Current status of intractable pediatric gastroesophageal reflux disease in Japan: a nationwide survey.

PURPOSE: A nationwide survey was conducted to investigate the current status of pediatric gastroesophageal reflux disease (GERD) in Japan, with special reference to the characteristics of intractable GERD. METHODS: Data were collected using a questionnaire from facilities specializing in the treatment of pediatric GERD in Japan. Intractable GERD was defined as follows: I, no symptomatic improvement after 8 weeks of optimal medical treatment (OMT) plus fundoplication; II, no symptomatic improvement after 8 weeks of OMT and with no indications for fundoplication; and III, no symptomatic improvement after surgery without OMT. RESULTS: We collected data from 3,463 pediatric patients with GERD from 91 institutions, and 81 satisfied the definition of intractable GERD. Additional clinical information was obtained from 56 patients, and 41 represented cases of definite intractable GERD. The main underlying disorders included neurological impairment (NI), esophageal atresia (EA), and congenital heart disease (CHD), which altogether accounted for 85% of patients. Of the 41 patients, 33 received fundoplication, and the remaining 8 received medical treatment alone because surgery was considered unsuitable. CONCLUSIONS: The nationwide survey revealed that pediatric intractable GERD is rare in Japan. Three main underlying disorders-NI, EA, and CHD-were implicated in the majority of cases of intractable GERD.

Standard protocol devised by the Japanese Pediatric Impedance Working Group for combined multichannel intraluminal impedance-pH measurements in children.

Multichannel intraluminal impedance-pH measurements (MII-pH) are useful for evaluating acid and non-acid gastroesophageal reflux (GER). However, the use of MIH-pH is not yet established in Japan. The Japanese Pediatric Impedance Working Group (Japanese-PIG) convened to devise a standard protocol for MII-pH in Japanese children. The expert members of the Japanese-PIG collected data on pediatric MII-pH from the relevant literature in English, including the standard protocol of MII-pH presented by the European PIG, and the insights of international experts. The resultant consensus was included in the contents of the standard protocol of MII-pH. The standard protocol included standardization of the indication, methodology, and interpretation of MII-pH in Japanese children. The criteria for abnormal GER by MII-pH were defined using the Reflux Index and number of total reflux episodes independently in children aged < 1 year and those aged ≥ 1 year. Moreover, a significant relationship between GER and symptoms was identified using the symptom index and symptom association probability approach. We conclude that the current version of the protocol for MII-pH is tentative because it is not based on data from Japanese children. Further studies are needed to render this protocol clinically beneficial and expand its use in Japan.

Correction to: Standard protocol devised by the Japanese Pediatric Impedance Working Group for combined multichannel intraluminal impedance-pH measurements in children.

The authors would like to add the following sentence in Acknowledgements in the original publication of this paper.

Nationwide survey of outcome in patients with extensive aganglionosis in Japan.

PURPOSE: Hirschsprung's disease-related short bowel syndrome (HDSBS) is characterized by aganglionosis that extends orally to 75 cm from Treitz's band. The condition is reported be associated with a high mortality rate of 50-80%. This retrospective study aimed to survey the current trends in HDSBS treatment in Japan. METHODS: Patient data were extracted from the results of a nationwide survey we conducted, resulting in the retrospective collection of the data of 1087 HD patients from 2008 to 2012 in Japan. RESULTS: A total of 11 (0.9%) cases of HDSBS were noted. All patients underwent jejunostomy as neonates. Radical procedures performed in five patients (A-colon patch method in four, Duhamel's procedure in one). Ziegler's myotomy-myectomy and serial transverse enteroplasty (STEP) were performed in each patient as palliative procedures. No radical operations were performed in 4 of the 11 cases. The mortality rate was 36.4%. Four patients died, 1 patient who underwent STEP and 3 patients who received no radical procedures. The causes of death were sepsis due to enterocolitis or central intravenous catheter infection, and hepatic failure. All patients who underwent radical procedures survived and showed satisfactory outcomes. CONCLUSION: HDSBS still showed a high mortality rate, although surgical approaches such as the A-colon patch method resulted in satisfactory outcomes.

Efficacy of the traditional Japanese medicine goreisan for the resolution of spermatic cord hydrocele in children.

PURPOSE: Goreisan, a traditional Japanese medicine, has previously been used for hydrostatic modulation. This retrospective study investigated the efficacy of goreisan for spermatic cord hydrocele resolution in children. METHODS: Seventy-two boys treated for spermatic cord hydrocele between 2012 and 2015 were included; Goreisan was administered to 16 [group G, median age 3 (1-8) years], and 56 were followed without medication [group C, median age 1 (0-8) years]. An age-matched comparison was conducted between 14/16 group G patients (group g) and 14/56 group C patients (group c). RESULTS: Incidences of resolution were higher in groups G and g than in groups C and c, respectively, both during the study period and within the first 6-month observation period; groups G and g also had a significantly lower incidence of surgery for hydrocele than in groups C and c, respectively. The interval from the commencement of observation until hydrocele resolution was significantly shorter in group G than in group C, but not in group g than in group c. CONCLUSION: Goreisan can effectively promote the resolution of spermatic cord hydrocele in children and may be a valid treatment choice for this condition.

Characteristics of gastroesophageal reflux in pediatric patients with neurological impairment.

PURPOSE: To clarify the characteristics of gastroesophageal reflux (GER) in pediatric patients with neurological impairment (NI). METHODS: Twenty-six patients with NI, 1-17-year-old, fed via a nasogastric tube were categorized based on the absence (group I) or presence (group II) of abnormal GER, defined with multichannel intraluminal impedance-pH monitoring as %time with an esophageal pH <4.0 being ≥5.0% or number of liquid/mixed bolus reflux events(RE) >70 in 24 h. RESULTS: %Time and number of distal and proximal bolus REs were not significantly different between acid and nonacid REs. %Time of acid bolus RE and that of acid and total number of distal and proximal bolus REs were significantly higher in group II than in group I. Mean acid clearance time was significantly longer in group II. Median bolus clearance time was similar between the groups. No bolus RE parameters were significantly different between acid and nonacid REs in group I. Acid bolus RE was significantly higher than nonacid RE in terms of %time and number of proximal bolus RE in group II. CONCLUSION: Acid REs significantly increased in pediatric patients with NI with abnormal GER. The number of acid and nonacid REs was comparable in patients without abnormal GER.

Mesenteric hernia causing bowel obstruction in very low-birthweight infants.

Internal hernia through a mesenteric defect, called mesenteric hernia, is an uncommon cause of acute intestinal obstruction in newborns. Strangulated mesenteric hernia results in intestinal necrosis or perforation and progressive deterioration with fatal outcome, especially when it occurs in low-birthweight infants. We report two very low-birthweight (VLBW) infants, who presented with acute intestinal obstruction related to mesenteric defect. The initial diagnosis was meconium obstruction in those cases, which is a common cause of bowel obstruction occurring in VLBW infants. Correct diagnosis of mesenteric hernia was difficult in these cases because of rapid deterioration and non-specific radiological findings. Awareness of the possibility of rare mesenteric hernia causing acute intestinal obstruction and surgical intervention in an appropriate timeframe are important for rescuing VLBW infants with such organic abnormalities.

Parenteral nutrition-associated liver disease in extremely low-birthweight infants with intestinal disease.

BACKGROUND: The aim of this study was to investigate factors associated with the development of parenteral nutrition-associated liver disease (PNALD) and to examine the clinicopathological relationship of PNALD in extremely low-birthweight infants (ELBWI). METHODS: The subjects were 13 ELBWI who had received PN because of intestinal perforation or functional ileus between 2000 and 2013. We measured the serum levels of biochemical parameters, including aspartate aminotransferase, alanine aminotransferase, and direct bilirubin. Liver histopathology was examined in relation to outcome. The subjects were categorized into two groups on liver histopathology: F(+), development of hepatic fibrosis and necrosis with/without cholestasis; and F(-), no hepatic fibrosis. RESULTS: Of 13 ELBWI, five died of hepatic failure, five died of sepsis, and the other three were alive at the time of the study. Of the five infants who died of hepatic failure, two developed fulminant hepatitis without cholestasis, and the other three developed chronic cholestasis and finally hepatic failure. Postmortem histopathology in F(+) indicated not only massive hepatic necrosis, but also massive hepatic fibrosis. These histopathological findings explained the clinical presentation of portal hypertension. There were significant differences in the fasting period after intestinal disease onset between the two groups. CONCLUSION: The prolonged fasting with PN is responsible for severe hepatocellular necrosis with fibrosis and consequent lethal portal hypertension.

Efficacy and safety of strong acid electrolyzed water for peritoneal lavage to prevent surgical site infection in patients with perforated appendicitis.

PURPOSE: Our previous experimental study of perforated peritonitis in rats proved that peritoneal lavage with strong acid electrolyzed water (SAEW) has no adverse effects, reduces the bacteria count in the ascitic fluid more effectively than saline, and increases the survival rate significantly. Thus, we conducted a randomized controlled study, applying SAEW in the treatment of perforated appendicitis in children. METHODS: Forty-four patients, aged 3-14 years, were randomly divided into two groups: Group S (n = 20), in which the peritoneal cavity was lavaged with 100 ml/kg saline and the wound was washed out with 200 ml saline; and Group E (n = 24), in which the peritoneal cavity was lavaged with 100 ml/kg SAEW and the wound was washed out with 200 ml SAEW. RESULTS: No adverse effect of SAEW was observed in Group E. There was no difference in the bacterial evanescence ratio of ascitic fluid after lavage between Groups S and E (11.1 and 15.8%, respectively). A residual abscess developed in one patient from each group (5.0 and 4.2%, respectively). The incidence of surgical site infection (SSI) was significantly lower in Group E than in Group S (0 and 20%, respectively; P < 0.05). There was no difference in the duration of pyrexia, positive C-reactive protein, leukocytosis, or hospital stay between the groups. CONCLUSION: Peritoneal lavage and wound washing with SAEW have no adverse effects and are effective for preventing SSI.

Causal relationship between delayed gastric emptying and gastroesophageal reflux in patients with neurological impairment.

PURPOSE: To investigate the causal relationship between delayed gastric emptying (DGE) and gastroesophageal reflux (GER) in patients with neurological impairment (NI). METHODS: Subjects included 30 NI patients (age, 1-34 years; median, 6 years). Combined multichannel intraluminal impedance-pH (MII-pH) monitoring and (13)C-breath test evaluated acid/non-acid reflux episodes (RE) and gastric emptying rates, respectively. Values are shown with medians and ranges. RESULTS: Percentage time for esophageal pH < 4.0 (reflux index: RI) and numbers for total RE and RE > 5 min were 8.3 (0-35.7), 44 (0-129), and 5 (0-22), respectively. Total percentage time and bolus RE numbers were 1.4 (0.0-6.9) and 49 (2-159), respectively. Median bolus clearance time was 16 s (9-45). T 1/2, T lag, and GEC were 103 s (75-204), 54 s (18-97), and 3.4 (2.3-4.3), respectively. Gastric emptying rates and acid/non-acid reflux parameters were not significantly correlated, except T 1/2 correlated significantly with the numbers of RE > 5 min (p = 0.04). T 1/2 inversely correlated with bolus clearance time (p = 0.01). Reflux parameters between DGE and non-DGE patients were not significantly different, except median bolus clearance time was significantly shorter in DGE patients (p = 0.01). CONCLUSIONS: NI patients showed a wide range of gastric emptying rates without any significant causal relationship between DGE and GER.

Esophago-gastric motility and nutritional management in a child with ATR-X syndrome.

X-linked alpha thalassemia mental retardation (ATR-X) syndrome is an X-linked recessive disorder that often involves gastrointestinal symptoms. Aspiration pneumonia related to gastroesophageal reflux has been reported as the major cause of death, but gastrointestinal function has not been well investigated. The present report describes a child with ATR-X syndrome who suffered from periodical episodes of refractory vomiting. We investigated the function of upper alimentary tract and found that esophago-gastric dysmotility and severe gastric volvulus were the major causes of gastrointestinal symptoms. This child was surgically treated with anterior gastropexy and jejunal alimentation through gastrostomy, and the symptoms were relieved with good weight gain. This report may provide insight into the gastrointestinal function and nutritional management in children with ATR-X syndrome.

Physiological analysis of the effects of rikkunshito on acid and non-acid gastroesophageal reflux using pH-multichannel intraluminal impedance monitoring.

PURPOSE: To clarify the effects of rikkunshito on acid reflux, non-acid reflux, and esophageal clearance in patients with gastroesophageal reflux disease (GERD). METHODS: We enrolled seven patients with vomiting and/or stridor (median 6 years; 1 month-17 years), with a percent total time of esophageal pH <4.0 (reflux index) over 4.0%. Rikkunshito (TJ-43; Tsumura Co, Tokyo, Japan) was given in three divided doses before meals. We retrospectively investigated its efficacy using pH-multichannel intraluminal impedance before and 7 (6-10) days after starting treatment. Statistical analyses were conducted using Wilcoxon signed-rank test. RESULTS: In the pH analyses alone, the median number of acid reflux episodes >5 min (14 versus 10, p = 0.046) and median acid-clearance time (184 versus 134 s, p = 0.03) decreased significantly, although median decrease in reflux index did not reach significance (16.0 versus 17.9%, p = 0.06). In the combined impedance and pH analyses, the median number (36 versus 36, p = 0.03) and median duration (1.9 versus 1.1%, p = 0.046) of acid reflux decreased significantly; non-acid reflux and bolus clearance time did not change. CONCLUSION: Rikkunshito effectively reduced acid reflux, but not esophageal clearance, in patients with GERD.

Parenteral-nutrition-associated liver disease after intestinal perforation in extremely low-birthweight infants: consequent lethal portal hypertension.

BACKGROUND: Parenteral nutrition (PN)-associated liver dysfunction (PNALD) in term infants usually manifests as intrahepatic cholestasis, which recovers with enteral nutrition (EN) in most cases; however, as the number of extremely low-birthweight infants (ELBWI) has been increasing, and consequently intestinal diseases associated with ELBWI have been increasing, more intractable PNALD has been encountered after surgical treatment in ELBWI, which does not resolve or rather worsens with EN. METHODS: Three cases of ELBWI with intestinal perforation, which developed PNALD and eventually died of hepatic failure with intractable portal hypertension, were reviewed. Their gestational age and birthweight ranged from 23 to 26 weeks, and from 434 to 968 g, respectively. The intestinal diseases included necrotizing enteritis in two and meconium-related ileus with focal intestinal perforation in one. RESULTS: The duration of total PN without EN in the three cases was 17, 24 and 24 days, respectively. The interval between the introduction of PN and the onset of PNALD was 14, 4 and 18 days, respectively. A marked elevation of serum endotoxin level was detected in both cases of necrotizing enteritis. Histopathological study of the liver revealed marked cholestasis, significant hepatic necrosis with fibrosis, and proliferation of ductules in all these cases, which was responsible for portal hypertension. CONCLUSIONS: PN after gastrointestinal disorders in ELBWI may cause refractory PNALD, which does not resolve, or rather worsens with the resumption of EN. Portal hypertension secondary to hepatic necrosis may be responsible for the exacerbation with the resumption of EN.

Impact of cow's milk allergy on enterocolitis associated with Hirschsprung's disease.

PURPOSE: To investigate the impact of cow's milk allergy (CMA) on infants with Hirschsprung's disease (HD). METHODS: Twenty-four patients, who developed gastrointestinal symptoms before the age of 60 days and underwent surgery for HD in the period between January 2003 and December 2012, were enrolled in this study. They were divided into two groups based on CMA-related findings: stimulation index of lymphocyte stimulation test >300 % and the presence of eosinophilic infiltration in the resected colon. Ten patients were determined specimen as not having CMA (Group A), because they did not satisfy any of the criteria. The remaining 14 were determined as having possible CMA (Group B), because they satisfied either or both findings. Patient background characteristics, pre- and postoperative clinical history, and laboratory data were compared between Groups A and B. RESULTS: Pre- and postoperative enterocolitis did not occur in Group A patients. Postoperative enterocolitis was more frequent in Group B than in Group A (p = 0.04). Other clinical and laboratory data did not show significant difference between the two groups. CONCLUSION: CMA is a possible risk factor for postoperative enterocolitis in patients with HD.

The clinical significance of intrahepatic cystic lesions in postoperative patients with biliary atresia.

PURPOSE: To clarify the significance of intrahepatic cystic lesions (ICLs) after Kasai procedure for biliary atresia (BA), we reviewed the BA patients with special reference to the shape of ICLs. METHODS: For the last two decades, 75 cases have been followed up at our institution. The patients were divided into two groups: ICLs (+) with ICL and ICLs (-) without ICL. Seventeen cases of ICLs (+) were divided into two categories: the round type and the multiple-bead type. A poor prognosis was defined as mortality or the need for liver transplantation (LT). RESULTS: The ratio of round to multiple-bead types was 6:11. The percentage of poor prognoses with ICLs (+) and ICLs (-) was 47 and 53 %, respectively. The percentage of poor prognoses with round and multiple-bead types was 27 and 83 %, respectively (p < 0.05). In cases of ICLs (+), an LT was required because of hepatic deterioration in all three of the round types, and intractable cholangitis in all five of the multiple-bead types (p < 0.05). CONCLUSION: The long-term prognosis of BAs after the Kasai procedure does not necessarily depend on the development of ICLs per se, but on their shape.

Management of perianal abscess with hainosankyuto in neonates and young infants.

BACKGROUND: Perianal abscess (PA) is a common condition acquired in infancy, yet its treatment method remains controversial. We reviewed the outcome of neonates and young infants with PA who were treated with the traditional Japanese medicine, hainosankyuto (TJ-122). METHODS: Fifteen male infants with PA under the age of 3 months were reviewed. The median age of infants at disease onset was 33 days (range, 18-88 days) and the median bodyweight was 4.1 kg (range, 2.5-6.4 kg). TJ-122 was administered at a dose of 0.20 g/kg/day (n= 13) or 0.25 g/kg/day (n= 2) orally in two or three divided doses before meals. Antibiotics were not used in any of the patients. RESULTS: Of the 15 patients, 14 were cured and had no recurrence, with a median TJ-122 administration of 28 days (range, 14-117 days). Eight patients were cured within 28 days (53%) and 12 were cured within 60 days (80%). One patient, who was later diagnosed with growth hormone deficiency, showed incomplete healing of PA with intermittent pus discharge and recurrence. The patient was cured by 1 year of age following repeated administration of TJ-122 and juzentaihoto (TJ-48). CONCLUSION: Medical management with TJ-122 was effective in most neonates and young infants with PA. It appears prudent to manage these patients with hainosankyuto before resorting to surgical intervention.

Meconium-related ileus in extremely low-birthweight neonates: etiological considerations from histology and radiology.

BACKGROUND: A nationwide survey on neonatal surgery conducted by the Japanese Society of Pediatric Surgeons has demonstrated that the mortality of neonatal intestinal perforation has risen over the past 15 years. The incidence of intestinal perforation in extremely low-birthweight (ELBW) neonates has been increasing as more ELBW neonates survive and as the live-birth rate of ELBW has increased. In contrast to necrotizing enterocolitis (NEC) and focal intestinal perforation (FIP), the pathogenesis of meconium-related ileus, defined as functional bowel obstruction characterized by delayed meconium excretion and microcolon, remains unclarified. METHODS: The histology of 13 ELBW neonates with intestinal perforation secondary to meconium-related ileus was reviewed, and the radiology of 33 cases of meconium-related ileus diagnosed on contrast enema was reviewed. Specimens obtained from 16 ELBW neonates without gastrointestinal disease served as age-matched controls for histological assessment. RESULTS: The size of the ganglion cell nucleus in meconium-related ileus and in control subjects was 47.3 ± 22.0 µm(2) and 37.8 ± 11.6 µm(2), respectively, which was not significantly different. In all cases of meconium-related ileus, contrast enema demonstrated a microcolon or small-sized colon, with a gradual caliber change in the ileum and filling defects due to meconium in the ileum or colon, showing not-identical locations of caliber changes and filling defects. CONCLUSION: Morphological immaturity of ganglia was not suggested to be the pathogenesis of meconium-related ileus. Impaction of inspissated meconium is not the cause of obstruction, but the result of excessive water absorption in the hypoperistaltic bowel before birth, although the underlying mechanism responsible for the fetal hypoperistalsis remains unclear.

Therapeutic strategy for persistent cloaca: the efficacy of antegrade continent enema as a salvage surgery.

PURPOSE: The aim of this study is to evaluate our therapeutic strategy for persistent cloaca from the viewpoint of long-term functional outcome. MATERIALS AND METHODS: This study covers 17 cases of persistent cloaca treated at our institution and followed for more than 3 years. As a definitive repair for anorectal and urogenital systems, simultaneous surgery with posterior sagittal approach or anorecto-urethrovagino-plasty (PSARUVP) was performed. The length of the common channel and the shape of the vagina determined the vaginoplasty methods. Fecal function was assessed with the scoring system of the Japan Study Group of Anorectal Anomalies. RESULTS: Anorectoplasty was performed with the posterior sagittal approach in 15 cases and with the perineal approach in two. Vaginoplasty was performed with total urogenital mobilization in nine cases, rectal interposition in four, vaginal flap in two and with other methods. Fecal function was classified as good in three cases, moderate in ten, and poor in four. In the poor cases, Malone's antegrade continence enema (MACE) was performed, which improved fecal function significantly. CONCLUSION: PSARUVP might be the optimal surgery for persistent cloaca at present; however, satisfactory fecal function could not be achieved in those cases with a longer common channel. MACE effectively compensated for the poor outcome and was especially successful at eliminating incontinence.

Importance of plasma ghrelin levels with special reference to nutritional metabolism and energy expenditure in pediatric patients with severe motor and intellectual disabilities.

BACKGROUND & AIMS: Nutritional metabolism is complex in pediatric patients with severe motor and intellectual disability (SMID), and therefore, appropriate estimation of the energy requirements is difficult. Focusing on ghrelin's role in energy metabolism regulation, we investigated plasma ghrelin levels in pediatric SMID patients and analyzed its nutritional significance as a regulatory marker of energy reserve. METHODS: Fasting plasma total, acyl, and des-acyl ghrelin levels in 40 patients with SMID, including cerebral palsy (CP) (n = 20) and muscular disease (MD) (n = 8), and healthy controls (n = 13) were investigated. The correlations of plasma ghrelin levels with anthropometry, blood nutritional markers, energy intake, and resting energy expenditure (REE) measured with indirect calorimetry were analyzed. A p value < 0.05 was considered significant. RESULTS: SMID patients had significantly higher acyl ghrelin, and lower body mass index (BMI), z-scores of body weight (BW), body height and BMI, and albumin than controls. CP patients had significantly higher total and acyl ghrelin, z-score of the mid-upper arm circumference (MUAC), retinol-binding protein, transthyretin, creatinine, and glucose than MD patients. Total and acyl ghrelin in CP patients and des-acyl ghrelin in MD patients had significant negative correlations with MUAC and upper arm fat area. In CP patients, total and acyl ghrelin had significant positive correlations with REE/BW (kcal/kg), and total ghrelin was predictive of REE/BW (r2 = 0.625, p < 0.0001). CONCLUSIONS: An increase in acyl ghrelin observed in SMID patients possibly indicates energy reserve deficiency. In CP patients, total and acyl ghrelin inversely reflected total body fat mass, resulting in strongly positive correlations with REE/BW. The measurement of plasma ghrelin may be useful to assess nutritional metabolism and energy reserve in pediatric SMID patients, such as CP and MD patients.

Impact of rikkunshito, an herbal medicine, on delayed gastric emptying in profoundly handicapped patients.

PURPOSE: Rikkunshito is used to treat functional dyspepsia in adults. This study investigated the effects of rikkunshito on delayed gastric emptying in handicapped patients. METHODS: A retrospective review was performed in nine profoundly handicapped patients (aged 1-19 years). All were diagnosed with delayed gastric emptying based on their half gastric emptying time (T(1/2)) over 90 min. Gastric emptying was evaluated after the ingestion of liquid meals using the (13)C-acetate breath test and the BreathID system. Participants were given rikkunshito [0.3 g/(kg day)] with the aim of accelerating gastric emptying. Parameters related to gastric emptying before and during rikkunshito administration were compared using the Wilcoxon signed-rank test. Data were expressed as the median (range). RESULTS: Emesis and hematemesis were relieved with rikkunshito administration in four symptomatic patients. The T(1/2) and T(lag) decreased significantly during rikkunshito administration from 115 min (94-167 min) to 107 min (64-66 min; p = 0.02), and from 60 min (42-90 min) to 47 min (29-59 min; p = 0.03), respectively. The gastric emptying coefficient did not show a significant change [3.1 (2.8-3.8) vs. 3.2 (2.6-4.0), p = 0.15)] with rikkunshito treatment. CONCLUSION: The administration of rikkunshito resulted in symptomatic relief and improved gastric emptying in profoundly handicapped patients with delayed gastric emptying.