In so many areas of pediatric gastroenterology, there is a gradual development of enthusiasm for a medical treatment. In the vast majority, the enthusiasm goes too far and closer scrutiny often determines a more limited role for this medical treatment or potential adverse effects that were not initially appreciated. The latest example of this may well be with the use of proton pump inhibitors (PPIs) for gastroesophageal reflux disease, particularly in infants and individuals with asthma. Although these medications may not have reached their apogee, more and more their effectiveness for so many ailments has been questioned. In this month’s issue of JPGN, this is highlighted (JPGN 2012; 54: 8-14). The article which emanates from the offices of the FDA discusses the fact that the usage of PPIs has increased 11-fold from 2002-2009 in infants <12months of age; 404,000 prescriptions were dispensed to 145,000 infants in the U.S. in 2009. At the same time, althougth there have been four randomized controlled trials of PPIs in infants, NO studies have demonstrated the effectiveness of these drugs in this population. As a consequence, the authors recommend that these drugs be restricted to infants with endoscopically-proven GERD/erosive esophagitis. No other tools are sufficient to identify infants who are likely to respond. Perhaps the reason why these agents work less well in infants is due to the fact that acid secretion is much less in infants than in children and adults. For example, at 4months of life, average acid secretion rate in infants is ~27-fold lower than in adults (Am J Dig Dis 1969; 14: 400-14). As a consequence, their symptoms may not be responsive to acid reduction treatments.
Other related references on GERD in infancy:
–JPGN 2010; 50: 609-18. Pantoprazole helped improve symptoms but there were no significant differences compared to placeblo in withdrawal rates due to lack of efficacy. n=128.
-NASPGHAN 2009, Abstract#21. Meds/Rx of NICU pts did not shorten hospital stay or promote wt gain, n=1149.
–JPGN 2009; 49: 498. NASPGHAN GERD guidelines. “In infants and toddlers, there is no symptom or symptom complex that is diagnositc of GERD or predicts response to therapy.” Identical response to placebo (vs prevacid) in largest double-blind randomized study (54% at 4 weeks) (J Pediatrics 2009; 154: 514-20.)-Reflux is “not a common cause of unexplained crying. irritability..in otherwise healthy infants.” “There is no evidence to support the empiric use of acid suppression for the treatment of irritable infants.”
GERD and respiratory/ENT issues:
–Gastroenterology 2010; 139: 1887. PPIs decreased postnasal drainage compared to placebo. n=75. (50% vs 5%) age discrepancy in patient populations.
–Clin Gastro & Hep 2010; 8: 741 (excellent editorial), 770 (article on rabeprazole improving heartburn Sx in pts with laryngitis), n=82. Editorial suggests 1-2month trial of BID PPI and if not effective, then little to offer. May change when studies looking at surgery (after impedance) outcomes.
–Gastroenterology 2010; 139: 754. 716 (editorial). Acoustic cough & reflux. Study recorded cough during pH measurement. n=71. ‘causality cannot be established until effective treatment’ available.
–Gastroenterology 2009; 137: 1844. Critical review of below NEJM article. ‘a subset of asthmatics will have objective detection of GERD without typical symptoms…work by Amer Lung Assn suggests that twice daily PPI will not be helpful’..however, ‘perhaps 3-6months of PPI may still be reasonable until we can accurately identify subgroups of pts who may respond.’ –Gary Falk, Cleveland Clinic
–NEJM 2009; 360: 1487, 1551. Use of PPIs (nexium 40mg bid) in poorly-controlled asthma with no symptoms of GER –did not help w asthma control & pH studies were not predictive of response. n=412 adults. 40% c abnl pH studies in each group (nexium vs. placebo).
–Clin Gastro & Hep 2007; 5: 1379. Review of ENT findings and reflux.
–Am J Gastro 2007; 102: 716. Poor specificity of ENT findings for diagnosis of laryngopharyngeal reflux.
–Aliment Pharm Ther 2007; 25: 385-92. meta-analysis. Rx c PPIs not more effective than placebo in resolving ENT symptoms presumed to be due to GER. Editorial suggests some patients may benefit, but better tools are needed to identify them.
GERD and surgery:
–Gastroenterology 2011; 141: 1938. LOTUS study in JAMA summarized in this review. (JAMA 2011; 305: 1969) Medical treatment outperformed surgery. 92% under control (remission) with long term medical Rx vs 85% with surgery & fewer side effects of medical treatment.
–Clin Gastro & Hepatology 2009; 7: 1292, 1264 (editorial). 12yr outcomes for surgery vs PPI. n=154 omeprazole, n=144 surgery. Similar long term outcome ~50% with long term remission.
–Pediatrics 2006; 118:1828. 48,665 antireflux surgeries done from 1996-2003 (~7000/yr) in US
–Clin Gastro & Hep 2006; 4: 299. Frequent complications post-op and frequent need for GERD meds. Dysphagia in 19%, dilatation in 6%, repeat surgery in 2%, mortality in 0.8% (n=3145). 50% required GERD meds.
–Clin Gastro & Hep 2004; 2: 978-984. Pediatric study. n=198. 63% required post-op treatment for recurrent GERD -retrospective review 1996-99.
Proton Pump Inhibitors and reported adverse effects:
-Risk of Hypomagnesemmia -2011. http://www.fda.gov/drugs/drugsafety/ucm245011.htm
–NEJM 2010; 363: 2114. large Denmark study. 5082 fetuses with PPI exposure (out of 840,968 live births). Risk of birth defects NOT increased with exposure during 1st trimester. Possible slight increase risk with preconception use except with omeprazole.
–Gastroenterology 2010; 139: 1115. Review of safety of PPIs.
–Gastroenterology 2010; 139: 93. n=167,000. PPIs associated with hip fracture risk, OR 1.3, in patients with other risk factors.
–Gastroenterology 2010; 138: 896-904. 5yrs of PPI -no increase risk in hip/spine fx.
–Arch Intern Med 2010; 170: 765-71, 747 (ed). PP not related to hip fx (n=161,806) women 50-79. INCREASE risk of spine fx, hazard risk 1.47
–Arch Intern Med 2010; 170: 772-8. PPIs increase risk of Clostridium difficile infection (hazard ratio 1.42 –42% increase in risk), n=1166.
–Arch Intern Med 2010; 170: 784-90. n=101,796. OR 1.74 for daily PPI, OR 2.36 if BID Rx; thus ~70% increase risk of nosocomial infection.
–Clin Gastro & Hep 2010; 8: 504. Increased bacterial overgrowth with PPI use.
-JAMA 2009; 301: 2120-2128. Use of PPIs associated with INCREASED hospital acquired pneumonia by ~30%. Could result in 180,000 HAP cases/yr with ~33,000 deaths. n+ 63,878 admissions, 52% on PPIs or H2RAs (83% PPIs, 17% H2RAs). H2RAs NOT associated with HAP cases.
–Gastroenterology 2009; 137: 80. PPIs induce acid-related symptoms in ~22% vs 7% of placebo in healthy volunteers.
–Ann Intern Med 2008; 149: 391-398. Risk for pneumonia associated with short-term PPI use, not long term
–Clin Gastro & Hep 2007; 5: 1418. Increases risk of bacterial gastroenteritis.
–JPGN 2007; 45: 395, 421. Increasing use of PPIs-4-fold from 2000-2003; 0.5% of all infants. No safety/efficacy data.
–J Pediatrics 2007; 150: 262. Long term use (up to 11yrs of usage) of PPIs in 166 children; minimal problems: 2 c nausea, 2 c skin rash, 1 c diarrhea, 1 c agitation.
–JAMA 2006; 296: 2947-53. Risk of bone fracture –odds ratio 1.44-2.65 with long-term PPI treatment (>1yr); UK study looked at 1.8million