adopted in clinical practice to standardize the symptom grading for patients with gastroparesis to formulate an appropriate management plan based on the severity of the condition. Medical Therapy A detailed history should be obtained with regard to therapeutic trials that have been undertaken for gastroparetic symptoms. Patient medication profiles should be reviewed to ensure that none of the medications used to treat other coexistent conditions have the potential to delay gastric emptying and try to avoid or substitute such medications. Important among this list are narcotic analgesics. We advise patients to consume small frequent meals, avoid a high-roughage diet, and use liquid nutritional supplements if needed. Diabetic patients must try to maintain glucose levels at less than 180 mg/dl to limit the adverse affect of hyperglycemia on gastrointestinal motility. It is also wise to ensure that patients have had a robust trial of combination prokinetic and anti-emetic agents for at least 3 to 6 months before terming them as a nonresponder to medical treatment. Patients with gastroparesis who do not respond to dietary modification often are started on metoclopramide at doses of 10 to 20 mg, 30 minutes before meals and at bedtime, and anti-emetics, usually phenothiazines, as needed for nausea. Patients are counseled regarding the possible adverse events with metoclopramide and informed about the recent Food and Drug Administration (FDA)-mandated black box warning that reemphasizes a concern we always had that chronic or high-dose use of metoclopramide has been associated with tardive dyskinesia. If patients do not achieve a desired response to the earlier-described measures or develop side effects with the use of metoclopramide, then we switch metoclopramide to domperidone (obtained through the FDA-approved compassionate

4 120 REDDYMASU ET AL CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 8, No. 2 use limited access program) and titrate from 20 mg 4 times a day upward to 30 mg 4 times a day for a trial duration of at least 2 months. It is recommended per the FDA-endorsed protocol for domperidone that the serum potassium level should be confirmed as normal and the QT interval is less than 475 microseconds on the electrocardiogram before starting this medication. Subcutaneous metoclopramide 10 mg (2 cc) up to 4 times a day and a transdermal scopolamine patch (1.5 mg every 72 hours) could be considered to achieve more consistent bioavailability in patients with frequent vomiting in whom absorption of oral medications is in doubt. Subcutaneous metoclopramide also can be used as a rescue strategy to hopefully abort vomiting and prevent hospitalization. The next step then would be to consider a tricyclic antidepressant: amitriptyline, nortriptyline, or desipramine ( mg at bedtime as tolerated). Although endoscopic pyloric injection of botulinum toxin has been used with varying success for the treatment of gastroparesis, we no longer condone its use in our practice given the lack of efficacy shown in double-blind trials. Serotonin receptor (5-hydroxytryptamine 3) antagonists, such as ondansetron, should be considered more as a back-up for chronic outpatient use given their cost profile; however, intravenous use of these agents is useful in the emergency department or hospitalized patients. Other agents occasionally used for nausea include aprepitant (Emend; Merck, Whitehouse Station, NJ), a neurokinin receptor-1 antagonist; Delta-9-tetrahydrocannabinol (Marinol; Solvay, Marietta, GA), a cannabinoid; and droperidol (Inapsine, Akorn, Lake Forest, IL), a butyrophenone (given intravenously in hospitalized patients when nausea and vomiting is not controlled with other first-line agents). In patients with persistent symptoms or in those who have side effects with metoclopramide and do not have access to or cannot afford domperidone (about $50 per month), erythromycin could be tried. The dose of 1.5 to 3 mg/kg intravenously every 6 hours is reserved for hospitalized patients and a dose of 125 mg 3 times a day as a liquid is the preferred dose in the outpatient setting to minimize tachyphylaxis. If patients seem to be developing dose tolerance to erythromycin, then it could be discontinued and be tried again after a drug holiday. Its best role is in combination with domperidone. Given the reports of sudden cardiac death, erythromycin should not be used concurrently with CYP-3A inhibitors such as diltiazem or verapamil (azithromycin could be substituted in this circumstance; however, the dose required is 2-fold higher). In gastroparetic patients with predominance of bloating and gas, small-bowel bacterial overgrowth should be investigated with a glucose breath test. Gall bladder disease also should be considered in patients in whom upper-abdominal pain is prominent and a hepatobiliary iminodiacetic acid scan could be considered. Approaches to treat accompanying epigastric abdominal pain would include tricyclic antidepressants, duloxetine (Cymbalta; Pfizer, New York, NY), pregabalin (Lyrica; Eli Lilly, Indianapolis, IN), tramadol, and use narcotic analgesics only as a last resort. Readers also are directed to the December 2008 issue of this journal for more information regarding approaches to pain in a patient with gastroparesis. Based on our experience at the University of Kansas (an academic referral center for gastroparesis), about 80% to 90% of the patients referred respond to aggressive dosing of these different combinations and permutations of medical therapies that we summarized earlier with a reasonable control of their symptoms and an acceptable quality of life. However, there is a subset of patients with diabetic, idiopathic, or postsurgical gastroparesis who do not seem to respond to these measures, for whom hospitalizations occur frequently; patients often require enteral or parenteral nutrition back-up, and gastric decompression also is being considered in some of these patients for symptom control. Discussions about gastric electrical stimulation usually begin around this time frame. Gastric Electrical Stimulation The clinical use of gastric electric stimulation (GES) as a possible treatment option for patients with gastroparesis was based on the experimental work performed by Familoni et al in the 1990s in animals and human beings that showed that electrical stimulation at higher frequencies than the intrinsic gastric slow wave frequency with a short or low-energy pulse duration (300 microseconds) induced gastric contractions in dogs and led to improvements in nausea, vomiting, and also enhanced gastric emptying in human beings. These observations concerning gastric contractility and peristalsis have not been able to be confirmed or reproduced in subsequent studies. The other type of GES is a high-energy/low-frequency (or frequency of intrinsic slow wave) longer pulse duration (300 milliseconds); this system also is known as gastric pacing. The gastric pacing system does induce gastric contractions and accelerates gastric emptying and currently is being evaluated in a research trial using an external pulse generator. To date only one double-blind study (Worldwide Anti-Vomiting Electrical Stimulation Study) evaluated the efficacy of the high-frequency/low-energy GES in patients with gastroparesis. Parameters used in this study were stimulation frequency of 12 cycles per minute, 0.1 seconds on and 5 seconds off, and trains of 14-hertz pulse frequencies with 5-milli-amp strength. This study had 33 patients (17 diabetic and 16 idiopathic) who initially were subjected to 1 month of on or off stimulation in a double-blind, cross-over design and later followed up for 11 months with the device turned on. During the blinded phase of the study, GES achieved a significant reduction in weekly vomiting frequency and the majority of patients preferred the on mode. In the next 11 months, 80% of patients reported a more than 50% improvement in vomiting and quality of life. Although the majority of patients had improvement in gastric emptying, it still had not returned to normal. Based on the results of this study, the FDA approved this therapy, the Enterra as a Human Use Device under the Humanitarian Device Exemption in April 2000 for patients with diabetic and idiopathic gastroparesis. Human Use Device usually means a device treating conditions affecting less than 4000 patients per year in the absence of other effective treatments. Under the FDA guidelines, the GES implantation should be limited only to institutions that have obtained prior institutional review board approval. Most insurance companies and Medicare reimburse Enterra implantation when used under the Humanitarian Device Exemption. Currently in the United States, more than 4000 devices have been placed during the past 10 years. Apart from this double-blind trial, all of the published literature on the efficacy of GES consists of open-label studies from centers with substantial experience with this device. Follow-up data for periods up to 10 years after device implantation report a sustained improvement in symptoms over many years.

5 February 2010 SEVERE GASTROPARESIS 121 Figure 2. Enterra system with pulse generator and programmer. An early improvement in symptoms can be appreciated in the first 3 to 6 months after placement of the device and generally predicts a long-term control of symptoms over many years. GES also improves quality of life, reduces requirement for health care use, improves glycemic control in diabetic patients, reduces dependence on enteral or parenteral nutrition, and also improves nutritional status. In addition it also is possible that patients with diabetic gastroparesis can become candidates for renal and pancreas transplant if needed because control of gastroparetic symptoms ensures more reliable bioavailability of immunosuppressants. Apart from diabetic and idiopathic gastroparesis, GES has been evaluated in patients with postvagotomy gastroparesis and seems to be as efficacious. In cases of prior gastric surgeries, available data indicate that more than 50% of the stomach should be remaining to relieve nausea and vomiting. A large double-blind trial with GES in diabetic and idiopathic gastroparesis was completed recently and data have been analyzed and findings were presented at the recent Digestive Disease Week meeting (2009) where it was shown that GES was beneficial in patients with refractory diabetic gastroparesis. The clinically available GES- Enterra (Figure 2) consists of a pair of electrodes sutured to the muscular layer of the greater curvature of the stomach, 8.5 cm and 9.5 cm proximal to the pylorus, and connected to a pulse generator, called the neurostimulator, which is implanted in a subcutaneous pocket in the abdominal wall, usually in the right upper quadrant. The pulse generator can be activated and programmed externally and the usual battery life expectancy is 8 to 10 years depending on the energy parameters programmed. The system can be implanted by laparotomy or laparoscopy; the former approach gives a greater control for lead implantation in the right location in the stomach and the opportunity for back-up jejunostomy tube placement and to obtain gastric wall biopsies. Laparoscopy has been associated with some reports of lead damage and insulation trauma that could result in shock waves and reports of pain. Although the initial double-blind data suggested some improvement in gastric emptying with GES, we have shown in a recent study in a larger number of patients that symptom improvement is independent of gastric emptying. Based on studies in animals and our recent data in human beings, the proposed mechanisms of action of GES (Figure 3) are as follows: (1) activation of the central mechanisms for controlling nausea and vomiting, (2) enhanced relaxation of the fundus that increases gastric accommodation and decreased sensitivity to distension, and (3) augmentation of the postprandial gastric slow wave amplitude, and (4) enhanced vagal function as evidenced by change in the low-frequency/high-frequency ratio documented during autonomic testing. Improvement in gastric emptying has been suggested as a mechanism for improvement in gastroparetic symptoms with GES; however, the reports have been inconsistent. The intended response for the GES device is improvement in nausea, vomiting, and quality of life, as well as elimination of the need for enteral and parenteral nutrition within 3 to 6 months of surgery. Nonresponders are defined as patients who have a less than 25% improvement in their symptoms. Based on our experience, 21% of patients with diabetic gastroparesis, 16% with post-surgical gastroparesis and 35% with idiopathic gastroparesis are nonresponders after 1 year of assessment. Predictors for suboptimal response, as shown by our group, include the following: (1) patients with idiopathic gastroparesis, (2) Figure 3. Proposed mechanisms of action of the GES (Enterra device). Produced with help from Sarah Williamson, MA, of the AGA Institute.

6 122 REDDYMASU ET AL CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 8, No. 2 Figure 4. Suggested management algorithm for gastroparesis. Reprinted with permission from the Expert Opinion in Pharmacotherapy Journal. chronic use of narcotic analgesics, (3) predominance of abdominal pain in the clinical presentation, (4) history of migraines, (5) marked gastric slow wave dysrhythmias (tachygastria) that represents a serious loss of ICCs, and (6) missed diagnosis of conditions such as the cyclic vomiting syndrome, anorexia nervosa, and rumination syndrome that continue after GES implantation. These observations were similar to the findings of the Philadelphia group published by Maranki et al who concluded that the predictors of a good clinical response to GES include patients with diabetic gastroparesis, those with predominance of nausea and vomiting in the clinical presentation, and patients not on opiate analgesics. In patients with suboptimal response to GES, changing the settings of the pulse generator in the form of increasing voltage and increasing the on time might help in some patients, especially in those in whom the initial desired response has waned over time. Some of the complications related to GES placement include infection of the pulse generator pocket site, pain, erosion of the pulse generator through the abdominal wall, and rarely detachment and/or displacement of the electrodes with possible penetration of the leads through the stomach wall into the lumen. About 10% of the devices have to be removed because of these complications based on our observations in more than 220 patients over the past 10 years. Re-implantation then can be pursued if clinically appropriate. Summary For the question of medical therapy versus GES for patients with gastroparesis severe enough to attract the attention of gastrointestinal consultants, there is only one study of

7 February 2010 SEVERE GASTROPARESIS patients by Abell et al comparing intensive medical treatment versus gastric electrical stimulation and the investigators believed that GES was more effective than medical therapy in improving upper-gastrointestinal symptoms and quality of life. Pending further studies evaluating this clinical dilemma, we recommend a rigorous regimen of medical therapy initially (as outlined in Figure 4), which seems to help the majority of patients with gastroparesis (documented by a 4-hour gastric emptying study). However, in the subgroup that does not respond to a robust trial of medical therapy of 3 to 6 months duration (10% 20% of gastroparetics referred to an academic medical center), GES appears to have an important role to improve gastroparetic symptoms and quality of life over a long duration ( 5 y). Although Enterra is not the ideal GES system for reversing gastroparesis, it is the only system currently available for clinical use and to improve gastroparetic symptoms. Patient selection seems to be the key for obtaining a good response with Enterra, and continuing advances in this technology will lead to development of a GES system that accelerates gastric emptying and reverses gastric dysrhythmias along with improving gastroparetic symptoms. Areas of Uncertainty Areas of uncertainty in the management of patients with gastroparesis are as follows. First, there is no uniform diagnostic methodology for the diagnosis of gastric emptying disorders. Adopting the recently published consensus guidelines from the American Neurogastroenterology and Motility Society and the Society of Nuclear Medicine hopefully will address this issue. More data on newer techniques for measuring gastric emptying, such as the SmartPill (Buffalo, NY) (a wireless ph and pressure-sensing nondigestible capsule) and the 13-C Octanoic acid breath test, are evolving, and these techniques will become the gold standards unless the 4-hour gastric emptying scintigraphy is embraced universally by nuclear medicine departments. Second, a role for GES therapy as a supplement to medical therapy could be advanced into the settings of nausea and vomiting in many other areas in which gastroparesis can occur, such as connective tissue disease, pseudo-obstruction, and neurologic disorders. An evolving area is the use of GES to treat refractory nausea and vomiting in patients with normal gastric emptying. Third, the role of the new generation GES devices including the multichannel stimulation approaches needs to be evaluated to address true pacing of the stomach with acceleration of gastric emptying and also reversal of gastric dysrhythmias. Fourth, although there is a subset of patients who seem to have an excellent response to Enterra, the preoperative predictors for this perfect patient need to be better defined. The possibility of endoscopically placing temporary gastric electrodes to perform a trial stimulation for 1 to 2 weeks to select potential responders for GES also needs to be explored. Fifth, an accurate figure for the prevalence, morbidity, and mortality related to gastroparesis is not known. Future studies to help us better understand the impact of this condition in the community will be forthcoming from the National Institutes of Health Gastroparesis Consortium database. Published Guidelines We have depicted a suggested approach to the management of gastroparesis in Figure 4. This represents a summary of the recommendations from the American Gastroenterological Association technical review on the diagnosis and management of gastroparesis (2004), the American Motility Society task force on gastroparesis clinical review (2006), and the consensus recommendations for gastric emptying scintigraphy from the American Neurogastroenterology and Motility society (2008) and the Society of Nuclear Medicine (2008). Recommendations for This Patient The patient presented here had a 4-hour gastric emptying study that showed 33% retention of the meal at the end of 4 hours (normal, 10% retention). She was started on domperidone 10 mg 4 times a day instead of metoclopramide and the dose was titrated up to 30 mg 4 times a day. Transdermal scopolamine transdermal patch 1.5 mg every 3 days and nortriptyline 20 mg at bedtime also were prescribed. The patient did well for about 4 months with improvement in symptoms and reduced need for hospitalization. However, after about 6 months her symptoms started worsening again and weight loss persisted. At that time the option of surgically implanting the Enterra device, including the risks and benefits of the procedure, were discussed with the patient and she wished to proceed. The GES was implanted successfully and a back-up jejunostomy tube also was placed during surgery. She had a favorable outcome with the procedure and reported a greater than 75% improvement in symptoms at the 6-month follow-up visit although her gastric emptying study still showed a 30% retention of the meal at the end of 4 hours. During this visit, the J tube was removed and her blood sugar control was better (HbA1c of 7.5%). The symptom response was sustained even after 1 year, and she was able to stop all antiemetics, scopolamine patch, and nortriptyline. However, we recommended that domperidone be continued at 20 mg 4 times a day as a background prokinetic in view of the continued delay in gastric emptying. Suggested Reading 1. de la Loge C, Trudeau E, Marquis P, et al. Cross-cultural development and validation of a patient self-administered questionnaire to assess quality of life in upper gastrointestinal disorders: the PAGI-QOL. Qual Life Res 2004;13: Revicki DA, Rentz AM, Dubois D, et al. Development and validation of a patient-assessed gastroparesis symptom severity measure: the Gastroparesis Cardinal Symptom Index. Aliment Pharmacol Ther 2003;18: Soykan I, Sivri B, Sarosiek I, et al. Demography, clinical characteristics, psychological and abuse profiles, treatment, and longterm follow-up of patients with gastroparesis. Dig Dis Sci 1998; 43: Parkman HP, Hasler WL, Fisher RS. American Gastroenterological Association medical position statement: diagnosis and treatment of gastroparesis. Gastroenterology 2004;127: Parkman HP, Hasler WL, Fisher RS. American Gastroenterological Association technical review on the diagnosis and treatment of gastroparesis. Gastroenterology 2004;127: Abell TL, Bernstein RK, Cutts T, et al. Treatment of gastroparesis: a multidisciplinary clinical review. Neurogastroenterol Motil 2006;18: Abell TL, Camilleri M, Donohoe K, et al. Consensus recommen-

8 124 REDDYMASU ET AL CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 8, No. 2 dations for gastric emptying scintigraphy: a joint report of the American Neurogastroenterology and Motility Society and the Society of Nuclear Medicine. Am J Gastroenterol 2008;103: Reddymasu SC, Soykan I, McCallum RW. Domperidone: review of pharmacology and clinical applications in gastroenterology. Am J Gastroenterol 2007;102: Reddymasu SC, McCallum RW. Pharmacotherapy of gastroparesis. Expert Opin Pharmacother 2009;10: Sawhney MS, Prakash C, Lustman PJ, et al. Tricyclic antidepressants for chronic vomiting in diabetic patients. Dig Dis Sci 2007; 52: Abell T, McCallum R, Hocking M, et al. Gastric electrical stimulation for medically refractory gastroparesis. Gastroenterology 2003;125: Lin Z, Sarosiek I, Forster J, et al. Symptom responses, long-term outcomes and adverse events beyond 3 years of high-frequency gastric electrical stimulation for gastroparesis. Neurogastroenterol Motil 2006;18: Lin Z, Hou Q, Sarosiek I, et al. Association between changes in symptoms and gastric emptying in gastroparetic patients treated with gastric electrical stimulation. Neurogastroenterol Motil 2008;20: Cutts TF, Luo J, Starkebaum W, et al. Is gastric electrical stimulation superior to standard pharmacologic therapy in improving GI symptoms, healthcare resources, and long-term health care benefits? Neurogastroenterol Motil 2005;17: Reddymasu SC, Lin Z, Sarosiek I, et al. Efficacy of gastric electrical stimulation in improving functional vomiting in patients with normal gastric emptying. Dig Dis Sci [Epub ahead of print] 16. McCallum RW, Sarosiek I, Cocjin J, Forster J, Lin Z. Mechanisms of symptomatic improvement after gastric electrical stimulation in gastroparetic patients. Neurogastroenterol Motil [Epub ahead of print] 17. Maranki JL, Lytes V, Meilahn JE, et al. Predictive factors for clinical improvement with Enterra gastric electric stimulation treatment for refractory gastroparesis. Dig Dis Sci 2008;53: Familoni BO, Abell TL, Voeller G, et al. Electrical stimulation at a frequency higher than basal rate in human stomach. Dig Dis Sci 1997;42: Reprint requests Address requests for reprints to: Richard W. McCallum, MD, Chairman of Medicine, Texas Tech University Health Sciences Center, Paul L. Foster School of Medicine, 4800 Alberta Avenue, El Paso, Texas richard.mccallum@ttuhsc.edu; fax: (915) Acknowledgments The authors thank Sarah L. Williamson, MA, Medical Illustrator, AGA Institute, for her help with Figures 1 and 3. Conflicts of interest The authors disclose no conflicts.