ࡱ> bjbjR|R|n00o@  ^H$PND<Bn@"&''''(((}lllllll$p4snl) >(((() l  ''m:iJiJiJ )@ ' 'ciJ(}liJiJ_a'xDMAO`cn<Bng`8sMA s0aa&s$a((iJ(((((lliJ(((Bn((((s((((((((( :B1 - What is the additional diagnostic value of the following diagnostic investigations to history taking and physical examination in infants and children 0-18 yrs with a suspicion of GERD? StudyPopulationIndex testIndex test cut-off/positivitySensitivity (%)Specificity (%)PPVNPVRemarks SubjectsAgeNPatients/controls (reference standard)pH-METRY Boix-Ochoa (1980) ADDIN EN.CITE Boix-Ochoa1980284(1)28428417Boix-Ochoa, J.Lafuenta, J. M.Gil-Vernet, J. M.Twenty-four hour exophageal pH monitoring in gastroesophageal refluxJ Pediatr SurgJournal of pediatric surgeryJ Pediatr SurgJournal of pediatric surgeryJ Pediatr SurgJournal of pediatric surgery74-81511980/02/01ChildChild, PreschoolEsophagitis, Peptic/*diagnosis/surgery/therapy*EsophagusGastric Acidity Determination/methodsGastric Juice/*analysisHumansHydrogen-Ion ConcentrationInfantMonitoring, Physiologic/*methodsPostureTime Factors1980Feb0022-3468 (Print) 0022-34687365661NLMeng(1)Patients2 18 mo44History of recurrent GER, and/or failure to thrive, and/or weight loss and/or feeding difficulties (not further specified)8h pH-metry glass probe, position manometrically determined (electrode 2.5cm above LES), supine, prone and semi-seated position, symptoms recorded.pH in distal esophagus <4. Overall score computed from seven components, 1SD from score of each component in controls used as 1 scoring unit, final score total of all single score components: 1) the percent time pH<4 in 24h (RI, for each position); 2) total number of single refluxes pH <4; 3) number of refluxes longer than 5 minutes; 4) duration of longest episode. Not calculable: no p-values or cut-off values for test-positivity provided. Final score calculated based on data of controls.* Final score was highest in patient group (27,4 9,2 vs 7,39 4,6). Definition of GER(D) not further specified. Older children included in control group compared to patient group. No maximal value nor unit of measurement provided for the final scoreControls2 mo 3 yrs20No history of GER (not further specified)Da Dalt (1989) ADDIN EN.CITE Da Dalt19894821(2)4821482117Da Dalt, L.Mazzoleni, S.Montini, G.Donzelli, F.Zacchello, F.Department of Paediatrics, University of Padova, Italy.Diagnostic accuracy of pH monitoring in gastro-oesophageal refluxArch Dis ChildArchives of disease in childhoodArch Dis ChildArchives of disease in childhoodArch Dis ChildArchives of disease in childhood1421-664101989/10/01AdolescentChildChild, PreschoolEsophagoscopyEsophagus/*physiopathologyFollow-Up StudiesGastroesophageal Reflux/*diagnosis/physiopathology/therapyHumansHydrogen-Ion ConcentrationInfantMonitoring, PhysiologicSensitivity and SpecificityTime Factors1989Oct0003-98882684030Pmc1792777NLMEng(2)Patients9.3 mo (1 mo 13.5 yrs)111Admitted patients with signs and symptoms typical of GER (vomiting (n=69), failure to thrive (n=29), feeding difficulties (n=20), hematemesis (n=15), recurrent wheezing (n=12) chronic cough (n=11), apnea (n=11), iron deficiency anemia (n=10), epigastric pain (n=10), irritability (n=7)24h pH-metry glass probe, position determined by formula of Strobel (tip of catheter 87% of the distance from nares to upper limit of LES. Normal feeding and daily activities were remained.Drop in esophageal pH <4 for >8 seconds. Percent time pH<4 in 24h (RI), total number of reflux in 24h, number of refluxes longer than 5 minutes, duration of longest episode, mean duration of all reflux episode. Upper limit of normal based on 2SD from score of each component in controls. Measurement abnormal if percentage of reflux time and two other measurements abnormal. Reflux time and two other measurements abnormal: 41 (45/111)Not calculable: values of controls used as normal values.For this population, nu cut-off values have been established nor validated for pH-metry. Cut-off value for test-positivity therefore arbitrarily. This study includes children with recurrent or persistent wheezing (>3 attacks requiring hospital visit or almost daily wheezing for >4 wks). Within this specific patient group, a division between children with and without a history suggestive or reflux is made. Therefore this study was included, but results should be interpreted in the light of the patient group (wheezers and not the general pediatric population) the study focuses on. Controls12.5 mo (3 68 mo)14No history or symptoms suggestive of GERCucchiara (1990) ADDIN EN.CITE Cucchiara199021(3)212117Cucchiara, S.Staiano, A.Gobio Casali, L.Boccieri, A.Paone, F. M.Department of Pediatrics, 2nd School of Medicine, University of Naples, Italy.Value of the 24 hour intraoesophageal pH monitoring in childrenGutGut129-333121990/02/01ChildChild, PreschoolEsophagus/*physiopathologyEvaluation Studies as TopicGastroesophageal Reflux/*diagnosis/physiopathologyHumansHydrogen-Ion ConcentrationInfantInfant, Newborn*Monitoring, Physiologic1990Feb0017-5749 (Print) 0017-57492311969Pmc1378365NLMeng(3)PatientsGERD: 26.6 mo (2 mo 10 yrs). GERD and esophagitis: 41.3 mo (1 mo 12 yrs)114Infants and children referred for symptoms suggestive of GE, all with well-documented history of vomiting/regurgitation, some with additional complications (weight failure (n=45), hematemesis (n=17), chronic respiratory symptoms (n=19). Based on endoscopy with biopsy: n=45 GERD only and n=69 GERD and esophagitis. 24h pH-metry glass probe, position determined by manometry or formula of Strobel (tip of catheter 87% of the distance from nares to upper limit of LES. Position confirmed by fluoroscopy. Normal feeding and daily activities were remained. Variables evaluated for entire period, wakefulness, sleep and postprandial.Distal esophageal pH <4 for >20 seconds, or additional decrease of >1 pH unit during period of pH <4. Percent time pH<4 in 24h (RI), total number of reflux in 24h, number of refluxes longer than 5 minutes, duration of longest episode, mean duration of all reflux episode. Normal acid exposure time/clearance time defined as <2SD from control means. RI: 81 (92/114) Number of refluxes > 5 min: 70 (80/114) (data on other parameters not provided)Not calculable: values of controls used as normal values.Definition of GER(D) not further specified. In this study, infants presenting with apnea and upper respiratory infection are considered as controls, despite that these symptoms can be regarded as reflux-related. It remains that these control children were not admitted/referred and did not have a clinical history suggesting GERD based on the information provided in the paper.Controls24.02 mo (2 mo 12 yrs)63Absence of typical GER symptoms, but presenting with functional abdominal pain (n=5), functional constipation (n=9), IBS (n=11), feeding problems due to maternal inexperience/anxiety (n=19), apnea (n=10), upper respiratory infections (n=9)Kahn (1990) ADDIN EN.CITE Kahn199012(4)121217Kahn, A.Rebuffat, E.Sottiaux, M.Blum, D.Yasik, E. A.Pediatric Sleep and Development Unit, University Children Hospital, Free University of Brussels, Belgium.Sleep apneas and acid esophageal reflux in control infants and in infants with an apparent life-threatening eventBiol NeonateBiology of the neonateBiol NeonateBiology of the neonateBiol NeonateBiology of the neonate144-9573-41990/01/01Esophagus/physiologyFemaleGastroesophageal Reflux/*complicationsHumansHydrogen-Ion ConcentrationInfantMaleSleep/physiologySleep Apnea Syndromes/*etiology19900006-3126 (Print) 0006-31262322598NLMeng(4)Patients9 wks (4 25 wks)10(Full-term) infants that had been found apneic, pale or cyanotic, loss of tone and consciousness and had received vigorous resuscitation, with no cause of apparent life treathening event ( ALTE) after diagnostic work-up. 8.5h pH-metry glass probe, position radiologically confirmed (3cm above cardia).Reflux episode if pH < 4. Total number of reflux in 8.5h, number of refluxes longer than 5 minutes, acid duration time (time spent with pH < 4). Not calculable: no p-values or cut-off values provided. Definition of GER(D) not further specified. This study includes children with ALTE. This study was included because ALTE was regarded by the authors as a possible presentation of GERD. Controls7 (4 16 wks)10Infants with no history related to apnea or ALTE.pH-METRY & ENDOSCOPY Cucchiara (1993)  ADDIN EN.CITE Cucchiara1993246(5)24624617Cucchiara, S.Bortolotti, M.Minella, R.Auricchio, S.Department of Pediatrics, 2nd School of Medicine, University of Naples, Italy.Fasting and postprandial mechanisms of gastroesophageal reflux in children with gastroesophageal reflux diseaseDig Dis SciDigestive diseases and sciencesDig Dis SciDigestive diseases and sciencesDig Dis SciDigestive diseases and sciences86-923811993/01/01ChildChild, PreschoolElectromyographyEsophagitis, Peptic/physiopathologyEsophagogastric Junction/physiopathologyEsophagus/physiopathologyGastroesophageal Reflux/*physiopathologyHumansHydrogen-Ion ConcentrationInfantManometryMuscle ContractionPeristalsis1993Jan0163-2116 (Print) 0163-21168420764NLMeng(5)Patients32.9 mo (2 141 mo)81Children referred for evaluation of GERD, symptoms and signs including recurrent emesis/regurgitation (n=63), hematemesis (n=5), asthma (n=4), pneumonia (n=10), poor weight gain (n=23), apnea (n=2), irritability (n=13), anorexia (n=12), dysphagia (n=6), chest pain (n=5), heartburn (n=3), epigastric pain (n=17)24h pH-metry glass probe, position determined by formula of Strobel (patients < 1 yr, tip of catheter 87% of the distance from nares to upper limit of LES) or position confirmed by fluoroscopy (patients >1 yr or >1meter height). Patients provided with standardized meals. Endoscopy Olympus panendoscope (2.8mm diameter bioptic channel), >2 biopies taken from distal esophagus (avoiding lower 20%) performed under general anesthesia.Distal esophageal pH <4 for >20 seconds. Percent time pH<4 in 24h (RI), total number of reflux in 24h, number of refluxes longer than 5 minutes. Normal acid exposure time/clearance time defined as <2SD from control means. Aberrant macroscopy: friability, granularity, erosions, ulcerations. Aberrant histology: basal zone hyperplasia, papillar elongation, increased number of eosinophils and/or neutrophils, mucosal erosions. Not calculable: no p-values or cut-off values provided. No data on number of patients with abnormal test provided. Macroscopy: 33 (27/81) Histology: 88 (71/81) Macroscopy: no data on controls provided. Histology: 100 (16/16) Macroscopy: no data on controls provided. Histology: 100 (71/71) Macroscopy: no data on controls provided. Histology: 62 (16/26) In all controls, histology as defined by the authors was normal . Controls7 mo (3 154 mo)16Children selected for absence of symptoms of GERD, including feeding problems due to maternal inexperience/anxiety (n=5), functional abdominal pain (n=4), previous respiratory complaints (n=4), transient decreased food intake (n=3)Ravelli (2006)  ADDIN EN.CITE  ADDIN EN.CITE.DATA (6)Patients3.95 yrs (2 mo 11.9 yrs)48Patients referred for diagnostic upper gastrointestinal endoscopy for symptoms suggestive of GERD: vomiting, regurgitation, epigastric pain, heartburn and/or dysphagia (n=26), crying, fussiness, back arching at meals (n=5), nocturnal cough, wheezing, recurrent pneumonia or apnea (n=17).24h pH-metry antimony probe, positioned confirmed between 9th and 10th dorsal vertebra by fluoroscopy. Method not further specified. Endoscopy Standard videoendoscopes (outer diameters 5.3, 7.4 and 9 mm), performed under general anesthesia. 2-4 biopsies from distal esophagus 3-5cm above Z-line.Percent time pH<4 in 24h (RI), total number of reflux in 24h, number of refluxes longer than 5 minutes, duration of longest episode. Aberrant macroscopy: erosive lesions. Aberrant histology: basal zone hyperplasia, papillar elongation, mucosal erosions, dilatation of interpapillary vascular spaces, increased number of neutrophils, eosinophils and lymphocytes, erosions or ulcerations and granulation tissue.RI: 52 (15/29) Macroscopy: 15 (7/48) Histology: 83 (40/48)No controls underwent pH-metry Macroscopy: no data on controls provided. Histology: 100 (22/22) Macroscopy: no data on controls provided. Histology: 100 (40/40) Macroscopy: no data on controls provided. Histology: 73 (22/30)Definition of GER(D) not further specified. Control group includes patients with potential abnormal macroscopy and/or histology. In all controls, histology as defined by the authors was normal. No information on other possible detected macroscopic and/or histologic abnormalities provided by the authors. Controls5.58 yrs (1 - 16.9 yrs)22Other manifestations, not compatible with GERD: food sensitive enterophaty (n=11), H. pylori infection with positive stool antigen or breath test (n=6), IBD (n=4), nonsteroidal anti-inflammatory drug gastropathy (n=1)pH-METRY & GE SCINTIGRAPHY Patra (2011) ADDIN EN.CITE  ADDIN EN.CITE.DATA (7)Patients10.4 mo (3 -24 mo, 5.24)16Children 0-2 yrs with recurrent or persistent wheezing (>3 attacks requiring hospital visit or almost daily wheezing for >4 wks) with a history suggestive or reflux (not further specified)GE scintigraphy dose of Tc-99m by nasogastric tube, infant placed supine, low-energy high sensitivity collimator anteriorly and posteriorly 24h pH-metry glass probe, position radiologically confirmed, position, feeding and medication recorded (reflux medication prohibited)Refluxing into the esophagus on both cine images and on the time activity curve, on at least two or three consecutive frames. RI > 10% in infants <1 yr and RI > 5% in children > 1 yr69 (11/16) RI: 50 (8/16)78 (28/36) RI: 82 (29/36) 58 (11/19) RI: 53 (8/15)85 (28/33) RI: 78 (29/37)Standards of interpretation of scintigraphy are poorly established. Criteria for pathologic GER defined based on studies of Patwari et al. (2002) and VandenPlas et al. (1992). For this population, nu cut-off values have been established nor validated for pH-metry. The two studies referred to do not support the cut-off values used by the authors as a clinical diagnostic tool.Cut-off therefore arbitrary. Controls36Children 0-2 yrs with recurrent or persistent wheezing (>3 attacks requiring hospital visit or almost daily wheezing for >4 wks) without a history suggestive or reflux (not further specified)pH-METRY & UPPER GI SERIES & GE SCINTIGRAPHY & ENDOSCOPY Arasu (1980) ADDIN EN.CITE  ADDIN EN.CITE.DATA (8)Patients5.3 yrs (3 mo - 17 yrs)30Infants/children referred with symptoms and signs suggestive of GER (not further specified)pH-metry probe not specified, position based on manometry (tip of catheter 85% of the distance from nares to upper limit of LES), 5-10 minutes in supine, left lateral and right lateral decubitus positions. Total time of measurement not clear. If no spontaneous reflux observed, manual abdominal compression was performed. Total time of measurement not clear. Upper GI series Fluoroscopy after barium swallow (volume of normal feeding), EGJ evaluated with intermittent fluoroscopy while rolling the patient from side to side, encountering maximum extent of reflux. GE scintigraphy - dose of Tc-99m by nasogastric tube, infant upright and supine position, one minute camera pictures in both positions. Endoscopy Olympus panendoscope (outer diameter of 7.2mm < 4 yrs and 10 mm > 4 yrs), performed under general anesthesia.Intra-esophageal pH < 4 for >2 occasions (duration of event not specified) Test positivity not further specified Esophageal activity (not further specified) Friability, erosion, ulceration or thickened mucosa with fine nodularity. 97 (29/30) Not calculable: no cut-off values for test-positivity provided. Not calculable: no cut-off values for test-positivity provided. 71 (15/21)100 (15/15) 100 (3/3)100 (29/29) 100 (15/15)94 (15/16) 33 (3/9)Definition of GER(D) not further specified. Positivity of pH-metry not based on any evidence. For this population, nu cut-off values have been established nor validated for pH-metry. Cut-off therefore arbitrary. Test positivity not further specified. Test positivity not further specified Controls3.8 yrs (4 mo 14 yrs)15Infants/children with failure to thrive (n=6), choking with feeding (n=2), pulmonary disease (n=2), vomiting from identifiable causes apart from GER (n=5), high intestinal obstructions (n=2)SALIVARY PEPSINFarhath (2013) ADDIN EN.CITE  ADDIN EN.CITE.DATA (9)PatientsGA 29 wks (24 - 35)36Premature infants, BW <2000g. Diagnosed with clinical GER if: (1) attending the neonatologist involved in clinical care and infants were on medication for GER at the time of sample collection or (2) presence of signs and symptoms of GER at the time of sample collection (persistent vomiting, apnea, bradycardia and desaturation attributed to GER, infant on prolonged or thickened feeding)Salivary pepsin Mouth swab samples were collected from the cheek and below the tongue at one, two and three hours after feeding. Pepsin detected by an enzymatic assay and Western blot analysis for pepsin A and C. (29/36 infants were on anti-reflux medication at time of sampling)Enzymatic assay positive for pepsin if concentration <12.5ng/ml. Test considered positive in case of >1 positive mouth swab sample.72 (26/36)71 (46/65)58 (26/45)82 (46/56)ControlsGA 30 wks (23 - 35)65Premature infants, BW <2000g, not fulfilling the above criteria for clinical GER.IBS = irritable bowel syndrome; IBD = inflammatory bowel disease; GER = gastroesophageal reflux; GERD = GER disease; LES = lower esophageal sphincter; EGJ = esophageal gastric junction; GE = gastro-esophageal; GI = gastrointestinal; ALTE = apparent life-threatening event; GA = gestational age, BW = birth weight; RI = reflux index, percentage of time that the esophageal pH <4; PPV = positive predictive value; NPV = negative predictive value. *As values of controls are used as normal values, specificity will always be 100%. B2 - What is the most effective and safe non-pharmacological treatment option on the reduction of signs and symptoms of GERD, when compared to no treatment, placebo, or alternative non-pharmacological treatment? AuthorDesignPopulationCochrane Risk of Bias ToolDureInterventionControlOutcome of interestOutcome measuresNAgeInclusionRandom sequence generationAllocation concealmentBlinding interventionBlinding outcome Selective reportingFollow-upFEED MODIFICATIONS Vander Hoof (2003)  ADDIN EN.CITE Vanderhoof2003101(10)10110117Vanderhoof, J. A.Moran, J. R.Harris, C. L.Merkel, K. L.Orenstein, S. R.Joint Section of Pediatric Gastroenterology and Nutrition, University of Nebraska Medical Center and Creighton University, Omaha, Nebraska, USA.Efficacy of a pre-thickened infant formula: a multicenter, double-blind, randomized, placebo-controlled parallel group trial in 104 infants with symptomatic gastroesophageal refluxClin Pediatr (Phila)Clinical pediatricsClin Pediatr (Phila)Clinical pediatricsClin Pediatr (Phila)Clinical pediatrics483-954262003/08/19Double-Blind MethodFemaleGastroesophageal Reflux/*diet therapyHumansInfant*Infant FormulaInfant, NewbornMaleTreatment Outcome2003Jul-Aug0009-9228 (Print) 0009-922812921449http://cpj.sagepub.com/content/42/6/483.full.pdfNLMeng(10)RCT; parallel11014 -120 de" 5 regurgitations per day for 2 daysYesNot ClearYesYesYes81/1105 wkRice starch pre-thickened formula (n=55)Standard formula (n=49)Crying distress Significant decrease in feedings followed by trouble sleeping (p=0.030). Trend towards decrease in feedings followed by pain (ns). No differences in fussiness (no data) Visible regurgitation/vomiting: Intervention vs control Regurgitation frequency per day Baseline: 13 1 vs 11 1 MD at 1 wk: -6 1 vs -6 1 MD at 5 wks: -7 1 vs -5 1 Regurgitation frequency (% of feeds) Baseline: 87 2 vs 85 2 MD at 1 wk: -34 5 vs -22 5 MD at 5 wks: -38 5 vs -24 5 Side effects Three SAEs: 1/55 vs 2/49 (intervention vs control) Discontinuation rates: 13% (7/55) intervention, 20% (10/49) control group No differences in constipation/diarrhea (reported as ns, no data)Frequency of regurgitation based on diary Volume of regurgitation based on diary Volume of formula consumed based on diary Chao (2007b)  ADDIN EN.CITE  ADDIN EN.CITE.DATA (11)RCT; parallel802-6 moe" 3 regurgitations per day Not clearNot clearNot clearNo clearYes63/808 wkCereal thickened formula (hydrolyzed rice > 90%, cornstarch <5%) (n=31)Regular formula postural therapy (n=32)Side effects No significant difference in stool frequency in diaries. Diarrhea >2 d: n=6 (2 in intervention, 4 in control group) N=2 with abdominal distension, N=1crying (intolerance)Episodes of regurgitation/vomiting as reported by parent Weight gain Gastric emptying by milk scintigraphy Hegar (2008)  ADDIN EN.CITE  ADDIN EN.CITE.DATA (12)RCT; parallel601-3 moe" 4 episodes of regurgitation/ vomiting per day Not clearYesNot clearNot clearYes60/604 wkStandard formula with B; 5g rice cereal/100ml (n=20) or C; bean gum (n=20) + parental reassuranceParental reassurance + standard formula (n=20)Side effects diarrhea No statistical differences in consistency/frequency (diary based) of stools. No data. Crying distress No difference in sleeping disturbance. No data.  Parent reported frequency of regurgitation and symptoms WeightIacono (2002)  ADDIN EN.CITE  ADDIN EN.CITE.DATA (13)RCT; parallel166< 4 mo (median: 1.5 mo)Frequent regurgitation / vomiting by uncomplicated GERNot clearNot ClearNot ClearNot clearYes166/166 14 drop out, not clear if excluded from analysis8 wkFormula thickened with carob flour (locust bean gum) (n=82)Standard formula (n=84)Side effects diarrhea 14 patients in intervention group dropped out in first 2 wksFrequency and entity of regurgitation + symptoms by scoring system GrowthChao (2007a)  ADDIN EN.CITE  ADDIN EN.CITE.DATA (14) RCT; parallel1002-4 moe" 3 regurgitations per day Not clearNot clearNot ClearNot ClearYes81/1008 wkCornstarch thickened formula (n=41)25% thickened formula (n=40)Crying distress Crying (intervention vs control group) Baseline: 4/41 vs 5/40 Wk 4: 1/41 vs 3/ 40 Wk 8: 1/41 vs 2/40 Irritability (intervention vs control group) Baseline: 12/41 vs 12/40 Wk 4: 4/41 vs 10/40 Wk 8: 1/41 vs 8/40 Significant decrease in intervention group, no p-value provided. Side effects diarrhea (not further specified) N = 8 (not specified in what arm of study) 19 drop-outs due to side-effectsGastric emptying using scintigraphy Regurgitation/vomiting as reported by parents Reflux symptomsMiyazawa (2006)  ADDIN EN.CITE  ADDIN EN.CITE.DATA (15)RCT; cross-over27<6 moe" 3 regurgitations per day Not ClearNot ClearNot ClearNot ClearYes24/27 1 wkLocust bean gum 0.45g/100ml (n=14) OR 0.35g/100ml (n=13)Standard formula (n=27)Visible regurgitation/vomiting: Intervention vs control mean (SD) during treatment (1wk) HL-350 vs standard: 12.9 (3.5) vs 22.6 (3.9) HL-450 vs standard 12.8 (3.0) vs 29.8 (3.6) (no baseline scores) Side effects diarrhea (increase in bowel movements) N = 3 (reported by mother) in intervention groups (no severe diarrhea) Regurgitation episodes as reported by parent Gastric emptying measurementsMiyazawa (2004)  ADDIN EN.CITE Miyazawa200457(16)575717Miyazawa, R.Tomomasa, T.Kaneko, H.Morikawa, A.Department of Pediatrics and Developmental Medicine, Gunma University Graduate School, Maebashi, Japan.Effect of locust bean gum in anti-regurgitant milk on the regurgitation in uncomplicated gastroesophageal refluxJ Pediatr Gastroenterol NutrJournal of pediatric gastroenterology and nutritionJ Pediatr Gastroenterol NutrJournal of pediatric gastroenterology and nutritionJournal of Pediatric Gastroenterology and Nutrition479-833852004/04/21FemaleGalactansGastroesophageal Reflux/*diet therapy/physiopathologyHumansInfant*Infant FormulaMaleMannansPlant Gums*PolysaccharidesTreatment Outcome2004May0277-2116 (Print) 0277-211615097434http://graphics.tx.ovid.com/ovftpdfs/FPDDNCOBFGEJPA00/fs046/ovft/live/gv023/00005176/00005176-200405000-00004.pdfNLMeng(16)RCT; cross-over30<6 moe" 3 regurgitations per day Not ClearNot ClearNot ClearNot ClearYes27/301 wkA; Locust bean gum 0.45g/100ml (n=16) or B; 0.35g/100ml (n=11)Standard formula (n=27)Side effects No complications reported Trouble sucking the formula 11 infants Visible vomiting/regurgitation Intervention vs control, median (IQR) HL-450 vs standard: 1.6 (IQR 0.8 to 2.0) vs 3.5 (IQR 2.3 to 4.9) HL-350 vs standard: 1.3 (IQR 0.6 to 2.3) vs 2.9 (IQR 2.0 to 3.2) Side effects diarrhea (bowel movement): Group A: SF: 1.4 (1.0-1.5) HL-450: 1.4 (1.1-1.6), p 0.48 Group B: SF: 1.4 (0.8-1.6) HL350: 1.6 (1.1-2.3), p=0.02Episodes of regurgitation reported by parents Growth Number of stoolsOstrom (2006)  ADDIN EN.CITE  ADDIN EN.CITE.DATA (17)RCT; parallel17913-32dRegurgitation in >25% of feedings (mean 7.8 times/day)YesYesYesYesYes135/1794 wkSoy formula with soy fiber (6g/L) (n=66/89)Standard formula + placebo (not soy based) (n=67/90)Side effects 6 SAEs, 4 in control and 1 in intervention group Crying/distress Parent reported on 5-point frequency scale. No significant differences. Crying: day 0 vs day 14 significant less likely to cry ( p=0.055) and less likely to cry >30min (p=0.092) in CM group. More likely to be in good mood at day 14 (p=0.007) and day 34 (p=0.044). No absolute numbers provided. Visible vomiting/regurgitation Intervention vs control group mean, SD: Number of regurgitations/day: Baseline = 3.9 (1.9), 3.6 (1.9) Day 7 = 2.3 (1.9), 3.4 (1.8) Day 28 = 2.0 (1.6), 2.4 (2.4), p = 0.029 % of feeds associated with regurgitation: Baseline = 50.9 (28.9), 48.6 (28.5) Day 7 = 31.0 (22.4), 48.3 (38.7) Day 28 = 28.8 (31.1), 36.0 (34.1), p = 0.015 (SD calculated manually) Number of infants with any regurgitation: Baseline = 87/87, 90/90 Day 7 = 86/87, 85/85 Day 28 = 56/67, 63/66, p = 0.027 Daily incidence of regurgitation (mean average during study period based on parent reports). Mean average number of feeds associated with regurgitation. Percentage of infants with reflux not associated with feeding Percentage of subjects with any regurgitation Volume of intake Mean size of regurgitation Parent response to questionnaire on regurgitation and tolerance Infant weight. Ummarino (2015)  ADDIN EN.CITE  ADDIN EN.CITE.DATA (18)RCT; parallel501-12 moInfant regurgitation according to ROME IIIYesNot clearNot clearYesYes40/508 wkRice starch thickened (14.3g/100ml or 14.2g100ml for infants < 6 mo) + conservative therapy (n=25)Conservative therapy (=life style changes + reassurance) (n=25)I-GERQ-R scores Significant reduction in symptom score in intervention group (p<0.001) at wk 8 (4 vs 0 pt symptom free) (no subscores provided) Visible regurgitation/vomiting Number of infants with regurgitation and vomiting, intervention vs control group: Baseline = 25/25 vs 25/25 4 wk = 25/25 vs 17/17 8 wk = 13/23 vs 15/17 Side effects (reported in diary) No SAEs reported.I-GERQ-R scores, <7 no clinical symptoms Side effects reported in diaryXinias (2005)  ADDIN EN.CITE  ADDIN EN.CITE.DATA (19)RCT; parallel9693 +/- 35dExcessive regurgitation and/or vomiting (mean 5x regurgitation, 3.5x vomiting)Not clearNot clear YesYesYes96/964wkCornstarch-thickened casein predominant formula (n=51)Standard formula (n=45)Visible regurgitation/vomiting Intervention vs control, episodes of regurgitation/day 2.57 (2.71) vs 4.31 (2.01), Intervention vs control, episodes of vomiting/day 1.45 (1.65) vs 2.74 (1.37), Side effects diarrhea (number of stools) Intervention group: Baseline: 3.80 +/- 2.34 4wk: 3.54 +/- 2.03 (p=0.78) Control group: Baseline: 2.62 +/- 0.77 4wk: 2.60 +/- 0.81(p=0.82) Baseline: Intervention vs control group: p=0.05 4 wk: Intervention vs control group: p=0.08 Side effects No side effects due to intervention recordedReflux index Number of reflux episodes per hour - Number of reflux episodes > 5 minutes Duration of longest reflux episode Parent reported outcomes: regurgitation episodes, vomiting, stools, weight gain Moukarzel (2007)  ADDIN EN.CITE  ADDIN EN.CITE.DATA (20)RCT; parallel743.24 1.28 moDiagnosis of GER based on Orenstein criteria, cut-off not specifiedNot clearNoNoNoNo60/744 wkPre-thickened formula, not further specified, viscosity 10x that of regular formula (Wyeth Nutritional) (n=28)Normal milk formula, not further specified (Wyeth Nutritional) (n=32)Visible vomiting/regurgitation Incidence of vomiting: Regular vs Thickened; mean (SD) Baseline: 2.1 (3.0), 2.6 (2.6) 4 wks: 1.2 (1.1), 0.5 (0.8) , baseline vs 4 wks p=0.0009 in intervention group, NS in control group Incidence of regurgitation: Regular vs Thickened; mean (SD) Baseline: 6.5 (3.7), 7.1 (3.9 4 wks: 52 (3.1), 2.3 (2.0), baseline vs 4 wks p=0.0003 in intervention group, NS in control group Outcome of pH-monitoring (longest reflux episode, number of reflux episodes >5 min, reflux index). ECG procedure outcomesMiyazawa (2007)  ADDIN EN.CITE  ADDIN EN.CITE.DATA (21)RCT; cross-over2036 13 daysInfants evaluated for frequent episodes of regurgitation or vomiting (>3 episodes per day)Not clearNot clearNot clearNot clearYes20/202 wkFormula thickened with locust bean gum 0.35g/100ml (n=20)Standard formula (n=20)Visible vomiting/regurgitation Intervention vs control group, episodes of regurgitation per day: 2.3 (1.6 to 3.6) vs 5.2 (3.7 to 7.8) Side effects: diarrhea Intervention vs control group, Bowel movements per day 1.8 (1.2 to 2.4) vs 1.2 (0.9 to 1.6) No data provided at moment of cross-overVandenPlas (1994)  ADDIN EN.CITE  ADDIN EN.CITE.DATA (22)RCT; parallel201-4 mo of ageInfants presenting with frequent regurgitation (>5 times per day) and pH-monitoring results pH<4 between 10-30% of timeNot clearNot clearYesYesNo20/201 wkAntiregurgitation formula, positional treatment and reassurance (n=10)Standard formula, positional treatment and reassurance (n=10)Visible regurgitation/vomiting Regurgitation severity score, intervention vs control group, mean +/- SD: Before: 4.60 0.84 vs 4.40 0.84 During (1wk): 2.20 1.92 vs 3.30 1.16 Difference between groups before and during treatment NS. Difference before and during treatment within groups significant (p=0.002 vs p=0.03)pH-monitoring results: reflux index, duration of longest reflux, number of reflux episodes > 5 min, regurgitation severity scoreOrenstein (1987)  ADDIN EN.CITE Orenstein19873795(23)3795379517Orenstein, S. R.Magill, H. L.Brooks, P.Thickening of infant feedings for therapy of gastroesophageal refluxJ PediatrThe Journal of pediatricsJ PediatrThe Journal of pediatricsJ PediatrThe Journal of pediatrics181-611021987/02/01CryingGastric EmptyingGastroesophageal Reflux/*diet therapy/physiopathology/radionuclide imagingHumansInfant*Infant FoodInfant, NewbornSleep1987Feb0022-3476 (Print) 0022-34763806287NLMEng(23)RCT; cross-over214-34 wksDiagnosis of GER based on symptoms and/or abnormal test results from pH monitoring or endoscopyNot clearNot clearNot clearNot clearNo20/2190 minsInfants regular formula with dry rice cereal (15ml/30ml formula)Infants regular formulaVisible regurgitation/vomiting: Episodes in 90 minutes, mean (SD): thickened, unthickened, 1.2 (0.7) vs 3.9 (0.9)Frequency of emesis in 90 minutes, crying time, sleep time, gastric emptying, gastric reflux by scintigraphyPOSITIONING THERAPYLoots (2014)  ADDIN EN.CITE  ADDIN EN.CITE.DATA (24)RCT; parallel6613.6 (2-26) wksGERD symptoms > 5 days or increasing in frequency or severity for 3 daysYesNot clearNoNot clearYes51/662 wksLeft-side positioning with PPI (n=12) or AA (n=13)Head of cot elevation with PPI (n=14) or AA (n=12)Infants with PPI Crying (total crying time) Intervention vs control group: Baseline: 92 34.6 vs 71 41.2 2 wk: 92 34.6 vs 81 37.4 MD = 11.00 (95% CI -16.7 38.70) MDchange = -10.00 (95% CI -32.34 12.34) Crying (number of cries) Intervention vs control group: Baseline: 48 31.2 vs 30 26.2 2 wk: 48 27.7 vs 49 26.2 MD = -1.00 (95% CI -21.83 19.83) MDchange = -12.00 (95% CI -33.90 9.90) Side effects (SAE): 2 SAEs in control group. RR = 0.23 (95% CI 0.01 4.38) Infants with AA Crying (total crying time) Intervention vs control group: Baseline: 106 68.5 vs 74 69.3 2 wk: 88 36.1 vs 66 45.0 MD = 22.00 (95% CI -10.15 54.15) MDchange = -9.00 (95% CI -52.51 34.51) Crying (number of cries) Intervention vs control group: Baseline: 60 43.3 vs 38 34.6 2 wk: 54 32.5 vs 35 24.2 MD = 19.00 (95% CI -3.35 41.35) MDchange = -2.00 (95% CI -34.14 30.14) Side-effects (SAEs) No side effects in either of the treatment arms I-GERQ-R GER monitoring (pH-MII) Gastric emptying Physiological monitoringMASSAGE THERAPYNeu, 2014RCT; parallel434-12 wkI-GERQ-R score e" 16YesYesYesYesNo 36/436 wkMassage therapy (n=18)Sham therapy (non-massage treatment)(n=18), intention to treat n=1 I-GERQ-R scores Intervention vs control Baseline: 224 vs 23.54 Wk 4: 15.04 vs 15.15 Wk 6: 14.44 vs 13.76 Crying Crying < 10 min: RR = 0.71 (95%CI 0.50-0.99) Crying < 1 h, < 3 h or > 3 h: RR = 1.00 Distress (salivary cortisol) Geometric mean 60% lower after 6 wks of treatment, adjusting for baseline (p=0.003). Hodges-Lehmann point estimate of between group difference: 18gr.hr/dl (95% CI -44 to 9gr.hr/dl, p=0.11)Weight Actigraphy Salivary Cortisol level (samples on 3 consecutive days at baseline and after 6 wk by mothers and at baseline, wk 4 and wk 6 by therapist) Maternal anxiety and depressionAA = antacid; AE = adverse event; CI = confidence interval; GER = gastroesophageal reflux; GERD = GER disease; I-GERQ-R = infant gastroesophageal reflux questionnaire revised; MD = mean difference; MDchange = change in mean difference; PPI = proton pump inhibitor; RCT = randomized controlled trial; RR = relative risk; SAE = serious adverse event  B3 What is the most effective and safe pharmacological treatment option of GERD, when compared to no treatment, placebo, non-pharmacological treatment or alternative pharmacological treatment? B3.1 - Anti-acids and alginates AuthorDesignPopulationCochrane Risk of Bias ToolDureInterventionControlOutcome of interestOutcome measuresNAgeInclusionRandom sequence generationAllocation concealmentBlinding interventionBlinding outcome Selective reportingFollow-upANTACID VS PLACEBOMiller (1999)  ADDIN EN.CITE  ADDIN EN.CITE.DATA (25)RCT; parallel904 0.28 mo (3.9 0.40 vs 4.1 0.39)Persistent , unmanageable vomiting/regurgitation or vomiting/regurgitation >2x day for 2 days prior to the start of the studyNot clearNot clearNot clearNot clearYes68/9014 dSodium alginate (225mg sodium alginate and magnesium alginate 87.5mg) in a total 0.65g. One sachet/day (<4.54kg) or two sachet/day (>4.54kg) (n=42)Matching placebo (n=48)Visible regurgitation/vomiting: Number of vomiting/regurgitation episodes in 24 hours, intervention vs control (medians): Baseline; 8.5 (2-50) vs 7.0 (2-36) 14 days: 3.0 (0-22) vs 5.0 (0-37) Mean number of episodes, SD not reported (intervention vs control group) Baseline: 10.2 vs 10.6 Wk 2: 10.6 vs 6.2, p = 0.056 Side effects - AEs AE: 57% of patients >1 AE (55% vs 59%) . Withdrawal from study because of AE: 4/42 vs 7/46. SAE: 2/42 vs 2/46 (not related to treatment). No statistically significant differences in the incidence of these adverse events were observed between treatment groups (p>0.1 in all cases). Frequency/cessation of regurgitation, patient reported improvement, safety analysisANTACID + SIMETHICONE VS NON-PHARMACOLOGICAL INTERVENTION (Feed thickeners/conservative treatment)Ummarino (2015)  ADDIN EN.CITE  ADDIN EN.CITE.DATA (18)RCT; parallel751-12 moInfant regurgitation according to ROME IIIYesNot clearNot clearYesYes67/758 wkMagnesium alginate aluminum-free formulation plus simethicone, 2.5mL 3x/day (weight <5kg) or 5mL 3x/day (weight >5 kg), 10 minutes after feeding + conservative therapy (A, n=25)Rice starch thickened (14.3g/100ml or 14.2g100ml for infants < 6 mo) + conservative therapy (A, n=25) Conservative therapy (=life style changes + reassurance) (A, n=25)I-GERQ-R scores Symptom scores, A vs B vs C Baseline: 15 (8-24) vs 13 (8-19) vs 13 (7-10), p = 02 Wk 4: 7 (1-20) vs 10 (5-16) vs 12 (7-14), p = 0.2 Wk 8: 1 (0-19) vs 5 (0-15) vs 8 (2-14), p =0.01 Median I-GERQ-R scores significantly lower in all groups (A p<0.002, B p<0.038, C p<0.03) at week 8 compared to baseline. No comparison between groups at week 8. Median I-GERQ-R scores more significantly reduced in intervention group vs control group (A vs B p<0.002, A vs C p<0.0001). (no subscores provided) Visible regurgitation/vomiting Number of infants with regurgitation and vomiting, intervention vs thickened formula vs conservative treatment: Baseline = 25/25 vs 25/25 vs 25/25 4 wk = 21/25 vs 25/25 vs 17/17 8 wk = 6/24 vs 13/23 vs 15/17 Side effects (reported in diary) No SAEs reported. AEs: 1/25 patients in group A presented with constipationI-GERQ-R scores, <7 no clinical symptoms Side effects reported in diaryAE = adverse event; CI = confidence interval; GER = gastroesophageal reflux; GERD = GER disease; I-GERQ-R = infant gastroesophageal reflux questionnaire revised; MD = mean difference; MDchange = change in mean difference; NS = not significant; PPI = proton pump inhibitor; RCT = randomized controlled trial; RI = reflux index; RR = relative risk; SAE = serious adverse event. B3.2 - PPIs  AuthorDesignPopulationCochrane Risk of Bias ToolDureInterventionControlOutcome of interestOutcome measuresNAgeInclusionRandom sequence generationAllocation concealmentBlinding interventionBlinding outcome Selective reportingFollow-upLANSOPRAZOLEOrenstein (2009)  ADDIN EN.CITE  ADDIN EN.CITE.DATA (26)RCT; parallel16216, 4-51 wks Infants with symptomatic GERD who remained symptomatic with crying, fussing or irritability during/within 1 hour after feeding despite at least 1 wk conservative non-pharmacologic management (1-2 wks before randomization)YesYesYesNot clearYes 96/1624 wksLansoprazole 0.2-0.3mg/kg day for infants d"10 wks and 1.0-1.5mg/kg/day for infants >10 wks (n=49)Placebo formulated identically dosed comparably (n=47)Side effects  (S)AEs Intervention vs control AE: 50 (62%); (46%); p = 0.058 SAE: 10 (12%); 2 (2%); p = 0.032 Crying/distress Intervention vs control - Percentage of feeds Baseline: 51.0 20.39 vs 52.4 20.46 4 wk: 31.0 25.41 vs 32.4 28.13 Change: -19.9 23.10 vs -19.9 23.83 (p=0.794) - Mins postfeed Baseline: 7.9 6.05 vs 9.0 7.25 4 wk: 4.3 5.52 vs 4.9 6.20 Change: -3.6 5.4 vs -4.1 6.63 (p=0.830) Mins/ day Baseline: 47.0 37.30 vs 55.4 46.11 4 wk: 22.1 29.96 vs 27.6 36.57 Change: -25.0 31.86 vs -27.8 41.41 (p=0.963) Visible regurgitation/vomiting: % of feeds with regurgitation per wk Mean (ie, averaged across infants) change from pretreatment baseline, intervention vs control group: -14% vs -10% (NS)Primary endpoint: efficacy scores (not assessed by I-GERQ-R), total scores and individual domainsESOMEPRAZOLELoots (2014)  ADDIN EN.CITE  ADDIN EN.CITE.DATA (27)RCT; parallel5713.6 (2-26) wksGERD symptoms > 5 days or increasing in frequency or severity for 3 daysYesNot clearNoNot clearYes51/572 wksEsomeprazole 1mg/kg/day 1x/day 2 hrs postprandially (all infants received positioning therapy, ie LLP or head of cot elevation to 20 degrees; (HE)n=12 in LLP, n=14 in HE)Antacid Mylanta, 1.5 (0-2mo), 3 (2-4 mo) or 6mL (4-6mo) once daily (all infants received positioning therapy, ie LLP or head of cot elevation to 20 degrees; n=13 in LLP, n=12 in HE) Crying/distress - In infants in LLP, PPI vs AA 1. Total crying time (mins) Baseline: 92 24.2 vs 106 68.5 2 wk: 92 34.6 vs 88 36.1 (difference: -1 24.2 vs -17 64.9) 2. No of cry Baseline: 48 31.2 vs 60 43.3 2 wk: 48 27.7 vs 54 32.4 (difference: 5 17.3 vs -7 46.9) - In infants in HE, PPI vs AA 1. Total crying time (mins) Baseline: 71 41.2 vs 74 69.4 2 wk: 81 37.4 vs 66 45.0 (difference: 9 37.7 vs -8 45.0) 2. No of cry Baseline: 30 26.2 vs 38 34.6 2 wk: 49 26.2 vs 35 24.2 (difference: 17 37.4 vs -5 34.6) Side effects AEs 5 AEs (not specified what treatment arm) 2 SAEs in PPI + HE group: 1 hospital admission for rota virus 1 hospital admission for reduced oral intake + weight lossI-GERQ-R GER monitoring (pH-MII) Gastric emptying Physiological monitoringDavidson (2013)  ADDIN EN.CITE  ADDIN EN.CITE.DATA (28)RCT; parallel5248.1 29.8 vs 46.5 31.2 days Suspected of having any two of (after 8h video monitoring): apnea with or without bradycardia and with or without oxygen desaturations, vomiting or gagging, and irritability or pain >1x every second feed or >2x in 8 hours YesYesNot clearNot clearNo51/522 wksEsomeprazole 0.5mg/kg in 2ml/kg of sodium bicarbonate solution (n=25)Placebo, not further specified, 0.5mg/kg in 2ml/kg of sodium bicarbonate solution (n=26)Crying/irritability No of events, intervention vs control Baseline: 88.87 24.71 vs 89.46 22.71 2 wk: 88.83 19.84 vs 88.85 20.18 Change from baseline: -0.05 17.27vs -0.61 22.85 Side effects AEs Intervention group: 6 patients experienced 10 AEs, no SAEs Placebo group: 9 patients experienced 14 AEs, 4 SAEs Visible regurgitation/vomiting: Number of vomiting, Mean SD, intervention vs control group: Baseline: 5.79 7.14 vs 4.17 4.31 2 wk: 5.21 6.75 vs 4.87 5.93 Mean difference at 2 wks: MD: 0.34 (95%CI -3.15 - 3.83) MDchange: -1.28 (95%CI -4.42 - 1.86) Change from baseline in total GERD symptoms (video recording) and GERD-related signs (cardiorespiratory monitoring. Secondary: mean difference in change of signs and symptoms, pH-metry, adverse events, laboratory assessmentWinter (2012)  ADDIN EN.CITE  ADDIN EN.CITE.DATA (29)RCT; parallel804.9 2.6 vs 4.9 3.2 moGERD suspected based on symptoms or endoscopically proven. >1 of symptoms of (extra-esophageal) GERD (vomiting/regurgitation, irritability, [cough, wheezing and/or stridor, labored breathing], respiratory symptoms triggered by feeding, feeding difficulties [food refusal, gagging/ choking, hiccups for >1 hour/day]) > 2x/wk in 4-wksYesNot clearYesNot clearYes77/804 wksEsomeprazole 2.5mg (weight 3-5kg), 5mg (weight 5-7.5kg), 10mg (weight 7.5-12kg) once a day (n= 39)Placebo, sachets containing inactive granulate dissolved into water (n=41)Crying/irritability Mean (SD) change from baseline in symptom score. Esomeprazole vs placebo: 0.06 0.58 vs 0.19 0.59 (no mean scores provided) Visible regurgitation/vomiting: Severity score (0-3, 3 = most severe). Mean SD, change from baseline in symptom score, intervention vs control group: 0.04 0.56 vs 0.09 0.61. Change in mean difference at 4 wks: MDchange: = -0.13 (95%CI -0.39 0.13) Side effects (S)AEs Esomeprazol vs placebo: AE: 23/39 vs 27/41 patients, NS SAE: 4/39 vs 1/41 Time from randomization to discontinuation Treatment success Daily symptoms PGA symptom severity Safety and tolerabilityRABEPRAZOLEHussain (2014)  ADDIN EN.CITE  ADDIN EN.CITE.DATA (30)RCT; parallel2684.7 2.54 vs 4.7 2.65 moGERD: recurrent vomiting or regurgitation in infants unresponsive to conservative interventions, and >1 of: poor weight gain as defined by failure to thrive; irritability, excessive crying, or disturbed sleep, or refusal to eat even if hungry, or arching back at meals. During screening, score >16 on I-GERQ-R within 6 days of the first dose Not clearNot clearNot clearNot clearYes231/2685 wksRabeprazole 5mg/day (A, n=90) or 10mg/day (B, n=88)Placebo (C, n=178)I-GERQ-R score Data only displayed in figure, insufficient information to calculate manually. No data on subscores. Side effects AEs Intervention vs control AE: no infants > 1 TEAE reported: 47% vs 47% SAE: 4.5% vs 2.2% infants SAE Visible regurgitation/vomiting: Frequency of regurgitation, no data reported, authors report results as non-significantly different. - Frequency of regurgitation - Weight for age z-score - I-GERQ-R weekly score - I-GERQ-R daily score - Adverse events OMEPRAZOLMoore (2003)  ADDIN EN.CITE Moore200332(31)323217Moore, D. J.Tao, B. S.Lines, D. R.Hirte, C.Heddle, M. L.Davidson, G. P.Centre for Paediatric and Adolesent Gastroenterology, Women's and Children's Hospital, North Adelaide, SA 5006, Australia. moored@wch.sa.gov.auDouble-blind placebo-controlled trial of omeprazole in irritable infants with gastroesophageal refluxJ PediatrThe Journal of pediatricsJ PediatrThe Journal of pediatricsJ PediatrThe Journal of pediatrics219-2314322003/09/13Anti-Ulcer Agents/*therapeutic useCross-Over StudiesDouble-Blind MethodEsophagitis, PepticFemaleGastroesophageal Reflux/*drug therapyHumansInfantInfant Behavior/*drug effectsMaleOmeprazole/*therapeutic use2003Aug0022-3476 (Print) 0022-34761297063710.1067/s0022-3476(03)00207-5NLMeng(31)RCT; cross-over345.4 2.1 moSignificant GER, RI>5% or esophagitis Not clearNot clearYesNot clearYes30/344 wksOmeprazole 10mg 1x/day (5-10kg) or 10mg 2x/day (>10kg)Placebo identical appearance to omeprazoleCrying/distress Intervention vs control, Period 1 after 2 wks, period 2 after 4 wks (no wash-out period between treatments) 1. Cry/fuss mins per 24 hours - Baseline: 246 105 vs 287 132 (p=0.481) - Period 1: 203 113 vs 204 87 (p=0.604) - Period 2: 179 129 vs 198 115 (p=0.534) Independent from treatment, baseline vs period 1, p=0.040 and vs period 2, p=0.008 2. VAS for irritability - Baseline: 7.1 1.4 vs 6.6 1.7 (p=0.262) - Period 1: 5.9 2.6 vs 6.0 2.1 (p=0.724) - Period 2: 4.0 3.3 vs 5.7 2.2 (p=0.105) Independent from treatment, baseline vs period 2, p=0.008, vs period 1 p=NS) Side effects AEs No AEs encounteredInfant behavior monitored by Barr diary and VASPANTOPRAZOLWinter (2010)  ADDIN EN.CITE  ADDIN EN.CITE.DATA (32)RCT; parallel 1065.15 2.81 vs 5.04 2.81 moI-GERQ-R > 16 at screening and baseline and a clinical diagnosis of suspected, symptomatic or endoscopically proven GERDNot clearNot clearNot clearNot clearYes86/1064 wksPantoprazole 1.2mg/kg/day (5 mg/day for infants 2.5-7 kg, or 10 mg/day for infants 7-15 kg)Placebo, not further specifiedCrying/distress Mean (SD) change from base line vs wk 4 Intervention group vs control group -0.39 0.58 (p<0.001 vs baseline) vs -0.55 0.55 (p<0.001 vs baseline) Mean (SD) change from base line vs wk 8 Intervention group vs control group -0.49 0.57 (p<0.001 vs baseline) vs -0.64 0.72 (p<0.001 vs baseline) (no baseline and end of treatment scores provided) Visible regurgitation/vomiting: Number of vomiting, Mean SD, change from base line vs wk 4, intervention vs control group: -0.45 0.68 (p<0.001 vs baseline) vs -0.41 0.52 (p<0.001 vs baseline. Mean SD, change from base line vs wk 8 intervention vs control group: -0.62 0.72 (p<0.001 vs baseline) vs -0.48 0.87 (p<0.001 vs baseline) Change in mean difference at 4 wks: MDchange : -0.04 (95% CI -0.27 - 0.19) Change in mean difference at 8 wks: MDchange : -0.14 (95% CI -0.44 - 0.16) Side effects (S)AEs Data on AEs not sufficient, only AEs described reported in >3% of patients, so no total numbers provided SAE: 8 patients had 1 or 2 serious AEs during the study, of which 5 occurred during treatment with pantoprazole (all considered treatment unrelated)Withdrawal rate due to lack of efficacy, frequency of GERD symptoms, safety via AEsOMEPRAZOL VS RANITIDINEUmmarino, 2012RCT; parallel3540.6 36.4 moGERD based on impact of symptoms on general well-being of the children and pH-MII results (SI>50% and SAP>95%); infants with manifestations of extra-esophageal GERDNot clearNot clearNot clearNot clearYes35/351 yrOmeprazole 1.4mg/kg/day (n=19)Ranitidine 15mg/kg/day (n=16)Crying/distress Symptom score irritability (score 0-3, 3 = most severe) Intervention vs control Baseline: 0.84 2.19 vs 0.81 1.77 3 mo: 0.16 0.69 vs 0.25 1 (p=0.6 between groups after therapy) Chest pain Symptom score (score 0-3, 3 = most severe) Mean SD, intervention vs control group: Baseline: 0.68 20.06 vs 0.56 2.25 3 mo: 0.05 0.23 vs 0.56 2.25 (p=0.01 between groups after therapy) Mean difference at 3 mo: MD: -0.51 (95%CI -1.62 0.60) Side effects AEs No adverse events of treatment were reportedRemission of symptoms, not further specified in methodsCucchiara, 1993RCT; parallel326 mo 13.4 yrsGOR based on 24h pH monitoring and endoscopy with histology, unresponsive to an antireflux treatment Not clearNot clearNot clearNot clearYes25/328 wksOmeprazole 40mg/day (n=13)Ranitidine 20mg/kg/day (n=12)Endoscopy/histology: Healing of esophagitis (score A E; E = most severe; healing is return to score A or B) intervention vs control: 9/13 vs 9/12Clinical score for GERD, pH-metry, endoscopy with histologyESOMEPRAZOLE VS ANTACIDLoots, 2014RCT; parallel5713.6 (2-26) wksGERD symptoms > 5 days or increasing in frequency or severity for 3 daysYesNot clearNoNot clearYes51/572 wksEsomeprazole 1mg/kg/day 1x/day 2 hrs postprandially (n=12 in LLP, n=14 in HE)Antacid, 1.5 (0-2mo), 3 (2-4 mo) or 6mL (4-6mo) once daily (n=13 in LLP, n=12 in HE) Crying/distress - In infants in LLP, PPI vs AA 1. Total crying time (mins) Baseline: 92 24.2 vs 106 68.5 2 wk: 92 34.6 vs 88 36.1 (difference: -1 24.2 vs -17 64.9) 2. No of cry Baseline: 48 31.2 vs 60 43.3 2 wk: 48 27.7 vs 54 32.4 (difference: 5 17.3 vs -7 46.9) - In infants in HE, PPI vs AA 1. Total crying time (mins) Baseline: 71 41.2 vs 74 69.4 2 wk: 81 37.4 vs 66 45.0 (difference: 9 37.7 vs -8 45.0) 2. No of cry Baseline: 30 26.2 vs 38 34.6 2 wk: 49 26.2 vs 35 24.2 (difference: 17 37.4 vs -5 34.6) Side effects AEs 5 AEs (not specified what treatment arm) 2 SAEs in PPI + HE group: 1 hospital admission for rota virus 1 hospital admission for reduced oral intake + weight lossI-GERQ-R GER monitoring (pH-MII) Gastric emptying Physiological monitoringLANSOPRAZOLE VS FEED INTERVENTIONKhoshoo, 2007RCT; parallel454.8 1.18 vs 4.3 1.01 vs 4.6 0.99 mo (A vs B vs C) Patients referred to pediatric gastroenterology clinic for evaluation and treatment of GERD, I-GERQ-R scores > 16 for 1 wkNot clearNot clearNoNoYes45/452 wksLansoprazole 15mg once a day (A, n=15) or 7.5mg twice a day (B, n=15)Extensively hydrolyzed formula (C, n=15), no placebo providedI-GERQ-R scores Mean SD, Group A vs Group C Baseline: 26.6 2.8 vs 25.9 3.3 2 wks: 20.6 4.2 vs 25.8 3.2 (no subscores provided) Mean SD, Group B vs Group C Baseline: 26.9 3.7 vs 25.9 3.3 2 wks: 20.0 3.3 vs 25.8 3.2 Side effects AEs - No clinical adverse reactions, no drop=outsNo other outcome measures assessed AE = adverse event; CI = confidence interval; GER = gastroesophageal reflux; GERD = GER disease; HE = head elevation; I-GERQ-R = infant gastroesophageal reflux questionnaire revised; LLP = left lateral position; MD = mean difference; MDchange = change in mean difference; NS = not significant; PPI = proton pump inhibitor; RCT = randomized controlled trial; RI = reflux index; RR = relative risk; SAE = serious adverse event; SI = symptom index; SAP = symptom association probability; VA =visual analogue  B3.3 H2RAsAuthorDesignPopulationCochrane Risk of Bias ToolDureInterventionControlOutcome of interestOutcome measuresNAgeInclusionRandom sequence generationAllocation concealmentBlinding interventionBlinding outcome Selective reportingFollow-upRANITIDINEOrenstein (2002)  ADDIN EN.CITE  ADDIN EN.CITE.DATA (33) RCT; parallel299.0 (4-11) (8.0 (4-11) vs 9.0 (7-11)) moInfants with a history of acid reflux symptoms over the previous 3 moNot clearNot clearNot clearNot clearNo29/296hRanitidine 75 mg, single dose (n=19)Placebo, not further specified, single dose (n=10)Side effects AEs 12 patients experienced a total of 15 AEs. Ranitidine vs control: AEs: 12/19 patients vs 0/10 patients (timepoint not clear)Pharmacokinetics and dynamics, Safety analysisCIMETIDINECucchiara (1989)  ADDIN EN.CITE  ADDIN EN.CITE.DATA (34)RCT; parallel3721.7 37.65 vs 29.03 39.73 moEstablished peptic reflux esophagitis, 18-24h intraesophageal pH monitoring, a drop of the distal esophageal pH <4.00 for >20 seconds Not clearNot clearYesNot clearYes32/3712 wksCimetidine - 30 to 40 mg/kg/day three time a day after meals for 12 wks (n=17)Placebo - 30 to 40 mg/kg/day three time a day after meals for 12 wks (n=15)Histologic/endoscopic healing Cimetidine vs placebo Histological score (score 0-9; 9 = most severe) Baseline: 6.35 +/- 2.78 vs 6.80 +/- 2.88 (p<0.01) 12 wks: 1.6 +/- 2.43 vs 5.43 +/- 3.81 (NS) Esophagitis (score mild-severe) Mild or moderate esophagitis: improved or healed: 9/9 vs 4/7(unchanged 3/7) Severe esophagitis: improved or healed: 7/8 vs 2/8 (unchanged or worsened 1/8 vs 6/8) Side effects AEs No adverse events were reported Clinical score, histological score, endoscopic healingNIZATIDINESimeone (1997)  ADDIN EN.CITE  ADDIN EN.CITE.DATA (35)RCT; parallel262.08 (0.5- 12) vs 1.16 (0.5- 9.5) yrs Patients with reflux esophagitis Not clearNot clearNot clearNot clearYes24/268 wksNizatidine 1 0mg/kg in a tablet of 150mg (n=13)Matching placebo (n=13)Histologic/endoscopic healing Esophagitis score (score 0-5; 5 = most severe) Nizatidine vs Placebo: Patients cured based on endoscopy: 9/12 vs 2/13 Histologic improvement: 2/12 vs 3/13 Histologic unchanged: 1/12 vs 6/13 Histologic worsened: 0/12 vs 1/13. Heartburn Chest pain, pyrosis symptom score (score 0-3; 3 = most severe) intervention vs control Baseline: 2.3 1.2 vs 2.2 0.8 4 wks: 1.7 1.1 vs 1.8 0.8 (p<0.01 in intervention group compared to baseline, placebo NS) 8 wks 1.0 1.7 vs1.6 0.9 (p<0.01 in intervention group compared to baseline, placebo NS)) Visible regurgitation/vomiting: Frequency score (score 0-3; 3 = most severe)severity of regurgitation, Mean SD, intervention vs control group: Baseline: 2.4 1.0 vs 2.5 0.8 4 wks: 1.3 1.1 vs 2.2 1.3 (NS compared to baseline for placebo and intervention group) 8 wks: 0.3 1.7 vs 1.7 1.4 (p<0.01 in intervention group compared to baseline, placebo NS)) Mean difference at 4 and 8 wks: MD 4 wks : -0.90 (95%CI -1.86 - 0.06) MD 8 wks : -1.40 (95%CI -2.29 - -0.51) Severity of vomiting (score 0-3; 3 = most severe) Mean SD, intervention vs control group: Baseline: 2.4 0.7 vs 2.6 0.5 4 wks: 0.8 0.9 vs 2.1 1.1 (p<0.01 in intervention group compared to baseline, placebo NS) 8 wks: 0.4 0.7 vs1.6 1.9 (p<0.01 in intervention and placebo group compared to baseline) Mean difference at 4 and 8 wks: MD 4 wks : -1.30 (95%CI -2.10 - -0.50) MD 8 wks : -1.20 (95%CI -2.24 - -0.16) Crying/distress Abdominal colic (for infants) Mean SD, intervention vs control group: Baseline: 2.7 0.5 vs 2.7 0.5 4 wks: 1.4 1.1 vs 2.2 1.0 (p<0.01 in intervention group compared to baseline, placebo NS) 8 wks: 0.7 1.2 vs 1.6 1.1 (p<0.01 in intervention group compared to baseline, placebo NS)) MD 4 wks : -0.80 (95%CI -1.64 0.04) MD 8 wks : -0.90 (95% CI -1.82 0.02) pH-metry, parental daily diary, endoscopyH2RA vs Alginate-antacidOderda (1990)  ADDIN EN.CITE  ADDIN EN.CITE.DATA (36)RCT; parallel4910 (2-15.5) vs 7.9 (2-15.8) yrsChildren with peptic esophagitis, > grade III or when grade I or II was seen esophagitis had to be histologically confirmedNot clearNot clearNot clearNot clearNo47/496 moFamotidine 1mg/kg before supper at 7 or 8 pm (n= 25)Alginate-antacid mixture, 30min after each meal and at bedtime (0.5gr alginic acid, 0.1gr allumium hydroxide, 0.025gr magnesium trisilicate and 0.17gr sodium bicarbonate)(n=24)Histologic/endoscopic healing Famotidine vs alginate-antacid Endoscopy (score 1-3; 3 = most severe): Healed: 10/24 vs 10/23 Improved: 8/24 vs 3/23 Unchanged: 5/24 vs 10/23 Worsened: 1/14 vs 0/23 Histology (mild severe): Healed: 17/24 vs 12/23 (p<0.001 between groups) Improved: 2/24 vs 6/23 Unchanged: 3/24 vs 3/23 Worsened: 2/24 vs 2/23Histologic/endoscopic healing, no other outcome measuresCucchiara (1984)  ADDIN EN.CITE Cucchiara198422(37)222217Cucchiara, S.Staiano, A.Romaniello, G.Capobianco, S.Auricchio, S.Antacids and cimetidine treatment for gastro-oesophageal reflux and peptic oesophagitisArch Dis ChildArchives of disease in childhoodArch Dis ChildArchives of disease in childhoodArch Dis ChildArchives of disease in childhood842-75991984/09/01Aluminum Hydroxide/therapeutic useAntacids/*therapeutic useChild, PreschoolCimetidine/*therapeutic useClinical Trials as TopicDrug Combinations/therapeutic useEsophagitis, Peptic/complications/*drug therapyFemaleGastroesophageal Reflux/complications/*drug therapyHumansHydrogen-Ion ConcentrationInfantMagnesium Hydroxide/therapeutic useMaleRandom Allocation1984Sep0003-98886385868Pmc1628726NLMeng(37)RCT; parallel338.9 (2-34) vs 9.4 (2-42) moHistory suggesting GER, shown by radiology (positive if >2 episodes of reflux at fluoroscopy) and acid reflux test (Tuttle test, pH drop <4 for >20 sec). GERD confirmed by endoscopy (esophagitis)Not clearNot clearNot clearNot clearYes29/3312 wksCimetidine syrup (20 mg/kg/day ) (n=17)liquid magnesium hydroxide and aluminum hydroxide in a dose of 700 mmol (mEq)/1 -73 ml/day, one and three hours after meals, and at bedtime. (n=16)Endoscopic/histologic healing Symptom scores (score mild severe), Cimetidine vs antacid Baseline: 8.14 2.17 vs 8.2 2.39 12 wks: 3.21 3.80 vs 3.4 3.18 (wk 12 vs baseline in both groups p<0.01) (no data on Clinical, pH-metry and endoscopic assessmentH2RA vs SucralfateMartin (1989)  ADDIN EN.CITE Arguelles-Martin198924(38)242417Arguelles-Martin, F.Gonzalez-Fernandez, F.Gentles, M. G.Department of Pediatrics, University Hospital Virgen de la Marcarena Seville, Spain.Sucralfate versus cimetidine in the treatment of reflux esophagitis in childrenAm J MedThe American journal of medicineAm J MedThe American journal of medicineAm J MedThe American journal of medicine73-6866a1989/06/09AdolescentChildChild, PreschoolCimetidine/*therapeutic useEsophagitis, Peptic/*drug therapy/pathologyFemaleHumansInfantMaleRandom AllocationSucralfate/administration & dosage/*therapeutic use1989Jun 90002-9343 (Print) 0002-93432735338NLMeng(38)RCT; parallel756.1 3.6 yrsGastroesophageal reflux symptoms and radiological diagnosis of reflux according to Cleveland criteria, and/or esophageal scintiscanning with a reflux index of >2.5% and endoscopic diagnosis of reflux esophagitisNot clearNot clearNot clearNot clearYes75/758 wksCimetidine dissolved in water in two doses, daily dose 20mg/kg1. Sucralfate tablets (<6 yrs: 0.5g 4x day, >6 yrs 1.0g 4x day) one half hour before meals and at bedtime 2. Sucralfate suspension (same dose and scheme)Endoscopic/histologic healing: Cimetidine vs sucralfate tablets vs sucralfate suspension: Healed: 14/25 vs 14/25 vs 15/25 Improved: 7/25 vs 7/25 vs 7/25 Without change/worsened: 4/25 vs 4/25 vs 3/25. (no baseline scores provided; criteria for healing/improving not further specified) Adverse events: No adverse events reported by any of subjects.Symptoms during the treatment, symptoms not further specified, no baseline data provided on symptom breakdown, no validated scoring tool used. AE = adverse event; CI = confidence interval; GER = gastroesophageal reflux; GERD = GER disease; I-GERQ-R = infant gastroesophageal reflux questionnaire revised; MD = mean difference; MDchange = change in mean difference; NS = not significant; PPI = proton pump inhibitor; RCT = randomized controlled trial; RI = reflux index; RR = relative risk; SAE = serious adverse event B3.4 - ProkineticsAuthorDesignPopulationCochrane Risk of Bias ToolDure InterventionControlOutcome of interestOutcome measuresNAgeInclusionRandom sequence generationAllocation concealmentBlinding interventionBlinding outcome Selective reportingFollow-upBACLOFENOmari (2006)  ADDIN EN.CITE Omari200640(39)404017Omari, T. I.Benninga, M. A.Sansom, L.Butler, R. N.Dent, J.Davidson, G. P.Department of Paediatrics, University of Adelaide, Adelaide, South Australia, Australia. taher.omari@adelaide.edu.auEffect of baclofen on esophagogastric motility and gastroesophageal reflux in children with gastroesophageal reflux disease: a randomized controlled trialJ PediatrThe Journal of pediatricsJ PediatrThe Journal of pediatricsJ PediatrThe Journal of pediatrics468-7414942006/10/03AdolescentBaclofen/*therapeutic useChildChild, PreschoolDouble-Blind MethodFemaleGABA Agonists/*therapeutic useGastroesophageal Reflux/*drug therapy/physiopathologyGastrointestinal Motility/drug effectsHumansMale2006Oct0022-3476 (Print) 0022-34761701131510.1016/j.jpeds.2006.05.029NLMeng(39)RCT; parallel3011.0 1.0 vs 9.1 1.1 yrsSevere GERD, infants referred for further investigation who failed to improve after routine therapeutic measures (ie, parental reassurance, postural advice, feed thickeners, antacids, H2RAs, PPIs)Not clearNot clearNot clearNot clearYes30/30?Baclofen 0.5 mg/kg (up to a maximum of 40 mg)Placebo consisting of an equivalent volume of isotonic salineSide effects AEs Baclofen vs placebo Total AEs 9, 5 vs 4 breathlessness (n = 2; 1 vs 1); tiredness (n = 2; 1 vs 1), nausea (n = 1; baclofen group), sore nostril/throat (n = 4; 2 vs 2).Gastric emptying, esophageal motility and refluxDOMPERIDONEDeLoore (1997)  ADDIN EN.CITE De Loore197942(40)424217De Loore, I.Van Ravensteyn, H.Ameryckx, L.Domperidone drops in the symptomatic treatment of chronic paediatric vomiting and regurgitation. A comparison with metoclopramidePostgrad Med JPostgraduate medical journalPostgrad Med JPostgraduate medical journalPostgrad Med JPostgraduate medical journal40-255 Suppl 11979/01/01Antiemetics/*therapeutic useBenzimidazoles/*therapeutic useChildChild, PreschoolChronic DiseaseClinical Trials as TopicDouble-Blind MethodFemaleGastroesophageal Reflux/*drug therapyHumansInfantInfant, NewbornMaleMetoclopramide/*therapeutic useNausea/drug therapyPiperidines/*therapeutic useVomiting/*drug therapy19790032-5473 (Print) 0032-5473382154NLMeng(40)RCT; parallel30Domperidone 9 mo (3wks 4 yr); Placebo: 6 mo (1mth 5 yr)Clinical diagnosis of GER: pronounced vomiting after meals. Not clearNot clearNot clearNot clearYes30/302 wksDomperidone 0.3 mg kg"1three times a day Placebo three times a daySide effects No AEs reported Visible vomiting/regurgitation Data only provided in figure and descriptively. No raw data provided. Authors report significant improvement of %patients vomiting in the domperidone vs placebo group (p<0.001). Symptoms of nausea and vomiting rated by investigator. Evaluation of treatment success (excellent, good, moderate or poor; based on symptom improvementCarroccio (1994)  ADDIN EN.CITE  ADDIN EN.CITE.DATA (41)RCT; parallel40Domperidone: Age median 5 mo (range 1 - 16 mo), Placebo: Age median 4 mo (range 1 - 16 mo) GER confirmed by presence of at least 2 reflux episodes during fluoroscopy and 24-hour pH monitoring (RI >5.2%) NoNot clearNot clearNot clearNo40/408 wksDomperidone (0.3 mg/kg/dose 15 minutes before meal) and placebo, administered 1 and 3 hours after meals (n=20)two different preparations of placebo administered 1 and 3 hours after meals (n=20) Side effects No AEs reported - 24-hour pH monitoring at baseline and 8 weeks (most of the children spent the monitoring period at home) - Reflux time - Number of reflux episodes - Duration of longest reflux (minutes) - Number of reflux episode > 5 minutes - Jolley score METOCLOPRAMIDEBellissant (1997)  ADDIN EN.CITE  ADDIN EN.CITE.DATA (42)RCT; parallel44105 74 (87 67 vs 122 79) days24hour esoph- ageal pH recording when the percentage of time at pH <4 was at least equal to 5% of the analyzable duration of the recording. GER determined by 24h pHmetry by percentage of time pH<4 >5% measurementNot clearNot clearNot clearNot clearYes39/4414 dMetoclopramide 2.6mg/ml solution (0.1mg/drop), 2 drops 3x/day before a meal (n=20)Placebo, not further specified (n=19)Side effects Treatment discontinued due to side effect Metoclopramide vs placebo: 1/20 vs 3/19pH-metry, weight, four-class qualitative evaluation of treatment efficacy by parentsDeLoore (1997)  ADDIN EN.CITE De Loore197942(40)424217De Loore, I.Van Ravensteyn, H.Ameryckx, L.Domperidone drops in the symptomatic treatment of chronic paediatric vomiting and regurgitation. A comparison with metoclopramidePostgrad Med JPostgraduate medical journalPostgrad Med JPostgraduate medical journalPostgrad Med JPostgraduate medical journal40-255 Suppl 11979/01/01Antiemetics/*therapeutic useBenzimidazoles/*therapeutic useChildChild, PreschoolChronic DiseaseClinical Trials as TopicDouble-Blind MethodFemaleGastroesophageal Reflux/*drug therapyHumansInfantInfant, NewbornMaleMetoclopramide/*therapeutic useNausea/drug therapyPiperidines/*therapeutic useVomiting/*drug therapy19790032-5473 (Print) 0032-5473382154NLMeng(40)RCT; parallel32Metoclopramide: 6 mo (3wks 8yr); Placebo: 6 mo (1mth 5 yr)Clinical diagnosis of GER: pronounced vomiting after meals. Not clearNot clearNot clearNot clearYes32/322 wksMetoclopramide 0.3 mg kg"1three times a day Placebo three times a daySide effects No AEs reported Visible vomiting/regurgitation Data only provided in figure and descriptively. No raw data provided. Authors report significant improvement of %patients vomiting in the metcolopramide vs placebo group (p<0.001) Symptoms of nausea and vomiting rated by investigator. Evaluation of treatment success (excellent, good, moderate or poor; based on symptom improvement)Tolia (1989)  ADDIN EN.CITE Tolia198944(43)444417Tolia, V.Calhoun, J.Kuhns, L.Kauffman, R. E.Department of Pediatrics, Children's Hospital of Michigan, Wayne State University School of Medicine, Detroit.Randomized, prospective double-blind trial of metoclopramide and placebo for gastroesophageal reflux in infantsJ PediatrThe Journal of pediatricsJ PediatrThe Journal of pediatricsJ PediatrThe Journal of pediatrics141-511511989/07/01Body Weight/drug effectsClinical Trials as TopicDouble-Blind MethodGastric Emptying/drug effectsGastroesophageal Reflux/*drug therapyHumansHydrogen-Ion ConcentrationInfantMetoclopramide/*therapeutic useProspective StudiesRandom AllocationTechnetium Tc 99m Sulfur Colloid1989Jul0022-3476 (Print) 0022-34762661788NLMeng(43)RCT; cross-over30Median age 2 mo (range 1 9 mo) pH probe confirmed GER, patients were only included if the pH result was abnormal during the initial 8 hours Not clearNot clearYesNot clearYes30/302 wksMetoclopramide 0.1 mg/kg x4 per day 30 minutes before feeding for 1 week (n=15) Identical vehicle to metoclopramide and prescribed in a volume equal to 0.1mg/kg/dose of active metoclopramide (n=15) Side effects No side effects observed during either study period RI, number of reflux episodes < 4, number of episodes > 5 minutes, daily report of all symptoms, gastric emptying ratesDOMPERIDONE VS METOCLOPRAMIDEDeLoore (1997)  ADDIN EN.CITE De Loore197942(40)424217De Loore, I.Van Ravensteyn, H.Ameryckx, L.Domperidone drops in the symptomatic treatment of chronic paediatric vomiting and regurgitation. A comparison with metoclopramidePostgrad Med JPostgraduate medical journalPostgrad Med JPostgraduate medical journalPostgrad Med JPostgraduate medical journal40-255 Suppl 11979/01/01Antiemetics/*therapeutic useBenzimidazoles/*therapeutic useChildChild, PreschoolChronic DiseaseClinical Trials as TopicDouble-Blind MethodFemaleGastroesophageal Reflux/*drug therapyHumansInfantInfant, NewbornMaleMetoclopramide/*therapeutic useNausea/drug therapyPiperidines/*therapeutic useVomiting/*drug therapy19790032-5473 (Print) 0032-5473382154NLMeng(40)RCT; parallel32Domperidone 9 mo (3wks 4 yr); Metoclopramide: 6 mo (3wks 8yr)Clinical diagnosis of GER: pronounced vomiting after meals. Not clearNot clearNot clearNot clearYes32/322 wksDomperidone 0.3 mg kg"1three times a day Metoclopramide 0.3 mg kg"1three times a day Side effects No AEs reported Visible vomiting/regurgitation Data only provided in figure and descriptively. No raw data provided. Authors report significant improvement of %patients vomiting in the domperidone vs metoclopramide group (p<0.05)Symptoms of nausea and vomiting rated by investigator. . Evaluation of treatment success (excellent, good, moderate or poor; based on symptom improvementAE = adverse event; CI = confidence interval; GER = gastroesophageal reflux; GERD = GER disease; I-GERQ-R = infant gastroesophageal reflux questionnaire revised; MD = mean difference; MDchange = change in mean difference; NS = not significant; PPI = proton pump inhibitor; RCT = randomized controlled trial; RI = reflux index; RR = relative risk; SAE = serious adverse event B4 What is the prognosis of GERD in infants and children and what are prognostic factors? StudySettingDesignPopulationTreatmentFollow-upOutcome measuresSubjectsAgeNDefinition of GERDEl-Serag (2004)  ADDIN EN.CITE  ADDIN EN.CITE.DATA (15) Pediatric gastroenterology department Retrospective/prospective cohort Cohort defined retrospectively from hospital database (1990-1996). Potentially eligible participants (based on database) were contacted by phone in 2000 and 2002.Excl. Cerebral palsy, mental retardation, tracheoesophageal fistula, congenital esophageal stenosis, severe comorbid illness such as solid organ or bone marrow transplant, cancer or cystic fibrosis; residence outside Houston area. mean age onset of symptoms 5 4.2 years80/207Erosive esophagitis (ICD-9 code for erosive esophagitis and ICD-9 for endoscopy prior to that diagnosis; code 530.1).No information provided at baseline, only at follow-up interview: 44/80 used over-the-counter medications; H2RA n=12 (15%), PPI n=13 (16%), H2RA or PPI 25 (30%), cisapride n=1 (1%).Minimum of 5 years after initial diagnosis. 1. GERD symptoms (at least monthly (any GERD) or at least weekly (frequent GERD), measured with GERQ, over past year); 2. Heartburn (GERQ); 3. Regurgitation (GERQ); 4. Erosive esophagitis and Barretts esophagus. Orenstein (2006)  ADDIN EN.CITE  ADDIN EN.CITE.DATA (21) General pediatric department Prospective cohort: placebo arm of pharmacotherapy RCT Excl. histologic evidence for infectious or eosinophilic esophagitis; gastrointestinal structural abnormalities or prior surgery; unacceptable risk for dual placebo (history of severe apparent life-threatening event or hematemesis); unacceptable risk from the study drugs; or inability to complete the study as predicted by the investigators. median age 3.5 (range 1.5 8.0) months10/19 non-rescue (n=6 required rescue-medication)Infants who did not respond symptomatically to a 2 week trial of conservative therapy, and who demonstrated histologic morphometric reflux esophagitis on a distal esophageal suction biopsy.No treatment (placebo arm of RCT; 10/19 children completed without rescue medication)12 months.1.Symptoms (I-GERQ and parent global score) 2.Esophagitis (by suction biopsy).Shepherd (1987)  ADDIN EN.CITE Shepherd198724(23)242417Shepherd, R. W.Wren, J.Evans, S.Lander, M.Ong, T. H.Gastroesophageal reflux in children. Clinical profile, course and outcome with active therapy in 126 casesClin Pediatr (Phila)Clinical pediatricsClin Pediatr (Phila)Clinical pediatricsClin Pediatr (Phila)Clinical pediatrics55-602621987/02/01ChildChild, PreschoolCimetidine/therapeutic useEndoscopyEsophagitis, Peptic/diagnosis/drug therapy/etiologyFeeding BehaviorFemaleFiber Optic TechnologyFollow-Up StudiesGastroesophageal Reflux/complications/diagnosis/*therapyHumansInfantInfant, NewbornMalePostureSleep Wake Disorders/etiology1987Feb0009-9228 (Print) 0009-92283802692NLMeng(23) General pediatric department Prospective cohort: series of consecutive patientsExcl. Not reported median age 2.5 months (range 0.1 10 years); 126Combination of clinical observation and investigations: cineradiography (90%), fiberoptic endoscopy (49%), gastric-scintiscan (25%), acid reflux tests (20%).All: positioning therapy, thickening, antacids, in some cases bethanechol or metoclopromide, cimetidine in case of esophagitis 1.5 3.5 years1. Persisting symptoms requiring GERD treatmentRuigomez (2015)  ADDIN EN.CITE  ADDIN EN.CITE.DATA (22)primary care setting  Prospective cohort using The Health Improvement Network (THIN) UK database. Excl. individuals with any record of reflux esophagitis or other esophageal injury (e.g. ulcer, stricture or Barretts esophagus) at their initial diagnosis. Pregnant girls were also excluded. 571 children (1-11 years) and 671 adolescents (12-17 years)1242Presence of reflux of gastric contents causing troublesome symptoms and/or complications. Enrolled were individuals aged 117 years registered in THIN who had a first diagnosis of GERD during 20002005. Patients were identified by using Read codes for gastro-esophageal reflux, reflux esophagitis, esophageal ulcer, stricture, esophageal inflammation and heartburn by computerised search. Not reported. 4 1.9 years1. Esophagitis; 2.GERD related esophageal complication (including esophageal ulcer, esophageal stricture, Barretts esophagus and esophageal cancer), validated by treating physician.  GER = Gastroesophgeal Reflux; GERD = GER disease; GERQ = GER quitionnaire; H2RA = histamine receptor antagonist; I-GERQ-R = Infant GER Questionnaire Revised; PPI = proton pump inhibitor; RCT = randomized controlled trial REFERENCES  ADDIN EN.REFLIST 1. Boix-Ochoa J, Lafuenta JM, Gil-Vernet JM. Twenty-four hour exophageal pH monitoring in gastroesophageal reflux. Journal of pediatric surgery. 1980;15(1):74-8. 2. Da Dalt L, Mazzoleni S, Montini G, Donzelli F, Zacchello F. Diagnostic accuracy of pH monitoring in gastro-oesophageal reflux. Archives of disease in childhood. 1989;64(10):1421-6. 3. Cucchiara S, Staiano A, Gobio Casali L, Boccieri A, Paone FM. Value of the 24 hour intraoesophageal pH monitoring in children. Gut. 1990;31(2):129-33. 4. Kahn A, Rebuffat E, Sottiaux M, Blum D, Yasik EA. Sleep apneas and acid esophageal reflux in control infants and in infants with an apparent life-threatening event. Biology of the neonate. 1990;57(3-4):144-9. 5. Cucchiara S, Bortolotti M, Minella R, Auricchio S. Fasting and postprandial mechanisms of gastroesophageal reflux in children with gastroesophageal reflux disease. Digestive diseases and sciences. 1993;38(1):86-92. 6. Ravelli AM, Villanacci V, Ruzzenenti N, Grigolato P, Tobanelli P, Klersy C, et al. Dilated intercellular spaces: a major morphological feature of esophagitis. Journal of pediatric gastroenterology and nutrition. 2006;42(5):510-5. 7. Patra S, Singh V, Chandra J, Kumar P, Tripathi M. Diagnostic modalities for Gastro-esophageal reflux in infantile wheezers. J Trop Pediatr. 2011;57(2):99-103. 8. Arasu TS, Wyllie R, Fitzgerald JF, Franken EA, Siddiqui AR, Lehman GA, et al. Gastroesophageal reflux in infants and children comparative accuracy of diagnostic methods. The Journal of pediatrics. 1980;96(5):798-803. 9. Farhath S, He Z, Saslow J, Soundar S, Amendolia B, Bhat V, et al. Detection of pepsin in mouth swab: correlation with clinical gastroesophageal reflux in preterm infants. The journal of maternal-fetal & neonatal medicine : the official journal of the European Association of Perinatal Medicine, the Federation of Asia and Oceania Perinatal Societies, the International Society of Perinatal Obstet. 2013;26(8):819-24. 10. Vanderhoof JA, Moran JR, Harris CL, Merkel KL, Orenstein SR. Efficacy of a pre-thickened infant formula: a multicenter, double-blind, randomized, placebo-controlled parallel group trial in 104 infants with symptomatic gastroesophageal reflux. 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M.Villanacci, V.Ruzzenenti, N.Grigolato, P.Tobanelli, P.Klersy, C.Rindi, G.Gastrointestinal Pathophysiology and Gastroenterology, University Department of Pediatrics, Children's Hospital, Brescia, Italy. alberto_ravelli@yahoo.comDilated intercellular spaces: a major morphological feature of esophagitisJ Pediatr Gastroenterol NutrJournal of pediatric gastroenterology and nutritionJ Pediatr Gastroenterol NutrJournal of pediatric gastroenterology and nutritionJ Pediatr Gastroenterol NutrJournal of pediatric gastroenterology and nutrition510-54252006/05/19AdolescentChildChild, PreschoolEpithelium/*pathologyEsophagitis/*pathologyEsophagus/*pathologyGastroesophageal Reflux/*pathologyHumansInfantProspective Studies2006May0277-21161670797210.1097/01.mpg.0000215312.78664.b9NLMeng$$If!v h#vM#v#v2#v#v#vs#v#vO#v #v #v :V F4% t0++++++ + + 5\55S555Z555 ~5 5 /  /  /  / apnytUHkdB$$IfF4%    ]%*.4:`\S `Z ```~`~`` t0000044 lapnytUH$$If!v h#vM#v#v2#v#v#vs#v#vO#v #v #v :V F4% t0++++++ + + 5\55S555Z555 ~5 5 /  / /  /  / /  apnytUHkdG$$IfF4%    ]%*.4: \S  Z    ~ ~   t0000044 lapnytUH$$If!vh#v@8#v:V F%  t055apytUH DPatra20114023(7)4023402317Patra, S.Singh, V.Chandra, J.Kumar, P.Tripathi, M.(Patra, Singh, Chandra, Kumar) Department of Pediatrics, Lady Hardinge Medical College, Kalawati Saran Children's Hospital, New Delhi, India (Tripathi) Department of Nuclear Medicine, INMAS, Timarpur, New Delhi, India S. Patra, Department of Pediatrics, Lady Hardinge Medical College, Kalawati Saran Children's Hospital, New Delhi-1, India. E-mail: dr_soumyapatra@rediffmail.comDiagnostic modalities for Gastro-esophageal reflux in infantile wheezersJournal of Tropical PediatricsJournal of Tropical PediatricsJ Trop Pediatr99-10357224-h pH monitoringGastro-esophageal refluxGI scintiscanInfantWheezingarticlechildcontrolled studydiagnostic test accuracy studydiagnostic valuefemalegastric pH monitoringgastroesophageal reflux/di [Diagnosis]humanintermethod comparisonmajor clinical studymalepredictive valuepreschool childscintiscanningsensitivity and specificitytreatment response2011April0142-6338 1465-36642011192246http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=emed10&AN=2011192246http://digitaal.uba.uva.nl:9003/uva-linker?sid=OVID:embase&id=pmid:&id=doi:10.1093%2Ftropej%2Ffmq056&issn=0142-6338&isbn=&volume=57&issue=2&spage=99&pages=99-103&date=2011&title=Journal+of+Tropical+Pediatrics&atitle=Diagnostic+modalities+for+Gastro-esophageal+reflux+in+infantile+wheezers&aulast=Patra&pid=%3Cauthor%3EPatra+S.%3BSingh+V.%3BChandra+J.%3BKumar+P.%3BTripathi+M.%3C%2Fauthor%3E%3CAN%3E2011192246%3C%2FAN%3E%3CDT%3EJournal%3A+Article%3C%2FDT%3Ehttp://dx.doi.org/10.1093/tropej/fmq056EmbaseOvid TechnologiesEnglish$$If!v h#vY#v#v2#v#v#vV#v#vO#v #v #v :V F4% t0+++++++ + + 5`55S555Q555 ~5 5 /  /  /  / apnytUHkdY$$IfF4%    ]%*.4:```S `Q ```~`~`` t0000044 lapnytUH$$If!v h#vY#v#v2#v#v#vV#v#vO#v #v #v :V F4% t0+++++++ + + 5`55S555Q555 ~5 5 /  / /  /  / /  apnytUHkd^$$IfF4%    ]%*.4: ` S  Q    ~ ~   t0000044 lapnytUH$$If!vh#v@8#v:V F%  t055apytUHXDArasu1980283(8)28328317Arasu, T. 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L.Gastroesophageal reflux in infants and children comparative accuracy of diagnostic methodsJ PediatrThe Journal of pediatricsJ PediatrThe Journal of pediatricsJ PediatrThe Journal of pediatrics798-8039651980/05/01AdolescentBarium Sulfate/*diagnostic useChildChild, PreschoolEndoscopyEsophagogastric Junction/physiopathologyEsophagus/radiographyFemaleGastric Juice/analysisGastroesophageal Reflux/*diagnosis/physiopathology/radionuclide imagingHumansInfantMaleManometryPressureProspective StudiesStomach/radiographyTechnetium/diagnostic use1980May0022-3476 (Print) 0022-34767365577NLMeng$$If!v h#vf#vx#v2#v#v3#v3#v#vO#v #v #v :V F4G t0++++++ + + 5d55S555F555 ~5 5 /  /  /  / / apnytUHkdl$$IfF4G    ]%*.4:`dS `F ```~`~`` t0000044 lapnytUH$$If!v h#vf#vx#v2#v#v3#v3#v#vO#v #v #v :V F4 t0++++++ + + 5d55S555F555 ~5 5 /  / /  /  / /  apnytUHkdq$$IfF4    ]%*.4: dS  F    ~ ~   t0000044 lapnytUH$$If!vh#v@8#v:V F%  t055apytUH DFarhath201344(9)444417Farhath, S.He, Z.Saslow, J.Soundar, S.Amendolia, B.Bhat, V.Pyon, K.Stahl, G.Mehta, D.Aghai, Z. 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E t0A;@@@@44 lapp֠yt-T DDavidson201328(28)282817Davidson, G.Wenzl, T. G.Thomson, M.Omari, T.Barker, P.Lundborg, P.Illueca, M.Women's and Children's Hospital, Children, Youth and Women's Health Service, North Adelaide, Australia.Efficacy and safety of once-daily esomeprazole for the treatment of gastroesophageal reflux disease in neonatal patientsJ PediatrThe Journal of pediatricsJ PediatrThe Journal of pediatricsJ PediatrThe Journal of pediatrics692-8.e1-216332013/06/27Administration, OralAnalysis of VarianceDouble-Blind MethodDrug Administration ScheduleEsomeprazole/*therapeutic useFemaleFollow-Up StudiesGastroesophageal Reflux/diagnosis/*drug therapyHumansInfantInfant, NewbornInfant, PrematureInfant, Premature, Diseases/diagnosis/drug therapyIntention to Treat AnalysisMaleMonitoring, Physiologic/methodsProton Pump Inhibitors/*therapeutic useTreatment OutcomeAeAdverse eventGerGerdGastroesophageal refluxGastroesophageal reflux diseaseIttIntent-to-treatLsmLeast square meanPpiProton pump inhibitorSaeSerious adverse event2013Sep0022-34762380040310.1016/j.jpeds.2013.05.007NLMeng$$IfJ!vh#v#v #v#v#v#v9#v#v#v 7#v #v B#v 6#v #v #v! #vE:V Fs t0A;55 55559555 75 5 B5 65 5 5! 5Eapp֠yt-Tkd$$IfFsd!AZ  mQ$e*4; 97B6! E t0A;@@@@44 lapp֠yt-TvDWinter201237(29)373717Winter, H.Gunasekaran, T.Tolia, V.Gottrand, F.Barker, P. N.Illueca, M.MassGeneral Hospital for Children, Boston, MA 02114, USA. hwinter@partners.orgEsomeprazole for the treatment of GERD in infants ages 1-11 monthsJ Pediatr Gastroenterol NutrJournal of pediatric gastroenterology and nutritionJ Pediatr Gastroenterol NutrJournal of pediatric gastroenterology and nutritionJ Pediatr Gastroenterol NutrJournal of pediatric gastroenterology and nutrition14-205512012/01/14Chi-Square DistributionDouble-Blind MethodEsomeprazole/adverse effects/*therapeutic useFemaleGastroesophageal Reflux/*drug therapyHumansInfantKaplan-Meier EstimateMaleProportional Hazards ModelsProton Pump Inhibitors/adverse effects/*therapeutic useTreatment Outcome2012Jul0277-21162224151310.1097/MPG.0b013e3182496b35NLMeng$$IfJ!vh#v#v #v#v#v#v9#v#v#v 7#v #v B#v 6#v #v #v! #vE:V F t0A;55 55559555 75 5 B5 65 5 5! 5E/ app֠yt-Tkd$$IfFd!AZ  mQ$e*4; 97B6! 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F.Frankel, E.Pediatric Gastroenterology, University of Pittsburgh School of Medicine, Children's Hospital of Pittsburgh, One Children's Place, Pittsburgh, PA 15213-2583, USA.Natural history of infant reflux esophagitis: symptoms and morphometric histology during one year without pharmacotherapyAm J GastroenterolThe American journal of gastroenterologyAm J GastroenterolThe American journal of gastroenterologyAm J GastroenterolThe American journal of gastroenterology628-4010132006/03/18Anti-Ulcer Agents/*therapeutic useBiopsyCombined Modality TherapyEsophagitis, Peptic/diagnosis/*drug therapy/pathologyEsophagus/pathologyFemaleFollow-Up StudiesGastrointestinal Motility/drug effectsHistamine Antagonists/*therapeutic useHumansInfantLife StyleMaleObservationReceptors, Histamine H2/*drug effectsRemission, Spontaneous2006Mar0002-9270 (Print) 0002-92701654229610.1111/j.1572-0241.2006.00442.xNLMeng$$IfJ!v h#v#v#v2#v#vr#vT#v#v.#v #v :V F t055505\5Z555/5 5 /  /  / /  appdytTgkd$$IfF J ~v#*/@;0\Z /  t0((((44 lappdytTg$$IfJ!v h#v#v#v2#v#vr#vT#v#v.#v #v :V F t055505\5Z555/5 5 /  /  / /  appdytTgkd$$IfF J ~v#*/@;0\Z /  t0((((44 lappdytTg|DRuigomez201025(22)252517Ruigomez, A.Lundborg, P.Johansson, S.Wallander, M. A.Garcia Rodriguez, L. A.Spanish Centre for Pharmacoepidemiologic Research (CEIFE), Madrid, Spain. aruigomez@ceife.esFollow-up of a cohort of children and adolescents with gastro-esophageal reflux disease who were free of reflux esophagitis at initial diagnosisScand J GastroenterolScandinavian journal of gastroenterologyScand J GastroenterolScandinavian journal of gastroenterologyScand J GastroenterolScandinavian journal of gastroenterology814-21457-82010/04/14AdolescentChildChild, PreschoolCohort StudiesEsophagitis, Peptic/*epidemiology/*etiologyFemaleFollow-Up StudiesGastroesophageal Reflux/*complications/*epidemiologyHumansInfantMale*Primary Health CareSeverity of Illness Index2010Aug0036-55212038452710.3109/00365521003793758NLMeng|DRuigomez201025(22)252517Ruigomez, A.Lundborg, P.Johansson, S.Wallander, M. A.Garcia Rodriguez, L. 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