Correlation Between SI, SSI, and SAP:
SI, SSI, and SAP significantly correlated with each other (P < 0.05 between SI and SSI, P < 0.001 between SI and SAP, and P < 0.01 between SSI and SAP). The correlation, however, was strongest between SI and SAP (r2 = 0.64).
Acid Suppression and MII-pH Data
A total of 10 infants (17%) were on acid suppression therapy (omeprazole = 5, 1 mg · kg−1 · day−1; raniditine = 3, 6 mg · kg−1 · day−1; lanzoprazole = 1, 1 mg · kg−1 · day−1; and famotidine = 1, 1 mg · kg−1 · day−1) during the MII-pH study and only 1 infant was on prokinetic therapy (metoclopramide, 0.3 mg · kg−1 · day−1). The median percent of time pH<4 was significantly lower in infants on acid suppression therapy (0.6% vs 3.2%, P = 0.04). The median number of acid reflux was also lower in infants on acid suppression (7 vs 13, P = 0.04). The total number of reflux episodes were, however, similar (37 vs 40, P = 0.4) in the 2 groups, and the number of nonacidic reflux was significantly higher in infants on acid suppression (28 vs 17, P = 0.046). There were no significant differences in symptom association analysis in infants with and without acid suppression therapy (data not shown); however, the number of infants on acid suppression was too small for this comparison.
GER is common during infancy. A large number of signs and symptoms during infancy are attributed to GER. Our data indicate that in preterm and term infants where there is a strong clinical suspicion for reflux, the true prevalence of GERD is low. In these infants with a high index of suspicion, only 10% to 13% of them had true GERD as determined by MII-pH study. Moreover, the majority of clinical behaviors attributed to GER do not correlate with the reflux episodes.
Making a diagnosis of GER during infancy may be difficult. A pH probe study is the most commonly used tool to diagnose GER in infants and children. The pH study, however, does not provide information about nonacidic reflux (3,19). Other methods used to aid in the diagnosis of GER include an upper gastrointestinal barium study (to assess anatomy) and nuclear scans (to assess microaspiration). These methods are unreliable because of the short time period of observation, and have the additional disadvantage of exposure to radiation. Recently, the multichannel intraluminal impedance (MII) has been increasingly used in adults and children, and considered as the criterion standard for the diagnosis of GER (6,20). MII-pH study can detect both acidic and nonacidic refluxate. Several investigators have reported normal impedance values for adults (18,21). The data, however, are limited regarding normal range and baseline reflux characteristics using MII-pH study during infancy. Lopez-Alonso et al (3) reported MII-pH data on 21 asymptomatic preterm neonates. The median number of reflux episodes in a 24-hour period was 71 (100, 95th percentile), the median total acid exposure was 5.59% (20%, 95th percentile)(3). More recently, Mousa et al (22) reported reference values for impedance data from 117 infants and children. They found similar results of total reflux episodes for 24 hours during infancy (median 54, 95th percentile 93). In our study, we used data from Lopez-Alonso et al as the reference value because the populations were more similar. Only 6 infants (10.3%) in our cohort had an abnormal MII-pH study defined as >95th percentile reflux episodes per hour or >95th percentile acid exposure time. Although we performed the MII-pH study in preterm and term infants in whom GERD was strongly suspected based on clinical symptoms, the prevalence of an abnormal MII-pH study was low.
Premature infants are more prone to GER because of immature tone of the lower esophageal sphincter, supine positioning, small stomach capacity, decreased esophageal capacitance, delayed gastric emptying, decreased gastrointestinal motility, and the presence of an NG tube (8,23,24). Premature infants are also less likely to have acidic reflux as gastric pH is >4, 90% of the time (3). We found no differences in the number of acidic, nonacidic, and total reflux events between preterm and term infants. Likewise, the percent time of acid exposure was similar between preterm and full-term infants. This is the first study to compare GER in preterm and term infants using MII-pH data. The finding of no differences in number and characteristics of the reflux episodes is likely because of selection bias as MII-pH studies were only performed in infants with a strong clinical concern for reflux. The majority of reflux events in preterm and term neonates were weakly acidic as described in previous reports (3,5). Therefore, MII-pH is a better study in infants to diagnose GERD, as the pH study will miss the majority of reflux episodes in this population.
It is commonly believed that an NG tube passing through the lower esophageal sphincter can trigger reflux episodes. The data, however, on the presence of NG tube and GER are conflicting (25,26). Dotson et al (26) reported that presence of NG tube did not cause reflux in healthy adults. In a small study on 16 neurologically impaired children (9 NG fed, 7 orally fed), there were no significant differences in total reflux events (P = 0.628) in NG fed versus orally fed children (27). There was, however, a trend (P = 0.058) toward higher nonacidic reflux events in NG fed children. In a study in term infants and children, a small size NG tube (8F) did not cause reflux, but GER was increased with a larger tube (12F) (28). Peter et al (29), reported data on 16 preterm infants who underwent a 48-hour MII study (24 hours with catheter tip in lower esophagus and 24 hours in stomach). The number of reflux episodes in 24 hours was significantly higher in gastric positioning of catheter versus esophageal placement (122 vs 72, P < 0.01). We speculate that increased GER in this study is due to a larger catheter size (8F in preterm baby). In our cohort, 20 preterm infants were receiving NG feeds (size of NG tube 5F) whereas the other 20 were on full PO feeds during MII-pH study. We found no differences in number and characteristics of reflux episodes between the 2 groups. In addition to this, the acid exposure time was also similar in infants receiving NG feed versus PO feed. The common signs and symptoms attributed to reflux during infancy are not specific for GERD. Several investigators have attempted to correlate symptoms in infants with reflux episodes detected by MII-pH study with conflicting results (4,11–13). Moreover, these studies were small, with a shorter duration of monitoring, and correlated fewer signs and symptoms. In a study on 19 preterm infants, apnea, bradycardia, or desaturation had no temporal correlation with reflux episodes (12). Wenzl et al (11), using SI and SSI to correlate apnea with reflux episodes in 22 infants, found that apnea was correlated with reflux episodes in 13.7% by SI and 54.5% by SSI. In a similar study, only 15.2% of apnea episodes were correlated with GER, and SAP was positive only in 4 of 25 infants (15). On the contrary, Conidino et al (13) reported a higher correlation with any symptoms (SI, 66% of infants and SSI 53.3% of infants) in 34 infants referred for evaluation of GER. Ours is the largest study investigating the temporal relations of a variety of common, nonspecific signs and symptoms with reflux episodes as detected by MII-pH study during 16 to 24 hours. A wide range of time intervals (20 seconds to 5 minutes) between symptoms and reflux episodes have been used for temporal relation (11–13,15,30). Similar to other investigators, we used a generous time interval (5 minutes before and 5 minutes after) to maximize the correlation between symptoms and reflux episodes (11,16). In addition, we used the presence of any refluxate into the esophagus to define a reflux episode compared with others who strictly use reflux episodes that reach the proximal esophagus for symptom association. Temporal association in our study was evaluated using all the 3 indices (SI, SSI, and SAP). Despite our most liberal approach, we did not find a temporal link between signs and symptoms commonly attributed to GER with reflux episodes. A temporal relation with reflux was established in only 1 in 20 (5%) infants with bradycardia and 6 of 32 (19%) infants with irritability. Gagging was the only symptom with positive correlation in more than 50% of infants. Arching and feeding, difficulty while commonly attributed to GERD, had poor temporal correlation with reflux events in our study.
The diagnostic accuracy of the MII-pH study may best be evaluated by the use of the SI and the SAP, which in our study appeared well correlated and the most predictive. The present study is in contrast to other studies in infants where no correlation between SI, SSI, and SAP were found (31). Although in adults there was no correlation of SI with symptoms, SAP and SSI were significantly related to symptomatic response; however, it was far from ideal with low positive predictive value (PPV) and negative predictive value (NPV) (32). Correlation of MII-pH and reflux related symptoms is better in younger infants compared with older children and adults (33).
Acid suppression therapy reduced the number of episodes of acid reflux, but had no impact on the total number of reflux events. Similarly, Turk et al (34) reported that, while proton pump inhibitors decreased the acidity of refluxate in children and adolescents, they did not affect the total number of reflux episodes. MII-pH study, in contrast to a pH probe, is useful in evaluating symptoms associated with reflux even in the presence of acid suppression (5). Our study did not show differences in symptom association in infants with and without acid suppression therapy. The number of infants receiving acid suppression therapy, however, was too small. A larger study is needed to evaluate the effects of acid suppression therapy on symptoms related to acidic reflux (arching, irritability, and difficulty in feeding).
The present study has limitations. This is a retrospective analysis from a single center of infants with a high index of suspicion for reflux. Based on the patient selection, we cannot provide reference values in the general infant population nor can we validate the symptom-reflux association analysis parameters. This review included preterm infants on oral, as well as NG feeding. Another important limitation is interobserver and intraobserver variability in interpretation of MII data. A validated automated computer analysis may improve reliability in interpretation of MII data. The strengths of our study include: the largest sample size of preterm and term infants, the number of clinical symptoms evaluated and correlated with reflux episodes, the duration of the MII-pH study, and use of the sensitive tool (SAP) for correlation.
In conclusion, the present study indicates that in preterm and term infants with strong clinical suspicion for reflux, the prevalence of significant GER as detected by MII-pH was low. The incidence and pattern of GER was similar in preterm and term infants. The presence of small-bore NG tube was not associated with increased GER in preterm infants. The majority of suspected clinical reflux behaviors did not correlate directly to actual reflux events. MII-pH study can be useful in these infants before initiating therapy for GERD. In infants with no temporal relation between symptoms and reflux episodes, other etiologies for reflux-like behavior should be sought.
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Keywords:© 2016 by European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology,
gastroesophageal reflux disease; multichannel intraluminal impedance; neonates; symptom association