“Absence of evidence is not evidence of absence.” Carl Sagan
If medicines work for infantile GERD, it is difficult to prove (Winter H, et al. JPGN 2012; 55: 14-20). The cited study is the latest having difficulty proving that proton pump inhibitors are effective in infants. In this randomized, double-blind, placebo-controlled multinational study from 33 centers, 98 infants (1-11 months) were enrolled. My colleague, Dr. Benjamin Gold, was one of the researchers. Initially, a 2-week open-label treatment was given which was followed by a 4-week randomized phase. Study participants had to have a clinical diagnosis of GERD with at least one GERD symptom –at least twice per week in a 4-week period:
- supraesophageal manifestations (cough, wheeze, stridor)
- respiratory symptoms triggered by feedings
- feeding difficulties
The treatment administered was weight-based dosing of esomeprazole:
- 3-5 kg: 2.5mg
- 5-7.5kg 5mg
- 7.5-12kg 10mg
Daily symptoms were captured with an interactive voice response system. Among the initial 98 patients enrolled, 80 reached the randomization phase. During the initial 2-week period, 81 (82.7%) had symptom improvement based on physician global assessment. During the double-blind phase, 48.8% of placebo-treated patients and 38.5% of esomeprazole-treated patients discontinued therapy due to symptom worsening. While the time for discontinuing esomeprazole was longer in a posthoc analysis, the primary outcome, discontinuation rate, was not significantly different.
So what is the reason that this was a negative study? While the reasons are unclear, all of the following are possible:
- Patient selection/lack of accurate diagnosis. Mixed-population was recruited for the study –though this type of population is similar to clinical practice.
- Dose of esomeprazole.
- Inadequately powered study. If the effectiveness of PPIs is small, a much larger population is needed.
- Maybe these agents don’t work in infants. Infants secrete less acid than children and adults; thus, acid blockers may not work as well. (The Medical Pendulum and Gastroesophageal Reflux)
Why not give PPIs even if they don’t work? The previous link discusses many of the potential adverse problems that are possible with medical treatment of GERD. However, even if a medicine does not harm does not mean you should do something because it ‘might’ do some good. An example of this is the apocryphal tale of the famous pianist who died one day in the middle of a recital. (I saw this in a journal article but cannot remember the reference.) The manager came out to announce his death. A man in the audience shouts, ‘Give him an enema.’ Initially, the manager tries to ignore him. After the man yells this three times, the manager responds, ‘the poor man is dead…what good will an enema do?’ The voice replies, ‘What harm will it do?
- -JPGN 2010; 50: 609-18. Pantoprazole helped improve symptoms but there were no significant differences compared to placebo 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. Abstract#26. prevacid more effective than ranitidine in infants.
- -J Pediatr 2009; 155: 601 (letter). Should not be used to treat symptoms unless proven to be reflux.
- -JPGN 2009; 49: 498. GERD guidelines. “In infants and toddlers, there is no symptom or symptom complex that is diagnostic of GERD or predicts a response to therapy.” Identical response to placebo (vs prevacid) in largest double-blind randomized study (54% at 4 weeks) (J Pediatr 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.”