The definition of GERD in neonates/infants remains controversial and debates continue about the use and abuse of anti-reflux medical and surgical interventions (1
). Given the complexity of refluxate composition and inability to distinguish symptoms due to physiological from pathological GER in the NICU infant, there is little recourse than to define GERD in an individualized setting. Establishing objective evidence of GER events and the relationship of symptoms with the physical or chemical composition of the refluxate is essential to characterize GERD.
Several important findings were observed with GER events in this study: 1) NARE are of equal frequency as ARE (17
), and majority of events spread proximally above the UES; 2) average BCT was prolonged with mixed
vs. liquid, with supra-UES
vs. infra-UES; 3) ACT per acid pH-impedance event was lesser than pH-only events; 4) infra-UES GER was correlated with higher percentage of ARE compared to supra-UES GER, and supra-UES GER were associated with greater proportion of NARE; 5) 54% of GER events documented by pH-impedance were associated with symptoms, and over 87% of the pH-only events were associated with symptoms; 6) the occurrence of symptoms was similar among different physico-chemical characteristics, although the distribution of respiratory symptoms, sensory symptoms, and physical symptoms was different in relation to physico-chemical characteristics; 7) subgroup analysis did not show any difference among the group of patients with and without CLD in symptom distribution, although the occurrence of symptom-associated pH-only reflux events was higher with CLD patients and that the sensory symptoms were greater in this group than non-CLD patients; 8) symptomatic ARE were associated with longer ACT; 9) prolonged acidity was associated with symptomatic ARE in CLD patients unlike non-CLD patients.
In this study we categorized chemical GER events into ARE and NARE, as used before (8
). We did not consider NARE to be synonymous with weakly alkaline reflux events, as we did not technically measure the degree of alkalinity (pH>7).
It is clear from this study that symptoms can occur with varying physico- chemical properties of refluxate or of its varying ascent. Some infants are more sensitive in reacting with symptoms (as in CLD) than others (without CLD). It is also clear why the management of GERD based on symptoms only is controversial, as there are ‘reflux-type symptoms’ in the absence of GER. Management of GERD based on the frequency of GER is also controversial as a substantial proportion of GER were not associated with symptoms. Therefore, clinical trials based on symptom profiles only in neonates cannot offer definitive conclusions about GERD management. Similarly, clinical trials that have been based on the frequency of acid GER cannot offer definite conclusions about GERD management. The value of NARE and other background disease characteristics may have been ignored in such trials. Anti-reflux prophylactic medical therapies have been associated with necrotizing enterocolitis when given within the first weeks of life in premature infants, digestive problems, alteration of aero-digestive flora (20
), abnormalities of calcium absorption and osteopenia (3
). Furthermore, aspirates of gastric juice in those treated with acid suppressants can be deleterious to the bronchial airway, and inflammatory reaction induced by bacteria and endotoxins have been reported in those CLD patients who were managed on proton pump inhibitors for GERD (21
). Anti reflux surgical therapies have been reported to be associated with early satiety, dyspepsia, and inability to vomit, fundoplication break-up, and GI dysmotility (3
Interestingly, in our study, the prolonged acid clearance and its association with increased symptom frequency supports the hypothesis that chemosensitive stimulation and prolonged dwell of the acid GER in the esophagus activates visceral, somatic and sensory aero-digestive pathways resulting in the generation of symptoms (irritability and arching, grimace, cry, cough, gagging, stridor, physical movement, etc). Indeed all these symptoms involve nerve-muscle interaction at various levels, and these phenomena may support sensitization of esophageal afferents. Prolongation of ACT may be due to alteration of clearance mechanisms, esophageal dysmotility, or decreased acid neutralization or larger volume of refluxate. Furthermore sensitization may be greater in CLD infants as the SSI was greater in these infants compared to those with non-CLD infants. It is still unclear as to the best choice of symptom indices (SI, SSI, SAP) regardless of the age spectrum. In neonate this association may be even more challenging owing to multiplicity of symptoms and non-verbal nature of subject. Future studies must address the complexity of neonatal symptoms and best predictors in relation to GERD. The discordance between the SI and SSI is noted, and may be due to the chance of the SI being higher in the presence of many GER episodes and the SSI tends to be higher in the presence of many symptoms. From our study, useful conclusions can be drawn based on discordant indices, in that, the combination of a high SSI and a low SI indicates that the patient’s esophagus is sensitive to reflux but causes other than reflux are likely to contribute to the symptoms (22
). Although there were multiple symptoms belonging to different classifications, i.e., respiratory, sensory or physical, a given symptom was counted only once to overcome the overlap. However, each symptom may have different sensory-motor basis for its occurrence. This study lends support to the activation of esophageal-airway reflexes in the genesis of symptoms. For example, in pH-only reflux events, where there was no ascending spread of the refluxate, the ACT was longer and SSI was of increased frequency. The reasons why pH-only events occur are not entirely clear, and have been reported by others (12
). Such events may happen because of swallow-related GER events, transient LES relaxation or incomplete LES relaxation reflex. During such scenarios, activation of esophageal vagal afferents and airway and supra-UES efferents can result in aero-digestive defensive reflexes and symptoms, thus forming the basis for esophago-glottal closure and pharyngo-glottal closure reflexes (24
). These protective reflexes prevent the refluxate from reaching the airway.
This study also lends support to the association of symptoms not only with acid events but also with non-acid, gas, liquid or mixed events. Esophageal clearance of a bolus depends on multiple factors involved with esophageal motility, i.e., sensory-motor characteristics of the peristaltic reflexes (Deglutition reflex response, secondary peristalsis), upper esophageal sphincter contractile reflex, lower esophageal sphincter relaxation reflex (9
). We have shown recently that the recruitment of esophageal and airway defensive reflexes increases with volume dependent provocation, chemosensitive stimulation, or graded volumes of esophageal distention. Thus, treatment strategies based on modification of gastric acidity alone can be ineffective as acid is not the lone provoking agent.
GER may therefore be an important co-morbidity factor especially in NICU neonates (4
). Although GER (physiologic form) may be more frequent in neonates, distinction from GERD (pathologic form) can be difficult. As such, there are no definite standards to aid in the diagnosis of GERD, or of symptom recognition, or with the management of GER among NICU neonates. Lack of clarity with diagnosis and therapeutic targets for neonatal GERD can lead to empiric therapies with resultant consequences (3
). Recent Pediatric GERD guidelines from NASPGHAN/ESPGHAN offer little evidence on the evaluation and management of suspected GERD in neonates, and the expert committee recognized lack of quality evidence that supports a) the diagnosis of GERD, b) medical therapies or c) life style changing surgical therapies (3
In conclusion: 1) The current study is the first study to have attempted classification of the GER and symptom indices based on physico-chemical and spatio-temporal attributes of the refluxate in neonates. 2) Given the complexity of the composition of refluxate in the definition of GERD, the relationship of symptoms vs. the physic-chemical composition of the refluxate is essential, so that therapeutic targets can be appropriate. 3) Infants with intractable CLD merit evaluation for alternate pathophysiology. 4) Locus of esophageal provocation may influence aero-digestive symptoms. 5) The occurrence of respiratory symptoms regardless of spatio-temporal distribution of refluxate suggests the activation of esophago-airway and pharyngeal-airway reflex interactions. 6) Clinical significance as measured by SSI and SI and characterization of spatial-temporal-physical-chemical nature of GER events as defined by pH-impedance methods clarifies the definition of GERD, i.e., GER with increased frequency of respiratory, sensory or movement symptoms.