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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Keywords:© 2012 by European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology,
etiologies; gastroparesis; identify; prevalence; retrospective; scintigraphy