The Role of Combined Multichannel Intraluminal Impedance-pH Monitoring in Infants with Brief, Resolved, Unexplained Events

Gastroesophageal reflux (GER) is common in preterm and term infants [1]. Harmful consequences of GER, called GER disease (GERD), have been associated with different manifestations such as obstructive apnea, oxygen desaturation, stridor, and wheezing [2, 3]. Apneas and brief resolved unexplained events (BRUE), irrespective of their nature, have been proposed to be GER-induced, although evidence is limited and inconclusive [4]. BRUE, previously known as Apparent Life Threatening event (ALTE), is described as a sudden, brief, and resolved episode in an infant that includes one or more of the following features: cyanosis or pallor, absent, decreased, or irregular breathing; marked change in tone (hyper- or hypotonia); and altered level of responsiveness. Criteria for low risk BRUE are as follows: age >60 days or born at gestational age ≥32 weeks and current postconceptional age is ≥45 weeks, if premature; occurrence of only one BRUE (no prior BRUE, and BRUE did not occur in clusters); duration of BRUE <1 minute; no cardiopulmonary resuscitation by a trained medical provider was required; no concerning historical features (social risk factors for child abuse, respiratory illness or exposure, recent injury, other symptoms in days preceding the event (fever, fussiness, diarrhea, or decreased intake), administration or access to medications, history of episodic vomiting or lethargy, developmental delay or congenital anomalies, and family history of BRUE or sudden unexplained death in a sibling; and no concerning physical examination findings (any signs of injury, including bleeding, bruising or bulging anterior fontanel; altered sensorium; fever or toxic appearance; respiratory distress; heart murmur or gallop; decreased pulses; hepatomegaly or splenomegaly; and abdominal distension or vomiting) [5]. In neonates and small infants, nonacid GER, rather than acidic GER, plays a major role in causing the symptoms [2]. Nonacid GER can only be detected using multichannel intraluminal impedance with esophageal pH monitoring (MII-pH) and should, therefore, be a method of choice. However, few studies have assessed the association between GER and apnea/BRUE in small infants [2, 6, 7, 8]. Therefore, the aim of this study was to identify the characteristics of MII-pH monitoring in infants who had experienced BRUE.

This study demonstrated that only MII-pH monitoring can be used to assess whether BRUE is associated with GER. In addition, better outcomes were found in infants with GER episodes associated with BRUE, indicating the importance of proper diagnosis and treatment. Two possible mechanisms were involved in the causal relationship of BRUE induced by GER: reflex laryngospasm induced by stimulation of the distal esophagus by the refluxate and a chemoreflex in the larynx triggered by the presence of the reflux [20]. The latter is supported by Davies et al. [21], who showed that instillation of water into the pharynx of sleeping human infants elicited a range of chemoreflex responses with predominant receptors for chemoreflex-prolonged apnea located in the pharynx or larynx.

Among infants experiencing BRUE, MII-pH monitoring revealed more than 100 GER episodes in almost half of the patients. Most of these GER episodes were non-acid and weakly acidic, which is consistent with previous studies that showed an association between non-acid GER and acute events (an unexpected change in an infant's breathing, appearance, or behavior). If only pH-metry was used, diagnosis would be missed in the majority of children with BRUE induced by GER because none of the non-acid and weakly acid reflux episodes would have been registered. These findings emphasize the importance of MII-pH monitoring in the diagnostic work-up of infants with BRUE induced by GER.

The association between non-acid reflux and BRUE has been previously described. Jarasvaraparn et al. [22] reported pathological GER in 66% of 53 BRUE infants, most of which were non-acid, which was confirmed in the present study. However, they did not find significant differences in the number of reflux episodes between preterm and term infants [22]. Blasco-Alonso et al. [23] reported that of 39 infants presenting with ALTE who underwent 24-hour MII-pH monitoring, 33 were diagnosed with GER. Moreover, they also showed that the number of non-acid reflux episodes was more dominant than that of acid reflux episodes. Furthermore, the latter was confirmed in other studies investigating preterm and term infants with apnea and ALTE, showing that non-acid reflux was more common than acid reflux [24, 25]. This is in line with our findings, emphasizing the importance of the combined 24-hour MII-pH monitoring in the diagnostic workup of infants with apnea or BRUE suspected to be induced by GER.

In a study of 23 preterm infants and neonates with apnea, by using 24-hour MII-pH monitoring, Shin et al. [26] found that of the total 998 GER episodes, 407 were acidic, 590 were weakly acidic, and 1 was weakly alkaline, indicating that these 591 episodes would have been missed by pH monitoring alone. Moreover, they showed that of 5 patients with a positive symptom association, 3 were diagnosed by MII-pH, 1 by both MII-pH and conventional pH, and 1 by conventional pH. On the other hand, some studies have shown that the frequency of apneas does not increase following reflux episodes, suggesting that GER does not cause apnea [6, 27]. Cresi et al. [8] compared the frequency of GER events between the positive and negative SAP groups. Contrary to our results, they found greater MII-GER frequency in the SAP-positive group than in the negative SAP group. Possible explanations for the discrepancy between the studies could be differences in sample size, diverse clinical characteristics of included infants, and different recording methodologies.

Our study confirmed that in infants, weakly acidic reflux precedes BRUE more frequently than acidic reflux. The importance of weakly acidic reflux as a cause of respiratory phenomena in infants was previously reported by Wenzl et al. [28]. In their study of 22 infants, by using MII-pH monitoring, they found that of all reflux related with breathing abnormalities, 92% were weakly acidic. The explanation for the predominance of weakly acidic reflux might be related to pH buffering due to frequent milk intake in infants. Additionally, the composition and volume of feeding in infants also differed in the study sample.

The appropriate management strategy for infants with BRUE is still controversial due to the limited literature and good prognosis. The latter is in line with the results of our study, since we showed that infants with BRUE have a good prognosis. Moreover, Ari et al. [29] reported a retrospective study of 87 hospitalized infants younger than 1 year who experienced BRUE and concluded that infants hospitalized because of a BRUE seem to have a generally excellent prognosis. It seems that food thickeners treat visible regurgitation/vomiting in infants with GERD; however, their effect on overall GER episodes remains controversial [19]. Medical therapy for GER related to BRUE has not been adequately studied. A systematic review published by van der Pol et al. [30] evaluated the benefits of PPI in reducing GER-related symptoms in infants and found conflicting results. According to that review, omeprazole has no benefit, while pantoprazole and lanzoprazole are effective in reducing GER-related symptoms in infants.

It is worth mentioning that some evidence suggests an association between acid-suppressive medication in infancy and allergic disease in early childhood [31]; therefore, it is important to confirm and evaluate GER before initiation of medication therapy. This is in line with our findings, since better outcomes were found in those infants in whom a GER-BRUE association was initially observed. This could be explained by the fact that proper treatment led to symptom cessation. However, Duncan et al. [32] showed increased odds of discharge on acid-suppressing medications in infants with BRUE even without GER testing, despite the lack of medication efficacy.

This study has some limitations. First, our study had a small sample size of only 21 infants with BRUE who underwent MII-pH monitoring. Second, we did not combine polysomnography during the MII-pH study, which might determine sleep disorders that can also cause a BRUE. Third, MII-pH tracings were evaluated by only one investigator. Therefore, given some degree of inter-observer variability, it is questionable whether the results reported here would be the same if MII-pH tracings were evaluated by another one. Fourth, we acknowledge the lack of a healthy control group in this study. However, considering the procedure of 24-hour MII-pH monitoring, it is unethical to include infants who are symptom-free. Nevertheless, this study adds important data on the paucity of evidence in infants experiencing BRUE.

In conclusion, our results indicate the superiority of MII-pH monitoring over pH monitoring in the diagnosis of BRUE induced by GER. Further longitudinal studies are needed to investigate the role of esophageal MII-pH monitoring in high-risk BRUE infants.