Stop the PPI Express: They Don't Keep Babies Quiet!
Article Outline
Abbreviations: GERD, Gastroesophageal reflux disease, PPI, Proton pump inhibitor
Gastric acid rivals mucus as the most maligned secretion from the body, if the millions of people taking drugs designed to block their production can be taken as evidence for the disdain in which they are held. In some ways, gastric acid is a biological luxury. Its participation in the degradation of foodstuffs is not required for effective digestion or absorption. Even protection from invasion by ingested microorganisms is less a requirement in the age of better sanitation and food handling practices, although dramatic failures of those practices that have resulted in recent epidemics of salmonella, hepatitis A, and Escherichia coli O157:H7 should make us pause. With little apparent physiological benefit, the only remaining role of gastric acid seems to be as a pathogen, which is well established.
See related article, p 514
Or is it? Gastric acid was incorrectly blamed for the majority of peptic ulcer disease until the discovery of the bacterium now known as Helicobacter pylori, which prefers achlorhydria and generates duodenal ulcers. Untold vagotomy and pyloroplasty procedures were done in the name of preventing acid-induced ulcers. Now, in this issue of The Journal, Orenstein et al1 remind us, in a nearly complete affront to the dogma du jour, that not only do most infants treated for presumed gastroesophageal reflux disease (GERD) not respond to acid blockade with the proton pump inhibitor (PPI) lansoprazole, but also the “response” rate is equaled by the “response” to placebo. A previous study that used a different PPI, omeprazole, produced similar results and impressions.2
This carefully crafted article precisely describes a large, multicenter, double blind, placebo-controlled trial of lansoprazole in infants with regurgitation and feeding-associated crying. The inclusion criteria included symptoms commonly reported by families to their care providers that are assumed to be reflux-induced. Formal diagnostic studies to prove esophagitis were not required for entry. The researchers prescribed a published dosing regimen based on age and size. The discussion appropriately concedes the limitations of the protocol, but casts none as a fatal flaw. Clinical improvement in feeding-associated crying with both acid blockade and placebo was 44%. An increase in respiratory infections associated with the use of the medication was noted.
The impact of GERD—complications arising from the retrograde movement of gastric contents, including those pesky protons, into and onto the esophagus, pharynx, larynx, trachea, lungs, sinuses, ears, and teeth—has long been attributed to the exposure to gastric acid. Without a great drug to prevent the wayward flow of chyme, clinicians using nonsurgical options to treat GERD have been forced to offer what is conceptually partial treatment by reducing the acid content of the refluxate, which they do with great zeal. The use of PPIs for this purpose is widespread, facilitated by nonprescription availability, ease of administration, formulations appropriate for infants and young children, and infrequent side effects. Advertised in the media with the same fervor as the need for sleep and erections, the “Purple Pill” is as familiar as Band-Aids. Barron et al3 reported a dramatic increase in the use of PPIs in infants (4-fold between 2000 and 2003), but with no evidence suggesting a change in the incidence of GERD.
Although the current study was not designed to examine pediatric practice or to determine the best use of PPIs in children, the findings indicate that there is much to consider. Given the evidence that the response of irritability to acid suppression in infants with clinical GERD is equal to the placebo rate, and that the ultimate outcome is improvement irrespective of therapy, we must now justify the continued prescription of PPIs for this indication.
Buried within the data for response rate are, no doubt, true responders who have acid-induced esophagitis and symptoms and who promptly improve in response to a therapeutic dose of PPI, but for the remainder, the empiric therapy is misapplied. Is there a way to predict who would be a true responder at the outset to ensure that only those with the correct diagnosis are treated? The results of commonly available tests—pH-metry and esophageal biopsy—correlate poorly with symptoms. Erosive esophagitis, which does respond well to PPIs, is distinctly uncommon in infants, such that routine endoscopy would be inappropriate. A recent study by Loots et al4 suggested that multichannel intraluminal impedance monitoring, which has replaced pH-metry in many institutions because it provides a far more complete and logical means for detecting reflux events, shows more correlation between nonacid reflux and symptoms. The outcome of therapy for those children was not reported, but acid suppression would be anticipated to offer no benefit.
Given that most infants who exhibit feeding-associated crying do not respond to lansoprazole (or omeprazole), is an empiric therapeutic trial of any PPI even warranted? PPIs have become the modern effector in the old instruction to “take two aspirins and call me in the morning” in clinical practice. Given the increasing evidence that they offer little benefit for some of the symptoms for which they are prescribed, a serious effort to curtail their empiric use is warranted. Increased primary care and subspecialist physician awareness and use of the results referenced herein, awareness of the response of uncomplicated infant reflux to nonpharmacologic management,5 and education of parents as part of anticipatory guidance to reset expectations will all help curtail the epidemic of inappropriate PPI prescription.
At the same time, the widespread use of PPIs in infants and children suggests that symptoms are commonly reported. What have not been reported are a more precise explanation for the pathogenesis of feeding-associated irritability in infants and a usable, effective treatment paradigm. The concept that this irritability is a manifestation of a functional gastrointestinal disorder is difficult to embrace after decades of bombardment with attention to acid; nonetheless, it is time to use the hammer for which acid has been the nail to seal the coffin on the notion that the only good proton is one that was never born.
In an era when evidence is supposed to be king, but habit and dogma trump the king, do we have the will to stop the PPI express?
References
- . Multicenter, double-blind, randomized, placebo-controlled trial assessing efficacy and safety of proton pump inhibitor lansoprazole in infants with symptoms of gastroesophageal reflux disease. J Pediatr. 2009;154:514–520
- . Double-blind placebo-controlled trial of omeprazole in irritable infants with gastroesophageal reflux. J Pediatr. 2003;143:147–148
- . Proton pump inhibitor utilization patterns in infants. J Pediatr Gastroenterol Nutr. 2007;45:421–427
- . Addition of pH-impedance monitoring to standard pH monitoring increases the yield of symptom association analysis in infants and children with gastroesophageal reflux. J Pediatr. 2009;154:248–252
- . Efficacy of conservative therapy as taught in the primary care setting for symptoms suggesting infant gastroesophageal reflux. J Pediatr. 2008;152:310–314
PII: S0022-3476(08)01044-5
doi:10.1016/j.jpeds.2008.11.037
© 2009 Mosby, Inc. All rights reserved.
Refers to article:
- Multicenter, Double-Blind, Randomized, Placebo-Controlled Trial Assessing the Efficacy and Safety of Proton Pump Inhibitor Lansoprazole in Infants with Symptoms of Gastroesophageal Reflux Disease , 04 December 2008
