Widespread use of gastric acid inhibitors in infants: Are they needed? Are they safe?

Table 1 Summary randomised control trials examining proton pump inhibitors efficacy in reducing symptoms in infants with gastro-oesophageal reflux disease

Parameter	Esomeprazole	Lansoprazole	Pantoprazole	Omeprazole	Omeprazole (independent)	Esomeprazole
Control group	Placebo	Placebo	Placebo	Dosing range	Placebo	Placebo
Blinding	Double	Double	Double	Single	Double	Double
Trial of conservative measures	No	Yes	Yes	Yes	Yes1	No
Antacids allowed as rescue	Yes	No	Yes	Yes	No	Yes
Open-label phase to identify PPI responders	Yes (2 wk)	No	Yes (4 wk)	No	No	Yes (2 wk)
Randomised withdrawal from PPI	Yes	No	Yes	No	Yes	Yes
Length of randomised phase (wk)	4	4	4	8	4	4
Age in months	1-12	1-12	1-12	0-243	3-12	1-11
n	40	81	50	35	30	80
GORD symptoms for clinical diagnosis	Vomiting; Regurgitation; Irritability; Supra-oesophageal disturbances; Respiratory Disturbance; Feeding difficulty	Crying; Fussiness; Irritability	Vomiting; Regurgitation; Spitting up; Irritability; Fussiness; Feeding Refusal; Choking; Gagging	Vomiting Regurgitation	4Frequent spilling Irritability/crying	Vomiting, regurgitation, irritability, cough, wheezing, stridor, labored breathing, resp symptoms triggered by feeding, food refusal, gagging, choking, hiccups for > 1 h/d
Primary endpoints	Time from randomisation to discontinuation because of symptom worsening perceived by parent or physician on symptom severity scale	Proportion with ≤ 50% reduction in PGA of symptoms	Proportion of infants who withdrew due to the “lack of efficacy” including worsening of symptoms, and/or antacid use for 7 consecutive days and/or oesophagitis and/or physician judgements	Change from baseline in daily symptoms based on PGA and parent perception	Reflux index from baseline	Time from randomization to discontinuation owing to symptom worsening in the double-blind phase
Primary end point efficacy result	Hazard ratio = 0.69 (PPI/Placebo); 95%CI: 0.35-1.35; P = 0.275	Responder rate: 54% (44/81) PPI vs 54% (44/81) Placebo; P = 1.000	Responder rate: 12% PPI vs 11% Placebo; P = 1.000	Mean daily vomiting/regurgitation episodes decreased by 4.34/d (0.5 mg/kg; 2.97/d – 1.0 mg/kg 4.35/d – 1.5 mg/kg; P > 0.50 in all group comparisons	Change from baseline of parent-recorded 24 h crying and fussing time and visual analogue scores of parental impression of the intensity of irritability Reflux index; -8.9% ± 5.6% PPI; -1.9% ± 2.0% Placebo P < 0.001 Cry/fuss times (min/24 h); 191 ± 120 (PPI); 201 ± 100 (Placebo) P = 0.400 Combined PPI and Placebo groups total cry fuss time2 Baseline vs 2 wk P = 0.040 Baseline vs 4 wk P = 0.008 VA Score 5.0 ± 3.1 (PPI); 5.9 ± 2.1 (Placebo) P = 0.214	Discontinuation rates owing to symptom worsening were 48.8% (20/41) for placebo-treated vs 38.5% (15/39) for esomeprazole-treated patients (hazard ratio 0.69; P = 0.28)
Limitations of studies	Small sample size Symptom-based diagnosis Subjective assessment	Small sample size; Symptom-based diagnosis; Subjective assessment	Small sample size Symptom-based diagnosis Subjective assessment	Single blinded; Not placebo-controlled; Small sample size; Symptom-based diagnosis; Subjective assessment	Small sample size; Subjective assessment	Small sample size; Symptom-based diagnosis; Subjective assessment

¹All infants were given empirical pharmacologic treatment (excluding PPIs) including cisapride (87%), H2 receptor antagonists (73%), antacid (67%) and thickening agent (20%);

²Significant decrease in cry-fuss time independent of treatment;

³Ninty percent of patients were younger than 12 mo;

⁴Entry into study required a reflux index of > 5% or endoscopic biopsy evidence of oesophagitis. Data adapted from Chen et al[23]; Moore et al[24]; Orenstein et al[27]; Shakhnovich et al[28]. PPI: Proton pump inhibitor; GORD: Gastro-oesophageal reflux disease; PGA: Physician global assessment; VA: Visual analogue.

Table 2 Outline of the proposed side effects associated with proton pump inhibitors use, and the evidence supporting the association

Potential side effects	Level of evidence showing an association with PPI use
Acute Interstitial Nephritis	Level III
Bacterial overgrowth in the stomach, small and large intestine	Murine models
Bacterial enteric infections Causative agents: Clostridium difficileSalmonella species Campylobacter species	Level I
Pneumonia (Community-acquired)	Level I
Necrotizing enterocolitis	Level III1
Blood stream infections, including candidemia	Level III1
Allergic sensitization in adults and in children with in utero exposure	Level III Study and Murine Models
Parietal and Enterochromaffin-like cell hyperplasia	Level II
Fundic gland polyps	Level III
Vitamin B12 deficiency	Level III
Fractures (osteoporotic and non-osteoporotic)	Level III
Hypomagnesemia	Level IV and one level III study
Reduced Antiplatelet effect of Clopidogrel	Level II
Adverse Cardiovascular outcomes due to Clopidogrel interactions	Level III2

¹Only single reports showing an association with acid inhibition induced by H2RA treatment;

²RCTs (level II) not shown an increase risk of adverse outcomes.