Sudarshan R. Jadcherla

Characteristics of upper oesophageal sphincter and oesophageal body during maturation in healthy human neonates compared with adults

Abstract  We evaluated the upper oesophageal sphincter (UOS) relationship with oesophageal body during primary peristalsis (PP) sequences in healthy human neonates during maturation and compared with that of healthy adult volunteers. Forty‐nine studies were performed using a water perfusion manometry system and a specially designed oesophageal catheter with a UOS sleeve concurrent with submental electromyogram in 31 subjects in supine position (18 preterm neonates, 29.9 ± 2.5 weeks gestation; four full‐term neonates, 39.3 ± 1.0 weeks gestation; and nine adults, 18–65 years). The preterm neonates were studied longitudinally at 33 and 36 weeks postmenstrual age (PMA) and full‐term born at 40 weeks PMA. Data were compared between the groups to recognize the effects of gestation, postnatal age and ageing. We evaluated 403 consecutive spontaneous solitary swallows during maturation (preterm at time‐1 vs time‐2) and growth (preterm and full‐term vs adults) and observed significant (P < 0.05) differences in the basal UOS resting pressure, UOS relaxation characteristics, proximal and distal oesophageal body amplitude, duration, propagation and peristaltic velocity. Characteristics of UOS and PP are well‐developed by 33 weeks PMA and undergo further maturation during the postnatal period, and are significantly different from that of adult.

Regulation of Migrating Motor Complexes by Motilin and Pancreatic Polypeptide in Human Infants

In adults, migrating motor complexes (MMCs) appear to be partially under hormonal modulation by motilin and pancreatic polypeptide. Preterm infants do not exhibit MMCs until 32 wk of gestation. Although plasma concentrations of motilin are similar in infants and adults, it is not known if actual hormonal modulation of MMCs is present in infants. In the first study we assessed whether plasma concentrations of motilin and pancreatic polypeptide surge with the occurrence of MMCs in term infants. In the second study we assessed whether erythromycin, a motilin receptor agonist, could induce migrating motor activity in preterm and term infants. In the first study we recorded motor activity in nine term infants who had never been fed. We determined plasma concentrations of motilin and pancreatic polypeptide in the presence and absence of MMCs. In the second study we gave the motilin agonist erythromycin intragastrically to 21 infants at a range of 24-42 wk of gestation to assess whether migrating activity could be induced via the motilin receptor. In the first study, plasma concentrations of motilin were similar during the presence and absence of MMCs, as were plasma concentrations of pancreatic polypeptide. In the second study, the administration of erythromycin induced the appearance of migrating activity in 7 of 14 infants who were older than 32 wk but in none of the infants who was younger than 32 wk. Although the motilin receptor appears to be functionally present beyond 32 wk of gestation, as assessed by in indirect pharmacologic challenge, hormonal modulation of migrating activity in the neonate by plasma motilin and pancreatic polypeptide is absent.

Esophago-Glottal Closure Reflex in Human Infants: A Novel Reflex Elicited With Concurrent Manometry and Ultrasonography

BACKGROUND AND AIMS:Our aims were to identify and characterize the glottal response to esophageal mechanostimulation in human infants. We tested the hypotheses that glottal response is related to the type of esophageal peristaltic response, stimulus volume, and respiratory phase.METHODS:Ten infants (2.8 kg, SD 0.5) were studied at 39.2 wk (SD 2.4). Esophageal manometry concurrent with ultrasonography of the glottis (USG) was performed. The sensory-motor characteristics of mechanostimulation-induced esophago-glottal closure reflex (EGCR, adduction of glottal folds upon esophageal provocation) were identified. Mid-esophageal infusions of air (N = 41) were given and the temporal relationships of glottal response with deglutition, secondary peristalsis (SP), and the respiratory phase were analyzed using multinomial logistic regression models.RESULTS:The frequency occurrence of EGCR (83%) was compared (P < 0.001) with deglutition (44%), SP (34%), and no esophageal responses (22%). The odds ratios (OR, 95% CI) for the coexistence of EGCR with SP (0.4, 0.06–2.2), deglutition (1.9, 0.1–26), and no response (1.9, 0.4–9.0) were similar. The response time for esophageal reflexes was 3.8 (SD 1.8) s, and for EGCR was 0.4 (SD 0.3) s (P < 0.001). Volume-response relationship was noted (1 mL vs 2 mL, P < 0.05). EGCR was noted in both respiratory phases; however, EGCR response time was faster during expiration (P < 0.05).CONCLUSION:The occurrence of EGCR is independent of the peristaltic reflexes or the respiratory phase of infusion. The independent existence of EGCR suggests a hypervigilant state of the glottis to prevent retrograde aspiration during GER events.

Effect of Postnatal Maturation on the Mechanisms of Esophageal Propulsion in Preterm Human Neonates: Primary and Secondary Peristalsis

OBJECTIVES:The changes in esophageal propulsive characteristics during maturation are not known. Our aim was to define the effects of postnatal maturation on esophageal peristaltic characteristics in preterm human neonates. We tested the hypotheses that: (i) maturation modifies esophageal bolus propulsion characteristics, and (ii) the mechanistic characteristics differ between primary and secondary peristalsis.METHODS:Esophageal motility in 10 premature neonates (mean 27.5 weeks gestational age) was evaluated twice at 33.8 weeks (time 1, earlier study) and 39.2 weeks (time 2, later study) mean postmenstrual age. Esophageal manometry waveform characteristics (amplitude and duration, peristaltic velocity, and intrabolus pressure domains) were analyzed during spontaneous primary peristalsis and infusion-induced secondary peristalsis. Repeated-measures and unstructured variance–covariance or compound symmetry matrixes were used for statistical comparison. Values stated as least squares means±s.e.m. or percent.RESULTS:A total of 200 primary peristalsis and 227 secondary peristalsis events were evaluated. Between time 1 and time 2: (i) proximal esophageal waveform amplitude increased (P<0.02), with primary peristalsis (38±6 vs. 48±7 mm Hg) and with secondary peristalsis (34±6 vs. 46±5 mm Hg); (ii) distal esophageal waveform amplitude was similar (P=NS), with primary peristalsis (42±4 vs. 43±4 mm Hg) and secondary peristalsis (29±3 vs. 32±4 mm Hg); (iii) proximal esophageal waveform onset to peak duration decreased (P=0.02) with primary (2.6±0.3 vs. 1.9±0.1 s, P<0.003) and with secondary peristalsis (2.2±0.2 vs. 1.8±0.1 s); (iv) distal esophageal waveform onset to peak duration decreased (P=0.01) with primary (2.4±0.3 vs. 1.8±0.1 s) and with secondary peristalsis (1.9±0.2 vs. 1.5±0.1 s); (v) effects of identical stimulus volume on intrabolus pressure were similar (P=NS); however, greater infusion volumes (2 vs. 1 ml) generated higher intrabolus pressure at both time 1 and time 2 (both Ps<0.05). Between primary and secondary peristalsis (mechanistic variable): (i) no differences were noted at either period, with proximal esophageal waveform amplitudes (P=NS); (ii) differences were noted with distal esophageal waveform amplitudes at each time period (P=0.0002); (iii) no differences were noted with both esophageal waveforms duration at either period (P=NS); (iv) peristaltic velocity was faster with secondary peristalsis than with primary peristalsis at either period (at earlier study, 7.9±1.4 vs. 2.5±1.4 cm/s and at later study 6.2±1.6 vs. 1.2±1.5 cm/s, both Ps<0.01).CONCLUSIONS:In preterm neonates, longitudinal maturation modulates the characteristics of primary and secondary peristalsis. Differences in proximal striated muscle and distal smooth muscle activity during peristalsis are evident. Peristaltic velocity is faster with secondary peristalsis. These findings may represent maturation of central and peripheral neuromotor properties of esophageal bolus propulsion in healthy preterm human neonates.

Spatiotemporal Characteristics of Acid Refluxate and Relationship to Symptoms in Premature and Term Infants with Chronic Lung Disease

BACKGROUND AND OBJECTIVES:The prevalence of gastroesophageal reflux (GER) is high among infants with chronic lung disease (CLD), and the associated pathogenic mechanisms are not clear. The relationship of symptoms to the extent or duration of acid reflux events (AREs) is not well known in preterm or term infants. Our aim was to evaluate the relationship between spatial (height) and temporal (duration) characteristics of AREs (pH <4.0) with symptoms in CLD. We tested the hypothesis that in infants with CLD, AREs into the pharynx are associated with increased symptom occurrence and delayed clearance.METHODS:Nine infants born at 29.8 ± 5.5 wk gestation (mean ± SD, range 24.7–39.0 wk) with CLD were evaluated for GER at 49.7 ± 8.0 wk postmenstrual age (mean ± SD, range 39.9–67.4 wk). Esophageal manometry was first performed to determine the nares–lower esophageal sphincter (LES) distance. A pH-impedance probe was placed at 87% of the nares–LES distance, and a recording was performed for about 24 h at cribside. Symptoms (respiratory, sensory, and movement) were documented by nurses that were blinded to the pH-impedance recordings. A symptom was considered associated with an ARE if it occurred 2 min before, during, or 2 min after the ARE. The proximal extent and associated clearance mechanisms were correlated with symptom sensitivity index (SSI = number of AREs with symptoms/total AREs * 100). Multiple logistic regression methods, analysis of variance (ANOVA) models, and χ2 tests were performed. Data are described as median, mean ± SD, or %.RESULTS:A total of 511 AREs, based on pH-Impedance methods, were analyzed from 203 h of recordings in the nine infants. The distal esophagus was the maximal height reached in 80% of AREs (P < 0.001, compared to other esophageal segments). Overall 33% of the AREs were associated with symptoms, and an SSI of 77% was noted with high AREs into the pharynx. The average acid clearance time was prolonged with symptomatic AREs versus nonsymptomatic AREs by 3.5-fold (P < 0.001).CONCLUSIONS:The occurrence and frequency of symptoms with AREs depend on the most proximal extent of the ARE and the acid clearance time.

Definition and implications of novel pharyngo-glottal reflex in human infants using concurrent manometry ultrasonography.

OBJECTIVES:Glottal relationships during swallowing dominate the etiology of dysphagia. We investigated the pharyngo-glottal relationships during basal and adaptive swallowing.METHODS:Temporal changes in glottal closure kinetics (frequency, response latency, and duration) with spontaneous and adaptive pharyngeal swallows were defined in 12 infants using concurrent pharyngoesophageal manometry and ultrasonography of the glottis.RESULTS:Frequency, response latency, and duration of glottal closure with spontaneous swallows (n=53) were 100%, 0.27±0.1 s, and 1±0.22 s, respectively. The glottis adducted earlier (P<0.0001 vs. upper esophageal sphincter relaxation) within the same respiratory phase as swallow (P=0.03). With pharyngeal provocations (n=41), glottal adduction (pharyngo-glottal closure reflex (PGCR)) was noted first and then again with pharyngeal reflexive swallow (PRS). The frequency, response latency, and duration of glottal closure with PGCR were 100%, 0.56±0.13 s, and 0.52±0.1 s, respectively. Response latency to PRS was 3.24±0.33 s; the glottis adducted 97% within 0.36±0.08 s in the same respiratory phase (P=0.03), and remained adducted for 3.08±0.71 s. Glottal adduction was the quickest with spontaneous swallow (P=0.04 vs. PGCR), and the duration was the longest during PRS (P<0.005 vs. PGCR or spontaneous swallow).CONCLUSIONS:Glottal adduction during basal or adaptive swallowing reflexes occurs in either respiratory phase, thus ensuring airway protection against pre-deglutitive or deglutitive aspiration. The independent existence and magnitude (duration of adduction) of PGCR suggests a hypervigilant state of the glottis in preventing aspiration during swallowing or during high gastroesophageal reflux events. Investigation of pharyngeal–glottal relationships with the use of noninvasive methods may be more acceptable across the age spectrum.

Lower esophageal sphincter relaxation reflex kinetics: effects of peristaltic reflexes and maturation in human premature neonates

We defined the sensory-motor characteristics of the lower esophageal sphincter relaxation (LESR) (stimulus threshold volume, response onset, and relaxation period, relaxation magnitude, nadir) during maturation in human neonates. We hypothesized that LESR kinetics differs during maturation and with peristaltic reflex type. Basal and adaptive esophageal motility testing was performed (N = 20 premature neonates) at 34.7 and 39.1 wk (time 1 and time 2). Effects of midesophageal provocation with graded stimuli (N = 1,267 stimuli, air and liquids) on LESR kinetics during esophagodeglutition response (EDR) and secondary peristalsis (SP) were analyzed by mixed models. Frequency of LESR with basal primary peristalsis were different during maturation (P = 0.03). During adaptive responses with maturation, 1) the frequencies of peristaltic reflexes and LESR were similar; 2) liquid stimuli resulted in a shorter LESR response latency and LESR nadir and greater LESR magnitude (all P < 0.05); 3) media differences were noted with LESR response latency (air vs. liquids, P < 0.02); and 4) infusion flow rate-LESR were different (P < 0.01 for air and liquids). Mechanistically, 1) frequency of LESR was greater during peristaltic reflexes at both times (vs. none, P < 0.0001); 2) LESR response latency, duration, and time to complete LESR were longer with EDR (all P < 0.05, vs. SP at time 2); and 3) graded stimulus volume LESR were different for air and liquids (P < 0.01). In conclusion, sensory-motor characteristics of LESR depend on the mechanosensitive properties of the stimulus (media, volume, flow), type of peristaltic reflex, and postnatal maturation. Maturation modulates an increased recruitment of inhibitory pathways that favor LESR.

Manometric evaluation of esophageal-protective reflexes in infants and children

In adults, esophageal motor responses facilitate forward, or aboral, transit during swallowing, and protect the aerodigestive tract during retrograde movement of the bolus, which may occur with gastroesophageal reflux. It is unclear in the pediatric literature whether the activation of appropriate esophageal motor defense responses occurs during these events in infants. This investigation therefore studied the esophageal motor responses during the basal state and upon esophageal stimulation in infants. Using the water-perfusion manometry technique and a specially designed manometric catheter, 3 likely mechanisms that may protect the aerodigestive tract were recognized: secondary peristalsis, esophago-upper esophageal sphincter contractile reflex, and esophagodeglutition response.

Gastroesophageal reflux in the neonate

Physiologic GER may be a maturational phenomenon, because infants outgrow this over time. Many aspects of GERD in neonates and young infants remain incompletely understood, however, particularly the pathophysiology and long-term problems in high-risk neonates. Diagnostic and therapeutic availability is vital in infants with GER and airway compromise, apnea events, or chronic lung disease. Although most infants improve with conservative therapy, there is a dire lack of ideal pharmacologic agents that work on all the mechanisms of GER with the least consequences. Studies that permit diagnosis not only of the disease but also of the causal mechanism, better feeding strategies, and prevention of morbidity from GERD will be beneficial.

Esophageal and upper esophageal sphincter motor function in babies

The incidence of concomitant feeding and airway-related disorders is high among premature infants and babies with congenital anomalies. The cause of these disorders is commonly attributed to foregut dysfunction, and the approach to diagnosis and management is largely empiric. Management strategies usually are based on the failure to improve feeding tolerance with advancing maturation and the presence of supraesophageal complications of reflux disease. Very little information exists about the functional development of deglutitive and airway-protective mechanisms in neonates. The purpose of this article is to review the available information on esophageal and upper esophageal sphincter (UES) motor function in human infants. Understanding the maturation of the motor functions of the pharynx-UES and esophagus and related airway-protection responses is essential for determining the pathophysiologic basis of feeding-related airway disorders.