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Understanding the neonatal oesophageal mysteries of gastro‐oesophageal reflux disease using baseline impedance

Definition of gastro-oesophageal reflux disease (GORD) or of the causal mechanisms of symptoms among convalescing enterally fed infants in theneonatal intensive careunit (NICU) remains a mystery. Using the pH-Impedance studies, GORD symptom associations can be determined by analysing the acid reflux index, and the presence, proximal extent and magnitude of the physico-chemical and spatiotemporal characteristics of the refluxate (1). When the symptoms are documented in real time, then the timing of the symptoms with reflux events using symptom-associated probability indices can be computed. All these methods can speculate an association at best (2). However, pathophysiology-based diagnosis of GORD symptoms is still a conundrum across the age spectrum, and definitive diagnosis or therapies remain to be developed that offers promise to the symptomatic infant. Parental experiences and physicians’ perception of these troublesome symptoms as related to GORD are evident from the high prevalence GORD diagnosis and the use of acid-suppressive therapies (3), along with or without dietary or postural modifications. Attribution of these symptoms due to GORD or when to call them ‘troublesome’ warrants appropriate tests, so that specific therapies can be developed. This manuscript from Rossor et al. leads us in that direction (4). The authors are to be congratulated for taking an old tool, that is pH-multichannel intraluminal impedance (pH-MII) methods to answer new questions concerning oesophageal mucosal integrity by aiming to determine the reliability of pH-metry vs impedance-metry in detecting the frequency of GOR. Specifically, they found that acid reflux was associated with lower distal oesophageal baseline impedance. They considered acid reflux index (% acid exposure duration over a 24-hour period) as abnormal if it was >10% or >79 impedance events during a 24-hour study. Significant findings were that one in five had abnormal studies, and baseline impedance negatively correlated with acid reflux index as well as with maximum acid clearance time. These findings suggest that baseline impedance is lower (i.e. mucosal integrity is compromised) with greater acid reflux index or acid clearance time. Their findings may be different from the other studies, and this may be due to the studied neonatal population, which is unique with rapidly changing physiology and pathophysiology. In a different study, the loss of mucosal integrity was associated with possible inflammation resulting from high acid reflux index and prolonged acid clearance among older children who underwent endoscopy, baseline impedance, biopsy and pH-Impedance tests (5). Validation and categorisation of the distal oesophageal baseline impedance correlated with 100% prediction with grade 3 and macroscopic esophagitis (5). Similarly, studies in adults using endoscopy and baseline impedance and biopsy diagnosis along with implanted mucosal electrodes to detect impedance have been carried out that yielded highly significant correlations between lower baseline impedance (6) and oesophagitis, nonerosive oesophagitis, pathological acid exposure or GORD (7). Endoscopy studies to diagnose oesophageal inflammation in this highly vulnerable NICU infant population can be highly invasive and difficult; however, based on cumulative evidence, it is highly likely that mucosal baseline impedance is low when regional mucosal integrity is compromised. True diagnosis and predictability of GORD remain controversial despite the use of multiple tests (8). The baseline impedance offers hope in clarifying the pathophysiology of disease. Reliability of baseline impedance is dependent on the contact of the impedance sensor with the oesophageal mucosa, as opposed to it being in the lumen. Suturing the probe to the mucosa can be invasive and requires endoscopy and is not practical. However, as the oesophagus is a collapsed organ at resting baseline state, the impedance rings are likely to be in close contact with the mucosa, and therefore, the values are reflective of ion movement changes at the mucosal level. Because electrical impedance is inversely related to the ionic concentration and highly correlated with transepithelial resistance, at baseline, impedance is high. This has been attributed to an increased conductivity of the oesophageal mucosa related to an increase in transcellular ionic transport caused by dilated intercellular spaces. Evidence from histology and baseline impedance studies in animal and human models suggests that the greater the distance between the mucosal intercellular spaces the lower the baseline impedance (9). These data suggest that low impedance levels do indeed indicate the compromise of the integrity of the oesophageal mucosa and have the potential for being a marker of the existence of mucosal