Alankar Gupta

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.

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.

The relationship between somatic growth and in vivo esophageal segmental and sphincteric growth in human neonates

Background: Measurement of aerodigestive tract length is an important determinant for accurate placement of esophageal probes and gavage tubes at the desired location. The relationship of esophageal body, upper esophageal sphincter (UES) and lower esophageal sphincter (LES) lengths with somatic growth in neonates is not well understood. Objectives: Our objectives were to (1) evaluate a relationship between segmental esophageal lengths and somatic growth parameters and (2) ascertain the relationship between segmental esophageal lengths and gestational age (GA) and postmenstrual age (PMA) in preterm and full-term born human neonates. Design/Methods: One hundred esophageal manometry studies were performed in 75 infants (30-60 weeks PMA) and the high-pressure zones of LES and UES identified. The distance from nares to LES and from nares to UES, esophageal body length, length of UES and LES derived from the manometry studies were correlated with somatic growth parameters. Growth rate of different esophageal segments was also determined in 26 subjects that underwent longitudinal studies. Analysis of variance and linear regression analysis were performed. Results: Seventy-five neonates of 23.0-40.6 weeks gestational age (0.6-4.4 kg) were studied at 29.1-58.6 weeks PMA (1.0-6.4 kg). Significant correlation (P < 0.001) of PMA and physical growth parameters with the growth of nares-LES (R2 = 0.8), esophageal body length (R2 = 0.6) and nares-UES (R2 = 0.4) were noted. Nares-to-LES length increased at a rate of 0.25 cm/wk PMA during 33.0-36.0 weeks of age. Conclusions: In vivo esophageal segmental lengths correlated strongly with somatic growth parameters and PMA in neonates. We speculate that this approach has many practical applications with the use of esophageal probes and catheters.

Evaluation and management of neonatal dysphagia: impact of pharyngoesophageal motility studies and multidisciplinary feeding strategy.

Background and objectives: Abnormal swallowing (dysphagia) among neonates is commonly evaluated using the videofluoroscopic swallow study (VSS). Radiological findings considered high risk for administration of oral feeding include nasopharyngeal reflux, laryngeal penetration, aspiration, or pooling. Our aims were to determine pharyngoesophageal motility correlates in neonates with dysphagia and the impact of multidisciplinary feeding strategy. Methods: Twenty dysphagic neonates (mean gestation ± standard deviation [SD] = 30.9 ± 4.9 weeks; median 31.1 weeks; range = 23.7–38.6 weeks) with abnormal VSS results were evaluated at 49.9 ± 16.5 weeks (median 41.36 weeks) postmenstrual age. The subjects underwent a swallow-integrated pharyngoesophageal motility assessment of basal and adaptive swallowing reflexes using a micromanometry catheter and pneumohydraulic water perfusion system. Based on observations during the motility study, multidisciplinary feeding strategies were applied and included postural adaptation, sensory modification, hunger manipulation, and operant conditioning methods. To discriminate pharyngoesophageal manometry correlates between oral feeders and tube feeders, data were stratified based on the primary feeding method at discharge, oral feeding versus tube feeding. Results: At discharge, 15 of 20 dysphagic neonates achieved oral feeding success, and the rest required chronic tube feeding. Pharyngoesophageal manometry correlates were significantly different (P < 0.05) between the primary oral feeders versus the chronic tube feeders for swallow frequency, swallow propagation, presence of adaptive peristaltic reflexes, oral feeding challenge test results, and upper esophageal sphincter tone. VSS results or disease characteristics had little effect on the feeding outcomes (P = NS). Conclusions: Swallow-integrated esophageal motility studies permit prolonged evaluation of swallowing reflexes and responses to stimuli under controlled conditions at cribside. The dysfunctional neuromotor mechanisms may be responsible for neonatal dysphagia or its consequences. Manometry may be a better predictor than VSS in identifying patients who are likely to succeed in vigorous intervention programs.

Correlation of Glottal Closure Using Concurrent Ultrasonography and Nasolaryngoscopy in Children: A Novel Approach to Evaluate Glottal Status

ObjectivesEndoscopic procedures to assess aerodigestive symptoms by evaluating glottal motion are not practical in neonates because of small nares, respiratory difficulties, or additional stress. Our objective was to determine the temporal correlation between concurrent nasolaryngoscopy (NLS) and ultrasonography (USG) evaluation of glottal motion.MethodsSimultaneous USG of the glottis was performed in 10 subjects (5 males, 5 females, age = 4.5 months to 7.1 years) that underwent diagnostic flexible outpatient NLS. The USG transducer was placed on the anterior neck at the level of the vocal cords. The video signals from NLS and USG were integrated and synchronized into real-time cine loops of 1-min duration.ResultsFrame-by-frame evaluation of 10,800 frames identifying glottal opening and closure time was compared between the two modalities by three observers and the timing of glottal closure was marked. Two investigators, blinded to NLS images, identified ultrasonographically determined glottal closure with 99% and 100% accuracy, and the mean probability of missing a closure frame was 0.007 (95% CI = 0.0008–0.024).ConclusionsTemporal characteristics of glottal motion can be quantified by USG with perfect reliability and safety. This method can be useful in measuring the presence and the duration of laryngeal adduction.

Neuromotor markers of esophageal motility in feeding intolerant infants with gastroschisis.

Background: Feeding problems in neonates with gastroschisis are commonly attributed to foregut dysmotility. However, the dysmotility mechanisms are not well understood. Objective: Our aim was to differentiate the pharyngoesophageal motility characteristics in neonates with gastroschisis compared with the controls. Specifically, the characteristics of swallowing, upper esophageal sphincter (UES), esophageal body, and lower esophageal sphincter (LES) were evaluated during basal state and upon provocation. Patients and Methods: Surgically repaired and recovered study infants with persistent feeding difficulties (n = 8; 36 ± 2 weeks gestational age) and controls (n = 8; 38 ± 2 weeks gestational age) were evaluated at 40 ± 2 weeks and 42 ± 2.5 weeks postmenstrual age, respectively. The basal and adaptive pharyngoesophageal motility characteristics were evaluated using a specially designed esophageal motility catheter with UES and LES sleeves and pneumohydraulic micromanometric water perfusion system at the crib side. Analysis of variance, chi-square, and t tests were applied; data are shown as mean ± standard deviation, and P < 0.05 was considered significant. Results: Birth weight was less in gastroschisis (P < 0.03, vs controls) and length was less at motility study (P < 0.01, vs controls). The study group (vs controls) needed prolonged respiratory support (21 ± 23 vs 1 ± 2 days; P < 0.001) and prolonged gavage feeding (167 ± 100 vs 9 ± 16 days; P < 0.01). Compared with the controls, the gastroschisis group had lower frequency (P < 0.05) and poor propagation of spontaneous swallows (P < 0.001), UES relaxation time was shorter (P < 0.05), rate of relaxation was faster (P < 0.001), and esophageal peristaltic propagation velocity was slower (P < 0.05). Upon esophageal provocation with air and liquids, frequency occurrence of the esophageal reflexes was low (P < 0.05) with respect to primary peristalsis, secondary peristalsis, UES contractile reflex, and LES relaxation reflex. Conclusions: In gastroschisis feeding milestones and respiratory milestones were delayed, basal pharyngoesophageal peristaltic failure was common, adaptive peristaltic reflexes were less frequent and failed to occur, and frequency occurrences of UES and LES responses were impaired. These neuromotor markers may provide clues to define the esophageal motor function abnormalities in infants with an abnormality thought to be limited to the intestine.

W1729 Volume Dependent Recruitment of Adaptive Esophageal Peristaltic and Upper Esophageal Sphincter Contractile Reflexes Is Preserved in Sleep State in Healthy Premature Infants

Background: Serotonin (5-HT) plays a major role in gastrointestinal (GI) functions. Of several subtypes of 5-HT receptors, 5-HT3 and 5-HT4 are involved in GI motility and pain. 5-HT4 receptor agonist tegaserod (TEG) has been shown to modulate visceral pain in both humans and animals. However, its underlying mechanism of action remains unknown. Aim: The objective of the present study is to examine the site of action of this drug in colorectal distension (CRD)-induced visceral pain in naive and post-inflamed sensitized rats. Methods: In each of 47 male Sprague-Dawley rats under fully anesthetized state, a bipolar electrode was implanted surgically into the external oblique muscle of the abdomen to measure the visceromotor response (VMR) represented as electrical activity (EMG) of the muscle to graded CRD (10-80mmHg). VMR was recorded in fully awake rats 72 hours following the surgery. To induce colonic inflammation, 0.5ml of tri-nitrobenzene sulfonic acid (TNBS) in 50% ethanol was infused into the colon under the influence of anesthesia and rats were tested 7days after TNBS injection. Drugs were injected either intraperitoneally (ip), intravenously (iv) or subcutaneously (sc). Electrophysiological recordings were made from the S1 sacral dorsal root receiving pelvic nerve innervating the colon. Responses of pelvic afferents to CRD were recorded before and after TEG injection. Results: Rats exhibited linear increasing VMR to graded CRD. TNBS-treated rats exhibited significantly (p<0.05 vs naive) greater VMR suggesting the sensitization following inflammation. High doses of TEG (5 and 10mg/ kg, ip) resulted in severe CNS effect including agitation, motor impairment and sedation (n=4). CNS effects were delayed in atropine (5mg/kg, ip) pretreated rats (n=4). Lower doses (0.5 and 1mg/kg, ip) of TEG did not produce any visible CNS effect. TEG (1mg/kg) significantly attenuated VMR in both naive and post-inflamed rats. Atropine failed to block the effect of TEG, suggesting that visceral analgesia was not mediated via muscariniccholinergic system. Selective 5-HT4 antagonist GR113808 (5mg/kg, sc) significantly reversed the effect of TEG. Similarly, opioid receptor antagonist naloxone (5mg/kg, iv) significantly reversed the effect of TEG. In electrophysiology experiments, TEG (1mg/kg, ip) did not attenuate the mechanotransduction of colonic pelvic nerve afferents in either naive or postinflamed rats. Conclusion: Results suggest that TEG produces visceral analgesia via the activation of central 5-HT4 receptors. Since opioid antagonist naloxone blocks the effect of TEG, it suggests that the central opioidergic system is linked to 5-HT4 mediated visceral analgesia.