Samuel Nurko

Constipation in infants and children: Evaluation and treatment

BACKGROUND Constipation, defined as a delay or difficulty in defecation, present for 2 or more weeks, is a common pediatric problem encountered by both primary and specialty medical providers. METHODS The Constipation Subcommittee of the Clinical Guidelines Committee of the North American Society for Pediatric Gastroenterology and Nutrition has formulated clinical practice guidelines for the management of pediatric constipation. The Constipation Subcommittee, consisting of two primary care pediatricians, a clinical epidemiologist, and pediatric gastroenterologists, based its recommendations on an integration of a comprehensive and systematic review of the medical literature combined with expert opinion. Consensus was achieved through Nominal Group Technique, a structured quantitative method. RESULTS The Subcommittee developed two algorithms to assist with medical management, one for older infants and children and the second for infants less than 1 year of age. The guidelines provide recommendations for management by the primary care provider, including evaluation, initial treatment, follow-up management, and indications for consultation by a specialist. The Constipation Subcommittee also provided recommendations for management by the pediatric gastroenterologist. CONCLUSIONS This report, which has been endorsed by the Executive Council of the North American Society for Pediatric Gastroenterology and Nutrition, has been prepared as a general guideline to assist providers of medical care in the evaluation and treatment of constipation in children. It is not intended as a substitute for clinical judgment or as a protocol for the management of all patients with this problem.

Eosinophilic esophagitis: It's not just kid's stuff

Increasing evidence suggests that the esophagus serves as both a conduit for food and a participant in immune responses.1-6 This complex structure possesses innate elements of defense and orchestrates the migration of inflammatory cells, such as lymphocytes and eosinophils, into the squamous epithelium. In that regard, recent clinical experiences have identified an emerging entity termed eosinophilic esophagitis (EE). Although it is thought to occur primarily in children, a significant body of evidence suggests EE affects adults as well. Diagnostic clues are often detected in the gross appearance of the esophageal mucosa, thus emphasizing the important role of GI endoscopists in recognizing this disease. To complete this review of EE, the MEDLINE database was searched for articles containing the words “eosinophilic esophagitis,” “allergic esophagitis,” “ringed,” or “corrugated esophagus.” This search yielded 83 articles dating back to 1978. Review articles, articles lacking any details of the esophageal histology, and those reporting eosinophilic esophagitis in association with eosinophilic gastroenteritis were excluded. Twenty-nine articles and 3 abstracts detailing the experiences of gastroenterologists, pathologists, allergists, and radiologists with 186 patients with EE (35% adults) were examined and form the basis for the clinical details of this article.4,7-37 In addition, 5 investigations examined the immunopathology and pathogenesis of this condition.4,10,38-40 More than two thirds of the articles were published during the last 5 years.

Evaluation and Treatment of Functional Constipation in Infants and Children: Evidence-Based Recommendations From ESPGHAN and NASPGHAN

Background: Constipation is a pediatric problem commonly encountered by many health care workers in primary, secondary, and tertiary care. To assist medical care providers in the evaluation and management of children with functional constipation, the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition and the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition were charged with the task of developing a uniform document of evidence-based guidelines. Methods: Nine clinical questions addressing diagnostic, therapeutic, and prognostic topics were formulated. A systematic literature search was performed from inception to October 2011 using Embase, MEDLINE, the Cochrane Database of Systematic Reviews and Cochrane Central Register of Controlled Clinical Trials, and PsychInfo databases. The approach of the Grading of Recommendations Assessment, Development and Evaluation was applied to evaluate outcomes. For therapeutic questions, quality of evidence was assessed using the Grading of Recommendations, Assessment, Development, and Evaluation system. Grading the quality of evidence for the other questions was performed according to the classification system of the Oxford Centre for Evidence-Based Medicine. During 3 consensus meetings, all recommendations were discussed and finalized. The group members voted on each recommendation, using the nominal voting technique. Expert opinion was used where no randomized controlled trials were available to support the recommendation. Results: This evidence-based guideline provides recommendations for the evaluation and treatment of children with functional constipation to standardize and improve their quality of care. In addition, 2 algorithms were developed, one for the infants <6 months of age and the other for older infants and children. Conclusions: This document is intended to be used in daily practice and as a basis for further clinical research. Large well-designed clinical trials are necessary with regard to diagnostic evaluation and treatment.

Deficient natural killer cell cytotoxicity in patients with IKK-γ/NEMO mutations

NF-κB essential modifier (NEMO), also known as IKK-γ, is a member of the I-κB kinase complex responsible for phosphorylating I-κB, allowing the release and activation of NF-κB. Boys with an expressed NEMO mutation have an X-linked syndrome characterized by hypohidrotic ectodermal dysplasia with immune deficiency (HED-ID). The immunophenotype resulting from NEMO mutation is highly variable, with deficits in both T and B cell responses. We evaluated three patients with NEMO mutations (L153R, Q403X, and C417R) and HED-ID who had evidence of defective CD40 signaling. All three patients had normal percentages of peripheral blood NK cells, but impaired NK cell cytotoxic activity. This was not due to a generalized defect in cytotoxicity because antibody-dependent cellular cytotoxicity was intact. This abnormality was partially reversed by in vitro addition of IL-2, which was also able to induce NF-κB activation. In one patient with recurrent cytomegalovirus infections, administration of IL-2 partially corrected the NK cell killing deficit. These data suggest that NEMO participates in signaling pathways leading to NK cell cytotoxicity and that IL-2 can activate NF-κB and partially overcome the NK cell defect in patients with NEMO mutations.

Multicenter, Randomized, Placebo-Controlled Trial of Amitriptyline in Children With Functional Gastrointestinal Disorders

BACKGROUND & AIMS There are no prospective, multicenter, double-blind, placebo-controlled, randomized pharmacologic trials for the treatment of pain-predominant functional gastrointestinal disorders in children. The aim of this study was to evaluate the efficacy of amitriptyline in children with pain-predominant functional gastrointestinal disorders. METHODS In this multicenter placebo-controlled trial, children with irritable bowel syndrome, functional abdominal pain, or functional dyspepsia were randomized to 4 weeks of placebo or amitriptyline (10 mg/d, weight <35 kg; 20 mg/d, weight >35 kg). Assessment of gastrointestinal symptoms, psychological traits, and daily activities occurred before and after intervention. Pain was assessed daily with self-report diaries. The primary outcome was overall response to treatment (childs assessment of pain relief and sense of improvement). Secondary outcomes were effect on psychosocial traits and daily functioning. RESULTS Ninety children were enrolled, and 83 completed the study (placebo, 40 children [30 girls]; drug, 43 children [35 girls]). A total of 63% of patients reported feeling better and 5% feeling worse in the amitriptyline arm compared with 57.5% feeling better and 2.5% feeling worse in the placebo arm (P = .63). Pain relief was excellent in 7% and good in 38% of children receiving placebo compared with excellent in 15% and good in 35% of children treated with amitriptyline (P = .85). Logistic regression analysis of those reporting excellent or good response versus fair, poor, or failed response showed no difference between amitriptyline and placebo (P = .83). Children who had more severe pain at baseline in both groups (P = .0065) had worse outcome. Amitriptyline reduced anxiety scores (P < .0001). CONCLUSIONS Both amitriptyline and placebo were associated with excellent therapeutic response. There was no significant difference between amitriptyline and placebo after 4 weeks of treatment. Patients with mild to moderate intensity of pain responded better to treatment.

The Importance of Multichannel Intraluminal Impedance in the Evaluation of Children with Persistent Respiratory Symptoms

OBJECTIVES:Previous evidence suggests an association between gastroesophageal reflux disease and chronic respiratory disease in children. Despite antisecretory antacid therapy, respiratory symptoms often persist supporting a role for nonacid reflux. The aim of this study was to determine whether nonacid reflux occurs in children with chronic respiratory disease.METHODS:Twenty-eight children (mean age: 6.5 ± 5.6 yr) with persistent respiratory symptoms on antacid medications underwent 24 h pH/multichannel intraluminal impedance (pH/MII) recording. The symptom index (SI) and the symptom sensitivity index (SSI) were calculated for each patient. Logistic regression was performed to determine which reflux characteristics were associated with a high degree of symptom correlation present during the occurrence of symptoms.RESULTS:A total of 1,822 reflux episodes were detected by pH/MII, 45% of which were nonacidic. The mean SI increased using pH/MII (35.7 ± 28.5) compared to pH probe alone (14.6 ± 18.9; p= 0.002); no differences in the mean SSI using pH/MII compared to pH probe alone were identified. Significantly more patients had a positive SI using pH/MII than pH probe alone (p= 0.035); there was no difference in the number of patients with a positive SSI using pH/MII compared to pH probe alone. Multivariate analysis revealed that symptoms occurred more frequently when the reflux was nonacidic, mixed, and full column. Also, younger children were more likely to have the simultaneous occurrence of symptoms and reflux.CONCLUSIONS:Nonacid reflux may be an important predictor of respiratory symptoms. pH/MII provided important information in the evaluation of children with intractable respiratory symptoms.

Cysteine metabolism and whole blood glutathione synthesis in septic pediatric patients.

ObjectiveTo investigate whole body in vivo cysteine kinetics and its relationship to whole blood glutathione (GSH) synthesis rates in septic, critically ill pediatric patients and controls. DesignProspective cohort study. SettingMultidisciplinary intensive care unit and pediatric inpatient units at a children’s hospital. PatientsTen septic pediatric patients and ten controls (children admitted to the hospital for elective surgery). InterventionsSeptic patients (age, 31 months to 17 yrs) and controls (age, 24 months to 21 yrs) received a 6-hr primed, constant, intravenous tracer infusion of l-[1-13C]cysteine. Blood samples were obtained to determine isotopic enrichment of plasma cysteine and whole blood [1-13C]cysteinyl-glutathione by gas-chromatography mass spectrometric techniques. The plasma flux and oxidation rate of cysteine and the fractional and absolute synthesis rates of GSH were determined. Septic patients received variable protein and energy intake, as per routine clinical management, and controls were studied in the early postabsorptive state. Measurements and Main Results Plasma cysteine fluxes were increased in the septic patients when compared with the controls (68.2 ± 17.5 [sd] vs. 48.7 ± 8.8 &mgr;mol·kg−1·hr−1;p < .01), and the fraction of plasma cysteine flux associated with oxidative disposal was similar among the groups. The absolute rates of GSH synthesis in whole blood were decreased (p < .01) in the septic patients (368 ± 156 vs. 909 ± 272 &mgr;mol·L−1·day−1). The concentration of whole blood GSH also was decreased in the septic group (665.4 ± 194 vs. 1059 ± 334 &mgr;M;p < .01) ConclusionsWhole blood glutathione synthesis rates are decreased, by about 60%, in critically ill septic children receiving limited nutritional support. Plasma cysteine fluxes and concentration of cysteine were increased in the septic patients, suggesting a hypermetabolic state with increased protein breakdown. The mechanisms whereby GSH synthesis rates are decreased in these patients are probably multifactorial, presumably involving an inflammatory response in the presence of limited nutritional support. The role of nutritional modulation and the use of cysteine prodrugs in maintaining GSH concentration and synthesis remain to be established.

The sensitivity of multichannel intraluminal impedance and the pH probe in the evaluation of gastroesophageal reflux in children.

BACKGROUND & AIMS Multichannel intraluminal impedance (MII) has been incorporated into gastroesophageal reflux evaluations in children despite a lack of evidence comparing it to the gold standard pH probe. The aim of this study was to compare these two technologies. METHODS Twenty-five consecutive, untreated children undergoing pH-MII recording were studied. Sensitivities for the pH probe and MII were defined as: (acid+pH-only episodes)/(acid+non-acid+pH-only episodes) and (acid+non-acid episodes)/(acid+non-acid+pH-only episodes), respectively. Sensitivities were compared using paired t testing. After the analysis was performed, the pH-MII tracings of 25 age-matched children taking acid suppression therapy were compared and sensitivity calculations were performed. RESULTS In untreated patients, 1845 reflux episodes were detected, and 1702 were detected in treated patients. The mean sensitivities of pH probe and MII in untreated patients were 80.6 +/- 18.2% and 76.1 +/- 13.5%, respectively (P = .41). The mean sensitivities of pH probe and MII in treated patients were 47.2 +/- 36.0% and 80.3 +/- 21.1%, respectively (P = .005). Twenty-five percent of reflux episodes were pH-only episodes. There were no differences in the mean number of acid or non-acid reflux episodes in patients with normal and abnormal pH probe studies. Instead, there were significantly more pH-only episodes in patients with abnormal probe studies. CONCLUSIONS The sensitivity of MII equals that of the pH probe in untreated patients but is superior to the pH probe in treated patients. pH-only episodes are numerous in pediatrics and should be included in pH-MII analyses.

Association of Schatzki Ring With Eosinophilic Esophagitis in Children

Objective: To describe the clinicopathologic characteristics of children with Schatzki ring and to determine if Schatzki ring is associated with eosinophilic esophagitis. Methods: The authors report 18 adolescents with radiographically diagnosed Schatzki ring (SR). Their clinical and histologic characteristics were reviewed in a blinded fashion. Results: The mean age of the patients was 15.8 ± 0.8 years and mean duration of symptoms was 2.6 ± 0.4 years. By histologic criteria, two groups of patients were defined. Eight had clinical and histologic criteria of eosinophilic esophagitis (EE) and 10 of peptic esophagitis. There were no differences in the symptoms or radiographic findings in the two groups. The SR was not identified by endoscopy in any EE patient and was identified in 70% of peptic esophagitis patients. Grossly apparent mucosal features associated with EE were significantly more common in those with EE. Those with peptic esophagitis had a significantly higher acid exposure than did those with EE (12.6 ± 2.9 v 2.0 ± 1.1%; P < 0.01) by esophageal pH probe. Patients with peptic esophagitis responded to proton pump inhibitors and/or dilatation, whereas those with EE did not have good response and required specific therapy for EE. Conclusions: EE may play a role in the pathogenesis of some patients with SR.

PEG3350 in the Treatment of Childhood Constipation : A Multicenter, Double-Blinded, Placebo-Controlled Trial

OBJECTIVE To establish the efficacy and best starting dose of polyethylene glycol (PEG)3350 in the short-term treatment of children with functional constipation. STUDY DESIGN Prospective, randomized, multicenter, double-blinded, placebo-controlled, dose-ranging study of PEG3350 in children with functional constipation. Patients were randomly assigned to either placebo or 0.2 g/kg per day, 0.4 g/kg per day, or 0.8 g/kg per day of PEG3350 after a 1 week run-in period, followed by 2 weeks of treatment. All received behavior modification. The primary outcome was the proportion of patients with a successful treatment response: >or=3 bowel movements (BM) in the second week. RESULTS 103 children (mean, 8.5 +/- 3.1 years) were enrolled. 77%, 74%, and 73% of the 0.2, 0.4, and 0.8 g/kg groups were successfully treated, as compared with 42% receiving placebo (P < .04). There was a significant increase in BM (P < .001) and straining improvement (P < .05) with the different PEG3350 doses. Stool consistency improved significantly for doses 0.4 g/kg or higher (P < .001). There was more abdominal pain and fecal incontinence in patients receiving 0.8 g/kg. PEG3350 was well tolerated. CONCLUSIONS This placebo-controlled study confirms the efficacy and safety of PEG3350 for the short-term treatment of children with functional constipation. We recommend a starting dose of 0.4 g/kg per day.