A total of 36 infants were included. The most common symptoms were vomiting in 25 (69%), failure to thrive in 5 (14%), irritability in 5 (14%), and abdominal pain in 1 (3%). The most common associated diagnoses were cow's-milk protein allergy (diagnosed clinically) in 12 (33%) and PVG in 6 (17%). Information on the response to addition of promotility therapy was available in 32, with 13 (40%) responders and 19 (59%) nonresponders. The distribution of medications used in infants was as follows: PPI in 32, metoclopramide in 29, domperidone in 4, tegaserod in 2, erythromycin in 12, and cyproheptadine in 2 patients. Outcome data were available in 36 patients, with 22 (61%) reporting resolution of symptoms at a mean duration of 10.7 ± 6.3 months and 82% reporting resolution within 1 year. All 12 infants with milk allergy were treated with a hypoallergenic formula, with 7 reporting resolution within 12 months, 4 remaining symptomatic, and 1 lost to follow-up.
A total of 109 children were included. The most common symptoms were vomiting in 49 (45%), abdominal pain in 36 (33%), and nausea in 28 (25%) patients. The most common diagnoses were PVG in 21 (19%), MD in 10 (9%), and gastroesophageal reflux in 10 (9.6%) patients. Information on the response to the addition of promotility therapy was available in 77 children: 49 (64%) responders and 28 (36%) nonresponders. The distribution of medications used in children was as follows: PPI in 81, metoclopramide in 71, domperidone in 15, tegaserod in 3, erythromycin in 13, and cyproheptadine in 7 patients. Outcome data were available in 97 (89%) patients, with 60 (62%) reporting symptom resolution at a mean duration of 9.2 ± 7.3 months (43% by 6 months, 85% by 1 year, 97% by 2 years, and 100% by 3 years).
A total of 85 adolescents were included. The most common symptoms were abdominal pain in 43 (50%), nausea in 38 (45%), and vomiting in 24 (28%) patients. The most frequent diagnoses were PVG in 15 (18%), irritable bowel syndrome in 9 (11%), depression in 7 (8%), and MD in 6 (7%) patients. Information on the response to the addition of promotility therapy was available in 53 adolescents: 28 (53%) responders and 25 (47%) nonresponders. The distribution of medications used in adolescents was as follows: PPI in 69, metoclopramide in 42, domperidone in 14, tegaserod in 15, erythromycin in 15, and cyproheptadine in 2 patients. Outcome data were available for 65 (76%) patients, with only 25 (38%) reporting resolution at a mean duration of 7.5 ± 7.3 months (60% by 6 months, 84% by 12 months, and 100% by 28 months).
Response to Therapy
Medications used included proton pump inhibitors (PPIs), promotility agents, antiemetics, and pain modulators. Medication-related AEs are listed in Table 2.
Proton Pump Inhibitors
Proton pump inhibitors (PPIs) were used in 181 (79%) patients and were the first-line drugs in 176. Dosing ranged from 1 to 2 mg · kg−1 · day−1 for a mean duration of 9.1 ± 10.2 months, with a maximum dose of 30 mg twice per day of lanzoprazole or 40 mg twice per day of omeprazole, esomeprazole, or pantoprazole. Follow-up was available in 173 (96%) patients, with 36 (20%) responders, although only 5 (3%) reported resolution of symptoms and the remainder required additional therapy. Only 5 patients reported AEs from PPI use.
Promotility therapy included medications with a solely promotility effect (tegaserod and erythromycin) and medications with promotility and antinausea effects (metoclopramide and domperidone). Of the 162 subjects with follow-up available, 90 (55%) were responders and 72 (45%) were nonresponders (Fig. 2). The most common symptoms in responders were vomiting in 45 (50%), abdominal pain in 27 (30%), and nausea in 25 (28%). We identified a tendency toward an association between a positive response to promotility therapy in children compared with adolescents and infants (P = 0.07) and in subjects with PVG (P = 0.09). No association was found between response to promotility agents and sex, presence of nausea, vomiting, or abdominal pain, duration of symptoms, or MD. Of the 90 responders, 52 (58%) reported resolution, 29 (32%) continued to require medication, and 9 (10%) were lost to follow-up. Among the 72 nonresponders to addition of promotility therapy, 25 ultimately underwent surgical procedures. The rest were either lost to follow-up or remained symptomatic through the last clinical encounter.
Metoclopramide was used in 142 patients, in 31 as first-line therapy and in the rest after a failed trial of PPI. The dose was 0.1 to 0.2 mg/kg per dose given 4 times per day to a maximum dose of 10 mg 4 times per day. Mean duration of therapy was 8.6 ± 8.7 months. Follow-up was available in 132 (93%) patients, with 26 (20%) responders and 15 (11%) of those reporting resolution. Overall, 24% of patients reported AEs. Domperidone was used in 33 patients, always after failing PPIs or metoclopramide. Dose was 0.1 to 0.2 mg/kg per dose given 4 times per day to a maximum dose of 10 mg 4 times per day. Mean duration of therapy was 7.6 SD 8.1 months. Follow-up was available in 31 (94%) patients, with 23 (74%) responders and 8 (26%) reporting symptom resolution, the highest rate being among promotility drugs. Only 6% reported AEs, the lowest rate of any drug therapy. Tegaserod was used in 20 patients, never as a first-line agent. Starting dose was 0.25 mg · kg−1 · day−1 (range 0.1–0.6 mg · kg−1 · day−1) divided in 2 doses per day, to a maximum dose of 6 mg twice per day. Mean duration of therapy was 5.4 SD 5.8 months. Follow-up was available in 18 patients, with 11 (61%) responders and 4 (22%) reporting symptom resolution. AEs were reported by 4 (20%) patients. Erythromycin was used in 40 patients and follow-up was available in 37 (93%), with 19 (51%) responders and only 2 (5%) reporting resolution. Starting dose was 3 mg/kg per dose given 4 times per day up to 10 mg/kg per dose 4 times per day up to a maximum dose of 250 mg 4 times per day. Mean duration of therapy was 4.1 SD 3.6 months. AEs occurred in 4 (10%) patients.
Cyproheptadine was used in 11 patients and follow-up was available in 8 (73%) patients, with 4 responders and no patients reporting resolution. Drowsiness occurred in 2 (22%) patients. Amitriptyline was used in 6 patients with follow-up available in 5 (83%). All were responders, with only 1 reporting resolution and 2 requiring dose adjustment because of drowsiness.
Diet modification, including small frequent meals, decreased fat intake, and lactose-free diet, was used as primary therapy in only 4 patients (3 responders and 1 nonresponder) and as adjunctive treatment in 11 patients, all of whom were responders.
Gastrostomy tubes were placed in 11 patients (most commonly for failure to thrive). All were responders and 2 reported symptom resolution, with 1 subject lost to follow-up. Pyloroplasty was performed in 6 patients; all were responders, including 2 who reported resolution. In 1 subject, pyloroplasty was performed in combination with a fundoplication after failure of PPIs and resulted in full resolution of symptoms. No AEs were reported. Jejunostomy tubes were placed in 3 patients who failed medical therapy, all reporting significant symptomatic improvement and no adverse effects. Fundoplication was performed in 5 patients, with 2 lost to follow-up. The other 3 had a gastrostomy placed at the time of fundoplication but required subsequent gastrojejunostomy tubes for feeding intolerance. No adverse events were reported.
Outcome data were available in 204 patients. Of those, 107 (52%) reported resolution, whereas 97 (48%) reported that their symptoms persisted at the end of follow-up. Median follow-up was 18 months, with a range of 2 to 84 months. Median time to achieve symptom resolution for all 204 subjects included in the survival analysis was 14 months, with a 95% CI of 12 to 24 months. The overall resolution rate was 22.4% at 6 months, 53.3% at 18 months, and 60.6% at 36 months from the Kaplan-Meier curve. Of the 107 subjects reporting resolution of symptoms, 42% reported within 6 months, 84% within 12 months, and 100% by 36 months. Figure 3 shows the cumulative resolution rate by age group.
Univariate analysis using the log-rank test showed that younger age, PVG, shorter duration of symptoms, response to addition of promotility therapy, presence of nausea, and absence of MD are associated with resolution of symptoms. In contrast, the presence of vomiting and abdominal pain showed no association, whereas male sex showed a tendency toward an association (P = 0.06) with symptom resolution. (Table 3). Multivariate survival analysis with Cox proportional hazards models demonstrated that longer duration of symptoms, older age, and presence of MD lead to lower rates of resolution, whereas a positive response to promotility therapy predicts a higher rate of resolution (Table 4).
Despite the prevalence of gastroparesis at all ages, little information is available on the clinical presentation and response to therapy in the pediatric population. The goal of the present study was to improve our understanding of childhood gastroparesis, to determine which therapies are most effective, and to identify the predictors and time course of symptom resolution. Several limitations of the present study are worth noting, including its retrospective nature and the fact that it is a single-institution study, with possible institutional biases that may affect the observations made and their applicability at other institutions. One of the greatest limitations in studying pediatric gastroparesis, however, is the lack of a standardized definition. Technical approaches to the performance of GET in children vary widely, and normative values for gastric emptying times are not available. The only data available are based on small cohorts tested with varied protocols (3,4,6,7). These are significant limitations that require prospective controlled trials. Despite this, this review of a large group of children with gastroparesis, defined as gastric emptying ≤40% at 60 minutes, identifies important clinical features that can help clinicians treat this difficult condition.
Idiopathic gastroparesis in adults is known to be more prevalent among women (8). Interestingly, we find that the male-to-female incidence changes with age. Among infants, boys predominate; in children, the sex ratio is equal; and in adolescents, girls are the majority. Clinical symptoms in children also vary with age. Infants experience more vomiting, possibly because they are less likely to report nausea or abdominal pain, which more commonly occurs in adolescents.
One of the most important factors to patients with gastroparesis and their families is knowing whether and when to expect resolution of this chronic and often debilitating condition. In the present study, the overall rate of symptom resolution was 52%, which was achieved at a median of 14 months from the time of diagnosis. In those patients in whom symptoms ultimately resolved, 84% did so by 12 months and all resolved by 36 months. Using multivariate regression, several factors were predictive of the likelihood of symptom resolution. These include younger age, shorter duration of symptoms, absence of MD, and response to promotility drugs. Adult studies have reported much lower resolution rates than we have observed in children. In a study of 21 patients with idiopathic GP, 30% had symptom resolution and were off medications at a mean follow-up of 5 years (9). Another study reported only 22% resolution of symptoms at a mean of 20 months. These findings suggest that pediatric and adult gastroparesis may be distinct disorders with varying outcomes.
PVG is a common cause of gastroparesis, accounting for 18% of all cases in the present study, with similar rates across all age groups. Reports in adults identified PVG in 18% (8) and 21% (9) of cases of idiopathic gastroparesis. In a previous retrospective case series of pediatric PVG, all 11 children reported resolution of symptoms by 24 months, with only 27% improving with promotility drugs (2). In contrast, of our 41 patients with PVG, 73% responded positively to promotility agents and 63% ultimately reported symptom resolution, findings that are similar to those seen in adults (8,9). In our study, a viral prodrome preceding gastroparesis was predictive of symptom resolution in univariate but not multivariate analysis.
The addition of promotility medications was associated with a favorable symptomatic response in 55% of subjects, independent of age. Metoclopramide use resulted in a low resolution rate and was associated with the highest rate of AEs among all of the promotility drugs, supporting a limited role for this drug in the management of gastroparetic children. Domperidone, however, produced the highest resolution rate and caused the fewest adverse effects. Consistent with our observations, others have also reported a higher incidence of neurological AEs from metoclopramide as compared to domperidone (10). More important, domperidone was used as a second-line promotility drug in all of our cases and resulted in significant improvement in cases in which metoclopramide did not. Tegaserod, a 5HT (hydroxytryptamine)-4 partial agonist removed from the market because of increased risk of stroke, heart attack, and unstable angina, resulted in a high response rate, but was associated with a high rate of adverse effects, none of which were cardiac in origin. Erythromycin produced the lowest resolution rate (5%), which is in contrast to studies in adults, in which marked clinical improvement with erythromycin has been reported (11). Other potential treatments, including cisapride, botulinum toxin injection to the pylorus (12), and gastric electrical stimulation (13,14), were not used in our patients.
We found by both univariate and multivariate regression analysis that a positive response to promotility drugs was predictive of resolution of gastroparesis symptoms. One may hypothesize that this results from the positive effects of these agents on gastric motility and emptying and/or the important antinausea effect of domperidone and metoclopramide; however, clinical trials in adults have not demonstrated a correlation between improvement in gastric emptying or motility and symptomatic relief (15–18). No improvement was found in gastric emptying times using metoclopramide in diabetic adult patients (19) and no correlation was seen between the improvement of gastric emptying after a single dose of intravenous metoclopramide and clinical symptomatic response to its chronic use (20). A significant clinical response to domperidone has been reported despite no measurable effect on gastric emptying (21,22), although others have shown improved gastric emptying after using domperidone for 6 months (23). In a pediatric study, 8 weeks of domperidone was superior to cisapride in improving symptoms as well as gastric emptying time and gastric myoelectrical disturbances (24), supporting a relation between improvements in measurable gastric function and clinical symptomatology. Small studies have also shown the efficacy of erythromycin in long-term use (25), with superiority to metoclopramide in improving both symptoms and gastric emptying time (26). More important, the methodology and gastric emptying protocols used differ across these studies. The higher rate of symptom resolution associated with promotility therapy may be explained by a milder degree of gastric dysfunction among responders; however, we found no difference in the severity of DGE between responders and nonresponders to support this. Prospective studies are needed to define standardized protocols for gastric emptying studies in children and age-based normative values, and also to define further the role of promotility drugs and other therapies in treating pediatric gastroparesis.
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Keywords:© 2012 by European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology,
delayed gastric emptying; gastroparesis; nausea; prokinetic therapy; vomiting