Role of endoscopic ultrasound-guided fine needle aspiration biopsies in diagnosing pancreatic neoplasms in the paediatric population: experience from a tertiary center and review of the literature.

BACKGROUND: Endoscopic ultrasound-guided fine needle aspiration biopsy (EUS FNAB) is a well established diagnostic method in adult patients, but is rarely used in the paediatric population. The Clinical Department of Gastroenterology at the University Clinical Centre Ljubljana and the Department of Cytopathology at the Institute of Pathology, Faculty of Medicine, University of Ljubljana, Slovenia, have been closely collaborating on EUS FNAB since the introduction in 2010. The aim of the study was to review the cases of EUS FNAB of pancreatic neoplasms in children. PATIENTS AND METHODS: In the digital archive of the Institute of Pathology (IP), Faculty of Medicine (FM), University of Ljubljana (UL), we found 6 cases of EUS FNAB in children, 3 had EUS FNAB of the pancreas, 2 of whom had a cytopathologic diagnosis of a tumour. In the first case, the lesion was ultrasonographically solid, and the cell sample contained branching papillary structures surrounded by aggregates of small cells with nuclear grooves. In the second case, the lesion was ultrasonographically cystic, and predominantly necrosis was seen, with only single preserved cells. Positive nuclear reaction for ß-catenin was found in both cases by immunohistochemical staining. RESULTS: In both cases, the cytopathological diagnosis of solid pseudopapillary neoplasm of the pancreas was made, the cases represent the totality of paediatric cases of pancreatic neoplasms from the Children's Hospital Ljubljana since 2010. There were no adverse events during and after EUS FNAB. A histopathological examination of the tumour resection specimens confirmed the cytopathological diagnosis. CONCLUSIONS: Our experience indicates that EUS FNAB is a safe and effective method for diagnosing pancreatic neoplasms in the pediatric population, as supported by the findings in the literature.

Clinical and genetic characteristics of a patient with phosphoribosyl pyrophosphate synthetase 1 deficiency and a systematic literature review.

Phosphoribosylpyrophosphate synthetase 1 (PRS-I) is an enzyme involved in nucleotide metabolism. Pathogenic variants in the PRPS1 are rare and PRS-I deficiency can manifest as three clinical syndromes: X-linked non-syndromic sensorineural deafness (DFN2), X-linked Charcot-Marie-Tooth neuropathy type 5 (CMTX5) and Arts syndrome. We present a Slovenian patient with PRS-I enzyme deficiency due to a novel pathogenic variant - c.424G > A (p.Val142Ile) in the PRPS1 gene, who presented with gross motor impairment, severe sensorineural deafness, balance issues, ataxia, and frequent respiratory infections. In addition, we report the findings of a systemic literature review of all described male cases of Arts syndrome and CMTX5 as well as intermediate phenotypes. As already proposed by other authors, our results confirm PRS-I deficiency should be viewed as a phenotypic continuum rather than three separate syndromes because there are multiple reports of patients with an intermediary clinical presentation.

Genotype-phenotype relationships of truncating mutations, p.E297G and p.D482G in bile salt export pump deficiency.

Background & Aims: Bile salt export pump (BSEP) deficiency frequently necessitates liver transplantation in childhood. In contrast to two predicted protein truncating mutations (PPTMs), homozygous p.D482G or p.E297G mutations are associated with relatively mild phenotypes, responsive to surgical interruption of the enterohepatic circulation (siEHC). The phenotype of patients with a compound heterozygous genotype of one p.D482G or p.E297G mutation and one PPTM has remained unclear. We aimed to assess their genotype-phenotype relationship. Methods: From the NAPPED database, we selected patients with homozygous p.D482G or p.E297G mutations (BSEP1/1; n = 31), with one p.D482G or p.E297G, and one PPTM (BSEP1/3; n = 30), and with two PPTMs (BSEP3/3; n = 77). We compared clinical presentation, native liver survival (NLS), and the effect of siEHC on NLS. Results: The groups had a similar median age at presentation (0.7-1.3 years). Overall NLS at age 10 years was 21% in BSEP1/3 vs. 75% in BSEP1/1 and 23% in BSEP3/3 (p <0.001). Without siEHC, NLS in the BSEP1/3 group was similar to that in BSEP3/3, but considerably lower than in BSEP1/1 (at age 10 years: 38%, 30%, and 71%, respectively; p = 0.003). After siEHC, BSEP1/3 and BSEP3/3 were associated with similarly low NLS, while NLS was much higher in BSEP1/1 (10 years after siEHC, 27%, 14%, and 92%, respectively; p <0.001). Conclusions: Individuals with BSEP deficiency with one p.E297G or p.D482G mutation and one PPTM have a similarly severe disease course and low responsiveness to siEHC as those with two PPTMs. This identifies a considerable subgroup of patients who are unlikely to benefit from interruption of the enterohepatic circulation by either surgical or ileal bile acid transporter inhibitor treatment. Impact and implications: This manuscript defines the clinical features and prognosis of individuals with BSEP deficiency involving the combination of one relatively mild and one very severe BSEP deficiency mutation. Until now, it had always been assumed that the mild mutation would be enough to ensure a relatively good prognosis. However, our manuscript shows that the prognosis of these patients is just as poor as that of patients with two severe mutations. They do not respond to biliary diversion surgery and will likely not respond to the new IBAT (ileal bile acid transporter) inhibitors, which have recently been approved for use in BSEP deficiency.

Clinical and genetic characteristics of two patients with tyrosinemia type 1 in Slovenia - A novel fumarylacetoacetate hydrolase (FAH) intronic disease-causing variant.

Tyrosinemia type 1 (HT1) is an inborn error of tyrosine catabolism that leads to severe liver, kidney, and neurological dysfunction. Newborn screening (NBS) can enable a timely diagnosis and early initiation of treatment. We presented the follow up of the only two Slovenian patients diagnosed with HT1. Metabolic control was monitored by measuring tyrosine, phenylalanine and succinylacetone from dried blood spots (DBSs). Retrograde screening of HT1 was performed from DBSs taken at birth using tandem mass spectrometry. First patient was diagnosed at the age of 6 months in the asymptomatic phase due to an abnormal liver echogenicity, the other presented at 2.5 months with an acute liver failure and needed a liver transplantation. The first was a compound heterozygote for a novel FAH intronic variant c.607-21A>G and c.192G>T whereas the second was homozygous for c.192G>T. At the non-transplanted patient, 66% of tyrosine and 79% of phenylalanine measurements were in strict reference ranges of 200-400 µmol/L and >30 µmol/L, respectively, which resulted in a favorable cognitive outcome at 3.6 years. On retrograde screening, both patients had elevated SA levels; on the other hand, tyrosine was elevated only at one. We showed that non-coding regions should be analyzed when clinical and biochemical markers are characteristic of HT1. DBSs represent a convenient sample type for frequent amino acid monitoring. Retrograde diagnosis of HT1 was possible after more than three years of birth with SA as a primary marker, complemented by tyrosine.

Non-Alcoholic Fatty Liver Disease in Children.

Background and Objectives: The prevalence of pediatric non-alcoholic fatty liver disease is increasing. A lot of new data are published regularly. Materials and Methods: Original clinical studies, review articles, and guidelines in children were searched for and the most relevant included in this review. Results: A total of 138 retrieved papers were classified into pathogenesis, epidemiology, diagnosis, and treatment. Pathogenesis is currently explained with the "multi hit hypothesis", with complex interactions of genetic and environmental factors which trigger inflammation in steatotic liver. The prevalence is rising. A diagnosis can be made with laboratory tests, imaging, and liver biopsy after the exclusion of other causes of liver steatosis. The mainstay of treatment is lifestyle modification consisting of dietary intervention and increased physical activity. The progression to liver cirrhosis can occur even in children. Conclusions: Non-alcoholic fatty liver disease in children is a part of a metabolic syndrome in the majority of patients. Due to its complex etiology and high prevalence, multidisciplinary teams, together with public health professionals, should be involved in its treatment.

Impact of Genotype, Serum Bile Acids, and Surgical Biliary Diversion on Native Liver Survival in FIC1 Deficiency.

BACKGROUND AND AIMS: Mutations in ATPase phospholipid transporting 8B1 (ATP8B1) can lead to familial intrahepatic cholestasis type 1 (FIC1) deficiency, or progressive familial intrahepatic cholestasis type 1. The rarity of FIC1 deficiency has largely prevented a detailed analysis of its natural history, effects of predicted protein truncating mutations (PPTMs), and possible associations of serum bile acid (sBA) concentrations and surgical biliary diversion (SBD) with long-term outcome. We aimed to provide insights by using the largest genetically defined cohort of patients with FIC1 deficiency to date. APPROACH AND RESULTS: This multicenter, combined retrospective and prospective study included 130 patients with compound heterozygous or homozygous predicted pathogenic ATP8B1 variants. Patients were categorized according to the number of PPTMs (i.e., splice site, frameshift due to deletion or insertion, nonsense, duplication), FIC1-A (n = 67; no PPTMs), FIC1-B (n = 29; one PPTM), or FIC1-C (n = 34; two PPTMs). Survival analysis showed an overall native liver survival (NLS) of 44% at age 18 years. NLS was comparable among FIC1-A, FIC1-B, and FIC1-C (% NLS at age 10 years: 67%, 41%, and 59%, respectively; P = 0.12), despite FIC1-C undergoing SBD less often (% SBD at age 10 years: 65%, 57%, and 45%, respectively; P = 0.03). sBAs at presentation were negatively associated with NLS (NLS at age 10 years, sBAs < 194 µmol/L: 49% vs. sBAs ≥ 194 µmol/L: 15%; P = 0.03). SBD decreased sBAs (230 [125-282] to 74 [11-177] µmol/L; P = 0.005). SBD (HR 0.55, 95% CI 0.28-1.03, P = 0.06) and post-SBD sBA concentrations < 65 µmol/L (P = 0.05) tended to be associated with improved NLS. CONCLUSIONS: Less than half of patients with FIC1 deficiency reach adulthood with native liver. The number of PPTMs did not associate with the natural history or prognosis of FIC1 deficiency. sBA concentrations at initial presentation and after SBD provide limited prognostic information on long-term NLS.

Infantile ATP7B-Related End-Stage Liver Disease: An Exceptional Wilson Disease Phenotype From Consecutive Generations.

Wilson disease (WD) is a rare autosomal recessive disorder of copper metabolism typically presenting after 3 years of age. We describe a girl presenting with neonatal cholestasis rapidly progressing to end-stage liver disease. She presented hepatosplenomegaly, neurological impairment, Coombs-negative hemolytic anemia, central hypothyroidism. A patient-parents whole exome sequencing identified a homozygous state for ATP7B mutations causing WD in the proband (p.Gln7fs/p.His1069Gln) and her mother (p.His1069Gln/p.His1069Gln), who was then confirmed to have cirrhotic WD. A causative role of copper toxicity due to ATP7B loss of function was indicated by the presence of extrahepatic features of WD, consistent tests of copper metabolism-including a 7-fold increase in liver copper-and similarity of patient's liver gene expression profile and ultrastructure with that of WD models. This exceptionally early presentation could result from the combination of the ATP7B impairment and the intrauterine copper overload due to maternal undiagnosed WD.

Genotype correlates with the natural history of severe bile salt export pump deficiency.

BACKGROUND & AIMS: Mutations in ABCB11 can cause deficiency of the bile salt export pump (BSEP), leading to cholestasis and end-stage liver disease. Owing to the rarity of the disease, the associations between genotype and natural history, or outcomes following surgical biliary diversion (SBD), remain elusive. We aimed to determine these associations by assembling the largest genetically defined cohort of patients with severe BSEP deficiency to date. METHODS: This multicentre, retrospective cohort study included 264 patients with homozygous or compound heterozygous pathological ABCB11 mutations. Patients were categorized according to genotypic severity (BSEP1, BSEP2, BSEP3). The predicted residual BSEP transport function decreased with each category. RESULTS: Genotype severity was strongly associated with native liver survival (NLS, BSEP1 median 20.4 years; BSEP2, 7.0 years; BSEP3, 3.5 years; p <0.001). At 15 years of age, the proportion of patients with hepatocellular carcinoma was 4% in BSEP1, 7% in BSEP2 and 34% in BSEP3 (p = 0.001). SBD was associated with significantly increased NLS (hazard ratio 0.50; 95% CI 0.27-0.94: p = 0.03) in BSEP1 and BSEP2. A serum bile acid concentration below 102 µmol/L or a decrease of at least 75%, each shortly after SBD, reliably predicted NLS of ≥15 years following SBD (each p <0.001). CONCLUSIONS: The genotype of severe BSEP deficiency strongly predicts long-term NLS, the risk of developing hepatocellular carcinoma, and the chance that SBD will increase NLS. Serum bile acid parameters shortly after SBD can predict long-term NLS. LAY SUMMARY: This study presents data from the largest genetically defined cohort of patients with severe bile salt export pump deficiency to date. The genotype of patients with severe bile salt export pump deficiency is associated with clinical outcomes and the success of therapeutic interventions. Therefore, genotypic data should be used to guide personalized clinical care throughout childhood and adulthood in patients with this disease.

Partial enteral nutrition induces clinical and endoscopic remission in active pediatric Crohn's disease: results of a prospective cohort study.

The aim of this study was to evaluate rates of clinical remission, endoscopic remission, and mucosal healing after a 6-week treatment period with partial enteral nutrition (PEN) and to compare them to those obtained by standard exclusive enteral nutrition (EEN) treatment in children with active Crohn's disease (CD). Twenty-five patients with active CD (median age 13.6 years, range 3.6-18.0) were recruited to either PEN (n = 12) or EEN (n = 13) treatment groups. The PEN group received 75% of their dietary needs from a polymeric formula plus one meal per day from an anti-inflammatory diet (AID). Patients were assessed at weeks 0, 1, 3, and 6 using clinical and laboratory parameters. Endoscopic assessment was performed at induction and week 6. On intention to treat analysis, clinical remission (Pediatric CD Activity Index < 10) was achieved in 69.2% and 75.0% of EEN and PEN patients, respectively (p = 0.999). The endoscopic remission (Simple Endoscopic Score for CD (SES-CD) ≤ 2) rates were 45.5% in both groups, while mucosal healing rates (SES-CD = 0) were 45.5% with EEN and 27.3% with PEN (p = 0.659).Conclusion: The results of our prospective pilot study suggest that PEN, allowing one meal from AID, could be as effective as EEN in inducing clinical and endoscopic remission in children with active CD. However, larger randomized controlled studies are warranted to confirm our findings.Trial registration: This clinical trial was registered under the number ClinicalTrials.govidentifier: NCT03176875.What is Known:• Exclusive enteral nutrition is a first-line treatment in active pediatric Crohn's disease; however, patients often find it difficult to adhere to.• Exclusive enteral nutrition is more effective than corticosteroids in achieving mucosal healing.What is New:• This is the first prospective study on partial enteral nutrition in active pediatric Crohn's disease, evaluating not only clinical, but also endoscopic remission.• A novel approach of partial enteral nutrition that allows one meal per day from an anti-inflammatory diet was as effective as exclusive enteral nutrition in inducing clinical and endoscopic remission in active Crohn's disease.

Comparison of liquid chromatography with tandem mass spectrometry and ion-exchange chromatography by post-column ninhydrin derivatization for amino acid monitoring.

OBJECTIVES: Precise quantification of amino acids (AAs) is mandatory for successful diagnosis and monitoring of patients with metabolic diseases. We compared ion-exchange chromatography (IEC) and liquid chromatography with tandem mass spectrometry (LC-MS/MS), the two methods most commonly used in clinical laboratories for the quantification of AAs in physiological samples. DESIGN & METHODS: 123 apparently healthy children were selected for the study. The plasma samples for LC-MS/MS were prepared accordingly to the aTRAQ Kit for Physiological Fluids on Sciex 3200 Qtrap, for IEC according to the protocol from Pickering laboratories on the AA analyzer Pinnacle PCX. Results were interpreted using the Pearson correlation coefficient and the percent difference Bland-Altman test. RESULTS: The Spearman correlation coefficients of the 14 AAs that we evaluated varied from 0.67 in Tau to 0.89 in Leu and Thr. The mean differences in measurements (IEC compared to LC-MS/MS) of 11 AAs complied with our acceptance criterion of <15%, the differences of Ser and Tyr were higher (19.5% and -19.0%, respectively), and the measured concentrations of Cit were much lower in LC-MS/MS than IEC (31% difference). CONCLUSION: The two methods are sufficiently comparable for most AAs and the reference values for individual AAs did not have to be refined, with the exception of citrulline. For the monitoring of patients on therapy (e.g. patients with phenylketonuria), it is still advisable to always use the same analytical method for the quantification of AAs.

Dual Role of PTPN22 but Not NLRP3 Inflammasome Polymorphisms in Type 1 Diabetes and Celiac Disease in Children.

Genetic polymorphisms in genes coding for inflammasome components nucleotide-binding oligomerization domain leucine rich repeat and pyrin domain-containing protein 3 (NLRP3) and caspase recruitment domain-containing protein 8 (CARD8) have been associated with autoinflammatory and autoimmune diseases. On the other hand several studies suggested that NLRP3 inflammasome contributes to maintenance of gastrointestinal immune homeostasis and that activation of NLRP3 is regulated by protein tyrosine phosphatase non-receptor 22 (PTPN22). PTPN22 polymorphism was implicated in the risk for various autoimmune diseases including type 1 diabetes (T1D) but not for celiac disease (CD). The aim of our study was to evaluate the role of inflammasome related polymorphisms in subjects with either T1D or CD as well as in subjects affected by both diseases. We examined PTPN22 rs2476601 (p.Arg620Trp), NLRP3 rs35829419 (p.Gln705Lys), and CARD8 rs2043211 (p.Cys10Ter) in 66 subjects with coexisting T1D and CD, 65 subjects with T1D who did not develop CD, 67 subjects diagnosed only with CD and 127 healthy unrelated Slovenian individuals. All results were adjusted for clinical characteristic and human leukocyte antigen (HLA) risk. PTPN22 rs2476601 allele was significantly more frequent among subjects with T1D (Padj = 0.001) and less frequent in subjects with CD (Padj = 0.039) when compared to controls. In patients with coexisting T1D and CD this variant was significantly less frequent compared to T1D group (Padj = 0.010). Protective effect on CD development in individuals with T1D was observed only within the low risk HLA group. On the other hand, we found no association of NLRP3 rs35829419 and CARD8 rs2043211 with the development of T1D, CD or both diseases together. In conclusion PTPN22 rs2476601polymorphism was significantly associated with the risk of developing T1D in Slovenian population, while no associations of proinflammatory NLRP3 and CARD8 polymorphisms with T1D and CD were observed. Interestingly, the same PTPN22 variant protected from CD. We hypothesize that this effect may be mediated through the NLRP3 inflammasome activation.

Success and safety of high infliximab trough levels in inflammatory bowel disease.

OBJECTIVE: A prospective trial suggests target infliximab trough levels of 3-7 µg/mL, yet data on additional therapeutic benefits and safety of higher trough levels are scarce. AIM: To explore whether high infliximab trough levels (≥7 µg/mL) are more effective and still safe. MATERIAL AND METHODS: In this cohort study of 183 patients (109 Crohn's disease and 74 ulcerative colitis) on infliximab maintenance treatment at a tertiary referral center we correlated fecal calprotectin and C-reactive protein to trough levels (426 samples) at different time points during treatment. Rates of infections were compared in quadrimesters (four-month periods) with high trough levels to quadrimesters with trough levels <7 µg/mL during 420 patient-years. RESULTS: Fecal calprotectin and C-reactive protein (median [interquartile range]) were lower in patients with high trough levels (fecal calprotectin 66 mg/kg [30-257]; C-reactive protein 3 mg/L [3-3]) compared to trough levels below 7 µg/mL (fecal calprotectin 155 mg/kg [72-474]; C-reactive protein 3 mg/L [3-14.5]) (p < .001). High trough levels were superior also after excluding samples with trough levels <3 µg/mL from analysis. No differences in rates of infections were observed in quadrimesters with high trough levels (16/129 [12.4%]) compared to quadrimesters with trough levels <7 µg/mL (32/344 [9.3%]) (p = .32). Maintaining high trough levels resulted in 32% (interquartile range: 2-54%) increase of infliximab consumption. CONCLUSION: High infliximab trough levels provide better control of inflammation in inflammatory bowel disease without increasing the risk of infection.

High-risk genotypes HLA-DR3-DQ2/DR3-DQ2 and DR3-DQ2/DR4-DQ8 in co-occurrence of type 1 diabetes and celiac disease.

Shared susceptibility alleles in the HLA region contribute to the co-existence of type 1 diabetes (T1D) and celiac disease (CD). The aim of our study was to identify HLA genotype variations that influence co-occurrence of T1D and CD (T1D + CD) and the order of their onset. Totally 244 patients, 67 with T1D, 68 with CD and 69 with T1D + CD, (split into "T1D first" and "CD first"), were analyzed. Control group consisted of 130 healthy unrelated individuals. Two-tailed Fisher's exact test was used for statistical analysis. The genetic background of Slovenian CD patients resembled more northern than southern European populations with DR3-DQ2/DR3-DQ2 (odds ratio [OR] = 19.68) conferring the highest risk. The T1D + CD was associated with DR3-DQ2/DR3-DQ2 (OR = 45.53) and even more with DR3-DQ2/DR4-DQ8 (OR = 93.76). DR3-DQ2/DR7-DQ2 played a neutral role in susceptibility for T1D + CD. The order of the onset of T1D or CD in patients with co-occurring diseases was not influenced by HLA risk genotype profile. DR3-DQ2/DR3-DQ2 was associated with an increased risk for developing CD in patients with T1D, whereas patients with CD carrying DR3-DQ2/DR4-DQ8 were at higher risk for developing T1D. In addition to other genetic factors including HLA class I alleles present on DR3-DQ2 extended haplotype, the second extended haplotype may moderate the risk for T1D + CD conferred by DR3-DQ2. Our results suggested that individuals carrying high-risk genotypes DR3-DQ2/DR3-DQ2 or DR3-DQ2/DR4-DQ8 would more likely develop both T1D and CD than either disease alone.

Morphological and Functional Assessment of Oesophageal Mucosa Integrity in Children With Cystic Fibrosis.

OBJECTIVES: The aim of the study was to investigate morphological and functional characteristics of oesophageal epithelial barrier in children with cystic fibrosis (CF) with or without gastro-oesophageal reflux disease (GORD) in comparison to healthy controls. METHODS: Oesophagogastroduodenoscopy with oesophageal biopsies and combined oesophageal multichannel intraluminal impedance-pH monitoring was performed in 17 children with CF (CFtot) with (CFgord) or without GORD (CFnorm). Histological combined severity score was calculated and widths of spaces between epithelial cells were measured. Basal impedance value was used to assess functional integrity of epithelial barrier. Results of each investigation were compared with a group of children without oesophageal disease. RESULTS: CFtot, but also CFnorm, had more severe pathohistological changes included in the compound severity score than controls (0.75 ±â€Š0.32 and 0.75 ±â€Š0.20 vs 0.27 ±â€Š0.25; P < 0.001 and P = 0.001, respectively). They also had more dilated intercellular spaces (2.6 µm ±â€Š0.6 and 2.7 µm ±â€Š0.5 vs 1.9 µm ±â€Š0.2; P = 0.001 and P < 0.001, respectively). Baseline impedance values between proximal and distal pairs of electrodes were significantly lower in CFtot (2876 Ω ±â€Š484, 2590 Ω ±â€Š1013) and also in CFnorm (2922 Ω ±â€Š363, 2844 Ω ±â€Š457) than in controls (3703 Ω ±â€Š859, 3753 Ω ±â€Š1070) (P = 0.012 and P = 0.002; and P = 0.027 and P = 0.005, respectively). The treatment of CFgord with proton pump inhibitor increased, but did not normalise the baseline impedance values (2860 Ω ±â€Š560 to 3355 Ω ±â€Š750 and 2178 Ω ±â€Š1564 to 3057 Ω ±â€Š594). CONCLUSIONS: Children with CF had morphological and functional changes of oesophageal mucosal integrity even in the absence of GORD.

Autoimmune hepatitis as a presenting manifestation of mixed connective tissue disease in a child. Case report and review of the literature.

BACKGROUND: Liver disease is rare in the course of mixed connective tissue disease. Most commonly liver steatosis or elevated liver function tests are reported and only a few cases of mixed connective tissue disease associated with autoimmune hepatitis were described. CASE PRESENTATION: We report a case of an 11-year old boy with hepatitis on admission to the hospital and symptoms and signs of mixed connective tissue disease. Autoimmune hepatitis has been confirmed by liver biopsy. CONCLUSION: To the best of our knowledge this is the youngest patient with autoimmune hepatitis as a presenting manifestation of mixed connective tissue disease.

Review on sedation for gastrointestinal tract endoscopy in children by non-anesthesiologists.

AIM: To present evidence and formulate recommendations for sedation in pediatric gastrointestinal (GI) endoscopy by non-anesthesiologists. METHODS: The databases MEDLINE, Cochrane and EMBASE were searched for the following keywords "endoscopy, GI", "endoscopy, digestive system" AND "sedation", "conscious sedation", "moderate sedation", "deep sedation" and "hypnotics and sedatives" for publications in English restricted to the pediatric age. We searched additional information published between January 2011 and January 2014. Searches for (upper) GI endoscopy sedation in pediatrics and sedation guidelines by non-anesthesiologists for the adult population were performed. RESULTS: From the available studies three sedation protocols are highlighted. Propofol, which seems to offer the best balance between efficacy and safety is rarely used by non-anesthesiologists mainly because of legal restrictions. Ketamine and a combination of a benzodiazepine and an opioid are more frequently used. Data regarding other sedatives, anesthetics and adjuvant medications used for pediatric GI endoscopy are also presented. CONCLUSION: General anesthesia by a multidisciplinary team led by an anesthesiologist is preferred. The creation of sedation teams led by non-anesthesiologists and a careful selection of anesthetic drugs may offer an alternative, but should be in line with national legislation and institutional regulations.

Effect of proton pump inhibition on acid, weakly acid and weakly alkaline gastro-esophageal reflux in children.

BACKGROUND: The effect of proton pump inhibitors on the characteristics of gastroesophageal reflux (GER) in children and adolescents was evaluated. METHODS: Twenty-one children and adolescents with symptoms suggesting GER disease (GERD) underwent upper endoscopy and a 24-hour multichannel intraluminal impedance/pH (MII-pH) monitoring before and at the end of 2 months of therapy with proton pump inhibitors (PPIs). RESULTS: Fourteen (67%) patients reported clinically relevant symptom improvement after 2 months of PPIs intake. At the first endoscopy, 8 (38%) patients had macroscopic signs of reflux esophagitis; after two months of therapy, 6/8 (75%) patients had a complete mucosal recovery. There was a significant reduction in the total percentage of mean acid reflux time (from 13.1% to 3.8%), and the De Meester score dropped to normal (from 46.4 to 13.1). The mean number of acid refluxes decreased significantly from 48 to 15 per 24 hours, while inversely, the mean number of weakly acid refluxes increased significantly from 26 to 64 per 24 hours. PPI therapy did not affect the total number of reflux episodes, the number of liquid and mixed refluxes, the duration of esophageal bolus exposure and proximal extent of the reflux. CONCLUSIONS: In children and adolescents with GERD, PPIs do not affect the total number of reflux episodes. PPIs only decrease the acidity of refluxate. Nevertheless, the majority of patients with typical reflux symptoms may report symptom improvement. Esophagitis can be healed after PPI treatment. The treatment of weakly acid and weakly alkaline reflux remains a challenge for physicians in the future.

Ketamine with and without midazolam for gastrointestinal endoscopies in children.

OBJECTIVES: Numerous publications on sedation of and anaesthesia for diagnostic procedures in children prove that no ideal scheme is available. Therefore, we decided to study the protocol with midazolam and ketamine used by nonanaesthetists at our institution. The study aimed to establish the lowest effective starting dose of ketamine and to estimate a difference in the frequency of adverse reactions with or without the use of midazolam as premedication, with special stress on emergence reactions. METHODS: During 1 year we prospectively randomised children scheduled for gastrointestinal endoscopies to a first group with and to a second group without midazolam premedication. The starting ketamine dose was increased until the appropriate dissociative state was reached. Physiological functions were closely monitored and adverse reactions noted. RESULTS: The median age of 201 analysed patients (111 girls, 90 boys) was 8.2 years. The median starting dose of ketamine was 0.97 mg/kg (the group with midazolam premedication) and 0.99 mg/kg TT (without midazolam premedication). Laryngospasm was observed in 6 patients without statistical difference between the 2 groups. All of the adverse reactions were short lasting; they resolved by symptomatic treatment without complications. Emergence reactions during the observation period at the hospital occurred more often in the group sedated with ketamine without midazolam premedication (P=0.02). CONCLUSIONS: : The sedation protocol with ketamine is safe and efficient. The starting dose of ketamine should be at least 1 mg/kg. There is an advantage to the use of midazolam as premedication before ketamine in paediatric patients because the frequency of emergence reactions in hospital was reduced compared with sole ketamine use.