Advances with Neonatal Aerodigestive Science in the Pursuit of Safe Swallowing in Infants: Invited Review

Abstract

Feeding, swallowing, and airway protection are three distinct entities. Feeding involves a process of sequential, neurosensory, and neuromotor interactions of reflexes and behaviors facilitating ingestion. Swallowing involves anterograde bolus movement during oral-, pharyngeal-, and esophageal phases of peristalsis into stomach. During these events, coordination with airway protection is vital for homeostasis in clearing any material away from airway vicinity. Neurological-airway-digestive inter-relationships are critical to the continuum of successful feeding patterns during infancy, either in health or disease. Neonatal feeding difficulties encompass a heterogeneous group of neurological, pulmonary, and aerodigestive disorders that present with multiple signs posing as clinical conundrums. Significant research breakthroughs permitted understanding of vagal neural pathways and functional aerodigestive connectivity involved in regulating swallowing and aerodigestive functions either directly or indirectly by influencing the supra-nuclear regulatory centers and peripheral effector organs. These neurosensory and neuromotor pathways are influenced by pathologies during perinatal events, prematurity, inflammatory states, and coexisting medical and surgical conditions. Approaches to clarify pathophysiologic mapping of aerodigestive interactions, as well as translating these discoveries into the development of personalized and simplified feeding strategies to advance child health are discussed in this review article.

Keywords: Aerodigestive reflexes; Deglutition; Deglutition disorders; GERD; Infant swallowing.

Figure 1. Schematic representation cumulative reflexes to pharyngo-esophageal stimuli

Pharyngeal (blue) or esophageal (green) stimulus evokes regional (pharyngo-esophageal reflex responses within the upper digestive tract), extraregional (responses within pulmonary and cardiac systems), and neurocognitive (sensation, perception, regulation of integrative reflexes) responses. Shaded color coded insets represent functional disturbances in the respectively shaded organs.

Figure 2. Mapping of pharyngo-esophageal reflexes in response to stimulation (pharyngeal: A, B and esophageal: C,D)

Potential pharyngo-esophageal responses to pharyngeal stimulation are A) Pharyngeal Reflexive Swallowing characterized by pharyngeal contraction, UES relaxation, esophageal body peristalsis, and pharyngo-LES-relaxation reflex, and B) Pharyngo-UES-Contractile Reflex characterized by UES contraction and pharyngo-LES-relaxation reflex. Potential responses to esophageal stimulation are C) Esophago deglutition reflex characterized by pharyngeal contraction, UES relaxation, esophageal body peristalsis, and esophago-LES- relaxation reflex and D) Secondary Peristalsis characterized by UES contraction, esophageal body peristalsis and esophageal-LES-relaxation reflex. DMN-Dorsal Motor Nucleus, NTS-Nucleus tractus solitaries, NA-Nucleus ambiguous, Px-pharynx, UES-upper esophageal sphincter, PE-proximal esophagus, ME-middle esophagus, DE-distal esophagus, LES-lower esophageal sphincter, Sto-stomach

Figure 3. Characterizing maturation effects of pharyngeal stimulus induced reflexes

A) Maturational comparison of responses to air and water pharyngeal infusion. (a) Response to air infusion 35 wk postmenstrual age. (b) Response to air infusion 39 wk postmenstrual age. (c) Response to water infusion 35 wk postmenstrual age. (d) Response to water infusion 39 wk postmenstrual age. Maturational differences are evident in both air and water infusion responses. Notice more rapid PRS onset in response to air infusions vs. water during both time-1 and time-2. Additionally, PLESRR onset time significantly decreases in response to air with time-2 infusions (vs. time-1). The magnitude of PLESRR is greater in response to water (vs. air) during time-2, as well as compared to water time-1. The duration of PLESRR is increases in response to water infusions (vs. air) at each time; however, PLESRR duration in response to water infusions decreases with maturation. LES, lower esophageal sphincter; PLESRR, pharyngo-lower esophageal sphincter relaxation reflex; PRS, pharyngeal reflexive swallow; UES, upper esophageal sphincter. B) Characterization of media and maturational responses. (a) Response latency to pharyngeal reflexive swallow (in seconds); *P = 0.04; **P = 0.007; triangle with a stroke: air; square with a stroke: water. (b) Frequency of pharyngeal reflexive swallow, %; *P = 0.0004; **P = 0.002; gray box: air; black box:water. (c) Frequency of complete propagation, %; *P = 0.01; **P = 0.007; gray box: air; black box: water. (d) Frequency of multiple pharyngeal reflexive swallows; %; *P < 0.0001; **P = 0.0003; gray box: air; black box: water. (e) Response latency to pharyngo-LES relaxation reflex (in seconds); *P = 0.05; triangle with a stroke: air; square with a stroke: water. (f) Frequency of pharyngo-LES relaxation reflex, %; *P = 0.01; gray box: air; black box: water. (g) Duration of LES nadir (in seconds); *P = 0.05; **P = 0.006; gray box: air; black box: water. (h) Magnitude of LES relaxation; mmHg; *P = 0.03; **P = 0.05; gray box: air; black box: water. Infants respond differently to air vs. water stimulus with maturation (time 1–35 wk postmenstrual age vs. time 2–39 wk postmenstrual age). Panels a–d characterize PRS responses to both media and maturation. Panels e–h characterize PLESRR responses to both media and maturation. PLESRR, pharyngo-lower esophageal sphincter relaxation reflex; PRS, pharyngeal reflexive swallow. Source: Jadcherla et al, Ped Research 2015.

Figure 4. Genesis of cough reflex: effect of esophageal and pharyngeal stimulus

Stimulus induced coughing associated with aerodigestive mechanisms: (a) Cough reflex in response to esophageal stimulation: Note (i) 2 ml air introduced into the mid-esophagus, (ii) associated with upper esophageal sphincter contractile reflex as the initial aerodigestive mechanism with respiratory rhythm disturbance (10.8 s) characterized by cessation or respiratory activity, (iii) cough, and (iv) complete primary peristalsis restoring aerodigestive and respiratory quiescence. (b) Cough reflex in response to pharyngeal stimulation: Note (i) 0.3 ml water introduced into the pharynx, the respiratory rhythm disturbance (74.7 s) characterized by irregularly spaced bursts of rapid breathing efforts during which there is (ii) multiple failed swallowing attempts as the initial aerodigestive mechanism, and (iii) multiple cough events, (iv) attempts of aerodigestive restoration, and (v) complete peristalsis restoring aerodigestive and respiratory quiescence. Source: Jadcherla et al, Ped Research 2015.

Figure 5. Pathophysiology of Aerodigestive reflexes: contributory factors and mechanisms

Contributory factors and potential central and regional mechanisms associated with neonatal dysphagia. BPD, bronchopulmonary dysplasia; CPG, central pattern generator; CNS, central nervous system; ENS, enteric nervous system; GERD, gastroesophageal reflux disease; GI, gastrointestinal; NEC, necrotizing enterocolitis. Source: Jadcherla, Am J Clin Nutr 2016.