Gastroparesis (GP) is a motor and sensory disorder of the stomach characterized by delayed gastric emptying in the absence of mechanical obstruction. Symptoms classically include nausea, vomiting, early satiety, bloating, postprandial fullness, abdominal pain, and weight loss. Although the etiology and management of GP have been studied well in the adult population (1), in the pediatric population, the literature is limited, with only a few case series and clinical trials and little in the way of randomized controlled trials (2–4). GP is often not recognized and thus can remain untreated in children (5,6).
The true prevalence of GP in the United States is unclear. In a study conducted by the Center of Health Outcomes Research (MEDTAP International Inc, Bethesda, MD), 7% to 15% of the adult population was found to have symptoms suggestive of GP (7); however, an adult epidemiological study conducted in Olmsted County, MN, revealed that the age-adjusted prevalence of definite GP per 100,000 population was only 9.6 for men and 37.8 for women (8).
Presently, no data are available to estimate the prevalence of GP in children. One study estimated that 65% of symptomatic adolescents who undergo upper endoscopy, have no abnormalities and are classified as having functional dyspepsia (9). Delayed gastric emptying has been demonstrated to be present in a subset of children with functional dyspepsia (10,11).
The etiology of GP in adults mainly stems from diabetes, idiopathic, and postsurgical (5). In children, most cases are considered to occur either after viral infection or are idiopathic cases (12). Delayed gastric emptying scintigraphy (GES) of a radiolabeled solid meal is the criterion standard for the diagnosis of GP. This test provides a physiological, noninvasive, and quantitative measure of gastric emptying. Liquid emptying may remain normal despite advanced disease.
Few randomized controlled clinical trials have directly compared the different therapeutic agents for GP (13,14) and even fewer data are available in children. In 1 study, domperidone was found to be more effective than cisapride in treatment of children with diabetic GP (15). In a case series of 2 neonates with congenital myotonic dystrophy, bethanechol improved symptoms of delayed gastric emptying (16). Consequently, the selection of drug treatment is commonly made by trial and error.
No published data are available describing the spectrum of pediatric GP. Our study aimed to provide an observational descriptive analysis of a large pediatric population with GP to determine clinical features, demographics, associations, treatment, and relevant outcomes.
Patient Ascertainment and Case Definition
The present study was approved by the institutional review board of the University of Florida (UF). All of the UF pediatric gastroenterology practice patients diagnosed as having GP by gastric scintigraphy between January 2002 and December 2008, were identified. Subsequently, electronic chart review was conducted to identify cases. Inclusion criteria were UF pediatric gastroenterology patients with a minimum of 1 follow-up visit; clinical symptoms of GP; and abnormal gastric scintigraphy results, that is, solid emptying ≥90 minutes or liquid emptying ≥60 minutes. We excluded the following patients: not UF pediatric gastroenterology practice patients; gastric emptying times were not extrapolated in half times; or had no follow-up visits after gastric scintigraphy.
The solid meal constituted 1 grade AA egg (∼85 cal) cooked scrambled with Tc-99 sulfur colloid (0.5 mCi) served with 2 pieces of white bread (133 cal) with 1 teaspoon of butter spread on the bread (36 cal), and 50 mL of water to help ingestion [total energy: 254 kcal, ∼30 g of carbohydrates, ∼13 g of protein, and ∼10 g of fat). The liquid meal consisted of 60 mL of radiolabeled formula or PediaSure (60 kcal). After administration of the meal, patients were imaged continuously for 115 to 120 minutes at 1 minute per frame using a single-headed γ-camera or dual-headed camera, positioned in the left anterior oblique position to minimize the effects of varying gastric attenuation on quantification of the gastric emptying rate. In addition, for liquid emptying, fast imaging acquisition at 10/frame was performed to allow for gastroesophageal reflux. A simple linear fit was applied to the rate of gastric emptying with calculation of half-time (t½) by extrapolation. Normal values for the solid meal and imaging methodology were obtained by the Director of Nuclear Medicine using 60 normal volunteers (age range 26–60) in 1981–1982 at Henry Ford Hospital (personal communication, 17,18). A linear rate of emptying to the data was applied from 0 to 75 minutes and obtained an extrapolated half time of emptying (normal t½ for solids was defined as 45–90 minutes and normal for liquids was <60 minutes). Because gastric emptying follows zero-order kinetics, the rate was effectively determined before 75 minutes. At 75 to 80 minutes into the examination, provocative testing with administration of intravenous (IV) erythromycin (EES), 2.8 mg · kg−1 · dose−1 up to a maximum of 250 mg, infused over 20 minutes was performed. Further imaging for 15 minutes was done to extrapolate the new postdrug t½. With liquid meals, IV EES was infused after 60 minutes instead of 80 minutes. Before the year 2005, IV metoclopramide (MCP) was also infused at 0.05 mg · kg−1 · dose−1 up to a maximum of 3 mg/dose. Responders to the drugs were defined as having normal postdrug t½, that is, 45 to 90 minutes for solids and <60 minutes for liquids.
We further divided our cohort into 4 categories of delayed solid emptying and 3 categories of delayed liquid emptying. Both were stratified by t½. Therefore, patients with solid emptying delay (n = 145) were divided into very severe (>241 minutes), severe (191–240 minutes), moderate (141–190 minutes), and mild (90–140 minutes). Similarly, patients with liquid emptying delay (n = 94) were divided into severe (>141 minutes), moderate (101–140 minutes), and mild (61–100 minutes) categories.
To ensure reliability and high-quality data collection, we designed a data collection form using Microsoft Access 2003 (Microsoft Corp, Redmond, WA). All of the data were collected from electronic medical records, including all of the inpatient and outpatient records. Patients were followed from the time of diagnosis to the last gastrointestinal encounter or until December 2008. The following information was collected.
Age, sex, height, and weight at diagnosis; t½ and type of meal; response to IV EES and/or IV MCP; prescribed acid suppression therapy, that is, proton pump inhibitors and H2 blockers; presenting symptoms, that is, nausea, vomiting, early satiety, bloating, abdominal pain, and weight loss; medication history; medical and surgical history; complications of GP, that is, anemia, esophageal stricture, esophagitis, gastritis, reflux, small bowel bacterial overgrowth, pneumonia, bronchitis, malnutrition, dehydration, and bezoars; treatment of GP, that is, prokinetic medications, dietary modifications, enteral feeds, total parenteral nutrition (TPN), gastric electrical stimulator, and surgery; last gastric scintigraphy and type of meal, time interval in months between first and last gastric scintigraphy; age, height, and weight at last encounter; symptoms at last encounter; etiology of GP, that is, idiopathic, postviral, drugs, that is, narcotics, anticholinergics, β-adrenergics, calcium channel blockers, glucagon, marijuana, alcohol, and tobacco; postsurgical, that is, fundoplication, vagotomy, Whipple procedure, and heart/lung transplant; rheumatologic, that is, scleroderma, lupus, polymyositis, and others; endocrine causes, that is, diabetes, hypothyroidism, hypoparathyroidism, neoplasms, and others; metabolic, that is, electrolyte imbalance, renal dysfunction; miscellaneous, that is, cystic fibrosis, chronic intestinal pseudo-obstruction, myotonia, milk-protein allergy, eosinophilic enteropathy, and others; comorbidities, that is, cerebral palsy, seizure disorder, developmental delay, and prematurity; finally, associated psychiatric disorders, that is, attention-deficit/hyperactivity disorder, depression, bipolar disorder, anxiety, and other behavioral disorders.
We used Minitab statistical software (Cary, NC) and SPSS 16.0 (SPSS Inc, Chicago, IL) for data analysis. Descriptive statistics were calculated for both continuous and binary variables. Data are presented as the mean ± standard deviation. The dataset was then divided into separate cohorts based on sex, age, type of meal, and severity of the GP. Continuous variables were analyzed using either paired t test or 2-sample t test as appropriate. Binary variables (yes/no) were studied with the Fisher exact test of proportions or χ2 test where appropriate. P < 0.05 was considered significant.
A total of 912 pediatric patients had undergone gastric scintigraphy from January 2002 to December 2008. From this group, 408 patients (45%) were identified to have delayed gastric emptying; however, 169 patients from the delayed gastric emptying group were excluded from the study based on the exclusion criteria. Demographics of the 239 eligible cases are shown in Table 1. The mean age (±standard deviation) at presentation was 7.9 (±5.9) years, and the mean body mass index (n = 212) at presentation was 18.6 (±5.3). Among all of the patients, the most common presenting symptoms were vomiting and abdominal pain.
TABLE 1-a Demographi...Image Tools
Girls presented at a later age (mean 9 ± 5.9 years compared with 6.7 ± 5.7 years for boys, P = 0.002). There were no differences in the presenting symptoms between both sexes (Table 2). We further categorized the data according to age groups: <1 year, 1 to 5 years, 6 to 10 years, 11 to 16 years, and >17 years (Table 3). The demographics revealed that whereas boys predominated (72.4% of patients) in the <1-year age group, sex ratios were equal in the 1- to 10-year age range and girls predominated in the >10-year age groups. In the >17-year age group, 66.7% of patients were girls.
Patient demographics and symptoms based on solid or liquid meal and severity of emptying delay (Table 4) also varied. There was no difference in the mean age of those presenting with mild, moderate, or severe delays in solid emptying (12.5, 13.8, and 11.4 years, respectively) and roughly two-thirds of individuals in each category were girls. There was also no difference in mean age of those presenting with mild, moderate, or severe delays in liquid emptying (2.3, 2.8, and 3.5 years, respectively). Those with mild and moderate delays in liquid-phase gastric emptying were slightly more likely to be boys, whereas there was equal sex distribution in those with severe delays in liquid-phase gastric emptying. Using the Pearson correlation test, we found a correlation between t½ and the presenting symptoms of nausea and abdominal pain only (r value of 0.3 and 0.1, respectively).
Provocative testing was performed on 113 patients with either or both IV EES and IV MCP infusion during scintigraphy (Table 1). A total of 126 patients (52.7%) were not tested with either of these drugs. χ2 testing revealed patients with solid emptying delay responded better to IV EES than those with liquid emptying delay, that is, 85.5% versus 51.3% (P < 0.001).
Most patients were treated with combination therapy, which predominantly consisted of EES (76.6%) and dietary modifications (74%), but drugs such as MCP (29.7%), tegaserod (6.7%), and azithromycin (5.4%) were also used. Other medications (4.2%) such as cisapride, antihistamines, antiemetics, and tricyclic antidepressants were also prescribed to patients. All of the patients were treated with one or more prokinetic agents at some point. In addition, 172 patients (72%) were receiving concomitant acid suppression therapy. Nutritional support was provided using enteral feeds and TPN. Subsequently, 62 patients (26%) were receiving enteral feeds or TPN at some point during their course. None of the patients in this cohort received pyloric botulinum toxin injections or gastric electrical stimulation.
Esophageal reflux diagnosed during scintigraphy or by fluoroscopy was the most common complication of GP (Table 1). Patients were found to have multiple presumed etiologies for GP making it impossible to differentiate a single etiology as the definitive cause (Table 1). Note that patients may be coded in >1 category, so the total number will not equal 239. In the majority of patients, no cause was identified, that is, idiopathic GP. In this group, there were 82 girls (49%) and 85 (51%) boys. Mean age at presentation was 8 years (±5.8). Drugs were the second most common cause, but interestingly, only 5 patients (2%) were taking narcotics. This was followed by postsurgical causes, almost half of which (53%) were due to Nissen fundoplication. Miscellaneous causes were seen in 6.3% patients and constituted chronic intestinal pseudo-obstruction, myotonia, eosinophilic gastroenteropathy, cow's-milk protein allergy, liver disease, celiac disease, hereditary pancreatitis, and cystic fibrosis. A significant number of patients had associated comorbid conditions such as cerebral palsy, seizure disorder, prematurity, and developmental delay as well as psychiatric conditions (Table 1). Subsequently, attention-deficit/hyperactivity disorder was 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%). We found no significant difference between the sexes with regard to these comorbid psychiatric disorders.
This hospital-based cohort study was followed for a mean of 24 months. Our outcome variables were changed in symptoms, for example, nausea, vomiting, early satiety, abdominal pain, bloating, and weight loss. Subsequently, a decrease in the frequency of all of the symptoms was observed at the last encounter. Using the Fisher exact t test, we found significant improvement in all of the outcomes at the end of the follow-up period, regardless of type of treatment used (Fig. 1). Improvements in weight loss occurred, despite the fact that 74% of patients were receiving dietary modifications but were not receiving supplemental nutritional support.
A total of 28 patients underwent a repeat gastric scintigraphy during a mean interval of 28.5 months (range 2–68 months). Of these, initially 10 patients (36%) had solid emptying delay, whereas 18 patients (64%) had liquid emptying delay. Gastric emptying normalized on repeat scanning in 3 girls and 4 boys (25%). First and last t½ differences in these patients were not significantly different (P = 0.1). Of those who underwent repeat GES (n = 28), improvements were noted only in vomiting (P ≤ 0.001) and weight loss (P = 0.009).
We did not find a significant difference in symptom outcomes when comparing boys with girls except for abdominal pain, which was more commonly reported by girls (Table 2). Patients in the 11- to 16-year age group had the most improvement in all of the symptoms (Table 3). Conversely, the least improvement was observed in the >17-year group, reported only in early satiety.
In a large cohort of pediatric patients (n = 239) referred to an academic medical center, we have attempted to describe the spectrum of GP in the pediatric population. Most of the previous data on this condition have been reported from adult studies, which may not reflect the true spectrum of GP in children (5,7). Adult cohorts have consistently revealed an overwhelming female predominance (∼80%) of GP (5,19). In addition, the etiologic categories in adults have been one-third idiopathic, one-third diabetic, and one-third postsurgical/miscellaneous causes (5,19,20). Adult literature establishes a high morbidity and mortality of this condition (19,21).
Our study revealed important differences with an almost equal distribution between female and male pediatric patients (51.5% and 48.5%, respectively) and similar etiologies for each sex. The sex differences started to increase as the ages increased, such that with patients older than 17 years of age, about two-thirds were girls. Boys presented at an earlier age of 6 years versus girls, who presented at 9 years, but both sexes were found to have similar outcomes. This finding differs from adult studies, in which women have shown a poorer prognosis than men (5,19).
Overall, the adult literature suggests no correlation between t½ and symptoms (22). With our data, we were able to demonstrate an association between severity of GP based on t½ and the frequency of nausea and abdominal pain, but not other presenting symptoms. Unfortunately, in this retrospective analysis, we could not assess the severity of the symptoms.
Etiologies in pediatric GP were found to differ from adults (5,23) because there was a predominance of idiopathic GP (70%). Of note, before gastric scintigraphy, patients were asked to bring a glucometer, and if the blood sugar was >275, then scintigraphy was not performed. The lack of a predominant diabetic cause in our cohort may reflect the time that is required for diabetes to cause gastric dysmotility. Diabetic GP was present only in 9 patients (4%) and all of these patients had type 1 diabetes. This information is contrary to the adult literature, in which one-third of patients with GP are diabetics (5). Four (44%) of the 9 patients also had cystic fibrosis. Whether the gastric emptying delay in these 4 patients was due to diabetes-related neuropathy or gastrointestinal dysmotility found in patients with cystic fibrosis is unknown. The correction of hyperglycemia in diabetics is essential in obtaining optimal management results (24).
Ninety-two patients (38.5%) had associated comorbidities that may contribute to GP. This information suggests the need for further investigation into the pathophysiology of GP and possibly a significant role of the CNS and its relation with the enteric nervous system in the pathogenesis of GP.
Another important factor to consider is that only 5 patients (2%) were taking 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 GP. For this reason, our cohort was essentially narcotic naïve. Most series describing GP in adults document the extensive use of such medications or behaviors (25).
Mandatory prokinetic 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 nonresponders to IV EES or IV MCP. We found that IV EES was more effective in improving solid emptying when compared with liquid emptying. A possible explanation may be that liquid emptying delay is considered an indicator of progressively worsening GP; 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, because tachyphylaxis still develops during clinical use.
Other differences from adults include the frequency of presenting symptoms, because adults usually present with nausea and vomiting rather than abdominal pain (5,19). In our pediatric cohort, we noted that abdominal pain was a common presenting feature. The prominence of abdominal pain in our patients with GP may be due to the pronounced association of pain with idiopathic GP, which in turn is a major cause of GP in children (5). The finding of gastroesophageal reflux disease as the most common complication of GP is a reminder that patients with reflux and functional dyspepsia can have delayed gastric emptying (19,26). Although 67% of gastroparetic patients were diagnosed as having gastroesophageal reflux disease, only 17% and 15% had histological evidence of esophagitis or gastritis, respectively.
Comparatively, differences in mental health associations were also important. When compared with the published adult literature, patients in the present study had far fewer (28.4% vs 62%) comorbid psychiatric conditions (5). Again, this may be due to the duration of symptoms; patients with chronic GP symptoms may have a tendency to become depressed and anxious. The frequency and prevalence of comorbid psychiatric conditions were the same in both sexes in our cohort.
Most patients were treated with EES and dietary modifications (73.6% and 74%, respectively). Patients who do not respond well to oral EES could be tried on IV EES (27). Subcutaneous MCP has also been tried in this setting as tolerated (28). Despite different therapeutic modalities, we found a statistically significant improvement in all of the symptoms at the end of the mean 2-year follow-up, with similar results in both sexes. One possible reason is that the natural history of idiopathic pediatric GP may result in improvement over time. In future studies, we plan to prospectively study the outcomes of patients with and without pharmacologic treatment and attempt to identify those patients who do not respond to conventional treatments.
The most prevalent age groups with GP were the 11- to 16-year and 1- to 5-year categories. The literature on liquid emptying delay is limited. Based on adult data, it is considered an end-stage indicator of GP. Most of our liquid emptying meals were performed due to the age (infants/toddlers) of patients and inability to ingest the solid meal. We had 6 patients who had t½ >240-minute delay with liquid emptying. Five of the 6 required enteral feeds, and underwent fundoplication, gastrostomy tube placement, and pyloroplasty. In addition, these 5 patients had CNS comorbidities and developmental delays. The remaining patient was thought to have postviral GP. This reinforces the fact that CNS conditions may play a major role in the pathophysiology of GP.
The present study has some limitations. First, this was a retrospective cohort and hence misclassification of GP 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. Third, we did not record ethnicity; therefore, our study may not be representative of all of the ethnic groups with GP. Fourth, because this is a hospital-based study instead of a population-based study, we were unable to estimate the prevalence of GP. Our study, therefore, may be biased because it represents more severe presentation of GP instead of a milder presentation in the general population. Fifth, a gastric emptying test was also ordered by other specialties such as pulmonologists, endocrinologists, surgeons, and so on. Most of these patients were not seen by UF gastroenterology. The indications of the test, that is, symptoms, were not assessed by UF gastroenterology. Some patients received second opinions from outside facilities with established diagnosis. The nuclear medicine database did not distinguish who ordered the test. In addition, patients lost to follow-up after initial diagnoses were also excluded because follow-up symptoms could not be assessed. We do not know whether lost to follow-up was due to resolution of symptoms. Only approximately 2% of patients had results of gastric emptying not extrapolated in half times. Whether the excluded patients had abnormal tests but were asymptomatic is unknown. We understand that obtaining data on asymptomatic patients with delayed gastric emptying is important and may be better assessed in a prospective design. A key issue is whether primary care providers underreport or underrecognize GP in children. Finally, the GES protocol used at UF is not in accordance with the recent consensus recommendations of GES published in 2008 (29); however, our protocol of continuous scanning for 2 hours is validated by the Nuclear Medicine Society and has been published (17,18).
In summary, this is, to our knowledge, the first large hospital-based study to describe the demographics, etiologies, and outcomes of GP in the pediatric population. GP is an uncommon condition in the community compared with tertiary-based hospital settings, but still represents a major disease burden. Most patients with GP need continuous medical care, but long-term outcome in the pediatric population seems promising despite limited therapeutic choices. This retrospective study provides the basis for future studies, which will focus on risk stratification of children with GP, develop and validate quality of life measures, classify patients based on severity of GP, and assess newer therapies for this debilitating condition based on the specific pathophysiology.
The authors thank Marian Limacher, MD, FACC, and JaneYellowleez Douglas, PhD, for reviewing and commenting on the manuscript. The authors also thank Wei Hou, PhD, for help with creating the Microsoft Access data collection form and statistical analysis.
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