|UFDC Home||myUFDC Home | Help|
This item has the following downloads:
1 SPECTRUM OF GASTROPARESIS IN CHILDREN By SHAMAILA WASEEM A THESIS PRESENTED TO THE GRADUATE SCHOOL OF THE UNIVERSITY OF FLORIDA IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF MASTER OF SCIENCE UNIVERSITY OF FLORIDA 2009
2 2009 Shamaila Waseem
3 To Rayyan, Lina and Lali
4 ACKNOWLEDGMENTS I would like to express my appreciation for the support of the Division of Pediatric Gastroenterology during the time of my fellowship which provided the needed time fo r completion of the requirements of this Master of Science degree. I am especially grateful to Genie Kahn for all of her assistance, as this could not have been completed without her. In addition, I would like to thank Saleem Islam, Baharak Moshiree and Ni cholas Talley for their guidance, mentorship, and patience. Also, I want to thank Dr. Limacher and Dr. Asal for giving me the opportunity to obtain this degree by accepting me into the A dvanced Postgraduate Program in Clinical Investigation fellowship and also agreeing to chair my thesis defense committee. Finally, I would like to thank my husband and my kids for putting up with me through all these years of training.
5 TABLE OF CONTENTS page ACKNOWLEDGMENTS ................................ ................................ ................................ ............... 4 LIST OF TABLES ................................ ................................ ................................ ........................... 7 LIST OF FIGURES ................................ ................................ ................................ ......................... 8 LIST OF ABBREVIATIONS ................................ ................................ ................................ .......... 9 ABSTRACT ................................ ................................ ................................ ................................ ... 10 CHAPTER 1 INTRODUCTION ................................ ................................ ................................ .................. 12 Epidemiology of Gastroparesis ................................ ................................ ............................... 12 Etiology ................................ ................................ ................................ ................................ ... 13 Pathophysiology ................................ ................................ ................................ ..................... 13 Symptoms ................................ ................................ ................................ ............................... 14 Diagnostic Tests ................................ ................................ ................................ ...................... 16 Treatment ................................ ................................ ................................ ................................ 19 Dietary Manipulation ................................ ................................ ................................ ....... 20 Improving Glycemic Control ................................ ................................ .......................... 21 Pharmacologic Therapy ................................ ................................ ................................ ... 21 Prokinetic agents ................................ ................................ ................................ ...... 21 Anti emetic medications ................................ ................................ .......................... 23 Medications for control of symptoms other than nausea and vomiting ................... 24 Nutritional Support ................................ ................................ ................................ .......... 25 Endoscopic Treatment ................................ ................................ ................................ ..... 26 Surgical Treatment ................................ ................................ ................................ .......... 27 Goals of the Study ................................ ................................ ................................ .................. 27 2 MATERIALS AND METHODS ................................ ................................ ........................... 29 Patient Ascertainment and Case Definition ................................ ................................ ............ 29 Data Collection ................................ ................................ ................................ ....................... 30 Statistical Analysis ................................ ................................ ................................ .................. 32 3 RESULTS ................................ ................................ ................................ ............................... 33 Patient Characteristics ................................ ................................ ................................ ............ 33 Outcomes for the Entire Cohort ................................ ................................ .............................. 35
6 Outcomes According to Gender ................................ ................................ ............................. 36 Outcomes According to Age Groups ................................ ................................ ...................... 36 Outcomes Based on Presumed Etiology of Gastroparesis ................................ ...................... 39 4 DISCUSSION ................................ ................................ ................................ ......................... 45 APPENDIX ................................ ................................ ................................ ................................ .... 51 REFERENCES ................................ ................................ ................................ .............................. 53 BIOGRAPHICAL SKETCH ................................ ................................ ................................ ......... 59
7 LIST OF TABLES Table page 3 1 Frequency of symptoms at first and last encounter ................................ ........................... 41 3 2 Etiology of gastroparesis ................................ ................................ ................................ .... 41 3 3 Frequency and outcomes of symptoms in males and females ................................ ........... 41 3 4 Sym ptom outcomes by age group ................................ ................................ ...................... 42 3 5 Outcomes of solid emptying delay based on severity ................................ ........................ 43 3 6 Outcomes of liquid emptying delay ba sed on severity ................................ ...................... 43
8 LIST OF FIGURES Figure page 3 1 Frequency of t in solids and liquids ................................ ................................ ............... 44 3 2 Symptom outcomes of all patients ................................ ................................ .................... 44
9 LIST OF ABBREVIATION S BMI Body mass index CF Cystic fibrosis CNS Cent ral nervous system EES Erythromycin GES Gastric emptying scintigraphy GESt Gastric electrical stimulator GI Gastroenterology GP Gastroparesis ICC Interstitial cells of Cajal IV Intravenous MCP Metoclopramide min Minutes MMC Migrating motor complex PNS Peripheral nervous system t Gastric emptying half time TPN Total parenteral nutrition UF University of Florida
10 Abstract of Thesis Presented to the Graduate School of the University of Florida in Partial Fulfillment of the Requirements for the Degree of Master of Science SPECTRUM OF GASTROPARESIS IN CHILDREN By Shamaila Waseem August 2009 Chair: Marian C. Limacher Major: Medical Sciences Clinical and Translational Science Gastroparesis is a conditio n of abnormal gastric motility characterized by delayed gastric emptying in the absence of mechanical outlet obstruction. Symptoms include nausea, vomiting, post pran dial fullness, early satiety, abdominal bloating and weight loss In adults, one third of gastroparesis is due to diabetes, one third idiopathic and one third is assumed post surgical. Delayed gastric e mptying of a solid phase meal assessed by radionuclear scintigraphy is considered the gold standard for the diagnosis of gastroparesis. The prev alence of gastroparesis is difficult to estimate due to the lack of a validated, widely available diagnostic test that can be applied in primary care. The extent of the problem with gastroparesis in children is unknown and there are no effective therapies for it. We studied a cohort of children with delayed gastric emptying to identify symptoms, co morbidities, possible risk factors treatment and outcomes. Patient s ranging from 0 21 years who underwent gastric scintigraphy fr om January 2002 to December 2008 at the University of Florida were identified Retrospective analysis of 239 patients (52% female, mean age 7.9 yrs) was performed. Variables measured were: indications for gastric scintigraphy (symptoms) ; gastric empyting half time ( t ) for gastric sc intigraphy for solid vs. liquid test meal s ; response to IV erythromycin or metoclopramide observed during scintigraphy; demographics ( age, g ender,
11 height/weight ; other medical/surgical diagnosis and psychological diagnosis ) ; identified etiologies ; complic ations; all therapeutic interventions ( dietary modification, prokinetic/anti emetic agents, nutritional support (enteral/parenteral), gastric electrical stimulation and others ) ; and most recent follow up encounter assessing gastroparesis symptomatology. Da ta were aggregated for frequency and percentage. The frequency of initial presenting symptoms incl uded: vomiting (68%), abdominal pain (51%) nausea (28%), weight loss (27 %) early satiety (25 % ), and bloating (7 %) The most common etiologies were: idiopath ic (7 0%), cerebral palsy (16%), seizure disorder (15.5%), prematurity (13%), and developmental delay (10.5%), Thirty five percent of patients responded to IV erythromycin injected d uring scintigraphy compared to only 8.4 % treated with IV metaclopramide during the same procedu re. The majority ( 73.6 % ) we re treated with EES, while 41% received dietary modifications, 29.7 % metoclopramide 23% enteral feeds, 6.7% tegaserod and 5.4% azithromycin. After an average of 24 months follow up, the most common compl ications from gastroparesis were esophageal reflux (67.4%), esophagitis (16.7%), gastritis (15%), and dehydration (3.7 %). Nevertheless by the end of the follow up period a significant improvement in all symptoms was reported despite different therapeutic modalities over time. Appreciation of different etiologies, symptom presentation, complications, and outcomes of the patients is the basis for better understanding of the course and outcomes for children with gastroparesis.
12 CHAPTER 1 INTRODUCTION Gast roparesis (GP) is a disorder of the stomach characterized by delayed gastric emptying in the absence of mechanical obstruction. Many controlled studies have been performed in adults, evaluating etiology and management strategies. The pediatric literature i s very limited, with only a few case series and a few randomized controlled trials. Gastroparesis is often not recognized and thus remains untreated in children. This review integrates available adult and pediatric data to summarize the clinical presentati on, etiologies, complications, treatments and outcomes, provide management recommendations, and identify areas for additional study. Epidemiology of Gastroparesis The true prevalence of gastroparesis in the United States is unknown. In a study conducted by the Center of Health Outcomes Research (MEDTAP International Inc., Bethesda, Maryland) 7 to 15% of the adult population were found to have symptoms suggestive of gastroparesis.  A large study on long term outcomes of gastroparetic adults reported that 82% of patients were female . The actual prevalence of gastroparesis is difficult to estimate due to inconsistent correlation of symptoms with scintigraphy proven delayed gastric emptying, low use of diagnostic testing and a higher prevalence reported from tertiary medical centers. Currently, no data are available to estimate the prevalence of gastroparesis in children. One study estimated 5% 10% of otherwise healthy adolescents have had symptoms of nausea and heartburn within a year . Also, 65% of symptomatic adolescents who undergo upper endoscopy have no abnormalities and are classified as having functional dyspepsia . Delayed gastric emptying and early post prandial upper gastrointestinal symptoms have been demonstrated to be present in childr en diagnosed with functional dyspepsia [5,6]. In our
13 experience, most patients with gastroparesis have had multiple other diagnoses and/or multiple other surgical procedures performed. Etiology The etiology of gastroparesis in adults is multifactorial T h e main categories are diabetes, idiopathic, and post surgical  especially if the vagus nerve is damaged. In children, most cases occur either after viral infection or are idiopathic cases [ 7 ] Patients with post viral gastroparesis usually present with chronic continuation of upper gastrointestinal symptoms after recovering from a viral syndrome [ 8 ]. Other causes of gastroparesis in children include prematurity, medications, thyroid dysfunction, cystic fibrosis, cow milk protein allergy, eosinophilic gas troenteropathy, neurologic disorders, diabetes, muscular dystrophy, inflammatory causes, autoimmune disorders and medications [ 8 ]. Gastroparesis may also occur in patients with chronic liver failure, chronic renal insufficiency and intestinal pseudo obstru ction [2, 9 ]. Post surgical gastroparesis is observed after surgical procedures such as vagotomy, nissen fundoplication, and organ transplantation. In addition, gastroparesis is a common gastrointestinal complication seen in individuals with eating disorder s, which are not uncommon in adolescents. Pathophysiology Gastric motility results from a complex interaction between gastric smooth muscle, the enteric nervous system and specialized cells, the interstitial cells of Cajal (ICC ) Gastric motility results f rom tonic contractions of the fundus and phasic contractions of the antrum [ 10,11 ]. Distinct patterns characterize the fasting (interdigestive) and fed (digestive) phases. During the interdigestive pattern, three cyclical phases known as migrating motor c omplex (MMC) recur every two hours: Phase 1, Phase II and Phase III. Gastroparesis is characterized by loss of normal fasting MMCs and reduced postprandial antral contractions and, in some cases, pylorospasm
14 [1 2 ]. Small intestinal dysmotilities are detecte d in 17% 85% of patients with gastroparesis [1 3 ]. 4 ]. The ICCs or gastric pacemaker cells are located along the greater curvature in the proximal to middle body of the stomach. Originating in the region of ICCs, gastric slow waves sweep across the stomach toward the pylorus. However, these slow waves do not result in contraction of the gastric smooth muscle, but, instead, in the simultaneous release of neurotransmitt ers from the enteric nerve endings, which leads to contraction of the gastric smooth muscle [1 5 1 6 ]. Several factors affect gastric motility. These factors include 1) motor dysfunction, e.g., hypomotility and pyloric spasm, 2) sensory dysfunction, e.g., impaired fundic relaxation, accommodation and abnormal sensation, 3) electrical dysfunction, e.g., gastric arrhythmias and abnormal propagation, 4) CNS effects resulting in nausea and vomiting, 5) autonomic nervous system dysfunction, 6) central nervous sy stem dysfunction and, 7) other factors such as bacterial overgrowth, visceral hyperalgesia and gastrointestinal hormones [1 7 ]. Moreover, the content of the meal, such as volume, acidity, osmolarity, nutrient density and fat content, also affect s gastric em ptying. The main pathogenic factors in diabetic gastroparesis are vagal autonomic neuropathy and possible defects in the interstitial cells of Cajal. Symptoms Symptoms in gastroparesis consist of a combination of nausea, vomiting, early satiety, bloating, post prandial fullness, abdominal pain and weight loss. Gastroparesis is diagnosed in a symptomatic patient by a delay in gastric emptying after mechanical obstruction is excluded. A simple severity grading scale has been proposed for stratification of sy mptoms by Abell, et al. [1 8 ]. They described three grades Grade 1 or mild GP is characterized by symptoms that are easily controlled and patients are able to maintain weight and nutrition on a regular diet or minor
15 dietary changes Grade 2 or compensate d GP is characterized by moderate symptoms with partial control with medications, patient ability to maintain nutrition with dietary and lifestyle adjustments, and rare hospitalizations Grade 3 or gastroparesis with gastric failure is characterized with refractory symptoms despite medical therapy, inability to maintain nutrition via oral route and frequent emergency room (ER) visits or hospitalizations. Also, a patient based symptom instrument, the gastroparesis cardinal symptom index (GCSI) has been deve loped to assess severity of gastroparesis [1 9 ]. The GCSI total scores are based on three subscales of nausea/vomiting, post prandial fullness/early satiety, and bloating. The GCSI scale is used to rate s own self evaluations. To date, no studies are available in children to confirm the validity of this instrument in the pediatric population. In a study of 146 adults with gastroparesis, nausea was present in 92%, vomiting in 84%, abdominal bloating in 75% and early satiety in 60%. Abdominal pain or discomfort was present in 46% 89% of patients but was not the predominant symptom . Constipation may also be associated with gastroparesis. Treatment of constipation with an osmotic laxative improved dyspept ic symptoms, as well as gastric emptying delay [ 20 ]. Complications of gastroparesis in the adult literature have been reported to include gastroesophageal reflux, esophagitis, gastritis, anemia, esophageal stricture, small bowel bacterial over growth, maln utrition, dehydration with acute renal failure secondarily, electrolyte disturbances and bezoar formation [ 21 2 2 ]. There are no reports available to determine if the pediatric complications of gastroparesis differ from those in adults
16 Diagnostic Tests Th e following diagnostic tests have mainly been used and validated in adults. There are no pediatric norms or reference values available T herefore, in children we use the available adult data/values. Gastric Scintigraphy Delayed gastric emptying scintigra phy (GES) of a radio labeled solid meal is the gold standard for the diagnosis of gastroparesis. This test provides a physiologic, non invasive and quantitative measure of gastric emptying and provides a sensitive measurement of emptying of solids. Liquid emptying may remain normal despite advanced disease. A variety of foods including chicken, liver, eggs, egg whites, oatmeal, and pancakes are being used as test meals. The content of the meal is one of the most important variables in gastric emptying. Cons umption of solids, fats, increased calories, increased fiber and high volumes of a test meal can delay gastric emptying time. Consensus recommendations for a standardized gastric emptying procedure have recommended a universally acceptable 99 m technetium sulfur colloid labeled low fat, egg white meal [2 3 ]. Medications that alter gastric emptying may be discontinued 48 72 hours in advance, and blood glucose in diabetics should be <275mg/dl on the day of the test GES is measured at minimum of 1, 2 and 4 ho urs after test meal ingestion and is performed in the upright position. This periodic measurement of radio labeled solid meal has a specificity of 62% and a sensitivity of 93% when compared to continuous GES [2 4 ]. Emptying of solids exhibits a lag phase fo llowed by a prolonged linear emptying phase. The results of GES can be reported in two ways. The simplest approach is to report percent retention at defined times (minimum 1, 2, and 4 hours). Retention of over 10% of the solid meal after 4 hours is abnorm al. The grading of severity based on 4 hour values has been suggested, i.e., grade 1 (mild), 11 20% retention at 4 hr; grade 2 (moderate), 21 35% retention at
17 4 hr; grade 3 (severe), 36 50% retention at 4 hr; and grade 4 (very severe), >50% retention at 4 hr [2 3 ]. Prokinetics may also be administered intravenously after the last measurement (i.e., 4 retained or extrapolated t can be calculated to assess response Radiopaque markers After ingestion of indigestible markers, i.e., ten small pieces of nasogastric tubing, none of the markers should remain in the stomach on an X ray taken 6 hours after ingestion with a meal [2 5 ]. This simple test correlates with clin ical symptoms of gastroparesis and is readily available and inexpensive. Ultrasonography Transabdominal ultrasound has been used to measure emptying of a liquid meal by serially evaluating cross sectional changes in the volume remaining in the gastric ant rum over time [2 6 ,2 7 ,2 8 ]. Emptying is considered complete when the antral area/volume returns to the fasting baseline. Some studies have revealed gastric emptying measurements similar to those seen with scintigraphy [2 9 ]. Magnetic resonance imaging Magnet ic resonance imaging (MRI) using gadolinium has been found to accurately measure semi solid gastric emptying and accommodation using sequential transaxial abdominal scans [ 30 ]. MRI provides excellent spatial resolution with a high sensitivity. MRI is also non invasive and radiation free. Antral propagation waves can be observed and their velocity calculated.
18 Single photon emission CT This technique uses intravenously administered 99 Tc pertechnetate that accumulates within the gastric wall rather than the lumen and provides a three dimensional outline of the stomach [ 31 ]. Measurement of regional gastric volumes can be made in real time to assess fundic accommodation and intragastric distribution. Stable isotope breath tests The noninvasive 13 C labeled oct anoate breath test is an indirect means of measuring gastric emptying. 13 C labeled octanoate is a medium chain triglyceride which can be bound to a solid meal such as a muffin. After ingestion and stomach emptying, 13 C octanoate is rapidly absorbed in th e small intestine and metabolized to 13 CO2 which is expelled from the lungs during expiration. The rate limiting step for the signal appearing in the breath is the rate of gastric emptying. Compared to scintigraphy done over a period of 4 hours, the breat h test has a specificity of 80% and sensitivity of 86% [3 2 3 3 ]. Swallowed capsule telemetry telemetry capsule offers a promising new non radioactive method for assessing gastric emptying. This capsule measures pH, pressure and temperature using miniaturized wireless sensor technology. This system has been developed for ambulatory assessment of gastrointestinal (GI) transit . It has been shown that gastric transit time calculated using the SmartPill correlates well with gastric scintigraphy with good sensitivity (82%) and specificity (83%) [3 4 ]. Antroduodenal manometry In antroduodenal manometry, a water perfused or solid state manometric catheter is passed from the na res or mouth and placed fluoroscopically into the stomach and small bowel to
19 measure actual gastroduodenal contractile activity. The frequency and amplitude of fasting MMCs, interdigestive and post prandial contractions can be recorded, and the response to prokinetic agents can be assessed. Gastroparesis is characterized by loss of normal fasting MMCs and reduced postprandial antral contractions and, in some cases, pylorospasm [3 5 ]. Electrogastrography Electrogastrography (EGG) measures gastric slow wave m yoelectrical activity via serosal, mucosal or cutaneous electrodes. EGG is most conveniently recorded with cutaneous electrodes positioned along the long axis of the stomach. Initially a pre prandial recording for 45 to 60 minutes is captured. Patients are given a 500 Kcal cheese or turkey sandwich and an equivalent postprandial recording is captured. The recorded signals are amplified and filtered to exclude contamination by noise from cardiorespiratory activity and patient movement. Computer analysis con verts raw EGG signals to a three dimensional plot. EGG abnormalities are present in 75% of patients with gastroparesis [3 6 ]. EGG is considered by some authors as more of an adjunct to gastric emptying measurement for a comprehensive evaluation of patients with refractory symptoms [3 6 ]. Treatment The general principles of treatment of symptomatic gastroparesis are to: 1) correct fluid, electrolyte, and nutritional deficiencies; 2) identify and rectify the underlying cause of gastroparesis if possible; and 3) reduce symptoms [1 8 3 7 ]. In addition, patient education and explanation of the condition is an integral part of management sense of wellbeing, mental state, behavior and social life. Sensitive caring from the clinical team and professional counseling might be necessary to help the patient cope with the disability. Patients should be informed that a number of drugs might be tried in an attempt to discover the
20 optimal thera peutic regimen and that the aim of treatment is to control rather than cure the disorder [3 8 ]. dysmotility. Common agents that may reduce gastric emptying are opiates, ant i cholinergics, B adrenergic drugs, calcium channel blockers, glucagon, marijuana, alcohol and tobacco. Management can be tailored to the severity of the gastroparesis. For Grade 1(mild) gastroparesis, dietary modifications should be tried first Low doses of antiemetic or prokinetic medications can be taken on an as needed basis. Grade 2 (compensated) gastroparesis is treated by combination of antiemetic and prokinetic medications given at regul arly scheduled intervals. These agents relieve more chronic sy mptoms of nausea, vomiting, early satiety and bloating. They frequently have no effect on abdominal pain. In Grade 3 (severe) gastroparesis or gastric failure, more aggressive treatments including hospitalizations for IV hydration and medications, enteral or parenteral nutritional support and endoscopic or surgical therapy may be needed [1 8 ]. Dietary Manipulation Dietary recommendations rely on measures that promote gastric emptying or, at least theoretically, do not retard gastric emptying. At the outset, it is advisable to engage an solids and liquids as well as dietary balance, meal size and timing of meals. Fats and fiber tend to retard emptying, thus their intake s hould be minimized. This recommendation should be stressed as many of these patients who often concomitantly also have constipation have been told to take fiber supplementation for treatment of their constipation. Multiple small low fat meals about 4 or 5 times each day should be recommended. Carbonated liquids should be avoided to limit gastric distention. Patients are also instructed to take fluids throughout the course of the meal and to sit or walk for 1 2 hours after meals. If above measures are ineffe ctive, the patient may be advised
21 to consume the bulk of their calories as liquid since liquid emptying is often preserved in patients with gastroparesis. Poor tolerance of a liquid diet is predictive of a future poor outcome [1 8 ]. Improving Glycemic Contr ol Patients with diabetes should be counseled to achieve optimal glycemic control. Hyperglycemia itself delays gastric emptying, which is likely mediated by reduced phasic antral contractility and induction of pyloric pressure waves. Hyperglycemia can inhi bit the accelerating effects of prokinetic agents [3 9 ]. Improvement of glucose control increases antral contractility, corrects gastric dysrhythmias and accelerates emptying [ 40 ]. Pharmacologic Therapy The pharmacotherapy of gastroparesis is stepwise, incr emental and long term. The most commonly used drug classes include pro motility and anti emetic agents. Few randomized controlled clinical tria ls have directly compared the different agents [ 41 ]. Consequently, the selection of drug treatment is commonly ma de by trial and error. Prokinetic agents Prokinetic medications enhance the contractility of the GI tract, correct gastric dysrythmias, and promote the movement of luminal contents in the antegrade direction. Prokinetics may predominantly improve symptoms of nausea, vomiting and bloating. They do not seem to relieve abdominal pain and early satiety associated with gastroparesis. They should be administered 30 minutes before meals to elicit maximal clinical effects. Bedtime doses are often added to facilita te nocturnal gastric emptying of indigestible solids. The response to treatment is usually judged clinically rather than following with serial gastric emptying tests because symptom improvements correlate poorly with the acceleration of gastric emptying [ 4 0 ]. A meta analysis assessing benefits of four different drugs in 514 patients in 36 clinical trials reported that the macrolide antibiotic erythromycin is the most potent stimulant of gastric
22 emptying while the erythromycin and dopamine receptor antagonis t, domperidone, is best at reducing symptoms of gastroparesis [ 41 ]. Several factors must be considered when choosing a prokinetic drug for patients with gastroparesis including efficacy, toxicity, regional availability and cost. Erythromycin: Erythromycin is a macrolide antibiotic which is also a motilin receptor agonist [4 2 ]. The intravenous form is the most potent stimulant of solid and liquid gastric emptying [4 3 4 4 ]. Motilin is a polypeptide hormone present in the distal stomach and duodenum which inc reases lower esophageal sphincter pressure and is responsible for initiating the MMC in the antrum of the stomach [4 5 ,4 6 ]. Interestingly, erythromycin has also shown to accelerate emptying in post vagotomy and antrectomy patients [4 7 ]. This may be due to i ts stimulatory effects on the fundus. Metoclopramide: Metoclopramide is a substituted benzamide with several prokinetic actions and anti emetic effects. The prokinetic properties of metoclopramide are limited to the proximal gut. Metoclopromide increases esophageal, fundic and antral contractile amplitudes, elevates lower esophageal sphincter pressure, and improves antropyloroduodenal coordination. Metoclopramide is administered orally in pill or liquid suspension form. Intravenous forms commonly are reser ved for inpatients that cannot retain oral medications. Domperidone: Domperidone, is a benzimidazole derivative with benefits similar to those of metoclopramide. Domperidone does not cross the blood brain barrier and consequently has fewer central side ef fects compared to metoclopramide. Because brainstem structures regulating vomiting are outside the blood brain barrier, domperidone has potent central anti emetic action. Tegaserod: Tegaserod is a 5 HT4 receptor partial agonist used in the treatment of co nstipation predominant with irritable bowel syndrome. In healthy volunteers the drug
23 stimulates small intestinal motility and post prandial antral and intestinal motility. Tegaserod has been shown to accelerate gastric emptying in some [4 8 ] but not all st udies of healthy volunteers [4 9 ]. Tegaserod was completely withdrawn from the US market in April, 2008, due to a reported increase in the risk of cardiovascular adverse effects. Cispride: Cisapride is a 5 HT4 receptor agonist with weak 5 HT3 antagonist pr operties that once was widely used for gastroparesis. This drug was withdrawn from the market in the United States in 2000 because of numerous reports of sudden death from cardiac arrhythmias [ 50 ]. Bethanechol: Bethanechol is an approved smooth muscle mus carinic agonist that increases lower esophageal sphincter pressure and evokes fundoantral contractions but does not induce propulsive contractions or accelerate gastric emptying [ 51 ]. Rarely, the drug may be used as an adjunct with other prokinetic medicat ions in patients refractory to standard treatment with prokinetics and anti emetic drugs. Anti emetic medications At least one component of the clinical benefits observed with some of the available prokinetic drugs, such as metoclopromide and domperidone, stem from their anti emetic actions on brain stem nuclei. Nausea and vomiting are the most disabling symptom s of gastroparesis found in adults and anti emetic agents without stimulatory activity are often used alone or in concert with prokinetic drugs to t reat gastroparesis. Antiemetic medications act on a broad range of distinct receptors subtypes in the peripheral and central nervous systems. Like prokinetics, the choice of antiemetic is empirical and a reasonable approach would initiate treatment with le ss expensive therapies. Phenothiazines: These are the most commonly prescribed traditional antiemetics which include prochlorperazine and tiethyperazine. These drugs are both dopamine and cholinergic
24 receptor antagonists. Prochlorperazine can be administe red in the tablet form, liquid suspension, suppository and by injection. These drugs are suitable for long term use, especially in children due to their extrapyramidal side effects. Serotonin 5 HT3 receptor antagonists: These medications include ondansetr on, granisetron, and dolasetron and are useful for treating nausea and vomiting. These drugs may act on the chemoreceptor trigger zone as well as on peripheral afferent nerve fibers within the vagus nerve [4 4 ]. Ondansetron has no effect on gastric emptying in healthy volunteers and patients with gastroparesis and moreover can cause constipation [5 2 5 3 ]. Antihistamines: Antihistamines acting on H1 receptors exhibit central antiemetic effects [3 7 ]. Commonly prescribed antiemetics include diphenhydramine, di menhydrinate and meclizine. These agents are most useful to treat symptoms related to motion sickness. The mechanism of action is poorly understood but is likely to involve both labyrinthine and chemoreceptor trigger zones. Low dose tricyclic antidepressan ts: Tricyclic antidepressants (TCAs) impair gastrointestinal motility through their anticholinergic activity but have been shown to relieve nausea, vomiting and pain in functional dyspepsia [5 4 5 5 ]. Formal prospective trials of these antidepressants for t he treatment of gastroparesis have not been performed, thus their use is still considered off label. Medications for control of symptoms other than nausea and vomiting Early satiety: Early satiety has been related to defects in fundic accommodation in pat ients with functional dyspepsia [5 6 ]. Nitrates, buspirone, sumitriptan, and selective serotonin reuptake inhibitors promote fundic relaxation in this condition [5 7 5 8 ]. The use of fundic relaxants in managing early satiety in gastroparesis has not been in vestigated.
25 Abdominal pain: Epigastric pain is disabling in some individuals with gastroparesis and can result in excessive utilization of healthcare resources. The pathogenesis of this pain is poorly understood and treatments for this symptom are largely unsatisfactory. The pain in gastroparesis has been postulated to be due to sensory rather than motor dysfunction, and therapies to reduce afferent dysfunction may be more effective for this symptom [5 9 ]; however, this hypothesis has not been tested. Althou gh non steriodal anti inflammatory drugs (NSAIDs) have been shown to ameliorate gastric slow wave dysrhythmias in several healthy subjects [ 60 ], their adverse effects including renal dysfunction and ulcerogenic properties limit their usage on a chronic bas is [ 60 ]. Anti depressent medications may help with gastroparesis associated neuropathic pain [ 61 ]. These include low dose tricyclic antidepressants (TCA), selective serotonin reuptake inhibitors (SSRI), selective noradrenaline reuptake inhibitors (SNRI) an d combined serotonin/noradrenaline reuptake inhibitors. Opiates, including milder agents such as tramadol, should be avoided because of their inhibitory effects on motility as well as risk of addiction. Nutritional Support Some patients with refractory gas troparesis benefit from enteral or parenteral nutrition intermittently for symptom flares or rarely, for permanent support. Patients with chronic symptoms of gastroparesis may develop dehydration, electrolyte abnormalities and/or extreme malnutrition. The choice of nutritional support and its administration route depends on the severity of disease. The indications for supplementation of enteral nutrition include unintentional loss of 10% or more of the usual body weight during a period of 3 to 6 months, ina bility to achieve the recommended weight by the oral route, repeated hospitalizations for refractory symptoms, interference with delivery of nutrients and medications, need for nasogastric intubation to relieve symptoms, and nausea and vomiting resulting i n poor quality of life [1 8 ]. Except in cases of profound malnutrition or electrolyte disturbance, enteral feeding is preferable
26 to chronic parenteral nutrition because of the significant risks of infection and liver disease in the latter treatment. On the other hand, short term total parenteral nutrition (TPN) can reverse rapid weight decline and ensure adequate fluid delivery. Home TPN may be needed for individuals who cannot tolerate enteral feeding. Several options for enteral access and feeding are avai lable and no data exists favoring one approach over the other. However, nasogastric tubes and gastrostomy tubes (G tubes) are not encouraged due to the possibility of worsening gastroparesis and risk of pulmonary aspiration. Jejunostomy tubes are preferred in order to bypass the gastroparetic stomach except if the patient has small bowel dysmotility. Short term nasojejunal feeding is often used to help determine if the patient will tolerate chronic small bowel feeding through a permanent enteral access. For mulas that are low in osmolarity (e.g., Peptamen, Isocal) and have a caloric density of 1.0 1.5 cal per ml are recommended. Initially, infusion rates should be low and then advanced every 4 12 hours as tolerated to meet caloric needs. Eventually, infusions can be converted to nocturnal feedings to free up daytime hours for optional oral intake and to participate in normal daily activities. Endoscopic Treatment Therapeutic endoscopy with pyloric injection of botulinum toxin A may provide benefit in some pati ents with gastroparesis. Botulinum toxin A is a bacterial toxin that inhibits acetylcholine release causing muscle paralysis. Manometric studies in patients with diabetic gastroparesis have shown evidence of prolonged pylorospasm producing a functional out let obstruction [3 5 ]. Use of botulinum toxin for gastroparesis is considered off label and should be considered when other accepted therapies have failed or produced unacceptable side effects. To date, few adverse effects have been reported with botulinum toxin therapy. At our pediatric gastroenterology practice, we do not use this modality of treatment.
27 Surgical Treatment Surgical intervention is increasingly used to treat medically refractory/severe gastroparesis. Limited data is available concerning sur gical treatment of gastroparesis [6 2 ]. The most common procedure is the implantation of the gastric electrical stimulator (GES t ) (Enterra Therapy, by Medtronic Inc.). This device delivers electrical stimulation by two electrodes placed in the seromuscular part of the stomach in proximity to the pacemaker area of the stomach. Although the exact mechanism of action of the GES t is unknown, the clinical effect is believed to be mediated by local neurostimulation [6 3 ]. The stimulation impulses used are able to e xcite nerves but are too weak to excite gastric smooth muscles. Other procedures offered include venting/feeding gastrostomy and jejunostomy tubes, surgical pyloroplasy, gastrectomy and surgical drainage procedures and pancreatic transplantation in diabeti c patients. Apart from GES t and feeding tubes, other surgical procedures are performed as a last resort in carefully evaluated patients with profound gastric stasis [6 2 ]. All of the above mentioned diagnostic tests and therapies are derived from adult lite rature. There is no published data available describing the spectrum of pediatric gastroparesis. The goal of our study is to provide a comprehensive analysis of a large population with gastroparesis, advance the understanding of pediatric gastric dysmotili ty and better plan therapeutic interventions for children. Goals of the Study All of the afore mentioned diagnostic tests and therapies are derived from adult literature. There are no published data available describing the spectrum of pediatric gastr oparesis. The goals of our study were to provide a comprehensive analysis of a large pediatric population with gastroparesis, advance the understanding of pediatric gastric dysmotility and better plan therapeutic interventions for children. While most case s in children are post viral and self
28 limited, chronic symptoms often occur in idiopathic cases. We therefore performed a retrospective study of pediatric patients with GP. The indications for gastric scintigraphy and the outcomes of patients with gastro paresis were defined. We accomplished this by: (a) recording characteristics such as demographics, symptoms, co morbidities, psychological aspects and etiologies of patients with gastroparesis, and (b) analyzing long term follow up to understand the effect iveness of therapy, the course of the disease and outcomes.
29 CHAPTER 2 MATERIALS AND METHOD S Patient Ascertainment and Case Definition This study was approved by the Institutional Review Board of the University of Florida (UF). All UF pediatric gastroente rology practice patients, ages ranging from 0 to 21 years, diagnosed with delayed gastric emptying between January, 2002, and December, 2008, were identified. This was done by using the UF radiology nuclear medicine database which identified all patients w ho had undergone gastric scintigraphy during that time period. Subsequently, electronic chart review was conducted to identify cases that fulfilled the following criteria: 1.) clinical symptoms of nausea, vomiting, abdominal pain, early satiety, bloating a nd weight loss were present without anatomical or mechanical obstruction, and 2.) radiologic evidence of delayed gastric emptying of a radionuclide solid meal ( t Gastric scintigraphy is routinely performed to evaluate patients with gastric emptying patients are not fed for 4 hours prior to the test. Smokers are asked not to smoke the morning of the exam and patients must stop all medications known to affect gastric emptying, e.g., prokinetics and narcotics, for 48 hrs. After an overnight fast patients are fed with either a solid or liquid meal. Solid meal constitutes one grade AA egg (~50ml) cooked scram bled with Tc 99 sulfur colloid (0.5mCi) served with two pieces of white bread with one teaspoon of butter spread on the bread, and 50 ml of water to help ingestion (total calories: 280 kcal, 30 grams of carbohydrates, 13 grams of protein and 10 grams of fa t). The liquid meal consists of 60 ml of radio labeled formula or Pediasure (60 kcals) administered with 0.5mCi of Tc 99m sulfur colloid. After administration of the meal, the patients are imaged continuously for 120 min at 1
30 min per frame using a single h eaded gamma camera, equipped with low energy, high resolution collimator, positioned in the left anterior oblique position to minimize the effects of varying gastric attenuation on quantification of the gastric emptying rate. Alternatively, a dual headed c amera may be used with similar positioning with calculation of geometric mean activity. In addition, for liquid emptying fast imaging acquisition at 10/frame is performed to allow for gastroesophageal reflux A simple linear fit is applied to the rate of gastric emptying with calculation of the gastric emptying half time by extrapolation Normal half time for solids is defined as 45 90 min and normal for liquids is <60min. At 80 min into the oral examination patients are administered IV EES at 2.8mg/kg/dos e up to a maximum of 250 mg (adult dose), infused over 20 min. Calculation of gastric emptying half times pre and post erythromycin is performed. With liquid meals IV EES is infused after 60 min instead of 80 min. Prior to the year 2005, IV metoclopramide was also infused at 0.05mg/kg/dose up to a maximum of 3 mg/dose. We excluded patients: 1) who were not UF pediatric gastroenterology practice patients, 2) whose gastric emptying times were not extrapolated in half times, 3) who had gastric scintigraphy pe rformed which was not ordered by pediatric GI faculty, 4) who were not followed by pediatric GI for gastroparesis, and 5) who had no follow up visits after gastric scintigraphy. Data Collection To ensure reliability and high quality data collection, we des igned a data collection form using Microsoft Access (Appendix). All data were collected from electronic medical records, including all inpatient and outpatient records. Variables were obtained from a thorough review of the physician notes, past medical and surgical history, medication history, review of symptoms, radiological studies, endoscopy and histology. Each clinical record was reviewed and data extracted by an experienced pediatric gastroenterologist and a second year pediatric resident in the same o ffice location. Any uncertainties in data abstraction were discussed thoroughly with
31 the pediatric gastroenterologist. Patients were followed from the time of diagnosis of gastroparesis to the last GI encounter or until December, 2008. The following inform ation was collected from the complete review of medical records: Demographics: age at the time of diagnosis and gender Height (in cm) and weight (in kg) at the time of diagnosis to calculate BMI Gastric emptying half time determined by GES and type of mea l used Response to IV EES and/or IV metoclopramide during gastric scintigraphy and response recorded as t returning within normal emptying range as recorded in the GES electronic report Presenting symptoms: nausea, vomiting, post prandial early satiety, b loating, abdominal pain and weight loss. Medication history: all medications prior to gastric scintigraphy were recorded, including use of PPI and H2 blockers which were recorded as a separate variable. Other medical diagnosis and surgical history. Compli cations of gastroparesis: anemia, esophageal stricture, esophagitis, gastritis, reflux, small bowel bacterial overgrowth, pneumonia, bronchitis, malnutrition, dehydration and bezoars. Psychological diagnosis: depression, anxiety, attention deficit hyper ac tivity disorder (ADHD), bipolar disorders and any other psychiatric/behavioral disorder. Treatment of gastroparesis: with medications, e.g., erythromycin, azithromycin, tegesarod, metoclopramide, and any other prokinetic/anti emetic medication, dietary rec ommendations, enteral feeds, TPN, gastric electrical stimulator, and any other treatments. Last gastric scintigraphy if any, type of meal used, time interval in months between first and last gastric scintigraphy Age at last encounter, height (in cm) and we ight (in kg) at last encounter to calculate last encounter BMI Symptoms at last encounter: nausea, vomiting, early satiety, bloating, abdominal pain and weight loss Etiology of gastroparesis was recorded based on medical record evidence of any of the follo wing : o Idiopathic causes o Post viral causes o Medication causes, e.g., opiates, anti cholinergics, B adrenergics, calcium channel blockers, glucagon, marijuana alcohol, tobacco and others o Surgical causes, e.g., vagotomy, fundoplication, resection, heart/lung transplant and others o CNS causes, e.g., cerebrovascular accidents/trauma, central tumors, labyrinthine disorders, cerebral palsy, seizures and others o PNS causes, e.g., Guillain Barre syndrome, multiple sclerosis, peripheral autonomic dysfunct ion and others o Neuropsychiatric disorders, e.g., anorexia nervosa, bulimia, rumination syndrome, and others
32 o Rheumatologic disorders, e.g., scleroderma, SLE, polymyositis/dermatomyositis, and others o Endocrine and metabolic causes, e.g., diabetes, hypothyroi dism, parathyroidism, cystic fibrosis, electrolyte imbalance, renal insufficiency, neoplastic/paraneoplastic disorders and others o Miscellaneous conditions, e.g., chronic intestinal pseudoobstruction, myotonic disorders, cow milk protein, prematurity, eosin ophilic gastroenteropathy including esophagitis Statistical Analysis We used Minitab statistical software (Cary, NC) and SPSS 16.0 (Chicago, IL) for data analysis. Data were imported into both software packages and descriptive statistics were calculated fo r both continuous and binary variables. These results were expressed as either a proportion or mean with standard deviation. The data set was then divided into separate cohorts based on age, gender, severity of the gastroparesis, type of meal used, and res ponse to medications. Continuous variables were analyzed using either paired T test or 2 sample T test as Chi squared test where appropriate. P values less than 0.05 were considered significant and 95% confidence intervals for each are also shown.
33 CHAPTER 3 RESULTS Patient Characteristics A total of 912 pediatric patients had undergone gastric scintigraphy from January, 2002, to December, 2008, at the Uni versity of Florida. From this group 408 patients (45%) were identified to have delayed gastric emptying. However, 169 patients (41%) from the delayed gastric emptying group were excluded from the study due to our exclusion criteria, i.e., those who were no t UF pediatric gastroenterology practice patients, gastric emptying times not extrapolated in t, gastric scintigraphy not ordered by pediatric GI faculty, patients not followed by pediatric GI for gastroparesis, and patients who had no follow up visits af ter gastric scintigraphy. Among the 239 eligible cases of delayed gastric emptying, 123 patients (51.5%) were female and 116 (48.5%) were male. The mean age (SD) at presentation among all the patients was 7.9 (5.9) years, mean BMI (n=212) at presentatio n was 18.6 (5.3). The mean t of amongst all patients irrespective of type of meal was 146 min (72.32). However, mean t for solid meal was 163 min (90 500 min) and 121 min (62 300 min ) for liquid meals. (Figure 3 1). Twenty eight patients underwent a r epeat gastric scintigraphy with a mean t of 108 min (66.6) during an interval of 2 to 68 months (mean 28.5 months 18.8). Of these, 10 patients (36%) had solid emptying delay while 18 patients (64%) were found to have liquid emptying delay. First and las t t differences in these patients were not significant (p value=0.098). Using the Pearson correlation test we found a correlation between t and presenting symptoms of nausea and abdominal pain only. But, when we performed this test on individual cohorts of solid and liquid emptying, we found a correlation between solid emptying and weight loss, but no correlation between liquid emptying and any of the symptoms.
34 Among the cohort of 239 patients, 84 patients (35%) responded to IV EES, 20 patients (8.4%) we re non responders to IV EES, 20 patients (8.4%) responded to IV MCP, 28 patients (11.7%) were non responders to IV MCP and 135 patients (56.5%) were not tested with either of these drugs at the time of scintigraphy. Of the 94 patients who underwent liquid testing of emptying, 19 patients (20%) responded to IV EES, 15 patients (16%) were non responders to IV EES, 1 patient (1%) responded to IV MCP and 11 patients (11.7%) were non responders of IV MCP. However, of the 145 patients who underwent solid meal te sting of gastric emptying, 65 patients (45%) responded to IV EES, 5 patients (3.5%) were non responders to IV EES, 19 patients (13%) responded to IV MCP and 11 patients (11.7%) were non responders to IV MCP. Chi squared test revealed patients with solid em ptying delay responded better to IV EES than those with liquid emptying delay, i.e., 45% vs. 20% (p value=<0.001). Among all the patients the most common presenting symptoms were vomiting and abdominal pain (67.8% and 50.6% respectively) (Table 3 1). Oth er symptoms included nausea (28.4%), weight loss (26.8%), early satiety (24.7%) and bloating (7.1%). Subsequently, a decrease in the frequency of all symptoms, especially vomiting, was observed at the last encounter. Most patients were treated with combina tion therapy which predominantly consisted of EES (73.64%) and dietary modifications (41.4%), but other forms of treatment with drugs such as metaclopramide (29.7%), azithromycin (5.4%), tegaserod (6.7%), enteral feeds (23%), and TPN (3%) were also tried. Medications such as cisapride, propulsid, anti histamines, anti emetics and tricyclic antidepressants were used by 4% of the patients. None of the patients received pyloric botox injections or gastric electrical stimulation.
35 The most common complication of gastroparesis was esophageal reflux (67.4%), followed by histologically diagnosed esophagitis and gastritis (16.7% and 15% respectively). Other complication s included dehydration (3.7%), anemia (2.5%), bezoars (1.67%), small bowel bacterial over growth (1.26%), malnutrition (1.26%), and esophageal strictures (0.42%). Patients were found to have multiple presumed etiologies for gastropareis. Among all the patients, the most common cause was identified to be idiopathic gastroparesis in 167 patients (70%) (Table 3 2). A significant number of patients had CNS disease, which was presumed as the etiology of their GP. CNS disorders included cerebral palsy, seizure disorder, developmental delay, cerebr o vascular accident and related p rematurity The other main ca tegories in descending order included fundoplication, post viral causes and others i.e diabetes, hypothyroid, eosinophilic esophagitis, eating disorders, cystic fibrosis etc Co morbid psychiatric conditions such as ADHD were reported in 20 patients (8.4% ), behavioral problems in 19 patients (8%), anxiety in 15 patients (6.3%), depression in 10 patients (4%), and bipolar disorder in 4 patients (1.7%). Outcomes for the Entire Cohort This hospital based cohort study was followed for a mean of 24 months. Our outcome variables were change in symptoms, e.g. nausea, vomiting, early satiety, abdominal pain, bloating, and weight loss. We found significant improvement in outcomes at the end of the follow up period regardless of type of treatment used (Figure 3 2). The mean BMI changed from 18.6 (5.3) to 19.8 (8.1) but this change was not significant (p value=0.415). Using the Fisher exact T test, we found a significant difference in all symptom outcomes (Table 3 1). The same test was applied to compare the symptom outcomes of total responders with total non responders of IV EES but showed no significant difference. Of those who underwent repeat GES (n=28),
36 improvements were noted in vomiting (p value=<0.001) and weight loss (p value=0.009). Other symptom outcomes w ere unchanged at the end of follow up for this group. Outcomes According to Gender For females, the mean age (SD) at presentation was 9 (5.9) years and for males it was 6.7 (5.7) years (p value=0.002). There was not a significant difference in the frequ ency of presenting symptoms between the genders except that females reported more nausea than weight loss (Table 3 6). In addition, their individual outcomes revealed significant improvement in last encounter symptoms. We did not find a significant differ ence in symptom outcomes when comparing males with females except for abdominal pain, which was more commonly reported by females (Table 3 3). Also, we found no significant difference between the genders in regard to co morbid psychiatric disorders, i.e., ADHD, depression, anxiety, behavior disorders and bipolar disorder. Outcomes According to Age Groups We categorized patients according to the following age groups, <1yr, 1 5 yrs, 6 10 yrs, 11 16 yrs and > 17 yrs, and then we performed descriptive analysis as well as Fisher exact test of proportion to measure outcomes (Table 3 4). <1 yr: A total of 29 patients who were <1yr of age were diagnosed with delayed gastric emptying with mean t of 120 min (61.8). Twenty one patients (72.4%) were males and 8 pati ents (27.5%) were females. Vomiting was the presenting symptom in the majority of the patients; second most common was weight loss. Improvement in both vomiting and weight loss were observed at follow up. Other symptom outcomes were unchanged at the end of follow up. 1 5 yrs: Sixty eight patients were diagnosed with gastroparesis in this age group with mean t of 128 min (66). Thirty four patients (50%) were males and 34 patients (50%) were females. Vomiting and abdominal pain were the most common presen ting symptom followed by
37 weight loss, early satiety, nausea, and bloating. At follow up we noted decreased vomiting, early satiety, and weight loss. 6 10 yrs: A total of 48 patients had gastroparesis with mean t of 144 min (70). Twenty five patients (5 2%) were males and 23 patients (48%) were females. Again, vomiting and abdominal pain were the most common presenting symptoms followed by early satiety, nausea, weight loss, and bloating. Only the rates of vomiting, early satiety and abdominal pain improv ed at follow up. 11 16 yrs: Seventy six younger teenage patients were identified with a mean t of 168 min (75). Forty six patients (60.5%) were females and 30 patients (39.5%) were males. Symptoms by decreasing frequency included abdominal pain, vomitin g, nausea, early satiety, weight loss, and bloating. All symptoms outcomes except for bloating were improved at follow up. >17 yrs: Eighteen patients in this age group were diagnosed with gastroparesis with a mean t of 175 min (75). Twelve patients (66. 7%) were females and 6 patients (33.3%) were males. Symptoms by decreasing frequency included abdominal pain, nausea, vomiting, early satiety, weight loss and bloating. Only early satiety improved at follow up. Severity Scale Related Outcomes We further di vided our cohort into 4 categories of delayed solid emptying and 3 categories of delayed liquid emptying. Both were stratified by t. Therefore, solid emptying delay (n=145) was divided into the following categories: very severe (>241 min), severe (191 240 min), moderate (141 190 min) and mild (90 140 min) (Table 3 5). Liquid emptying delay (n=94) was divided into categories of: severe (>141 min), moderate (101 140 min) and mild (61 100 min) (Table 3 6).
38 Solid Emptying Delay Outcomes Very severe (>241 min) : We had 24 patients with very severe solid emptying delay who had a mean age at presentation of 12.5 yrs (4.7). Sixteen patients were females (66.6%) and 8 patients were males (33.3%). Patients presented with abdominal pain, nausea, vomiting, weight los s, early satiety and bloating in decreasing frequency. Improvements in weight loss, abdominal pain, vomiting and nausea were noted at follow up. Severe (191 240 min): Thirteen patients were identified with severe delay with mean age at presentation of 13.8 (3.6). Ten patients (77%) were females and 3 patients (23%) were males. Most patients presented with abdominal pain, followed by vomiting, nausea, weight loss, early satiety and bloating. With this small group only vomiting improved at follow up. Moderat e (141 190 min): Twenty four patients were identified with moderate delay in gastric emptying with mean age at presentation of 11.4 yrs (3.7). Females were 15 in number (62.5%) and males 9 (37.5%). This group presented primarily with abdominal pain and vo miting, t hen in decreasing frequency with nausea, early satiety, weight loss and bloating. Improvements in vomiting and early satiety were seen at follow up. Mild (90 140 min): We had eighty four patients in this group with mean age of 10.5 yrs (4.5). For ty five patients (53.7%) were females and 39 patients (46.4%) were males. Abdominal pain and vomiting were predominant, followed by nausea, early satiety, weight loss and bloating. Improvements in abdominal pain, early satiety, vomiting and nausea were see n at follow up. Liquid Emptying Delay Outcomes Severe (>141 min): Seventeen patients were identified with mean age of 3.5 yrs (4.6). Of these, 9 patients (53%) were females and 8 patients (47%) were males. Vomiting was present
39 in the majority of the patie nts, then weight loss, nausea, abdominal pain, early satiety and bloating. Improvement was seen only in vomiting. Moderate (101 140 min): We had 30 patients in this group with mean age at presentation of 2.8 yrs (3.5). Twelve females (40%) and 18 males (6 0%) were identified. Again, most presented with vomiting, then weight loss, abdominal pain, early satiety and bloating. Improvements in vomiting and weight loss only were observed at follow up. Mild (61 100 min): Forty seven patients were in this group, wi th mean age of 2.3 yrs (3.3). Sixteen patients (34%) were females and 31 patients (66%) were males. In decreasing frequency, presenting symptoms were vomiting, weight loss, abdominal pain, early satiety, nausea and bloating. Improvements in weight loss, a bdominal pain, and vomiting were observed at follow up. Outcomes Based on Presumed Etiology of Gastroparesis Most of the patients had multiple presumed e tiologies of GP. It was impossible to differen t iate a single etiology as the definitive cause of GP i n these patients. Nevertheless w e divided our cohort into 6 most common categories of etiology : 1) idiopathic GP, 2) GP due to cerebral palsy, 3) GP due to seizure disorder, 4) GP due to prematurity, 5) post fundoplication GP, and 6) post viral GP. Outco mes based on these categories follow. Idiopathic causes: The majority of GP patients (167 patients, 70%) belonged to this group. There were 82 females (49%) and 85 (51%) males. Mean age at presentation was 8 yrs (5.8) and mean t was 143 min (69.6). Six ty four percent had vomiting, 55.7% had abdominal pain, 31% had nausea, 29% had satiety, 23% had weight loss and 6% had bloating. Improvement in all symptoms except weight loss was observed at follow up. Cerebral palsy: Thirty nine patients were identified to have cerebral palsy and GP with mean age of 4.8yrs (4.7) and mean t of 147 min (72). There were more males (22 patients,
40 56%) than females (17 patients, 43.6%) in this group. Patients presented mostly with vomiting (82%) and weight loss (31%). The rest of the symptoms in decreasing frequency were abdominal pain (18%), nausea (18%), early satiety (13%) and bloating (10%). Symptom improvement in this group was observed for abdominal pain and vomiting only. Seizure disorder: There were 37 patients in this group, with mean age of presentation at 5.2 yrs (5.4), mean t of 131 min (60.6) and male/female percentages of 51 (19 patients) and 49 (18 patients) respectively. Again, patients mainly presented with vomiting (84%) and weight loss (24%). Other fr equencies were abdominal pain 16%, nausea 13.5% and bloating 2.7%. None of the symptoms improved at follow up. Prematurity: Thirty two patients were born prematurely and presented at mean age of 6 yrs (5) and mean t of 123 min (45). Their male/female r atio was 56% (18 patients) and 4 4% ( 14 patients) respectively. Eighty one percent had vomiting, 28% had abdominal pain, 15.6% had nausea, 15.6% had early satiety, 12.5% had weight loss and 6% had bloating. Improvement only in abdominal pain and early satie ty was observed at follow up. Post fundoplication : Sixteen patients who developed GP underwent Nissen fundoplication. Mean age was 5 yrs (5.8) at presentation with mean t of 142 min (67) Ten patients (62.5%) were females and 6 patients were males (37 .5%). Again, vomiting and weight loss were predominant presenting symptoms (87.5% and 25% respectively) followed by abdominal pain (12.5%) and nausea (6.2%). At follow up there was improvement only in weight loss. Post viral GP: Twelve patients were diagn osed with post viral GP, with mean age of 12 yrs (5) at onset and mean t of 179 min (91). Males and females were 41.6% (5 patients) and 58.3% (7 patients) respectively. Both vomiting and abdominal pain presented with equal
41 frequency of 66.6% each, foll owed by both nausea and early satiety at 41.7% each, weight loss in 33.3% and bloating in 8.3%. These patients had symptom improvements in vomiting, early satiety, abdominal pain and weight loss. Other symptoms did not improve at follow up. Table 3 1. Freq uency of symptoms at first and last encounter Table 3 2. Etiology of gastroparesis Cause of gastroparesis n (%) Idiopathic Cerebral palsy Seizure disorder Prematurity Fundoplication Post viral Others 167 (70) 39 (16.3) 37 ( 1 5 .5 ) 32 (13.4) 16 (6.7) 12 (5) 77 (32) Table 3 3. Frequ ency and outcomes of symptoms in males and females Males n=116 (%) Females n=123 (%) Comparison of outcomes between males and females Symptoms First encounter Last encounter P value First encounter Last encounter P value P value Vomiting 87 (7 5) 25 (21.5) <0.001 75 (61) 22 (18) <0.001 0.5 Abdominal pain 52 (45) 24 (20.7) <0.001 69 (56) 46 (37.4) <0.001 0.004 Weight loss 30 (26) 8 (7) <0.001 34 (27.6) 14 (11.4) 0.004 0.23 Nausea 29 (25) 13 (11.2) 0.002 38 (31) 23 (18.7) 0.014 0.104 Ear ly satiety 30 (26) 6 (5) <0.001 29 (23.5) 9 (7.3) <0.001 0.5 Bloating 5 (4) 3 (2.6) 0.687 12 (9.7) 4 (3.2) 0.057 0.76 Symptoms N (%) first encounter N (%) last encounter p value Vomiting Abdominal pain Nausea Weight loss Early satiety Bloating 162 (67.8) 121 (50.6) 68 (28.5) 64 (26.8 ) 59 (24.7) 17 (7.1) 47 (19.7) 70 (29.3%) 36 (15) 22 (9.2) 15 (6.3) 7 (2.9) <0.001 <0.001 <0.001 <0.001 <0.001 0.035
42 Table 3 4. Symptom outcomes by age group Symptoms < 1 yr (n=29) 1 5 yr (n=68) 6 10 yr (n=48) 11 16 yrs (n=76) >17 yrs (n=18) F irst symp ** % Last symp % p value First symp % Last symp % p value First symp % Last symp % p value First symp % Last symp % p value First symp % Last symp % p value Nausea 0 3.5 10 4.4 25 18.7 48.7 18.4 61 50 Vomiting 96.5 20.7 72 19 73 21 5 2.6 17 55.5 28 Early satiety 7 0 16 3 27 6.2 33 10.5 44.4 11 Abdominal p ain 3.5 3.5 28 17.6 67 31 75 43.4 66.7 50 Bloating 0 7 6 1.5 10.4 2 5.3 1.3 22 11 Weight loss 31 7 25 5.9 20 8 27.6 11.8 39 16.6 p value<0.05 ** S ymp = symptom
43 Table 3 5. Outcomes of solid emptying delay based on severity Symptoms Very severe (>241min) n=24 Severe (191 241 min) n=13 Moderate ( 141 190min) n=24 Mild (90 140min) n=84 1st symp ** % Last symp % p value 1 st symp % Last symp % p value 1 st symp % Last symp % p value 1 st symp % Last symp % p value Nausea 62.5 12.5 38 23 37.5 25 42 25 Vomiting 85.3 20.8 61.5 23 58 16.6 56 23 Early satiety 37.5 16.7 23 7.7 33.3 8.3 37 7 Abdominal pain 71 41.7 84.6 53.8 6 6.6 41.7 74 43 Bloating 8.3 4 7.6 0 12.5 0 9.5 3.5 Weight loss 41.6 12.5 31 23 21 12.5 16.7 8.3 *p value<0.05 ** Symp = symptom Table 3 6. Outcomes of liquid emptying delay based on severity Symptoms Severe (141 min) N=17 Moderate (101 140 min) N=30 Mild (61 100 min) N=47 1 st symp ** % Last symp % p value 1 st symp % Last symp % p value 1 st symp % Last symp % p value Nausea 11.7 0 2 3.3 2 4.3 Vomiting 88 5.9 83 16.7 83 21.3 Early satiety 6 5.9 8.5 0 8.5 2 Abdominal pain 11.7 11.7 17 10 17 4.3 Bloating 6 11.7 2 3.3 2 0 Weight loss 35 17.6 32 0 32 6.4 p < 0.05 ** symp = symptom
44 Figure 3 1. Frequency of t in solids and liquids Figure 3 2. Symptom out comes of all patients 0 100 200 300 400 500 600 1 10 19 28 37 46 55 64 73 82 91 100 109 118 127 136 145 Frequency Minutes solid half time liquid half time 0 10 20 30 40 50 60 70 80 Nausea Vomiting Abdominal pain Early satiety Bloating Weight loss Symptoms Percentage of patients First encounter Last encounter
45 CHAPTER 4 DISCUSSION In a large cohort of pediatric patients (n=239) referred to a large academic medical center, we have attempted to define the full spectrum of gastroparesis in the pediatric population. Most of the previous data o n this condition has been reported from adult studies, which may not reflect the spectrum of gastroparesis in children. Adult cohorts have consistently revealed an overwhelming female predominance (~80%) in this condition [2, 6 4 ]. In addition, the etiologi c categories in adults have been 1/3 idiopathic, 1/3 diabetic and 1/3 post surgical/miscellaneous causes [2, 1 7 6 4 ]. Adult literature establishes high morbidity and mortality of this condition [1 8 ,6 4 ]. Our study revealed important differences from the rep orted adult literature with an almost equal distribution of between male and female pediatric patients (51.5% and 48.5% respectively) and similar etiologies for each gender. The gender differences started to increase as the age increased, such that with p atients over 17 yrs of age, about 2/3 were female. Males presented at an earlier age of 6 yrs versus females who presented at 9 yrs, but both genders were found to have similar outcomes. This finding has differs from adult studies, where females have shown a poorer prognosis [2, 6 4 ]. Existing literature does not reveal any correlation between t and symptoms. With our data we were able to correlate between severity of gastroparesis by t and frequency of presenting symptoms of nausea and abdominal pain. Un fortunately, in this retrospective analysis, we could not assess the severity of the symptoms by other measures such as number of episodes of emesis per day. Etiologies in pediatric GP were found to differ from adults, as there was a predominance of idiopa thic gastroparesis (70 %) whereas t he single most common cause of gastroparesis in the
46 adult population is diabetes. The lack of a predominant diabetic cause in our cohort may reflect the time that is required for diabetes to cause gastric dysmotility. The next most common causes or associated factors were CNS causes, e.g., cerebral palsy, seizure disorder, and developmental delay. Again, in this retrospective study, it is difficult to separate associated diagnoses from actual causative factors. Also, premat urity seemed to be a risk factor for developing gastroparesis. This information suggests the need for further investigation into the pathophysiology of GP and possibly a significant role of the CNS and its relationship with the enteric nervous system in th e pathogenesis of gastroparesis. Two hundred and six patients out of 239 had associated co morbidities which may be contributing to GP or reflect complications of the condition itself. Another important factor to consider is that only 3 patients were takin g opiates and 4 patients were smokers, therefore a majority of our patients were not exposed to medications or behaviors that have been implicated in adult gastroparesis. Most series describing gastroparesis in adults document the extensive use of such med ications or behaviors. Mandatory p rokinetic testing during scintigraphy is a valuable addition to the GES protocol in our institution and to our knowledge is not widely performed. This practice enabled us to further divide the cohort to responders and non responders to IV EES or IV MCP. We found that IV EES was more effective in improving solid emptying when compared to liquid emptying at the time of gastric emptying study. A possible explanation maybe that liquid emptying delay is considered an indicator of progressively worsening gastroparesis; therefore, these patients may have more severe disease with poorer response rates to prokinetics. It is unclear whether patients who respond to these medications have an improved outcome or not, as
47 tachyphylaxis st ill develops during clinical use. We plan to further study this sub population of patients to assess the effect of medications. The frequency of presenting symptoms is different from adults, who usually present with nausea and vomiting [2, 6 4 ]. In our coho rt, we noted that abdominal pain was a very common presenting feature. This was observed even in the older children and in adolescents. Interestingly, in our older age group (>17 yrs), abdominal pain and nausea were prominent presenting symptoms. The promi nence of abdominal pain in our pediatric patients with gastroparesis may be due to the pronounced association of pain with idiopathic gastropareis, which in turn is a major cause of GP in children . Another important finding is related to mental health. When compared to adults, patients in this study had far fewer (28.4% vs 62%) co morbid psychiatric conditions . Again, this may be due to the duration of symptoms patients with severe gastroparesis have a tendency to become depressed and anxious. Th e finding of gastroesophageal reflux as the most common complication of GP is a reminder that patients with reflux and non ulcer dyspepsia can have delayed gastric emptying [63, 64]. Although 67% of GP patients were diagnosed with gastroesophageal reflux, only 17% and 15% were found to have histological evidence of esophagitis or gastritis respectively. Hence, whether vomiting symptoms are due to GP or reflux cannot be distinguished in the pediatric population. Most patients were treated with EES and dietar y modifications (73.6% and 41% respectively). Although IV EES significantly improves gastric emptying of a solid meal, oral EES is not as effective. Nevertheless, significant improvement was observed in the outcomes of patients regardless of type of therap y. Patients who do not respond well to oral EES could be tried on IV EES. Subcutaneous MCP has also been tried in this setting if tolerated [1 8 ].
48 Whatever the form of treatment used, we found a statistically significant improvement in all symptoms at the e nd of the mean 2 year follow up with similar results in both genders. One possible reason is that the natural history of idiopathic pediatric gastroparesis may result in improvement over time. In future studies, we will plan to study the outcomes of patien ts with and without pharmacologic treatment and attempt to identify those cases which do not respond to conventional treatments. The frequency and prevalence of co morbid psychiatric conditions was the same in both the genders, and since the overall incide nce of these disorders compared to adults was also lower, this indicated that psychiatric conditions are not a major risk factor in pediatric GP co morbidity as reported in adults . The most common age groups with GP were the 11 16 yrs (76) or 1 5 yrs ( 68) categories. We will analyze these groups in detail for future studies, as the likely etiologies and treatments will differ. The most prominent outcome improvement within all age groups was seen in vomiting. As for severity of emptying delay, patients w ith either mild or very severe emptying delay had more improvement in all their symptoms; however patients with moderate or severe delay had improvement in vomiting only. Literature on liquid emptying delay is very limited. Based on adult data it is consi dered as due to the age (infants/toddlers) of patients instead of intolerance to solid meals. We had six patients who had t >240 min (>4 hrs emptying delay) w ith liquid emptying. These patients had very severe emptying delay. Five of those six required enteral feeds, and underwent fundoplication, g tube placement and pyloroplasy. In addition, these five patients had CNS disorders and developmental delays. The r emaining patient was thought to have post viral
49 gastroparesis. This again reinforces the fact that CNS conditions may possibly play a major role in the pathophysiology of GP. Diabetic gastroparesis was present only in nine patients (4%) of the cohort and these patients were all type 1 diabetics. This information is contrary to adult literature, where 1/3 of GP patients are diabetics. Four (44%) of the 9 patients also had cystic fibrosis. Whether the gastric emptying delay in these 4 patients was due to dia betes related neuropathy or GI dysmotility found in CF patients is unknown. The correction of hyperglycemia in diabetics is essential in obtaining optimal management results. The current study has some limitations. First, this was a retrospective cohort an d hence misclassification of gastroparesis variables in records may potentially change our estimates. Second, we did not record duration of treatment, which was difficult to extrapolate solely from electronic records; therefore, outcomes based on duration of treatment could not be performed. This limitation may be the basis of a future prospective study. Third, we did not report ethnicity in this study, and it may not be representative of all ethnic groups with GP because our cohort consisted mainly of a wh ite population. Hence, whether ethnic differences influence the epidemiology of pediatric GP is unknown. Fourth, since this is a hospital based study instead of a population based study or case control study, we were unable to estimate the prevalence of GP Tertiary care center bias was present and this study may be representative of more severe cases instead of milder presentation in the general population. A key issue is whether primary care providers under report or under recogn ize GP in children Finall y, the gastric emptying scintigraphy protocol used at UF is not in accordance with the recent consensus recommendations of gastric emptying scintigraphy published in 2008 [2 3 ]. However, our protocol of continuous scanning for 2 hrs is validated by the Nucl ear Medicine Society .
50 In summary, this is, to our knowledge, the first large hospital based study to describe the demographics, etiologies and outcomes of gastroparesis in the pediatric population. Gastroparesis is an uncommon condition in the commun ity compared with tertiary based hospital settings, but still represents a major disease burden. Most patients with gastroparesis need continuous medical care, but long term outcome in the pediatric population seems promising despite limited therapeutic ch oices. This study will be the springboard for future studies in which we will more accurately describe sub populations of children with gastroparesis, develop and validate quality of life and severity tools for this condition, and assess newer therapies fo r this debilitating condition.
51 APPENDIX Data collection form
53 REFERENCES 1. Frank L, Kleinman L, Ganoczy D, et al. Upper gastrointestinal symptoms in North America: prevalence and relationship to healthcare utilization and quality of lif e. Dig Dis Sci. 2000 Apr;45(4):809 18. 2. Soykan I, Sivri B, Sarosiek I, et al. Demography, clinical characteristics, psychological and abuse profiles, treatment, and long term follow up of patients with gastroparesis. Dig Dis Sci 1998 Nov;43(11):2398 404 3. Hy ams JS, Burke G, Davis PM, et al. Abdominal pain and irritable bowel syndrome in adolescents: a community based study. J Pediatr. 1996 Aug;129(2):220 6 4. Hyams JS, Davis P, Sylvester FA, et al. Dyspepsia in children and adolescents: a prospective study. J Pe diatr Gastroenterol Nutr. 2000 Apr;30(4):413 8. 5. Chitkara DK, Camilleri M, Zinsmeister AR, et al. Gastric sensory and motor dysfunction in adolescents with functional dyspepsia. J Pediatr. 2005 Apr;146(4):500 5. 6. 6. Chitkara DK, Delgado Aros S, Bredenoord AJ et al. Functional dyspepsia, upper gastrointestinal symptoms, and transit in children. J Pediatr. 2003 Nov;143(5):609 13. 7. Ali T, Hasan M, Hamadani M, et al. Gastroparesis. South Med J. 2007 Mar;100(3):281 6 8. Park MI, Camilleri M. Gastroparesis: clinical u pdate. Am J Gastroenterol 2006 May;101(5):1129 39 9. Huizinga JD. Neural injury, repair, and adaptation in the GI tract. IV. Pathophysiology of GI motility related to interstitial cells of Cajal. Am J Physiol. 1998 Sep;275 (3 Pt 1):G381 6 10. Mearin F, Camilleri M, Malagelada JR. Pyloric dysfunction in diabetics with recurrent nausea and vomiting. Gastroenterology. 1986 Jun;90(6):1919 25 11. Camilleri M, Malagelada JR. Abnormal intestinal motility in diabetics with the gastroparesis syndrome. Eur J Clin Invest. 1984 Dec;14(6):420 7 12. Hyman PE, Di Lorenzo C, McAdams L, et al. Predicting the clinical response to cisapride in children with chronic intestinal pseudo obstruction. Am J Gastroenterol. 1993 Jun;88(6):832 6. 13. Peeters TL. New motilin agonists: a long and winding r oad. Neurogastroenterol Motil. 2006 Jan;18(1):1 5 14. Murray CD, Martin NM, Patterson M, et al. Ghrelin enhances gastric emptying in diabetic gastroparesis: a double blind, placebo controlled, crossover study. Gut. 2005 Dec;54(12):1693 8. Epub 2005 Aug 5.
54 15. Park man HP, Hasler WL, Fisher RS; American Gastroenterological Association. American Gastroenterological Association technical review on the diagnosis and treatment of gastroparesis. Gastroenterology. 2004 Nov;127(5):1592 622. 16. Abell TL, Bernstein RK, Cutts T, et al. Treatment of gastroparesis: a multidisciplinary clinical review. Neurogastroenterol Motil. 2006 Apr;18(4):263 83 17. Revicki DA, Rentz AM, Dubois D, et al. Gastroparesis Cardinal Symptom Index (GCSI): development and validation of a patient reported ass essment of severity of gastroparesis symptoms. Qual Life Res. 2004 May;13(4):833 44. 18. Boccia G, Buonavolont R, Coccorullo P, et al. Dyspeptic symptoms in children: the result of a constipation induced cologastric brake? Clin Gastroenterol Hepatol. 2008 May ;6(5):556 60 19. Parkman HP, Schwartz SS. Esophagitis and gastroduodenal disorders associated with diabetic gastroparesis. Arch Intern Med 1987 Aug;147(8):1477 80 20. Blam ME, Lichtenstein GR. A new endoscopic technique for the removal of gastric phytobezoars. Ga strointest Endosc 2000 Sep;52(3):404 8. 21. Abell TL, Camilleri M, Donohoe K, Hasler WL, Lin HC, Maurer AH, McCallum RW, Nowak T, Nusynowitz ML, Parkman HP, Shreve P, Szarka LA, Snape WJ Jr, Ziessman HA. Consensus recommendations for gastric emptying scintigr aphy: a joint report of the American Neurogastroenterology and Motility Society and the Society of Nuclear Medicine. Am J Gastroenterol 2008 Mar;103(3):753 63. Epub 2007 Nov 19 [PMID: 18028513] 22. Camilleri M, Zinsmeister AR, Greydanus MP, Brown ML, Proano M Towards a less costly but accurate test of gastric emptying and small bowel transit. Dig Dis Sci. 1991 May;36(5):609 15 [PMID: 2022162] 23. Feldman M, Smith HJ, Simon TR. Gastric emptying of solid radiopaque markers: studies in healthy subjects and diabetic patients. Gastroenterology. 1984 Oct;87(4):895 902 [PMID: 6468877] 24. Bateman DN, Whittingham TA. Measurement of gastric emptying by real time ultrasound. Gut. 1982 Jun;23(6):524 7 [PMID: 7076028] 25. Bolondi L, Bortolotti M, Santi V, Calletti T, Gaiani S, Lab G Measurement of gastric emptying time by real time ultrasonography. Gastroenterology. 1985 Oct;89(4):752 9 [PMID: 3896910] 26. Holt S, Cervantes J, Wilkinson AA, Wallace JH. Measurement of gastric emptying rate in humans by real time ultrasound. Gastroenterol ogy. 1986 Apr;90(4):918 23 [PMID: 3512357]
55 27. Gentilcore D, Hausken T, Horowitz M, Jones KL. Measurements of gastric emptying of low and high nutrient liquids using 3D ultrasonography and scintigraphy in healthy subjects. Neurogastroenterol Motil. 2006 Dec;1 8(12):1062 8 [PMID: 17109689] 28. Feinle C, Kunz P, Boesiger P, Fried M, Schwizer W. Scintigraphic validation of a magnetic resonance imaging method to study gastric emptying of a solid meal in humans. Gut. 1999 Jan;44(1):106 11 [PMID: 9862835] 29. Kuiken SD, Sams om M, Camilleri M, Mullan BP, Burton DD, Kost LJ, Hardyman TJ, Brinkmann BH, O'Connor MK. Development of a test to measure gastric accommodation in humans. Am J Physiol 1999 Dec;277(6 Pt 1):G1217 21 [PMID: 10600819] 30. Viramontes BE, Kim DY, Camilleri M, Lee JS, Stephens D, Burton DD, Thomforde GM, Klein PD, Zinsmeister AR. Validation of a stable isotope gastric emptying test for normal, accelerated or delayed gastric emptying. Neurogastroenterol Motil 2001 Dec;13(6):567 74 [PMID: 11903917] 31. Braden B, Adams S Duan LP, Orth KH, Maul FD, Lembcke B, Hr G, Caspary WF. The [13C]acetate breath test accurately reflects gastric emptying of liquids in both liquid and semisolid test meals. Gastroenterology. 1995 Apr;108(4):1048 55 [PMID: 7698571] 32. Kuo B, McCallum RW, K och KL, Sitrin MD, Wo JM, Chey WD, Hasler WL, Lackner JM, Katz LA, Semler JR, Wilding GE, Parkman HP. Comparison of gastric emptying of a nondigestible capsule to a radio labelled meal in healthy and gastroparetic subjects. Aliment Pharmacol Ther. 2008 Jan 15;27(2):186 96. Epub 2007 Oct 28 [PMID: 17973643] 33. Mearin F, Camilleri M, Malagelada JR. Pyloric dysfunction in diabetics with recurrent nausea and vomiting. Gastroenterology. 1986 Jun;90(6):1919 25 [PMID: 3699409] 34. Parkman HP, Hasler WL, Barnett JL, Eaker EY; American Motility Society Clinical GI Motility Testing Task Force. Electrogastrography: a document prepared by the gastric section of the American Motility Society Clinical GI Motility Testing Task Force. Neurogastroenterol Motil. 2003 Apr;15(2):89 10 2. Review [PMID: 12680908] 35. Quigley EM, Hasler WL, Parkman HP. AGA technical review on nausea and vomiting. Gastroenterology. 2001 Jan;120(1):263 86. Review. No abstract available [PMID: 11208736] 36. Patrick A, Epstein O. Review article: gastroparesis. Aliment Pharmacol Ther. 2008 May;27(9):724 40. Epub 2008 Feb 4 [PMID: 18248660] 37. Petrakis IE, Vrachassotakis N, Sciacca V, Vassilakis SI, Chalkiadakis G. Hyperglycaemia attenuates erythromycin induced acceleration of solid phase gastric emptying in idiopathic and diabetic gastroparesis. Scand J Gastroenterol. 1999 Apr;34(4):396 403 [PMID: 10365900]
56 38. Talley NJ. Diabetic gastropathy and prokinetics. Am J Gastroenterol. 2003 Feb;98(2):264 71. Review [PMID: 12591039] 39. Sturm A, Holtmann G, Goebell H, Gerken G. Prokinetics in patients with gastroparesis: a systematic analysis. Digestion. 1999 Sep Oct;60(5):422 7 [PMID: 10473966] 40. Farrugia G, Macielag MJ, Peeters TL, Sarr MG, Galdes A, Szurszewski JH. Motilin and OHM 11526 activate a calcium current in human and canine jejuna l circular smooth muscle. Am J Physiol 1997 Aug;273(2 Pt 1):G404 12 [PMID: 9277420] 41. DiBaise JK, Quigley EM. Efficacy of prolonged administration of intravenous erythromycin in an ambulatory setting as treatment of severe gastroparesis: one center's experi ence. J Clin Gastroenterol. 1999 Mar;28(2):131 4 [PMID: 10078820] 42. Kendall BJ, Chakravarti A, Kendall E, Soykan I, McCallum RW. The effect of intravenous erythromycin on solid meal gastric emptying in patients with chronic symptomatic post vagotomy antrecto my gastroparesis. Aliment Pharmacol Ther. 1997 Apr;11(2):381 5 [PMID: 9146779] 43. Peeters TL. Agonist effect of erythromycin and its analogues on motilin receptors. A new family of prokinetics? Clinical interest. Acta Gastroenterol Belg. 1993 May Aug;56(3 4): 257 60 [PMID: 8266766] 44. Parkman HP, Pagano AP, Vozzelli MA, Ryan JP. Gastrokinetic effects of erythromycin: myogenic and neurogenic mechanisms of action in rabbit stomach. Am J Physiol. 1995 Sep;269(3 Pt 1):G418 26 [PMID: 7573453] 45. Ramirez B, Eaker EY, Drane WE, Hocking MP, Sninsky CA. Erythromycin enhances gastric emptying in patients with gastroparesis after vagotomy and antrectomy. Dig Dis Sci. 1994 Nov;39(11):2295 300 [PMID: 7956594] 46. Degen L, Matzinger D, Merz M, Appel Dingemanse S, Osborne S, Lchinger S Bertold R, Maecke H, Beglinger C. Tegaserod, a 5 HT4 receptor partial agonist, accelerates gastric emptying and gastrointestinal transit in healthy male subjects. Aliment Pharmacol Ther 2001 Nov;15(11):1745 51 [PMID: 11683688] 47. Prather CM, Camilleri M, Z insmeister AR, McKinzie S, Thomforde G. Tegaserod accelerates orocecal transit in patients with constipation predominant irritable bowel syndrome. Gastroenterology 2000 Mar;118(3):463 8 [PMID: 10702196] 48. Griffin JP. Prepulsid withdrawn from UK & US markets Adverse Drug React Toxicol Rev. 2000 Aug;19(3):177 [PMID: 11059358] 49. McCallum RW, Fink SM, Lerner E, Berkowitz DM. Effects of metoclopramide and bethanechol on delayed gastric emptying present in gastroesophageal reflux patients. Gastroenterology. 1983 Ju n;84(6):1573 7 [PMID: 6132852]
57 50. Netzer P, Gaia C, Lourens ST, Reber P, Wildi S, Noelpp U, Ritter EP, Ledermann H, Lscher D, Varga L, Kinser JA, Bchler MW, Scheurer U. Does intravenous ondansetron affect gastric emptying of a solid meal, gastric electrical activity or blood hormone levels in healthy volunteers? Aliment Pharmacol Ther 2002 Jan;16(1):119 27 [PMID: 11856086] 51. Nielsen OH, Hvid Jacobsen K, Lund P, Langoholz E. Gastric emptying and subjective symptoms of nausea: lack of effects of a 5 hydroxytryp tamine 3 antagonist ondansetron on gastric emptying in patients with gastric stasis syndrome. Digestion 1990;46(2):89 96. Erratum in: Digestion 1990;47(4):following 235 [PMID: 2147664] 52. Loldrup D, Langemark M, Hansen HJ, Olesen J, Bech P. Clomipramine and mianserin in chronic idiopathic pain syndrome. A placebo controlled study. Psychopharmacology (Berl). 1989;99(1):1 7 [PMID: 2506594] 53. Mertz H, Fass R, Kodner A, Yan Go F, Fullerton S, Mayer EA. Effect of amitriptyline on symptoms, sleep, and visceral percep tion in patients with functional dyspepsia. Am J Gastroenterol 1998 Feb;93(2):160 5 [PMID: 9468233] 54. Tack J, Piessevaux H, Coulie B, Caenepeel P, Janssens J. Role of impaired gastric accommodation to a meal in functional dyspepsia. Gastroenterology 1998 D ec;115(6):1346 52 [PMID: 9834261] 55. Tack J, Broekaert D, Coulie B, Fischler B, Janssens J. Influence of the selective serotonin re uptake inhibitor, paroxetine, on gastric sensorimotor function in humans. Aliment Pharmacol Ther. 2003 Feb 15;17(4):603 8 [PMID : 12622770] 56. Coulie B, Tack J, Sifrim D, Andrioli A, Janssens J. Role of nitric oxide in fasting gastric fundus tone and in 5 HT1 receptor mediated relaxation of gastric fundus. Am J Physiol 1999 Feb;276(2 Pt 1):G373 7 [PMID: 9950810] 57. Hasler WL. Gastropare sis: symptoms, evaluation, and treatment. Gastroenterol Clin North Am. 2007 Sep;36(3):619 47, ix. Review [PMID: 17950441] 58. Hasler WL, Soudah HC, Dulai G, Owyang C. Mediation of hyperglycemia evoked gastric slow wave dysrhythmias by endogenous prostagla ndins. Gastroenterology. 1995 Mar;108(3):727 36 [PMID: 7875475] 59. Gorelick AB, Koshy SS, Hooper FG, Bennett TC, Chey WD, Hasler WL. Differential effects of amitriptyline on perception of somatic and visceral stimulation in healthy humans. Am J Physiol. 1998 Sep;275(3 Pt 1):G460 6 [PMID: 9724256] 60. Jones MP, Maganti K. A systematic review of surgical therapy for gastroparesis. Am J Gastroenterol. 2003 Oct;98(10):2122 9. Review [PMID: 14572555] 61. Abell T, McCallum R, Hocking M, Koch K, Abrahamsson H, Leblanc I, Lin dberg G, Konturek J, Nowak T, Quigley EM, Tougas G, Starkebaum W. Gastric electrical
58 stimulation for medically refractory gastroparesis. Gastroenterology. 2003 Aug;125(2):421 8 [PMID: 12891544] 62. Jung H, Choung R, Locke III G, Schleck C, Zinmeister A, Szarka L, Mullan B, Tall ey N. The incidence, prevalence and outcomes of patients with Gastroparesis in Olmsted County, Minnesota, f rom 1996 2006. Gastroenterology. 2009;136:1225 1233. 63. McCallum RW, Berkowitz DM, Lerner E: Gastric emptying in patients with gastro esophageal reflux. Gastroenterology 80:285 291, 1981 64. Klauser AG, Voderholzer WA, Knesewitsch PA, Schindlbeck NE, Muller Lissner SA: What is behind dyspepsia? Dig Dis Sci 38:147 154, 1993 65. Sigurdsson L, Flores A, Putnam PE, et al. Postviral gastroparesis: P resentation, treatment and outcome. J Pediatr 1997;131:751 4. 66. Hussain SZ Di Lorenzo C Motility disorders. Diagnosis and treatment for the pediatric patient. Pediatr Clin North Am. 2002 Feb;49(1):27 51. 67. Donohoe KJ, Maurer AH, Ziessman HA, Urbain JLC, Ro yal HD, Martin Comin J. Society of Nuclear Medicine Procedure Guideline for Gastric Emptying and Motility, Version 2.0, approved 6 June 2004. Virginia: Society of Nuclear Medicine, 2005. Available from: http://interactive.snm.org/docs/pg_ch08_0403.pdf (Accessed 28 September 2005).
59 BIOGRAPHICAL SKETCH Shamaila Waseem received her medical degree from the most prestigious and oldest medical school in Pakistan, King Edward Medical Coll ege, in 1997. She completed her pediatric training at the University of Florida, Jacksonville, in 2006. She will be completing sub specialty training in pediatric g astroente rology, hepatology and n utrition at the University of Florida, Gainesville, in Augu st 2009. Her Master of Science was completed during her time as a gastroenterology fellow. She will be joining the University of Indiana, Indianapolis, as faculty assistant professor in the D ivision of Pediatric Gastroenterology, Hepatology and Nutrition.