Gastroesophageal reflux disease (GERD) is common in infants and causes irritability, frequent vomiting, apnea, aspiration pneumonia and failure to thrive (1). Recent studies in preterm infants have shown that transient lower esophageal sphincter relaxation (TLESR) is the predominant mechanism of acid GER in both healthy premature infants and those with GERD (2–5). In infants, substantial feed buffering of gastric pH due to frequent feeding means that relatively few GER episodes cause esophageal acidification to pH <4. Nevertheless, the triggering of acid GER in association with TLESR is higher in infants with GERD compared with controls, suggesting that acid GER may be important in the pathophysiology infantile GERD (5). Acid suppression therapy using proton pump inhibitors (PPI) is increasingly being used to treat premature infants with GERD; however, the efficacy of PPI on acid production in this population has yet to be assessed in this patient group. The aim of this study was to determine the effect of 0.7 mg/kg/d omeprazole on gastric acidity and GER in premature infants with reflux symptoms and pathological acid reflux on 24-h pH probe.
PATIENTS AND METHODS
We enrolled preterm infants with symptoms suggestive of GERD (feeding problems, vomiting, irritability, xanthine-resistant apnea and weight loss) who had not responded to conservative therapy (feed thickeners, postural changes, antacids) and who had undergone 24-h pH monitoring, which confirmed significant esophageal acid exposure as defined by a reflux index (%time pH <4) of >5%. Ten infants with a mean postmenstrual age (PMA) of 36.1 ± 0.7 weeks (range, 34–40 weeks), mean postnatal age of 50 ± 9 d and mean weight of 2217 g ± 112 (range, 1810–2700 g) were enrolled. Infants were excluded if they were <32 weeks PMA, required continuous positive airway pressure or ventilation, had an acute illness (eg, necrotizing enterocolitis), neurological disease (eg, intraventricular hemorrhage grades 3/4), significant hepatic or renal impairment or bone marrow abnormalities. The study was approved by the Ethics Committee of the Women's and Children's Hospital and informed consent was obtained before each study. Nurses assigned to the trial obtained informed consent.
Drug Dosing and Preparation
Previous studies in term infants and children have evaluated omeprazole doses ranging from 0.3 to 0.7 mg/kg/d (6–8) and a dose of 0.7 mg/kg once daily was approved by the Drug Advisory and the Human Ethics Committees of the Women's and Children's Hospital. A liquid intravenous formulation of the drug was used and a stock solution containing either 5 mg/mL omeprazole or sterile water (the vehicle used in the IV formulation) was prepared and dispensed by pharmacy according to a randomization schedule determined using a random number generator. To administer the drug/placebo, a volume of the stock solution equivalent to 0.7 mg/kg omeprazole was added to 2 mL/kg of an antacid solution (Mylanta) and the mixture was then gavaged via a nasogastric tube. Using Mylanta to prevent denaturing of the omeprazole by gastric acid was the standard method recommended by the Drug Advisory Committee of the Women's and Children's Hospital for administration of omeprazole by feeding tube. Drug dosing occurred on the morning of each study day just before the scheduled feeding time.
A randomized, double-blind, placebo-controlled, crossover design trial was performed. After enrollment, the infants were given a 1-week regimen of omeprazole or placebo (days 1–7). At the end of the first week (day 7) a 24-h pH monitoring study was performed and then the alternative treatment regimen was given for the second week (days 8–14), with a further 24-h pH monitoring study performed at the end of the second week (day 14).
A 1.5- to 2.0-mL venous blood sample was also taken on days 6 and 13 of the trial for the purpose of assessing plasma omeprazole levels and undertaking routine safety screening for any changes in complete blood picture and blood biochemistry. This blood sample was taken using routine neonatal unit procedures precisely 2 h after administration of drug/placebo to coincide with the predicted time to reach maximum plasma concentration. The assay of plasma concentrations of omeprazole was performed by Bioanalytical Chemistry AstraZeneca R&D Mölndal, Sweden, using reverse-phase liquid chromatography and mass spectrometric detection. Routine blood picture and blood biochemistry assays were performed by the laboratories of the Women's & Children's Hospital.
For the duration of the trial, clinically significant symptomatic episodes were evaluated using a GER symptom assessment chart (5) that allowed for the recording of feeding times and the frequency of vomiting, apnea, choking and behavioral changes (ie, irritability/fussing, back arching, grimacing, gagging). Staff responsible for routine care of the infants completed the chart whenever these events were observed.
pH Monitoring Procedure
Twenty-four-hour esophageal pH monitoring was performed using the Medtronic Digitrapper pH monitoring system (Medtronic, Salt Lake City, UT). A disposable antimony pH probe with a diameter of 1.9 mm and pH sensors spaced 9-cm apart was used (GastroTech Pty Ltd, Adelaide, Australia). The probe was positioned with the esophageal sensor 3 cm above the lower esophageal sphincter and the gastric sensor 6 cm below the lower esophageal sphincter. This position of the gastric sensor is optimal for gastric pH recording in this age group (9). Parameters of gastric and esophageal pH were determined using the Esophagram analysis program.
Omeprazole therapy significantly reduced gastric acidity, esophageal acid exposure and the number and duration of acid reflux episodes compared to placebo (Fig. 1, Table 1). Plasma omeprazole levels at 2 h postdosing ranged from 178 to 1970 nmol/L (mean 1231 ± 206 nmol/L). A significant correlation was observed between higher plasma omeprazole level and lower %time gastric pH <4 (Fig. 2). Eight of the 10 infants had a reflux index of >5% on placebo (7 had >10%, 3 had >20%). Omeprazole therapy normalized the reflux index to <5% in 7 of these infants. The infant who did not respond to omeprazole had a low level of plasma omeprazole (245 nmol/L) on therapy, suggesting low exposure to the drug and therefore low efficacy in this patient. Despite the normalization of acid reflux in most patients, the number of symptomatic events of vomiting, apnea, bradycardia or behavioral changes was not significantly changed by omeprazole (Table 1). Omeprazole therapy did not significantly alter blood biochemistry or complete blood picture (Table 1) and was not associated with the occurrence of any serious adverse events.
Proton pump inhibitor therapy is increasingly being used in neonatal units; however, the safety and efficacy of PPI has not been adequately determined in premature infants. This placebo-controlled trial evaluated the pharmacodynamic effect of omeprazole on gastric acidity and acid GER in preterm infants. Before randomization, the infants had clinical symptoms suggestive of GERD and an esophageal acid reflux index of >5% on 24-h esophageal pH monitoring. Omeprazole therapy with 0.7 mg/kg once daily significantly reduced gastric acidity, an effect that correlated with the presumed peak plasma concentration as measured 2 h after omeprazole intake. Our study shows that 0.7 mg/kg omeprazole given once daily is effective in reducing the frequency of acid reflux episodes and the overall degree of esophageal acid exposure. In most infants, omeprazole therapy reduced esophageal acid exposure to below currently defined normal levels.
The drug-dosing regimen used appeared safe based on adverse event reporting and blood screening. These data show no acute adverse effects of omeprazole, but they need to be considered in the context of routine use over prolonged periods, developmental changes and polymorphism in cytochrome P450 2C19 expression, which may result in pronounced variations in omeprazole plasma concentrations (10). Nevertheless, the average 2-h plasma levels measured lay within the range for Cmax values observed at therapeutic doses for omeprazole in older children (10).
Using bedside symptom charts completed by nursery staff we were unable to demonstrate any significant change in symptom frequency. This apparent lack of clinical efficacy, despite a clear pharmacodynamic effect on gastric acid production and acid reflux, was surprising and may have been be due to several reasons:
- The infants may not have had GERD. We have previously demonstrated (11) that behaviors generally considered to be “reflux related” occur commonly in premature infants independent of acid reflux episodes. The clinical diagnosis of this condition in this age group is also difficult and the use of pH monitoring in diagnosis is controversial.
- The period of therapy may have been too short to produce any significant change in symptoms.
- The accuracy of the symptom scoring may have been compromised by the fact that symptoms were scored if and when they were observed by nursery staff undertaking routine duties in the nursery and therefore could not continuously observe the infant for symptoms.
- The putative reflux symptoms for which the patients were enrolled were due to volume rather than acid reflux and therefore were unchanged by a reduction in overall esophageal acid exposure times. In adults omeprazole has been shown to reduce the frequency of acid GER but not the frequency of total liquid reflux as determined by intraluminal impedance techniques (12,13).
In light of the above, the symptom findings of this study should be treated with caution.
We conclude that an omeprazole dose of 0.7 mg/kg is safe and highly effective in normalizing pathological acid GER. The far more complex issues of clinical efficacy and safety of acid suppression for treatment of symptoms of GER requires a systematic assessment of symptom outcomes in a larger group using more powerful evaluation tools and performed by consistently trained personnel.
The authors greatly appreciate the efforts of our research nurses Ros Lontis and Louise Goodchild and the staff of the Neonatal Unit of the Women's and Children's Hospital, without whom this trial would not have been possible. We would like to thank AstraZeneca R&D Mölndal for assistance with performing the plasma omeprazole assays.
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