Gastro‐Oesophageal Reflux Disease in Infants and Children: New Insights, Developments and Old Chestnuts

Research into the physiology and pathophysiology of pediatric gastro-oesophageal reflux (GOR) has advanced markedly over the last decade through the use of technologies such as micro-manometry, non-invasive breath testing and multichannel intraluminal impedance (MII). These techniques when used on their own or in combination have given us a much greater understanding of the mechanisms of ALL reflux (liquid, gas, acidic, weakly acidic and non acidic), oesophageal volume clearance and gastric emptying and how these mechanisms may be interrelated and altered in reflux disease. These techniques, above all, have demonstrated that transient lower oesophageal sphincter relaxation (TLOSR) is the predominant mechanism of all GOR in infants and children thus have clearly identified a therapeutic target for reflux inhibitor research, beyond current acid suppression based therapy. The impact of MII measurement on reflux diagnosis is potentially of great significance. This is because, in infants in particular, the pH of refluxate during majority of GOR episodes is above pH 4 due to gastric pH buffering related to frequent EBM/formula feeding (1). It is therefore impossible to detect ALL reflux using pH-based criteria. Intraluminal impedance measurement has been extremely useful in understanding reflux physiology and pathophysiology particularly during the early post-pradial period when GOR episodes and reflux symptoms occur most frequently. In this context MII measurement has clearly demonstrated the limitations of 24 hour oesophageal pH monitoring for the global assessment of reflux. Despite these limitations, oesophageal pH monitoring is still performed in most centres due to the fact it is readily available, cost effective and the result of the test can be interpreted in relation to established normative values for oesophageal acid expose time. In support of the continued use of 24 pH monitoring, even though this technique fails to record ALL reflux episodes, existing evidence shows that acid reflux is a significant pathophysiological factor in GOR disease. This appears to be the case in all human age groups, even premature infants as it has been shown that (TLOSR triggered) acid GOR occurs more commonly in patients with GOR disease compared to asymptomatic controls (2). How useful, therefore, is MII measurement in the diagnosis of pediatric reflux disease? In this early phase of establishment of this technology as a routine clinical diagnostic test, the absence of normative data is a significant limitation, which is difficult to overcome because, due to the invasive nature of the test, it would be unethical to evaluate healthy infants and children. One possible exception would be premature infants who were asymptomatic for reflux, but require supplemental feeding via nasogastric tube. Such infants could be assessed using an impedance catheter incorporating a feeding lumen. However, the categorisation of these infants as ‘normals’ would no doubt be questioned by those who would consider them to be abnormal by virtue of their prematurity and related poor progression onto full oral feeding as indicated by the continued requirement for nasogastric feeding. The use of adult normative data is also problematic as it is well established that the degree of ‘physiological reflux’ is higher in infants, particularly in the first 6 months of life. In the absence of impedance-based normative data, the major advantage of impedance measurement of reflux over pH probe is that it enables, by virtue of measuring ALL reflux, the precise temporal association of reflux events with putative ‘reflux-related symptoms’. For example, reflux as a cause of respiratory symptoms such as apnoea or cough, can be relatively easily determined by concurrent impedance measurement during polysomnographic assessment. The association of reflux with other symptoms such as irritability or crying could also be determined, provided that the recognition of symptoms was done objectively using time-coded video of audio recordings. Because impedance measurement is performed along the full length of the oesophagus, rather than at 1 or 2 positions as is the case with pH monitoring, it allows the proximal extent of reflux to be precisely determined. The occurrence of supra-oesophageal reflux that extends proximally into the pharynx and higher structures is more likely in infants due to a proportionately shorter oesophagus and lower ratio of oesophageal to gastric volume. Hence the likelihood of an interaction of refluxate with pharyngeal and laryngeal structures and the airways is increased. Such interactions will initiate neural reflexes that are protective against aspiration such as swallowing and/or glottal closure and these protective mechanisms are a potential cause of apnoea triggering. The ability to reliably determine super-oesophageal penetration of refluxate may therefore be a further advantage of impedance measurement over pH monitoring alone. An ‘Old Chestnut’, as the saying goes, is a story, idea or concept that is often repeated. In pediatric reflux research there are several Old Chestnuts relating to the physiology, pathophysiology and treatment of this disease. Often these are widely accepted, but based on empirical evidence when the hard scientific evidence is either inconclusive or incomplete. Such examples include the association of reflux with apnoea, the role of delayed gastric emptying (GE) in reflux disease and the role of manometry for the preoperative assessment of children undergoing antireflux surgery. With respect to these issues the published literature is substantial but on balance, negative or inconclusive. Frequent apnoea and bradycardia, particularly with feeding, is widely accepted to be a common clinical correlate of reflux disease. It is hypothesised that GOR may be a direct or indirect trigger for apnoeic episodes via the mechanisms related to poor coordination of swallowing with breathing and neural reflex mechanisms initiated by chemical stimulation of the larynx/pharynx or oesophageal distension. Alternatively the likelihood of GOR occurring may be exacerbated by a transient increase in the gastro-oesophageal pressure gradient resulting from airways obstruction. The evaluation of the temporal association between reflux and apnoea requires prolonged simultaneous monitoring of both reflux and respiratory events. Conflicting findings of either little or no association or an association between apnoea and GOR, recorded by either pH probe of MII, have been reported (3,4). Delayed gastric emptying is hypothesised to play a role in reflux disease, particularly a cause of regurgitation in those children with failure to thrive and/or vomiting. Both normal and delayed GE have been reported in children with GOR disease. More recent studies in infants suggest that GE was, if anything, faster in those infants with more severe GER disease (2). Studies that have examined the effect of posture on gastric emptying and/or GOR have consistently reported more rapid gastric emptying with right-side positioning compared to left-side positioning but, paradoxically, more reflux with right-side positioning compared to left-side positioning (5). No studies have similarly examined the relationship between GE and GOR in a setting of pharmacologically modified GE (eg erythromycin) although the GABA(b) agonist baclofen, which has been shown to delay gastric emptying in a mouse model (6), is known to reduce reflux through the inhibition of transient LES relaxation. On balance the literature on this issue suggests that gastric emptying and reflux poorly related, if at all. Fundoplication procedures mechanically increase the resistance to bolus flow across the lower oesophageal sphincter due to an elevated residual LOS pressure. This reduces the likelihood of reflux triggering during TLOSR but also places a greater demand on oesophageal peristalsis during bolus swallowing. The preoperative assessment of oesophageal motility in children may be useful to establish that oesophageal pressures initiated during peristalsis are normal and therefore sufficient to facilitate bolus flow across the fundoplicated sphincter. If a motility disorder is present, dysphagia may occur post operatively. Oesophageal manometry can be used for the diagnosis of a range of oesophageal motility disorders such as hypotensive peristalsis, non-specific motor disorder, diffuse oesophageal spasm and achalasia. Oesophageal manometry however cannot detect bolus flow and clearance, and therefore diagnostic assessments of oesophageal function based upon manometry alone rely upon the inference that oesophageal dismotility leads to ineffective oesophageal bolus transit. The most likely explains why manometric findings alone tend to be poorly predictive of the development of postoperative dysphagia. The concurrent assessment of manometry with bolus transit using MII improves the sensitivity and specificity of manometric assessments of oesophageal function. Recent studies have used MII to re-evaluate the minimal requirements for effective bolus propulsion by oesophageal peristalsis and suggest that effective passage of a bolus can be facilitated by oesophageal pressure waves of lower amplitude than defined previously based on fluoroscopic assessments of bolus flow (7,8). Indeed, up to one third of patients with oesophageal functional defects exhibit normal bolus transit (8). Thus, the combination of manometry and impedance for routine clinical oesophageal function testing may be better able to discriminate between normal and abnormal oesophageal function and therefore may be more predictive of dysphagia following anti-reflux surgery.