Blaming Reflux for BRUEs -Not Changing Despite Guideline Recommendations

Briefly noted: DR Duncan et al. J Pediatr 2019; 211: 112-9.

In this retrospective cohort study of infants with brief resolved unexplained events (BRUEs) at Boston Children’s Hospital, the authors examined guideline implementation among 359 subjects in the year before and the year after AAP guidelines.

Key findings:

  • There were no significant changes in practice after guideline publication
  • Only 13% had videofluoroscopic swallow study performed; 72% of these showed aspiration/penetration
  • No subject had reflux testing, “yet reflux was implicated as the cause” for BRUE in 40%. Children continued to be “discharged on acid suppression despite lack of efficacy”

My take: The pendulum is (slowly) starting to swing back from blaming everything (including BRUEs) on reflux but this change is not evident in this study.

Related blog posts:

Which Symptom is Best for Indicating Reflux in Infants?

A recent study (CR Collins et al. J Pediatr 2019; 206; 240-7) showed that symptoms alone are not able to predict the degree/presence of reflux in infants.

Methods: The authors recruited ‘symptomatic’ infants with median 41 weeks postmenstrual age (median 29 weeks at birth) and employed a combination of 24-hour pH-impedance to determine acid reflux index (ARI) and subsequently used provocative esophageal infusions (with air, water then apple juice) to assess manometry and symptoms. In total, they analyzed 2635 separate esophageal stimula in 74 infants.

The authors considered ARI <3% as normal, 3-7% as indeterminate ARI, and >7% as abnormal ARI.

Symptoms that they recorded included arching, irritability, cough, gag, sneeze, gasp, bradycardia, desaturation, throat clearing, startle, grimace, grunting, mouthing, and yawning.

Key findings:

  • “The presence of physical symptoms (ARI <3: 80%; ARI 3-7: 77%; ARI >7: 81%; P=0.4), cardiorespiratory symptoms (ARI <3: 27%; ARI 3-7: 40%; ARI >7: 26%; P=0.4),or sensory symptoms (ARI <3: 26%; ARI 3-7: 22%; ARI >7: 35%; P=0.3) were also not significantly different by ARI groups”
  • All infants had a normal symptom index (SI) for acid, nonacid, or total reflex.
  • Accepted metrics, SI, SSI, and SAP, had higher association with nonacid events compared with acid events.
  • Cardiorespiratory symptoms are more likely to be elicited by esophageal infusions with both water and apple juice than air.  “Symptoms are indicators of esophageal dysmotility and maladaptive aerodigestive protective mechanisms.”
  • The authors in their discussion state that “GERD severity plays no role in the generation of symptoms.”

My take: All infants with and without reflux have a lot of “symptoms.”  Nonacid reflux is much more likely to provoke symptoms in this population than acid reflux reinforcing the idea that acid suppression is likely ineffective and potentially harmful.  “The findings of this study challenge the rationale for instituting anti-GERD therapies in neonates based on either symptoms alone or the existing acid-reflux indices or pH-impedance metrics.”

Related blog posts:

Link to article cited below from The Onion: Dog Feels Like He Always Has To Be ‘On’ Around Family Thanks to Jennifer for this reference.

Disclaimer: These blog posts are for educational purposes only. Specific dosing of medications/diets (along with potential adverse effects) should be confirmed by prescribing physician/nutritionist.  This content is not a substitute for medical advice, diagnosis or treatment provided by a qualified healthcare provider. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a condition.


Do Acid Blockers Given to Infants Increase the Risk of Allergic Disease?

A recent retrospective study (Mitre E, et al. JAMA Pediatr. 2018;doi:10.1001/jamapediatrics.2018.0315) suggests that acid blockers, both histamine receptor antagonists and proton pump inhibitors increase the risk of developing allergic disease.  Since this is a retrospective study, this association with allergic diseases has NOT been proven to have a causal relationship; thus, an alternative explanation would be that infants who are likely to develop allergic diseases could be prescribed these agents more frequently due to symptoms attributed to reflux.

Here is an excerpt from a summary of this study (from Healio):  Acid-suppressor, antibiotic use in infancy tied to later allergic disease

Of the 792,130 children included in the study (49.9% female), 7.6% were prescribed a histamine-2 receptor antagonist (H2RA) and 1.7% were prescribed a proton pump inhibitor (PPI) within the first 6 months of life. Antibiotics also were prescribed for 16.6% of infants included in the study during this time. Mitre and colleagues noted that data continued to be collected on these infants for a median of 4.6 years…

When children were prescribed an H2RA, the researchers noted adjusted HRs of 2.18 (95% CI, 2.04-2.33) for food allergy, 1.70 (95% CI, 1.60-1.80) for medication allergy, 1.51 (95% CI, 1.38-1.66) for anaphylaxis, 1.50 (95% CI, 1.46-1.54) for allergic rhinitis and 1.25 (95% CI, 1.21-1.29) for asthma.

Infants who were prescribed PPIs had comparable aHRs, which the researchers observed at 2.59 (95% CI, 2.25-3.00) for food allergy, 1.84 (95% CI, 1.56-2.17) for medication allergy, 1.45 (95% CI, 1.22-1.73) for anaphylaxis and 1.44 (95% CI, 1.36-1.52) for asthma.

Mitre and colleagues also calculated the aHRs related to later allergic disease in children who were prescribed antibiotics within the first 6 months of life. They observed these rates at 2.09 (95% CI, 2.05-2.13) for asthma, 1.75 (95% CI, 1.72-1.78) for allergic rhinitis, 1.51 (95% CI, 1.38-1.66) for anaphylaxis and 1.42 (95% CI, 1.34-1.50) for allergic conjunctivitis.

My take: This study is another reminder that these agents may be more detrimental than beneficial in the vast majority of infants.

Related blog post:

Better to Do a Coin Toss than an ENT Examination to Determine Reflux

A recent study (R Rosen et al. J Pediatr 2017; 183: 127-31) adds additional data to the literature which has shown that ENT doctors are NOT able to tell if there is reflux by examining the airway.

Prior post on this topic: Accuracy of ENT diagnosis of Reflux Changes

This prospective, cross-sectional cohort study of 77 children correlated ENT examinations with “reflux finding score” (RFS) by three blinded otolaryngologists with objective measures of reflux: pH-metry and impedance.  All children had chronic cough and underwent bronchoscopy and esophagogastroduodenoscopy.

Key findings:

  • “There was no correlation between pH-MII variables and mean RFS”
  • The concordance correlation for RFS between ENT doctors was low (intraclass correlation coefficient =0.32)
  • Using pH-metry as a gold standard, the positive predictive value for the RFS was 29% whereas with MII as the gold standard, the positive predictive value for the RFS was 40%.

My take: ENT doctors are unable to tell if a patient has reflux.  The finding of a red or swollen airway has poor predictive value in determining the presence of reflux –a coin toss is more reliable.  Based on this study and others, starting a PPI because of an abnormal airway exam does not make sense.

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Monet, Musee de l’Orangerie

Update on Chronic Cough

It is not uncommon for a pediatric gastroenterologist to see a patient with a chronic cough due to concerns about potential gastroesophageal reflux disease (GERD).  As such, a recent clinical practice article (JA Smith, A Woodcock. NEJM 2016; 375: 1544-51) by lung specialists was of interest, even though this article was not targeted to the pediatric population.

Key points:

  • The authors define a chronic cough as lasting more than 8 weeks and note that it common with respiratory conditions (eg. chronic obstructive pulmonary disease, asthma, and bronchiectasis) and some non-respiratory conditions (eg. gastroesophageal reflux and rhinosinusitis).  Medications, particularly ACE inhibitors, can trigger a chronic cough as well.
  • Steps in evaluation: 1. H&P, CXR, spirometry. 2. Consider metacholine challenge, ENT evaluation, consider empiric treatment (eg. inhaled glucocorticoids, PPI), and consider GERD evaluation. 3. High-resolution CT and bronchoscopy.
  • For many patients, there is likely to be an abnormality in neuronal pathways controlling cough and the term “cough hypersensitivity syndrome” has been coined.  Figure 2 (below) illustrates the neuronal pathways.
  • For refractory patients, potential therapies would include low-dose morphine, gabapentin or pregabalin, and speech language therapy.



  • Guidelines “suggest a trial of treatment with acid-suppression therapy” (eg. twice-daily PPIs for up to 3 months).
  • “Most randomized, controlled trials of reflux treatment for cough have not shown a significant improvement in association with this type of treatment.”
  • Subgroups of patients with heartburn, regurgitation, or excessive acid reflux on esophageal pH monitoring “appeared marginally more likely to have a response to PPI treatment.”  pH or impedance tests “are poorly predictive of a response of cough to acid suppression.”

My take: In the absence of clinical reflux, reflux therapy is unlikely to help with chronic cough.  However, in patients with an adequate workup, an empiric course of a PPI is likely more preferable than empiric morphine or gabapentin.

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Guidelines for Esophageal Atresia-Tracheoesophageal Fistula

From a NASPGHAN-ESPGHAN working group of surgeons and pediatric gastroenterologists. a recent guideline (U Krishan et al JPGN 2016; 63: 550-70) regarding esophageal atresia (EA) and tracheoesophageal fistula (TEF) has made 36 specific statements and graded the evidence for these recommendations.


  • Low level evidence: The authors recommended starting PPIs in the neonatal period and continuing them “up to the first year of life or longer, depending on persistence of GERD.”
  • High level evidence: pH monitoring is useful in evaluating the severity of acid reflux in patients with EA.  Low level evidence: pH-impedance monitoring is useful to evaluate and correlate non-acid reflux in selected patients.
  • High level evidence: “Endoscopy with biopsies is mandatory for routine monitoring of GERD in patients with EA.” The authors recommend evaluation (pH, impedance, and/or endoscopy) at time of stopping anti-acid treatment and during long-term follow-up. Specifically,  with low level of evidence, the authors advocate for one endoscopy after stopping PPI therapy, one before age 10 years, and one at transition to adulthood.”
  • High level evidence: Fundoplication has accepted role, despite dysmotility, in patients with recurrent anastomotic strictures and poorly controlled GERD despite maximal PPI therapy. Full evaluation prior to fundoplication is recommended.

Other Statements:

  • Low level evidence: the authors recommend regular multidisciplinary evaluation, the authors note that symptoms of aspiration during swallowing may be identical to GERD symptoms, and evaluation of dysphagia with EGD/UGI.
  • High level evidence: ENT evaluation may disclose other anatomic abnormalities
  • Low level evidence: The authors recommend that anastomotic strictures be excluded in symptomatic children and that there is no “evidence that routine screening and dilatation” is necessary in asymptomatic patients.
  • Low level evidence: Management of EA patients with eosinophilic esophagitis (EoE) should follow the treatment of EoE in non-EA patients.
  • High level evidence: Incidence of Barrett’s esophagus is increased in adults with EA.
  • No level evidence: Potential treatments for recurrent strictures: steroids, mitomycin C, stents, and endoscopic knife.

While some these recommendations noted above are based on low level evidence, it is worthwhile for experts to provide their opinions.  At the same time, there are some completely useless statements included in the guidelines, like those that suggest tailoring the treatment to the underlying problem.  For example: “Statement 19: We recommend tailoring management of post-fundoplication dysphagia to the underlying mechanism(s).”  Another useless statement: “Statement 21: No data are available on the most efficacious methods of avoiding feeding disorders in children with EA. However, the committee recommends a multidisciplinary approach to prevent and treat feeding difficulties.” (very low level evidence).  In my view, shortening the number of recommendations, mainly by eliminating the useless ones, would have been helpful.

My take: Despite my view that about 20% of the recommendations are useless (Statements 17, 19, 21, 25, 26A & 26B, 31, and 34), the overall guideline is helpful and it is still worthwhile for experts to provide their recommendations.

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Rockland Harbor Lighthouse

Rockland Harbor Lighthouse

How often are acid blockers used in neonates?

A recent study (JL Slaughter et al. J Pediatric 2016l 174: 63-70) shows a high rate of acid blockers in neonatal intensive care units.  This study retrospectively analyzed the Pediatric Health Information System database (PHIS) from 2006-2013.

  • Of 122,0002 infants: 23.8% received either a histamine-2-receptor antagonist (H2RA) or proton pump inhibitor (PPI).
  • 19.0% had received an H2RA
  • 10.5% had received a PPI

My take (borrowed from authors): “despite limited evidence and  increasing safety concerns, H2RAs/PPIs are frequently prescribed to extremely preterm neonates…Our findings support the need for innovative studies.”  Wouldn’t it be nice if there was proof of efficacy in this population?

Vickery Creek, Roswell

Vickery Creek, Roswell