Tag Archives: GERD

Will This Change ALTE-GERD Practice?

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This blog has highlighted several publications which have shown the lack of benefit and potential harm of pharmaceutical agents for gastroesophageal reflux “disease” (GERD) in infancy (see links below). However, in current practice, proton pump inhibitors and histamine receptor antagonists are used frequently.  Now, another influential study (J Pediatr 2014; 165: 250-5) has shown the lack of GERD as a causal mechanism in acute life-threatening events (ALTEs) and demonstrated other pathophysiologic mechanisms. However, changing physicians’ practice in this regard may prove to be as difficult as avoiding overprescribing antibiotics, or convincing reluctant parents to vaccinate their children.

So what did this study show?

This study of 20 infants (10 with proven ALTE and 10 healthy controls) had pharyngoesophageal manometry.  Key findings:

  • Infants with ALTE (vs controls) had delays in restoring aerodigestive normalcy (P=.03).  This was indicated by more frequent and prolonged spontaneous respiratory events (SREs)
  • Infants with ALTE had a lower magnitude of protective upper esophageal sphincter contractile reflexes (P=.01)
  • Infants with ALTE had swallowing as the most frequent esophageal event associated with SREs (84%), a higher proportion of failed esophageal propagation (10% vs 0%, P=.02), an more frequent mixed apnea mechanisms (P=<.01) along with gasping breaths (P=.04)

The associated editorial (pg 225-26) explains some of the limitations of the study, including the fact that the patients had a mean gestational age of 28 weeks.

The authors conclusion: “In infants with ALTE, prolonged SREs are associated with ineffective esophageal motility ,,,suggestive of dysfunctional regulation of swallow-respiratory junction interactions.  Hence, treatment should not target gastroesophageal reflux, but rather the proximal aerodigestive tract.”

Take-home message: (from the editorial): “Far too many low birth weight (and term) infants are being unnecessarily treated with a variety of antireflux medications that have serious side effects and few, if any, demonstrable benefits.”

Related blog posts:

“If You Never Give Up, You Cannot Possibly Lose”

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Recently I was reviewing the “Black Knight scene” from Monty Python’s Holy Grail.  This scene in which the Black Knight continues to insist on fighting King Arthur even after losing all of his limbs came to mind as I was reading a recent study (JPGN 2014; 58: 226-36).  The blog title comes from an explanation of the scene from John Cleese who intended the scene to mock this philosophy. (Wikipedia link: Black Knight (Monty Python) – Wikipedia, the free encyclopedia)

The study is another trial of a proton pump inhibitor (rabeprazole) for 1- to 11-month old infants with symptomatic GERD.  In the discussion the authors note that this is the “fourth DB randomized placebo-controlled study published in the last 4 years that fails to show the efficacy of PPIs to treat symptomatic GERD in infants younger than 1 year.”

If anything, the design of this study should have allowed a therapeutic effect to be witnessed if present.  Infants selected for participation (n=268 in the double-blind phase) had been responsive to a 10 mg open-label usage of rabeprazole before randomization.  Yet, those infants who continued to receive 5 mg or 10 mg daily fared no better than placebo-treated patients.

The good news: no new safety signals in those who were treated compared to placebo.

The findings of this study are in marked distinction to clinical practice which has embraced PPIs in all age groups. In the same issue of JPGN, using a national database, De Bruyne et al (JPGN 2014; 58: 220-25) show a huge increase in PPI usage over the past decade in the Netherlands, especially in children ages 2 years and younger.  From 2004 to 2008, use of PPIs nearly doubled in this population.

The rabeprazole study manuscript which had nearly as many pediatric GI investigators as enrolled patients discusses the potential drawbacks of PPI therapy in infants including enteric infections like Clostridium difficile, lower respiratory infections (e.g.. pneumonia), and “perhaps even an increased incidence of necrotizing enterocolitis in premature infants.”  Unlike the Black Knight, after four blows to the PPI cause, the authors recommend yielding on PPIs except under much more stringent criteria (1 of 3):

  • Nonimproving symptoms at 1 year of age & resistant to conservative measures
  • Presence of underlying conditions that predispose to a natural history of severe chronic unremitting reflux
  • Erosive reflux esophagitis proven on endoscopy

Take-home message: PPIs have not been shown to be effective in infants…again!

Related blog posts:

Even the Experts Agree: pH-MII is a “Flawed Test”

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A recent study (JPGN 2014; 58: 22-26) reports on the combination of a new technique of intraesophageal pressure recording (IEPR) along with multichannel intraluminal impedance with pH (pH-MII).  While this prospective study is small with only 20 children who had a history of chronic intractable cough, some of its observations are important, especially for those who have embraced pH-MII.

In determining whether the pH-MII studies were abnormal the authors relied on symptom index (SI) defined as the number of symptoms associated with reflux/total number of symptoms.  SI is considered positive if >50%.  In addition, the authors calculated the symptoms sensitivity index (SSI) which is defined as the total number of reflux episodes associated with symptoms/total number of reflux episodes; it is considered positive if it is >10%.  The authors note SAP and SI have a comparable positive predictive value and “our experience suggests that SAP calculation using software is unreliable.”

Key Results/Discussion:

  • IEPR changed the diagnosis in 15-20% of patients depending of scoring index used.  That is, IEPR assisted the detection of reflux-associated cough.
  • IEPR detected 106% more coughs than patient report alone.  Thus, this study, if accurate, indicates that “symptom reporting during pH or pH-MII testing is significantly flawed and, if possible, should not be used alone for clinical decision making.”
  • “We did not find a significant association between cough production and the height of the refluxate.”
  • The authors argue that since nonacid reflux can be associated with cough and is not always detected with pH-MII, that this could “explain why studies that have tried to use pH criteria to predict clinical outcome after acid suppression therapy have been negative.”  The two studies cited at that point by the authors were landmark studies (referenced below) showing that proton pump inhibitors are not effective in children or adults in improving asthma.  I think the authors’ comment misses the importance of these studies entirely.  There are no proven effective GERD (acid or nonacid) therapies that alter the course of asthma.

Take-home message from authors: “Studies are now needed to determine whether this increased detection improves therapeutic outcomes, but clearly, relying on symptom reporting by patients is flawed and clinical decision making based on patient report alone should be done with caution.”

Referenced studies:

  • JAMA 2012; 307: 373-81
  • NEJM 2009; 360: 1487-99

Related blog posts:

‘Little’ Knowledge Exists Regarding Medicines for Neonates

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Despite federal legislation encouraging the study of products used in the pediatric population, very little of these studies has translated into meaningful information regarding neonates (JAMA Pediatr 2014; 168: 130-36, thanks to Ben Gold for this reference).

This publication reviewed studies submitted to the FDA between 1997-2010.  The authors identified all drugs with pediatric studies that included neonates.  Subsequently, the use of these drugs was examined in a oohort of neonates admitted to 290 neonatal intensive care units (NICU) (Pediatrix Data Warehouse) in the U.S. form 2005-2010.

Key findings:

  • 28 drugs (in 41 studies) were examined in neonates. This led to 24 labeling changes.
  • 11 of 24 neonatal labeling changes included an approval for use in neonates, including 4 for HIV and 3 for anesthesia.
  • 13 of 24 labeling changes were the following: “safety and effectiveness have not been established.”  These drugs included several reflux medications: esomeprazole, lansoprazole, pantoprazole, and ranitidine.
  • In the Pediatrix database involving 446,335 hospitalized neonates, there were 399 different drugs identified that had been administered.  Of the 28 studied drugs, the gastroesophageal reflux medicines were used most frequently.  13 of the 28 studied drugs were not used at all in the NICUs.
  • Of the 11 drugs with a neonatal indication, 7 were never used in the Pediatrix neonatal population and the other 4 drugs were used infrequently.

Conclusions:

  • Neonates are a vulnerable and an understudied population
  • Most of the exposure to drugs was off-label for neonates.
  • Most often, off-label drugs were prescribed “despite studies indicating they were not effective…For example, ranitidine, lansoprazole, and inhaled nitric oxide (for the prevention of bronchpulmonary dysplasia) were the top 3 drugs used in neonates…none have FDA labelling for the indication studied because of lack of efficacy.”
  • Furthermore, drugs like ranitidine and lansoprazole” are associated with serious adverse effects in neonates.” (Clin Perinatol 2012; 39: 99-109)

Related blog entries:

Expert Commentary on GERD Surgery in Infants

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In this month’s “GI & Hepatology News,” Dr. Ben Gold and Dr. Jose Garza comment on antireflux surgery in infants (page 12) (related article on page 1 of same issue). Initial reference: JAMA Surg 2013 [doi: 10.1001/jamasurg.2013.2685]. See the following link.  They comment on the lack of workup for many of these infants who undergo this major surgery and the frequent lack of involvement by pediatric gastroenterologists.

PDF: December issue – American Gastroenterological Association

What to do with ALTEs?

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While apparent life-threatening events (ALTEs) in infants are quite disturbing, the best management for these events is far from clear. A recent systematic review of ALTEs in infants was undertaken and included studies from 1970-2011 (J Pediatr 2013; 163: 94-9). The authors ultimately identified 37 relevant studies: 18 prospective observational studies and 19 retrospective observational studies.

Results:

  • None of the 37 studies yielded “a high level of evidence for diagnostic or prognostic investigations.”
  • Risk factors for ALTE: prematurity, previous ALTEs, and suspected child maltreatment.
  • Routine screening for gastroesophageal reflux, meningitis, bacteremia, and seizures are “highly unlikely to be helpful in patients who are well-appearing and have no other findings suggestive of a diagnosis.”
  • Testing for GERD “is unnecessary in children with ALTEs.”  “A positive test does not necessarily inform management because causation cannot be established.”  Patients with recurrent ALTEs “may benefit from pH monitoring in combination with symptom recording.

Additional references:

NASPGHAN Consensus guidelines on GERD (2009)

Link: Gastroesophageal Reflux Disease in the Pediatric … – NASPGHAN.o

  • In premature infants, a relationship between GER (i.e. reflux) and pathologic apnea and/or bradycardia has not been established.Despite a lack of convincing evidence, if pathological apnea occurs in the face of pre- existing reflux, then the following two statements are the most common features:
  • Although reflux causes physiologic apnea, it causes pathologic apneic episodes in only a very small number of newborns and infants.
  • When reflux causes pathological apnea, the infant is more likely to be awake and the apnea is more likely to be obstructive in nature.
  • A diagnosis of an acute life-threatening event (ALTE) warrants consideration of causes other than GER (i.e. reflux).Reflux of gastric acid seems to be related to ALTEs (episodes of combinations of apnea, color change, change in muscle tone, choking, and gagging) in < 5 % of infants with ALTE. 
  • -J Pediatr 2009; 155: 516. Bradycardia not improved in preemies treated for GER. n=18. Editorial 464 urges not using GER Rx in neonates –outside clinical trials.
  • -J Pediatr 2009; 154: 374. Apnea associated with reduction in LES tone in premature infants; therefore, GER may be secondary to apnea rather than the reverse. Small study -12 apneic event in 7 infants.
  • -J Pediatr 2008; 152: 365. Compared risk factors with SIDS. One of 153 (0.6%) with ALTE died.
  • -Pediatrics 2005; 116: 1059 & 1217 (editorial). Apnea in preemies is unrelated to GER.
  • -Pediatrics 2004; 113: e128-132. Apnea is unrelated to GER in most preemies; airway problems due to GERD is hard to establish.
  • -J Pediatr 2000; 137: 321 & 298. Poor temporal association between GER & apnea in ALTE patients.
  • -J Pediatr 2001; 138: 355. Metoclopropramide/cisapride do not help apnea in preemies with GER
  • -Pediatrics 2002; 109: 8-11. GER does not cause apnea of prematurity.

Predicting duration of reflux symptoms in babies

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A recent study identified two factors on multichannel intraluminal impedance pH monitoring (MII/pH) that correlated with the duration of gastroesophageal reflux symptoms in newborns (J Pediatr 2013; 162: 770-5).

This study examined 64 newborns who underwent MII/pH in the first weeks of life and then were enrolled in followup at 1, 3, 6, 9, 12, 18. 24, and 36 months. 53 patients completed the three-year study.

These patients were enrolled consecutively.  All preterm infants had to have a minimum postmenstrual age of 36 weeks.  Other criteria included a MII/pH study with a minimum duration of 19 hours, absence of GERD pharmacology for at least 1 week, and absence of infection, metabolic disease or central nervous system disease.

Results:

  • Impedance bolus exposure index (IBEI) and proximal reflux frequency positively correlated with duration of GERD symptoms.
  • IBEI was 1.45 in the short duration group (0-3 months), 1.85 in the medium duration group (4-9 months) and 2.46 in the long duration group (> 9 months).
  • Proximal reflux frequency (events/hour) was 1.56 in the short duration group (0-3 months), 1.95 in the medium duration group (4-9 months) and 2.38 in the long duration group (> 9 months).
  • Overall, one-half of patients were asymptomatic within the fifth month of age and the vast majority were asymptomatic by one year of age.
  • Weakly acidic events but not acid reflux events were significant in determining the differences in IBEI and proximal reflux.  As such, this study adds weight to the idea that acid blockers have little benefit in the first months of life.

Related blog entries:

Fundoplication effects on esophageal motility

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Trying to decide whether a child should undergo a fundoplication is often quite difficult.  The best candidates with gastroesophageal reflux disease (GERD) don’t need surgery because medical treatment is usually effective.  Typical patients who fail medical treatments may have numerous comorbidities that could cause a complicated postoperative course or failure of the procedure.

One aspect about the surgery that has been questioned has been whether surgery causes dysmotility of the esophagus.  A recent article describes a study, which enrolled only ten children who had surgery; however, these patients underwent extensive preoperative and postoperative evaluations to try to provide more information about the motility effects of fundoplication (J Pediatr 2013; 162: 566-73).

Patients were considered for surgery if they had failed medical therapy. Four of the ten patients were neurologically-impaired. Testing included automated impedance manometry, 24-hour pH-impedance, gastric emptying breath test, and GERD questionnaires (though the authors note that GERD questionnaires are not validated in children aged 1-12 years).  Median patient age was 6.4 years, with a range of 1-17 years.

Surgery: laparascopic anterior partial fundoplication

Results:

  • 4 patients developed postoperative dysphagia, two patients had redo fundoplications (one due to dysphagia and one due to persistent emesis).
  • Postsurgery, GER measures were reduced.  Total number of acid reflux episodes dropped from an average of 37 to an average of 10.  Total GER (acid and nonacid) episodes dropped from an average of 97 to an average of 66.  The percentage of time with pH<4 dropped as well from an average of 12.5% to an average of 3.1%.
  • Average gastric emptying time was unchanged: 64 minutes pre surgery and 63 minutes post surgery.
  • Conventional esophageal motility measures/peristaltic contractions were unaltered.  However, patients with postoperative dysphagia had longer gastric emptying times compared with those who did not develop postoperative dysphagia.

Related blog posts:

The Medical Pendulum and Gastroesophageal Reflux | gutsandgrowth

Gastroesophageal Reflux: I know it when I see it | gutsandgrowth

Related references:

  • -Gastroenterology 2011; 141: 1938 LOTUS study in JAMA summarized. JAMA 2011; 305: 1969. Medical rx outperformed surgery. 92% under control (remission) with long-term medical Rx vs 85% with surgery & fewer side effects of medical Rx.
  • -Clin Gastro & Hepatology 2009; 7: 1292, 1264 (editorial). 12 yr outcomes for surgery vs PPI. n=154 omeprazole, n=144 surgery. Similar long-term outcome ~50% with long-term remission.
  • -JPGN 2010; 50: 25. Reflux detected by impedance does NOT determine fundoplication outcome. n=34.
  • -JPGN 2006; 43: 185.  Effect of fundo: no change in  gastric motor activity & increased discomfort with distention
  • -Pediatrics 2006; 118: 2326. n=1142. Fundoplication decreased hospitalization rates for children <4yrs; in older children with developmental delay, there were increased hospitalization rates after fundoplication. (47% had no hospitalizations prior to fundoplication.)
  • -Clin Gastro & Hep 2004; 2: 978-984. Gilger et al. n=198. 63% required p-op medical treatment for recurrent GERD -retrospective review 1996-99.
  • -J Pediatrics 2011; 159: 597. Hypoglycemia (likely due to dumping) was common post-op. n=285. 24% of screened children with low glucose (only 1.3%of those without formal screening). 2/3rds with hypoglycemia had preceding hyperglycemia. Only 53% had dumping symptoms.  Many in this cohort were NICU pts -~1/3rd of pts had mean age of 3months & another ~1/3rd with mean age of 6months.Rx often was continuous feeds.
  • -Pediatrics 2006; 118:1828. 48,665 antireflux surgeries done from 1996-2003 (~7000/yr) in US
  • -Clin Gastro & Hep 2006; 4: 299. Frequent complications p-op and frequent need for GERD meds. dysphagia in 19%, dilation in 6%, repeat surgery in 2%, mortality in 0.8% (n=3145). 50% required GERD meds.
  • -Gastroenterology 2001; 121: 5-14 & 214.  Dysmotility with GER reflects severe disease & is present ~30%. According to this study, dysmotility does not affect postoperative outcome, is not corrected by fundoplication, may occur p-op, and requires no tailoring of surgical mgt.

More intriguing than helpful

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A recent study reports that a pH-impedance (pH-MII) may help identify children with allergen-induced gastroesophageal reflux disease (GERD) after exposure to cow’s milk (J Pediatr 2012; 161: 476-81).  The study population included 17 children (average age 14 months) with a clinical diagnosis of cow’s milk allergy (CMA) who had responded to an elemental diet.

Given the limitations of the study, it is hard to take seriously the conclusions of the authors that in “selected cases of children with CMA in whom GERD is suspected” pH-MII “should be considered as part of diagnostic workup.”

The limitations:

  • CMA diagnosed clinically based on response to dietary therapy
  • GERD diagnosed based on Infant GER Questionnaire, though authors acknowledge that “we are aware that no symptom or cluster of symptoms have been shown to reliably predict the diagnosis of GERD”
  • Statistically-significant findings only for weakly acidic reflux which was induced on second day after switching from elemental formula to cow’s milk
  • No endoscopic correlation of mucosal disease or exclusion of eosinophilic esophagitis
  • Small number of patients

I cannot see how obtaining a pH-MII study would offer a meaningful benefit to these patients; though, it is intriguing that one potential measure of clinical deterioration like increased weakly acid episodes can be detected when these patients are challenged with cow’s milk.

Some related blog entries:

Impedance recommendations from PIG

Gastroesophageal Reflux: I know it when I see it

Guidelines for Eosinophilic Esophagitis

Why didn’t patient with documented reflux get better with PPI?

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There are numerous problems with pH studies; many of these problems have been alluded to in previous blog entries (see below).  Another problem is that these studies are not highly predictive of response to therapy (Gut 2012; 61: 501-506).

This French study from three centers examined 100 consecutive patients (58 females) with an average age of 50 years.  All patients had reflux symptoms, namely regurgitation and/or heartburn.  PPI dosage was not standardized and reflux symptoms were quantified with recall questionnaires.

The authors note that up to 40% of patients with reflux symptoms have inadequate symptom relief with a 4-week course of single dose proton pump inhibitor (PPI) therapy; the aim of their study was to investigate which factors on pH probe-impedance (pH-MII) would predict a response to therapy.

Definition: Nonresponders were patients who had more than 2 days of mild symptoms per week while receiving a standard or double dose of PPI treatment for 4 weeks

Results:

  • No reflux pattern on pH-MII was associated with a response to PPIs. Table 2 in the study looked at multiple factors including SI, SAP, time for acid exposure, and number of reflux events.
  • Lower BMI (≤ 25 kg/m-squared), non-erosive reflux, and normal pH study were associated with poor PPI response
  • Other factors associated with poor PPI response: female gender, irritable bowel syndrome (IBS), and functional dyspepsia.
  • Response rates: 58% of individuals with BMI >25, 71% with esophagitis, 23% with functional dyspepsia, 30% with IBS
  • Among responders, 77% were receiving a single dose PPI

Some of the poor response may be related to the study population.  Only 35% had abnormal acid exposure.  In total, 67% were determined to have abnormal pH studies, though this was due to a large fraction having a positive symptom-reflux association analysis.

However, this study population likely reflects a typical clinical group of patients diagnosed with GERD and demonstrates some of the shortcomings of pH-MII in clinical practice.  Even patients with abnormal pH-MII studies, the presence of functional dyspepsia and IBS were strongly associated with PPI failure.

Previous related blog entries:

HEROES trial

Impedance recommendations from PIG

Gastroesophageal Reflux: I know it when I see it

Treating reflux does not help asthma

Unexplained chest pain