Gastroesophageal Reflux in infants & Proton Pump Inhibitors

Gastroesophageal Reflux in infants & Proton Pump Inhibitors
By: Khalil Ebrahim Manal Darwish Shihadeh, MD, FAAP

Clinical Cases 5 month old who effortlessly spits-up 6–10x/day, but seems comfortable and is growing well 4 month old who is losing weight is reported to vomit 2–3x/day, and seems increasingly fussy with feeds 15 year old who presents complaining of heartburn

Gastroesophagyeal Reflux GER without D
GER is a physiologic Phenomenon that occurs at all ages and it allows depressurization of the stomach

GER Gastroesophageal Reflux GER is a normal physiologic process
The passage of gastric contents into the esophagus Occurs with/without regurgitation and vomiting GER is a normal physiologic process Several times/day in healthy infants, children, and adults

Physiology of GER GER occurs during transient relaxations of the lower esophageal sphincter (LES) Relaxation of the LES that is unaccompanied by swallowing permits gastric contents into the esophagus LES is not a “true” sphincter Comprised of crural support, an intra‑abdominal segment, and the “angle of His” The main underlying mechanism that allows GER to occur across all ages Allows air to vent from the stomach

Composition of the LES The lower esophageal sphincter (LES) constitutes the major barrier to GER. The LES is a specialized region of smooth muscle that is tonically contracted. In the healthy adult, this region is about 3 cm in length and located at the level of the diaphragm. In the neonate, the sphincter length is about 1.5 cm and it is located about 2 cm above the level of the diaphragm. In the older child and adult, the crus of the diaphragm (skeletal muscle) contracts during inspiration and increases the high-pressure barrier in the region of the LES. Other anatomic components of the antireflux barrier include the phrenoesophageal ligament, which anchors the distal esophagus to the crural diaphragm [1], and the angle of His [2]. References 1. Mittal RK, Balaban DH. The esophagogastric junction. N Engl J Med 1997;336: 2. Bardaji C, Boix-Ochoa J. Contribution of the His angle to the gastroesophageal antireflux mechanism: an experimental study in dogs. Pediatr Surg Int 1986;1:172-6. Healthy adult – LES 3cm in length, at level of diaphragm Neonate – LES 1.5cm in length, above the diaphragm 7

Esophageal Capacity Shorter esophagus Smaller capacity Gravity Infant
A number of factors contribute to the frequency of regurgitation in infants. A shorter esophagus, the small capacity of the esophagus, and recumbent posture (lack of gravity) make it more likely that refluxed material in the infant will fill the esophagus and pass into the pharynx. The infant is thus more likely to regurgitate than the adult when gastric contents empty into the esophagus. The esophagus is approximately 11 cm at birth, with a diameter of 5 mm. By adulthood, the esophagus is cm long, with lateral and anteroposterior diameters of 30 and 19 mm, respectively [1]. Reference 1. Weaver TL. Anatomy and embryology. In: Walker WA, Durie PR, Hamilton JR, et al, eds. Pediatric Gastrointestinal Disease, 1st ed. Philadelphia: BC Decker; 1991: Gravity Infant Adult 8

Most Episodes of GER Last < 3 minutes
Occur in the postprandial period Cause few or no symptoms GER can cause vomiting A coordinated autonomic and voluntary motor response with forceful expulsion of gastric contents Regurgitation (“spitting up”) is the most visible symptom of GER Occurs daily in 50% of infants < 3 months of age Resolves spontaneously in most by 12–14 months

Prevalence of Regurgitation in Infancy
 1 time a day  4 times a day % of Infants Age (months) n=948 Regurgitation is the most common manifestation of GER in childhood. A cross-sectional survey completed by 948 parents showed that the prevalence rate of regurgitation (at least 1 episode daily) was 50% in 0- to 3-month-old infants, reached a peak of 67% at 4 months, and dropped dramatically to 5% in 10- to 12-month-old infants [1]. A similar pattern was reported for regurgitation of at least 4 episodes daily. Many subjects in this survey “outgrew” GER by 7 months and most by 1 year. At 1-year follow-up, infants with previously reported daily regurgitation no longer were symptomatic—not one of their parents described spitting up as a current problem [2]. These findings support the concept that GER in most infants and children is a physiologic, self-limited condition. References 1. Nelson SP, Chen EH, Syniar GM, Christoffel KK. Prevalence of symptoms of gastroesophageal reflux during infancy. Arch Pediatr Adolesc Med 1997;151: 2. Nelson SP, Chen EH, Syniar GM, Christoffel KK. One-year follow-up of symptoms of gastroesophageal reflux during infancy. Pediatrics 1998;102(6):1470. Abstr e67. 0-3 4-6 7-9 10-12 Adapted from Nelson SP, Chen EH, Syniar GM, et al. Prevalence of symptoms of gastroesophageal reflux during infancy. A pediatric practice-based survey. Pediatric Practice Research Group. Arch Pediatr Adolesc Med. 1997;151(6):569–572 10

WHEN DOES GER “become” GERD
Aberrance in normal physiology Insufficient clearance and buffering of refluxate Decreased rate of gastric emptying Abnormalities in efficacy of epithelial repair Decreased neural protective reflexes

Risk Factors for GERD Hiatal Hernia Neurodevelopmental Delay
Anatomic Abnormalities: -TEF Obesity Delayed Gastric emptying??? -Pro-motility agents have not proven to reduce bolus GER

Genetics of Reflux Cluster studies suggest inheritability of GER/GERD and their complications Hiatal hernia Erosive esophagitis Barrett’s esophagus Esophageal adenocarcinoma Swedish Twin Registry Increased concordance in monozygotic vs. dizygotic Vandenplas Y, Rudolph CD, Di Lorenzo C, et al. Pediatric gastroesophageal reflux clinical practice guidelines: joint recommendations of the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition (NASPHAN) and the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition (ESPGHAN). J Pediatr Gastroesophageal Nutr. 2009;49(4):548–557

How much reflux is too much
How much reflux is too much? Gastroesophageal Reflux, as Measured By 24- Hour pH Monitoring, in 509 Healthy Infants Screened for Risk of Sudden Infant Death Syndrome Pediatrics 1991 Yvan Vandenplas, MD, PhD; Harry Goyvaerts, RN*; Rudy Helven, RN; and Liliane Sacre, MD From the Academisch Ziekenhuis Kinderen, Vrije Universiteit Brussel and *Janssen Pharmaceuticals, Belgium

Frequency of Reflux in 24hour among Infants
Percentile Reflux Index Number 95 10 71.5 99 13.9 99.7

Physician beliefs, according to specialty, based on overall clinical impression.
Pediatric Specialists’ Beliefs About Gastroesophageal Reflux Disease in Premature Infants WHAT’S KNOWN ON THIS SUBJECT: Antireflux medicines are widely prescribed in NICUs, despite the absence of guidelines for GERD treatment in premature infants. In addition, proton pump inhibitor use has dramatically increased, although evidence demonstrating improvement of symptoms in treated infants is lacking. WHAT THIS STUDY ADDS: This study confirms the lack of a standard of care for the management of GERD in premature infants, suggests differences in care among pediatric specialists, and raises questions about physician interpretation of the medical literature. abstract + BACKGROUND: Wide variation exists in the treatment of suspected gastroesophageal reflux disease (GERD) in premature infants; it is unknown to what degree diagnosis and treatment are affected by the treating physician’s medical specialty or interpretation of the medical literature. METHODS: This study involved an online survey of board-certified neonatologists, pediatric pulmonologists, and pediatric gastroenterologists about their beliefs regarding the symptoms, diagnosis, and treatment of GERD in premature infants in the NICU on the basis of both clinical impression and interpretation of the literature. RESULTS: A total of 1021 neonatologists, 232 pediatric pulmonologists, and 222 pediatric gastroenterologists participated in the study (47.5% response rate). There was disagreement among specialists in nearly all aspects of the survey. Pulmonologists were most likely to report that respiratory symptoms are caused by GERD (P .001). Neonatologists were least likely to report that a therapeutic trial of pharmacologic agents would be useful for diagnosing GERD (P.001) or that lansoprazole, ranitidine, or cimetidine are safe or effective (P .001). No pharmacologic therapy had 50% of respondents supporting its effectiveness. There was moderate correlation between physician belief based on the medical literature and belief based on clinical impression (Spearman rank correlation: 0.47– 0.75). For therapies supported by multiple meta-analyses in infants versus therapies with few infant trials, physicians rated the evidence for effectiveness similarly. CONCLUSIONS: There is wide variation among pediatric specialists regarding beliefs about GERD in premature infants, as well as about the weight of evidence in the medical literature for this patient population. Physician beliefs do not seem to be driven by the degree of evidence in the neonatal literature. With no agreed-on standard of care in the setting of widespread use of antireflux medications, greater understanding is needed about the ways physicians form clinical impressions, access and process medical evidence, and apply it to patient Physician beliefs, according to specialty, based on overall clinical impression. A, Likelihood that symptoms are caused by GERD; B, usefulness of tests for diagnosing GERD; C, effectiveness of therapies for GERD; D, safety of therapies for GERD. a Difference between specialties achieved statistical significance (P ≤ .05 by Kruskal Wallis overall test); difference is based on overall distribution across 5-point Likert scales. Results of pairwise comparisons are given in the main text. GI indicates gastrointestinal; MII, multichannel intraluminal impedance. Golski C A et al. Pediatrics 2010;125:96-104 ©2010 by American Academy of Pediatrics

CASES OF INFANTS WITH INFANTILE SPASMS MISDIAGNOSED AS GERD
Acta Paediatr October; 100(10): e178–e180. doi: /j x PMCID: PMC Gastroesophageal reflux disease at any cost: a dangerous paediatric attitude Andrea Taddio,1 Chiara Bersanini,2 Lucio Basile,3 Massimo Fontana,2 and Alessandro Ventura1 1Department of Pediatrics, Institute of Child Health IRCCS Burlo Garofolo, University of Trieste, Trieste, Italy CASES OF INFANTS WITH INFANTILE SPASMS MISDIAGNOSED AS GERD Infantile spasm (IS) is a specific rare type of seizure seen in an epilepsy syndrome of infancy; it is also known as West syndrome and is characterized by developmental regression and a specific pattern on electroencephalography (EEG) testing called hypsarrhythmia (chaotic brain waves). Gastroesophageal Reflux Disease (GERD) is considered a common clinical problem in every day paediatrics clinical practice. However, GERD diagnosis seems to be overestimated, mainly because such symptoms as crying, regurgitation, feeding refusal, back arching, wheezing, coughing and hoarseness are still considered suggestive for GERD, although they have already been demonstrated to be inaccurate (1), with consequent risk for disease overdiagnosis and inappropriate unnecessary Proton Pump Inhibitors (PPI) prescription. Herein, we report the cases of three patients with classical symptoms referable to IS who were initially misdiagnosed as having GERD.

A GLOBAL, EVIDENCE-BASED CONSENSUS ON THE DEFINITION OF GASTROESOPHAGEAL REFLUX DISEASE IN THE PEDIATRIC POPULATION GERD is present when reflux of gastric contents causes troublesome symptoms and/or complications, but this definition is complicated by unreliable reporting of symptoms in children under the age of 8 years

Troublesome symptoms or complications of reflux
Recurrent vomiting and poor weight gain in infant Recurrent vomiting and irritability in infant Recurrent vomiting in older child Heartburn in child/adolescent Esophagitis Dysphagia or feeding refusal Apnea or ALTE Asthma Recurrent pneumonia Upper airway symptoms Unusual arching or seizure-like movements (Sandifer syndrome) GER in infants most often manifests as vomiting. A small minority of infants develop GERD, with symptoms including weight loss or poor weight gain (failure to thrive), irritability, dysphagia, odynophagia, and arching of the back during feedings. In infants, GER may cause apparent life-threatening events (ALTE) and has been associated with chronic respiratory disorders such as reactive airways disease, recurrent stridor, chronic cough, and recurrent pneumonia. In preschool-aged children, GER may present as intermittent vomiting. Older children are more likely to have an adult-type pattern of chronic heartburn or regurgitation with reswallowing. Esophagitis in older children may present as dysphagia or food impaction. Rarely, esophageal pain causes stereotypical repetitive stretching and arching movements that are mistaken for atypical seizures or dystonia (Sandifer syndrome). More severe inflammation may cause chronic blood loss with anemia and hematemesis. Chronic inflammation may result rarely in Barrett’s esophagus. 19

What about complications of GERD?
e.g. Is there a danger to not recognizing and treating it?

Complications of Reflux
Normal mid- and distal esophagus Z-line EGD and biopsy can determine the presence and severity of esophagitis and other GER complications. This slide contrasts endoscopic views of the normal esophagus and erosive esophagitis. A normal appearance of the esophagus on endoscopy does not exclude histopathologic esophagitis. Because there is a poor correlation between endoscopic appearance and histopathology, esophageal biopsy is recommended when diagnostic endoscopy is performed [1]. In a single-center review of children with GERD who underwent EGD, 34.6% (139/402) had erosive esophagitis [2]. Mean age was 9.7 years (range, 1.5 to 25 years); only 3/402 patients were older than 18. The children were neurologically normal and without congenital esophageal anomalies. The prevalence of erosive esophagitis increased with age in this pediatric population. Normal mid- and distal esophagus and Hetzel-Dent grades 2 and 4 erosive esophagitis; endoscopic views courtesy of Benjamin D. Gold, MD. References 1. Rudolph C, Mazur LJ, Liptak GS, Baker R, Boyle JT, Colletti RB, Gerson W, Werlin S. Evaluation and treatment of gastroesophageal reflux in infants and children: recommendations of the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition. J Pediatr Gastroenterol Nutr 2001;32:S1-31. 2. El-Serag HB, Bailey NR, Gilger M, Rabeneck L. Endoscopic manifestations of gastroesophageal reflux disease in patients between 18 months and 25 years without neurological deficits. Am J Gastroenterol 2002;97: Erosive esophagitis: grade 2 and grade 4 Erosions 21

Complications of Reflux
Esophageal stricture secondary to GERD: radiography and endoscopy Stricture Barrett’s esophagus: endoscopy and histology If esophageal inflammation caused by GER is untreated, strictures may form. In this slide at top, an esophagram and an endoscopic view show an esophageal stricture secondary to GERD. Chronic inflammation may also result in replacement of distal esophageal mucosa with a metaplastic, potentially malignant specialized epithelium known as a Barrett’s esophagus. In this slide at bottom, both endoscopic and histologic views contrast Barrett’s epithelium and normal epithelium. In the single-center review of 402 children with GERD who underwent EGD, esophageal stricture was reported in 1.5% and Barrett’s esophagus was suspected in 2.7% (due to a finding of columnar-lined esophagus) [1]. However, intestinal metaplasia was seen in no biopsy samples. In a review of the published literature, Barrett’s esophagus was estimated in 0.02% of children undergoing endoscopy, most of whom had risk factors for severe GERD (e.g., congenital esophageal anomalies, cerebral palsy) [2]. Esophageal stricture and Barrett’s esophagus; images courtesy of Benjamin D. Gold, MD. References 1. El-Serag HB, Bailey NR, Gilger M, Rabeneck L. Endoscopic manifestations of gastroesophageal reflux disease in patients between 18 months and 25 years without neurological deficits. Am J Gastroenterol 2002;97: 2. Hassall E. Co-morbidities in childhood Barrett’s esophagus. J Pediatr Gastroenterol Nutr 1997;25: Barrett’s Barrett’s Normal Normal 22

Diagnostic Approach Upper GI Radiography
Advantage Useful for detecting anatomic abnormalities Limitation Cannot discriminate between physiologic and nonphysiologic GER episodes Upper GI (or barium contrast) radiography cannot discriminate between physiologic and nonphysiologic GER episodes. The brief duration of the upper GI series results in false-negative findings, while the frequent occurrence of non-pathologic reflux results in false-positive findings. Therefore, it is not a reliable diagnostic test for GERD. An upper GI series is useful for ruling out anatomic disorders that may present similarly to GERD. In the vomiting infant, for example, contrast radiography can detect an anatomic abnormality such as an esophageal or antral web, malrotation, or pyloric stenosis. Disorders of esophageal motility, such as achalasia, may also be detected. In the infant or child with recurrent pneumonia, aspiration during swallowing or a tracheoesophageal fistula may be detected. Complications of GER occasionally are detected by barium contrast radiography, such as esophageal stricture or severe esophagitis with thickening of the esophageal mucosa. Barium flowing retrograde from stomach into esophagus; x-ray courtesy of APHS Inc. 23

Pyloric stenosis Malrotation
An upper GI series is useful for detecting anatomic abnormalities such as a malrotation or pyloric stenosis. In this slide, the upper GI series at left revealed pyloric stenosis (shown by arrow) in a 10-week-old boy with an 8-week history of non-bilious vomiting. The upper GI series at right was obtained from an 8-year-old child with chronic vomiting and heartburn. The ligament of Treitz does not cross the midline, a picture consistent with intestinal malrotation. Pyloric stenosis (left) and malrotation (right); x-rays courtesy of Harland S. Winter, MD. Pyloric stenosis Malrotation 24

Esophagogastroduodenoscopy (EGD)
Advantages Enables visualization and biopsy of esophageal epithelium Determines presence of esophagitis, other complications Discriminates between reflux and non-reflux esophagitis Limitations Need for sedation or anesthesia Endoscopic grading systems not yet validated for pediatrics Poor correlation between endoscopic appearance and histopathology Generally not useful for extra-esophageal GERD Esophagogastroduodenoscopy (EGD) enables visualization and biopsy of the esophageal epithelium. EGD and biopsy can determine the presence and severity of esophagitis, stricture, and Barrett’s esophagus, as well as exclude other disorders, such as eosinophilic or infectious esophagitis. Limitations include the need for sedation or anesthesia. Grading systems for the severity of erosive esophagitis, such as the Los Angeles classification [1], have not yet been validated in pediatric patients. There is a poor correlation between endoscopic appearance and histopathology. Therefore, esophageal biopsy is recommended when diagnostic endoscopy is performed. In general, EGD is not useful for extraesophageal manifestations of GERD. Hetzel-Dent grade 4 erosive esophagitis; endoscopic view courtesy of Benjamin D. Gold, MD. Reference 1. Lundell LR, Dent J, Bennett JR, et al. Endoscopic assessment of oesophagitis: clinical and functional correlates and further validation of the Los Angeles classification. Gut 1999;45: 25

Esophageal pH Monitoring
Advantages Detects episodes of reflux Determines temporal association between acid GER and symptoms Limitations Cannot detect nonacidic reflux Cannot detect GER complications associated with “normal” range of GER Not useful in detecting association between GER and apnea unless combined with other techniques Esophageal pH monitoring measures the frequency and duration of acid reflux episodes and is used widely as an index of esophageal acid exposure. It is useful for establishing the presence of abnormal acid reflux, for determining whether there is a temporal association between acid reflux and frequently occurring symptoms, and for assessing the adequacy of dosage of histamine-2 receptor antagonist (H2RA) or proton pump inhibitor (PPI) in unresponsive patients. It may be used to determine if a patient is at increased risk for airway complications of GER. This test cannot detect non-acidic reflux episodes, such as occur postprandially in infants, or GER complications such as an apparently life-threatening event (ALTE) or aspiration pneumonia when they are associated with brief reflux episodes that are within the range of “normal” GER. Esophageal pH monitoring is useful for detecting apnea only if performed simultaneously with measurement of respiration and chest wall movement. 26

Multiple Intraluminal Electrical Impedance Measurement
Advantages Detects nonacidic GER episodes Detects brief (< 15 s) acidic GER episodes Useful for studying respiratory symptoms and GER in infants Limitations Normal values in pediatric age groups not yet defined Analysis of tracings time-consuming Portable device unavailable for outpatient studies pH channel pH 4 Z 1 Impedance channels Multiple intraluminal electrical impedance measurement (IMP) is a research tool developed in the late 1980s. IMP is pH independent, capable of detecting nonacidic as well as acidic GER episodes [1]. Thus, the technique is useful for investigating clinical situations of gastric hypoacidity. IMP may also be useful for describing the physiology of reflux clearance and swallowing. Unlike pH monitoring, IMP can detect postprandial GER episodes, which have a pH>4 because of neutralization by ingested food. IMP also can identify acidic reflux episodes that are too brief (<15 seconds) to be detected on pH monitoring. In infants, nonacidic GER has been documented in association with respiratory symptoms. Studies using IMP have documented a strong temporal association between GER episodes and irregular breathing [2]. Such findings have led investigators to hypothesize that apneic episodes in infants may be caused by “overreaction” of a protective neurorespiratory reflex. There are current limitations to its use [1]: Normal values in pediatric age groups remain to be defined. Software for the analysis of IMP tracings is needed, as manual and visual interpretation is time consuming. A portable recording device is currently unavailable for outpatient studies. Nonacidic GER depicted on IMP tracing. Arrow indicates bolus passage from distal (Z6) to proximal (Z1). Reprinted with permission from Wenzl, 2002 [1]. References 1. Wenzl TG. Investigating esophageal reflux with the intraluminal impedance technique. J Pediatr Gastroenterol Nutr 2002;34:261-8. 2. Wenzl TG, Silny J, Schenke S, Peschgens T, Heimann G, Skopnik H. Gastroesophageal reflux and respiratory phenomena in infants: status of the intraluminal impedance technique. J Pediatr Gastroenterol Nutr 1999;28:423-8. Z 4 27

Non-Acid Reflux 28

History and Physical Exam
Symptoms and signs associated with GER are non-specific i.e. Not all children with GER have heartburn or irritability Conversely, heartburn and irritability can be caused by conditions other than GER Major roles of History/Physical Exam when evaluating GERD To exclude other worrisome disorders that present with vomiting To recognize complications of GERD

Important to Obtain a Feeding and Vomiting History
Feeding and dietary history Amount/frequency (overfeeding) Preparation of formula Recent changes in feeding type or technique Position during feeding Burping Behavior during feeding: choking, gagging, cough, arching, discomfort, refusal Pattern of vomiting Frequency/amount Pain Forceful or not Blood or bile Associated fever, lethargy, diarrhea

History/Physical Examination
Severity of reflux or esophagitis found on diagnostic testing does not directly correlate with symptom severity In infants and toddlers, there is no symptom or group of symptoms that can reliably diagnose GERD or predict treatment response In older children and adolescents, history and physical examination are generally sufficient to reliably diagnose GERD and initiate management Vandenplas Y, Rudolph CD, Di Lorenzo C, et al. Pediatric gastroesophageal reflux clinical practice guidelines: joint recommendations of the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition (NASPHAN) and the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition (ESPGHAN). J Pediatr Gastroesophageal Nutr. 2009;49(4):548–557

Treatment with PPI’s

>11 fold increase in new PPI prescriptions(2002-2009)
A liquid formulation of a PPI saw a 16-fold increase( ) despite the fact that PPI are not FDA approved for use infants 25% of extremely LBW infants discharged on antisecretory meds. Drugs on which most advertising spent: PPI In 2005, PPI sales grossed approx $13 billion in US alone.

21 Preterm neonate mean gestational age 32 weeks.
Twenty-Four Hour Esophageal Impedance-pH Monitoring in Healthy Preterm Neonates: Rate and Characteristics of Acid, Weakly acidic, and weakly alkaline Gastroesophageal Reflux Pediatrics 2006 21 Preterm neonate mean gestational age 32 weeks. Non acid Reflux > acid Median 70 events Majority reached proximal esophagus No difference between healthy and those with cardio respiratory events Twenty-four-hour pH monitoring is used in adults and children for diagnosis of pathologic GER. Abnormal reflux is considered with detection of increased esophageal acid exposure; however, in neonates, relatively few GER episodes cause esophageal acidification to pH <4.6 Although premature infants may have a well-developed capacity to acidify gastric pH to <4, they receive frequent feeds, often every 2 to 4 hours, which can induce a weaker acid secretory response than that observed in older infants and adults.7–9 As a consequence, gastric pH may be >4 for prolonged periods, and reflux of gastric contents might be less acidic or even alkaline. Esophageal impedance monitoring is currently considered the most sensitive technique to detect GER of liquid and/or gas, regardless of its acidity.

Esophageal pH-Impedance Monitoring in Patients With Therapy-Resistant Reflux Symptoms: 'On' or 'Off' Proton Pump Inhibitor? Gerrit J.M. Hemmink, M.D., Albert J. Bredenoord, M.D., Ph.D., Bas L.A.M. Weusten, M.D., Ph.D., Jan F. Monkelbaan, M.D., Robin Timmer, M.D., Ph.D., André J.P.M. Smout, M.D., Ph.D. Disclosures Am J Gastroenterol. 2008;103(10): RESULTS: The total number of reflux episodes and proximal extent were not affected by PPI therapy. On PPI, there were fewer acid reflux episodes while more weakly acidic reflux episodes were identified. Abstract BACKGROUND: In patients with proton pump inhibitor (PPI)-resistant symptoms, ambulatory 24-h pH-impedance monitoring can be used to assess whether a relationship exists between symptoms and reflux episodes. Until now, it is unclear whether combined pH-impedance monitoring in these patients should be performed on or off PPI. METHODS: Thirty patients with symptoms of heartburn, chest pain, and/or regurgitation despite PPI twice daily underwent ambulatory 24-h pH-impedance monitoring twice, once on PPI and once after cessation of the PPI for 7 days. The order of the measurements was randomized. Reflux episodes were identified and classified as acid, weakly acidic, or weakly alkaline reflux. In addition, the symptom association probability (SAP) was calculated for each measurement. RESULTS: The total number of reflux episodes and proximal extent were not affected by PPI therapy. On PPI, there were fewer acid reflux episodes (49 +/- 34 off PPI vs 20 +/- 25 on PPI) while more weakly acidic reflux episodes were identified (24 +/- 17 off PPI vs 48 +/- 31 on PPI). Symptom association analysis identified 15 and 11 patients with a positive SAP in the measurement off and on PPI, respectively, the difference in yield of the SAP not being statistically significant. Eight of the 19 patients who had no symptoms or a negative SAP during measurement on PPI had a positive SAP off PPI therapy. In contrast, only 4 patients with a positive SAP on PPI were missed in the measurement off PPI therapy. CONCLUSIONS: In order to demonstrate or exclude GERD in patients with PPI-resistant symptoms, ambulatory 24-h pH-impedance monitoring should preferably be performed after cessation of PPI therapy because this approach seems to offer the best chance to assess a relationship between symptoms and reflux episodes.

Combined Esophageal Intraluminal Impedance, pH and Skin Conductance Monitoring to Detect Discomfort in GERD Infants Discomfort was significantly associated with reflux events and did not differ between weakly acidic and acid refluxes. The results may raise concerns about the over-prescription use of antacid drugs in the management of gastroesophageal reflux symptoms in infancy. Abstract Background The clinical significance of weakly acidic reflux in infants is unclear. Skin conductance is a novel not-invasive method to evaluate discomfort. The aim of our study was to evaluate reflux-induced discomfort in infants with gastroesophageal reflux disease using simultaneously combined skin conductance and esophageal multichannel intraluminal impedance and pH monitoring. Methodology/Principal Findings Infants with gastroesophageal reflux symptoms were investigated for almost 20 hours divided into 120-second intervals. Temporal relationships between refluxes and discomfort were evaluated calculating the symptom association probability. Twelve infants aged 17–45 days were studied. Out of hours of adequate artifact-free MII/pH and skin conductance monitoring, 584 reflux events were observed; 35.78% were positive for stress, of which 16.27% were acid and 83.73% weakly acidic. A significant association between refluxes and discomfort (p<0.05) was present in all infants. The intervals with reflux events showed increased skin conductance values compared to reflux-free intervals (p<0.001); SC values were similar for acid and weakly acidic reflux events. Conclusion/Signficance Discomfort was significantly associated with reflux events and did not differ between weakly acidic and acid refluxes. Our results may raise concerns about the over-prescription use of antacid drugs in the management of gastroesophageal reflux symptoms in infancy.

PMID: 21946832 [PubMed - indexed for MEDLINE]
Proton pump inhibitor use in infants: FDA reviewer experience. Division of Gastroenterology and Inborn Errors Products, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, MD , USA. The Food and Drug Administration has completed its review of 4 clinical trials evaluating the use of proton pump inhibitors (PPIs) in infants (ages 1 month to <12 months) for the treatment of gastroesophageal reflux disease (GERD) in November 2010. Advisory Committee members agreed that PPIs should not be administered to treat the symptoms of GERD in the otherwise healthy infant without the evidence of acid-induced disease. Use of PPIs should be reserved for infants with an endoscopically documented acid-induced condition such as erosive esophagitis. The risk/benefit relation of administration of PPIs in infants with GER or GERD without a documented acid-induced condition is not favorable because no benefit can be attributed to the PPI. Furthermore, there may be risks associated with long-term PPI use that require further study in this young population PMID: [PubMed - indexed for MEDLINE]

PPIs are not effective in reducing GERD symptoms in infants.
Efficacy of Proton-Pump Inhibitors in Children With Gastroesophageal Reflux Disease: A Systematic Review PPIs are not effective in reducing GERD symptoms in infants. Placebo-controlled trials in older children are lacking. Although PPIs seem to be well tolerated during short-term use, evidence supporting the safety of PPIs is lacking. Pediatrics 2011;127:925–935 abstract INTRODUCTION: Use of proton-pump inhibitors (PPIs) for the treatment of gastroesophageal reflux disease (GERD) in children has increased enormously. However, effectiveness and safety of PPIs for pediatric GERD are under debate. OBJECTIVES: We performed a systematic review to determine effectiveness and safety of PPIs in children with GERD. METHODS: We searched PubMed, Embase, and the Cochrane Database of Systematic Reviews for randomized controlled trials and crossover studies investigating efficacy and safety of PPIs in children aged 0 to 18 years with GERD for reduction in GERD symptoms, gastric pH, histologic aberrations, and reported adverse events. RESULTS: Twelve studies were included with data from children aged 0 –17 years. For infants, PPIs were more effective in 1 study (compared with hydrolyzed formula), not effective in 2 studies, and equally effective in 2 studies (compared with placebo) for the reduction of GERD symptoms. For children and adolescents, PPIs were equally effective (compared with alginates, ranitidine, or a different PPI dosage). For gastric acidity, in infants and children PPIs were more effective (compared with placebo, alginates, or ranitidine) in 4 studies. For reducing histologic aberrations, PPIs showed no difference (compared with ranitidine or alginates) in 3 studies. Six studies reported no differences in treatment-related adverse events (compared with placebo or a different PPI dosage).

PPI The Wolf in Sheep’s clothing

Reported Adverse Events of Acid suppression
1- C. difficile infection 2- Community acquired pneumonia Necrotizing enterocolitis Osteopenia/ osteoporosis Candidemia Infant pneumonia Bacterial Overgrowth Vitamin B12 deficiency Hypomagnesaemia Interstitial nephritis

Pediatrics 2012;129;e40; originally published online December 12, 2011; Salvia, Laura Lega, Francesco Messina, Roberto Paludetto and Roberto Berni Canani Ranitidine is Associated With Infections, Necrotizing Enterocolitis, and Fatal Outcome in Newborns

FDA Drug Safety Communication: Clostridium difficile-associated diarrhea can be associated with stomach acid drugs known as proton pump inhibitors (PPIs) Safety Announcement [ ] The U.S. Food and Drug Administration (FDA) is informing the public that the use of stomach acid drugs known as proton pump inhibitors (PPIs) may be associated with an increased risk of Clostridium difficile–associated diarrhea (CDAD). A diagnosis of CDAD should be considered for patients taking PPIs who develop diarrhea that does not improve. The US Food and Drug Administration has issued alerts that PPIs may increase the rate of osteoporosis-related Other concerns include increased rates of pneumonia, Clostridium difficile infection, and other infections. A prudent approach to managing these concerns in day-to-day practice is required: PPIs, like any other drugs, should be prescribed only if indicated.

New Evidence: PPI Stomach Acid Drugs Cause Pneumonia Sunday, May 31, 2009 by: S. L. Baker, features writer a new study just published in the Journal of the American Medical Association (JAMA) concludes that by disrupting the body's natural balance, PPIs may cause deadly pneumonia. DO PPIs INCREASE THE RISK OF PNEUMONIA? Several recent studies have also raised concern about an association between PPI use and pneumonia. Normally, the stomach remains free of bacteria (except for Helicobacter pylori) because its acidic milieu destroys nearly all bacteria swallowed. If the stomach becomes less acidic, it loses this protective mechanism, and ingested organisms can survive and proliferate.35 In theory, when gastroesophageal reflux occurs, these bacteria could be carried up to the hypopharynx where microaspiration into the lower airways could lead to pneumonia, especially in patients with compromised oropharyngeal protective reflexes (eg, patients on mechanical ventilation). This possible association came to the attention of the general medical community when a Dutch study,36 in which 5,551 cases of community-acquired pneumonia developed in 364,683 people, found that the incidence of pneumonia was about 4.5 times higher in people exposed to acid-suppressive drugs (both PPIs and histamine-2-receptor antagonists) than in unexposed individuals. Patients who developed pneumonia also had higher odds of significant comorbid conditions, including heart failure and chronic obstructive pulmonary disease. The authors calculated that about one case of pneumonia per 226 patients treated with a PPI would be attributable to the PPI. A major limitation of this study, however, was that only 18% of the patients diagnosed with pneumonia actually had radiologic or microbiologic confirmation of pneumonia. Other studies later examined the relationship between PPIs and community-acquired pneumonia,37–41 and most have revealed a modestly higher risk of community-acquired pneumonia in patients exposed to PPIs. This risk was confirmed in a recent metaanalysis, which found a higher risk of community-acquired pneumonia with PPI use (odds ratio 1.36, 95% CI 1.12–1.65).42 However, the authors refrained from drawing definitive conclusions from these data because of significant heterogeneity between the studies. One study37 found that recent onset of use (within 7 days) had a much stronger association with community-acquired pneumonia than longer-term use, which is contradictory to a causal association, since longer-term use should lead to more cases of pneumonia.

FDA labeling: Possible risk of fracture with PPIs
Based on the data so far, it appears possible that there is a small, albeit statistically significant, association between PPI use and fracture risk. The association is indeed biologically plausible, but it remains to be seen if this association is clinically significant, as the risk is relatively low. Even though the studies had methodologic limitations, on May 25, 2010, the FDA announced a change in the required labeling information for PPIs to indicate a possible risk of fracture with these drugs.34

Proton pump inhibitor side effects and drug interactions: Much ado about nothing?
Ryan D. Madanick, MD, Division of Gastroenterology and Hepatology, University of North Carolina School of Medicine, CB #7080, Chapel Hill, NC 27599;

Available Prokinetic Agents Are Unproven or Ineffective
Cisapride: withdrawn Bethanechol: only 1 randomized controlled trial (RCT) Erythromycin: no RCT Domperidone: available in Canada, no RCT Metoclopramide: Esophageal pH improvement in 1 of 6 RCT Clinical improvement in 1 of 4 RCT High incidence (~30% prevalence) of adverse events The rationale for prokinetic therapy in the treatment of GERD is based on evidence that such medications enhance esophageal peristalsis and accelerates gastric emptying [1]. The only prokinetic agent that has been shown to reduce esophageal acid exposure in children is cisapride, a mixed serotonergic agonist. However, cisapride has been withdrawn and is available in the USA only through a limited-access program to patients for whom other antireflux therapies are ineffective. Studies evaluating bethanechol, a direct cholinergic agonist, and domperidone, a dopamine antagonist available in Canada, have been few and have reported mixed results [1]. Only one randomized controlled trial (RCT) has evaluated bethanechol [2] and no RCTs have evaluated domperidone in pediatric patients with gastroesophageal reflux. Studies with erythromycin have suggested prokinetic effects on the GI tract at doses lower than antimicrobial doses [3]. Erythromycin has been evaluated in various pediatric populations, but no RCT in children with GER has been performed. RCTs have evaluated the efficacy of metoclopramide, an antidopaminergic agent, in children with GER. Esophageal pH improvement was reported in 1 of 6 RCTs; clinical improvement in 1 of 4 RCTs. Use of metoclopramide has been hampered by a high incidence of adverse events, including central nervous system (CNS) effects. References 1. Rudolph C, Mazur LJ, Liptak GS, Baker R, Boyle JT, Colletti RB, Gerson W, Werlin S. Evaluation and treatment of gastroesophageal reflux in infants and children: Recommendations of the North American Society for Pediatric Gastroenterology and Nutrition. J Pediatr Gastroenterol Nutr 2001;32:S1-S31. 2. Euler AR. Use of bethanechol for the treatment of gastroesophageal reflux. J Pediatr 1980;96:321-4. 3. Curry JI, Lander TD, Stringer MD. Review article: erythromycin as a prokinetic agent in infants and children. Aliment Pharmacol Ther 2001;15: Vandenplas Y, Rudolph CD, Di Lorenzo C, et al. Pediatric gastroesophageal reflux clinical practice guidelines: joint recommendations of the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition (NASPHAN) and the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition (ESPGHAN). J Pediatr Gastroesophageal Nutr. 2009;49(4):548–557 46

Increasing Concern about Safety of Prokinetics
Prokinetic Adverse Events Bethanechol Malaise, abdominal cramps, colicky, pain, nausea and belching, diarrhea, urinary urgency; contraindicated in hyperthyroidism, bronchial asthma, and other conditions Domperidone Hyperprolactinemia, dry mouth, rash, headache, diarrhea, nervousness Erythromycin Abdominal pain, nausea, vomiting, diarrhea, pyloric stenosis Metoclopramide Restlessness, drowsiness, fatigue and lassitude (10%); insomnia, headache, confusion, dizziness, mental depression; extrapyramidal reactions including parkinsonian-like symptoms, tardive dyskinesia, and motor restlessness; galactorrhea, gynecomastia, cardiovascular effects, nausea, diarrhea The safety profiles of bethanechol and metoclopramide have limited their use for the treatment of GERD in adults [1]. Bethanechol 25 mg QID has been associated with significant abdominal cramping, blurred vision, fatigue, and urinary urgency [1]. This slide lists adverse reactions reported in the Prescribing Information (PI) for Urecholine® [2]. Bethanechol is contraindicated in hyperthyroidism, bronchial asthma, and other conditions [2]. In adult studies, adverse effects with domperidone, such as prolactinemia, occurred in 10% to 15% of patients [1]. Occasionally, dry mouth, skin rash, headache, diarrhea, and restlessness have been reported [1]. The clinical experience with erythromycin as a prokinetic agent in pediatric patients was recently reviewed [3]. Associated GI side effects include abdominal pain, nausea and vomiting, and diarrhea. Apart from GI side effects, erythromycin is a well-tolerated antibiotic, with few adverse effects in children [3]. Pyloric stenosis has been reported in neonates given antimicrobial doses of erythromycin [3]. No serious adverse effects have been reported in children in association with low-dose erythromycin used for prokinetic effects [3]. Adverse effects associated with metoclopramide include CNS complications, such as parkinsonian reactions and tardive dyskinesia, which may be irreversible. This slide summarizes adverse reactions listed in the Reglan® PI [4]. Strict limitation of dosage is important to prevent extrapyramidal reactions. Irritability and sleep disturbances may result from being administered even a relatively low dose of metoclopramide (0.1 mg/kg QID). References 1. Ramirez B, Richter JE. Review article: promotility drugs in the treatment of gastro-oesophageal reflux disease. Aliment Pharmacol Ther 1993;7:5-20. 2. Prescribing Information for Urecholine® (bethanechol chloride). Odyssey Pharmaceuticals Inc, East Hanover, NJ, revised November 2000. 3. Curry JI, Lander TD, Stringer MD. Review article: erythromycin as a prokinetic agent in infants and children. Aliment Pharmacol Ther 2001;15: 4. Prescribing Information for Reglan® (metoclopramide). AH Robins Company, Richmond, VA, May 17, 2001. Prescribing Information for Reglan® and Urecholine®; Curry JI, Lander TD, Stringer MD. Erythromycin as a prokinetic agent in infants and children. Aliment Pharmacol Ther 2001;15(5):595–603; Ramirez B, Richter JE. Review article: promotility drugs in the treatment of gastro-oesophageal reflux disease Aliment Pharmacol Ther. 1993;7(1):5–20 47

Conservative Therapy for GER
For Infants For Older Children Normalize feeding volume and frequency Consider thickened formula Consider non-prone positioning during sleep Consider trial of hypoallergenic formula Avoid large meals Do not lie down immediately after eating Lose weight, if obese Avoid caffeine, chocolate, and spicy foods that provoke symptoms Eliminate exposure to tobacco smoke Conservative therapy, or lifestyle changes, is recommended for all infants and children with GER irrespective of disease severity. A complete history can reveal provocative aspects of lifestyle, such as huge feedings at infrequent intervals in infants. It is important to normalize feeding volume and frequency. Thickened feedings may be beneficial when regurgitation has resulted in poor weight gain. Prethickened formula may be purchased, or infant formula may be thickened by adding rice cereal. Frequent, smaller feedings are encouraged. There is evidence to support a 1- or 2-week trial of a hypoallergenic formula in formula-fed infants with vomiting. Positioning therapy is a traditional part of antireflux management. Supine positioning confers the lowest risk for SIDS, and non-prone positioning during sleep is recommended. For older children, conservative therapy is similar to recommendations for adults: Avoid large meals, and do not lie down immediately after eating. Lose weight if obese; a recent study confirmed that obesity is a strong risk factor for reflux disease [1]. Avoid caffeine, chocolate, and spicy foods that provoke symptoms. Eliminate exposure to tobacco smoke. Reference 1. Locke GR III, Talley NJ, Fett SL, Zinsmeister AR, Melton LJ III. Risk factors associated with symptoms of gastroesophageal reflux. Am J Med 1999;106:642-9. 48

Efficacy of conservative therapy as taught in the primary care setting for symptoms suggesting infant gastroesophageal reflux. Orenstein SR, McGowan JD. Source University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA. Abstract OBJECTIVE: To determine the efficacy of non-pharmacologic conservative therapy for infant gastroesophageal reflux disease (GERD). STUDY DESIGN: Consenting parents of the first 50 screened infants who met inclusion/exclusion criteria including abnormal (>16/42) scores on the Infant Gastroesophageal Reflux Questionnaire-Revised (I-GERQ-R; n = 40) were taught conservative therapy measures by each site's study nurse: feeding modifications, positioning, and tobacco smoke avoidance. We compared I-GERQ-R scores and symptom response details before and 2 weeks after institution of these measures with 2-tail Wilcoxon signed ranks test in the 37 infants (age range, 4-43 weeks; median age, 13 weeks) who completed the run-in. RESULTS: The median initial and final scores were 23 (16-36) and 18 (7-34; P < ). The median score change was -5 (+6--16). Scores of 78% improved at all; 59% improved at least the threshold of 5 points; 24% became normal. Scores for individual symptoms related to regurgitation, crying, and arching improved significantly. CONCLUSIONS: Two weeks of conservative therapy measures taught in primary care improved 59% beyond the 5-point threshold and normalized 24% of infants with symptom severity diagnostic for GERD, as substantiated with a responsiveness-validated instrument.

Thickened formula Unthickened formula
In the USA, thickening is usually achieved with the addition of rice cereal to formula. If an infant formula has a caloric density of 20 kcal per ounce, the addition of 1 tablespoonful of rice cereal per ounce of formula increases the caloric density to about 34 kcal per ounce [1]. This slide contrasts ready-to-use milk-based infant formula and the same formula thickened with dry rice cereal (1 tablespoonful per fluid ounce of formula). Reference 1. Rudolph C, Mazur LJ, Liptak GS, Baker R, Boyle JT, Colletti RB, Gerson W, Werlin S. Evaluation and treatment of gastroesophageal reflux in infants and children: recommendations of the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition. J Pediatr Gastroenterol Nutr 2001;32:S1-31. Unthickened formula 50

Thickening a 20Kcal/oz infant formula with
1 Tbp/2oz kcal/oz 1Tbp/1oz kcal/oz

Effect of Thickening Milk Formula Feedings With Rice Cereal
Unthickened Thickened n=20 p=.015 p=.026 p=.042 Infants with regurgitation may benefit from thickening of milk formula with rice cereal. This slide summarizes a study in 20 infants with GER who were observed after a pair of feedings, once with radiolabeled infant formula and once with radiolabeled formula thickened with dry rice cereal [1]. Thickening resulted in a decrease in the number of episodes of emesis, an increase in sleep time, and reduction in crying time. Reports of the effect of thickened feedings on the incidence of reflux and other esophageal acid parameters have been inconsistent [2, 3]. References 1. Orenstein SR, Magill HL, Brooks P. Thickening of infant feedings for therapy of gastroesophageal reflux. J Pediatr 1987;110:181-6. 2. Bailey DJ, Andres JM, Danek GD, Pineiro-Carrero VM. Lack of efficacy of thickened feeding as treatment for gastroesophageal reflux. J Pediatr 1987;110:187-9. 3. Vandenplas Y, Belli D, Cadranel S, Cucchiara S, Dupont C, Heymans H, Polanco I. Dietary treatment for regurgitation—recommendations from a working party. Acta Paediatr 1998;87:462-8. Caloric Density (cal/cc) Emesis (episodes/90 min) Sleep Time (min asleep/90 min) Crying Time (min crying/90 min) Adapted from Orenstein SR, Magill HL, Brooks P. Thickening of infant feedings for therapy of gastroesophageal reflux. J Pediatr. 1987;110(2):181–186 52

Positioning and GER Sitting Supine Prone 60°
The effects of prone and supine positioning, as well as sitting, on the air-fluid interface in an infant’s stomach are illustrated in this slide [1]. The propensity to reflux is greatest when the gastroesophageal junction is below the air-fluid interface. Reference 1. Ramenofsky ML, Leape LL. Continuous upper esophageal pH monitoring in infants and children with gastroesophageal reflux, pneumonia, and apneic spells. J Pediatr Surg 1981;16:374-8. Supine Adapted from Ramenofsky ML, Leape LL. Continuous upper esophageal pH monitoring in infants and children with gastroesophageal reflux, pneumonia, and apneic spells. J Pediatr Surg. 1981;16(3):374–378 Prone 53

Effect of Sleep Position on GER in Infants and Sudden Infant Death Syndrome (SIDS) Mortality
Reflux Index1 (% time pH <4) SIDS Mortality2 (per 1000 live births) Reflux Index Odds Ratio SIDS Mortality Odds Ratio3 Supine * Left side * † Right side * † Prone Clinicians must decide whether the benefits of strategies to reduce the risk of GER are outweighed by the potential for an increased risk of SIDS. In most cases, the risk of SIDS outweighs the benefits of prone positioning. The effects of sleep position on GER in infants and mortality from SIDS have been quantified. In a study of 24 infants younger than 5 months of age [1], the prone and left-side (left lateral) positions were most effective in reducing the reflux index (percent of time esophageal pH <4). However, based on an analysis of data from a population-based case reference study [2], the SIDS mortality rate associated with sleeping prone was 4.4 per 1000 live births, compared with 0.05 per 1000 live births for supine and lateral sleeping positions combined. In terms of odds ratios, sleeping supine was 2.3 times more likely than sleeping prone to induce GER, while a right-sided sleep position was 1.8 times more likely than a prone position to induce GER [1]. These effects must be weighed, however, against odds ratios for SIDS mortality of 13.9 with prone positioning and 3.5 for side-sleeping, when compared with supine positioning [3]. Other studies have supported the avoidance of prone positioning during sleep. In a trial from New Zealand [4], the relative risk for SIDS with sheepskin use was significantly increased in infants placed prone to sleep (odds ratio, 1.70) but not in infants placed supine or laterally (odds ratio, 0.82). In California, the SIDS rate declined from 1.2 to 0.7 per 1000 live births in the first five years after a public health campaign (“Back to Sleep”) to reduce prone sleeping [5]. Data suggest that airway protection is compromised in the prone position during active sleep [6]. References 1. Tobin JM, McCloud P, Cameron DJS. Posture and gastro-oesophageal reflux: a case for left lateral positioning. Arch Dis Child 1997;76:254-8. 2. Skadberg BT, Morild I, Markestad T. Abandoning prone sleeping: effect on the risk of sudden infant death syndrome. J Pediatr 1998;132:340-3. 3. Oyen N, Markestad T, Skjaerven R, Irgens LM, Helweg-Larsen K, Alm B, Norvenius G, Wennergren G. Combined effects of sleeping position and prenatal risk factors in sudden infant death syndrome: the Nordic Epidemiologic SIDS Study. Pediatrics 1997;100: 4. Mitchell EA, Thompson JMD, Ford RPK, Taylor BJ. Sheepskin bedding and the sudden infant death syndrome. J Pediatr 1998;133:701-4. 5. Adams EJ, Chavez GF, Steen D, Shah R, Iyasu S, Krous HF. Changes in the epidemiologic profile of sudden infant death syndrome as rates decline among California infants: Pediatrics 1998;102: 6. Jeffery HE, Megevand A, Page M. Why the prone position is a risk factor for sudden infant death syndrome. Pediatrics 1999;104:263-9. *Mortality rate for all non-prone positions combined †Combined odds ratio 1 Tobin JM, McCloud P, Cameron DJ. Posture and gastro-oesophageal reflux: a case for left lateral positioning. Arch Dis Child. 1997;76(3):254–358 2 Skadberg BT, Morild I, Markestad T. Abandoning prone sleeping: Effect on the risk of sudden infant death syndrome. J Pediatr. 1998;132(2):340–343 3 Oyen N, Markestad T, Skaerven R, et al. Combined effects of sleeping position and prenatal risk factors in sudden infant death syndrome: the Nordic Epidemiological SIDS Study. Pediatrics. 1997;100(4):613–621 54

Allergic gastroenteropathy in preterm infants
Allergic gastroenteropathy in preterm infants. D'Netto MA, Herson VC, Hussain N, Ricci A Jr, Brown RT, Hyams JS, Justinich CJ. Division of Neonatology, Department of Pediatrics, Connecticut Children's Medical Center, Hartford, CT 06106, USA. Abstract OBJECTIVES: To determine the clinical presentation, histopathologic features, and outcome of biopsy-proven allergic gastroenteropathy (AGE) in preterm infants. We hypothesized that AGE is a more frequent cause of gastrointestinal disease in this population than previously suspected. STUDY DESIGN: The retrospective portion of the study, from 1992 to 1997, included preterm infants <37 weeks' gestation who underwent biopsy because of suspected AGE. The prospective portion, from January to December 1998, included 20 infants undergoing endoscopy and biopsy because of suspected AGE. RESULTS: Twenty-five infants (12 retrospective/13 prospective) with mean gestational age of 29 weeks at birth and mean postnatal age at diagnosis of 78 days were diagnosed with AGE. Three clinical patterns of presentation were noted: group 1, gastroesophageal reflux disease (n = 5); group 2, non-specific feeding intolerance (n = 8); and group 3, lower gastrointestinal bleeding (n = 12). Ten patients had negative biopsy findings (3 retrospective/7 prospective) and had clinical features indistinguishable from those of groups 1 and 2. Patients in group 3 were most likely to have positive biopsy findings (12 of 12). Fifteen patients responded to a casein hydrolysate formula, and 10 patients required an amino acid-based formula. Patients with AGE who had eosinophilic infiltration and villous atrophy took longer to recover than those with eosinophilic infiltration alone (P <.03). Subsequently, most have tolerated formula challenges and are currently tolerating cow's milk. CONCLUSIONS: AGE may be an under-recognized cause of gastrointestinal symptoms in preterm infants. Confirmation with endoscopy and biopsy can be done safely and provides the basis for appropriate dietary management. J Pediatr Oct;137(4):480-6

Cow’s Milk Allergy -Symptoms may be identical to GERD -Atopic families -Eczema -History of crying when swallowing -2week trial with hydrolysate formula

Conclusions It is important to clarify whether a pediatric patient has physiologic GER or pathologic GERD There are guidelines for appropriate testing and treating of children with reflux disease…

Recommended Approach to the Infant With Recurrent Regurgitation and Vomiting
Vandenplas Y, Rudolph CD, Di Lorenzo C, et al. Pediatric gastroesophageal reflux clinical practice guidelines: joint recommendations of the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition (NASPHAN) and the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition (ESPGHAN). J Pediatr Gastroesophageal Nutr. 2009;49(4):548–557

Recommended Approach to the Infant With Recurrent Regurgitation and Weight Loss

GERD in older Children Heartburn, epigastric pain, and regurgitation
Explore lifestyle in adolescents – cigarettes, alcohol.. PPI if symptoms are typical and the child is old enough to express the symptoms - 2,4 weeks and if symptoms resolve continue and stop in 3 months - wean off PPI

Recommended Approach to the Older Child or Adolescent With Heartburn

Special thanks to Dr. Manal Darwish
Thank you Special thanks to Dr. Manal Darwish

Gastroesophageal Reflux in infants & Proton Pump Inhibitors

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