Kathryn Hasenstab

Esophageal Reflexes Modulate Frontoparietal Response in Neonates: Novel Application of Concurrent NIRS and Provocative Esophageal Manometry

Central and peripheral neural regulation of swallowing and aerodigestive reflexes is unclear in human neonates. Functional near infrared spectroscopy (NIRS) is a noninvasive method to measure changes in oxyhemoglobin (HbO) and deoxyhemoglobin (HbD). Pharyngoesophageal manometry permits evaluation of aerodigestive reflexes. Modalities were combined to investigate feasibility and to test neonatal frontoparietal cortical changes during pharyngoesophageal (visceral) stimulation and/or swallowing. Ten neonates (45.6 ± 3.0 wk postmenstrual age, 4.1 ± 0.5 kg) underwent novel pharyngoesophageal manometry concurrent with NIRS. To examine esophagus-brain interactions, we analyzed cortical hemodynamic response (HDR) latency and durations during aerodigestive provocation and esophageal reflexes. Data are presented as means ± SE or percent. HDR rates were 8.84 times more likely with basal spontaneous deglutition compared with sham stimuli (P = 0.004). Of 182 visceral stimuli, 95% were analyzable for esophageal responses, 38% for HDR, and 36% for both. Of analyzable HDR (n = 70): 1) HbO concentration (μmol/l) baseline 1.5 ± 0.7 vs. 3.7 ± 0.7 poststimulus was significant (P = 0.02), 2) HbD concentration (μmol/l) between baseline 0.1 ± 0.4 vs. poststimulus -0.5 ± 0.4 was not significant (P = 0.73), and 3) hemispheric lateralization was 21% left only, 29% right only, and 50% bilateral. During concurrent esophageal and NIRS responses (n = 66): 1) peristaltic reflexes were present in 74% and HDR in 61% and 2) HDR was 4.75 times more likely with deglutition reflex vs. secondary peristaltic reflex (P = 0.016). Concurrent NIRS with visceral stimulation is feasible in neonates, and frontoparietal cortical activation is recognized. Deglutition contrasting with secondary peristalsis is related to cortical activation, thus implicating higher hierarchical aerodigestive protective functional neural networks.

Effect of nasal noninvasive respiratory support methods on pharyngeal provocation-induced aerodigestive reflexes in infants

The pharynx is a locus of provocation among infants with aerodigestive morbidities manifesting as dysphagia, life-threatening events, aspiration-pneumonia, atelectasis, and reflux, and such infants often receive nasal respiratory support. We determined the impact of different oxygen delivery methods on pharyngeal stimulation-induced aerodigestive reflexes [room air (RA), nasal cannula (NC), and nasal continuous positive airway pressure (nCPAP)] while hypothesizing that the sensory motor characteristics of putative reflexes are distinct. Thirty eight infants (28.0 ± 0.7 wk gestation) underwent pharyngoesophageal manometry and respiratory inductance plethysmography to determine the effects of graded pharyngeal stimuli (n = 271) on upper and lower esophageal sphincters (UES, LES), swallowing, and deglutition-apnea. Comparisons were made between NC (n = 19), nCPAP (n = 9), and RA (n = 10) groups. Importantly, NC or nCPAP (vs. RA) had: 1) delayed feeding milestones (P < 0.05), 2) increased pharyngeal waveform recruitment and duration, greater UES nadir pressure, decreased esophageal contraction duration, decreased distal esophageal contraction amplitude, and decreased completely propagated esophageal peristalsis (all P < 0.05), and 3) similarly developed UES contractile and LES relaxation reflexes (P > 0.05). We conclude that aerodigestive reflexes were similarly developed in infants using noninvasive respiratory support with adequate upper and lower aerodigestive protection. Increased concern for GERD is unfounded in this population. These infants may benefit from targeted oromotor feeding therapies and safe pharyngeal bolus transit to accelerate feeding milestones.

Mechanisms of cough provocation and cough resolution in neonates with bronchopulmonary dysplasia

Background:Cough and deglutition are protective mechanisms that defend against aspiration. We identified mechanisms associated with cough provocation as well as those associated with cough resolution in infants with bronchopulmonary dysplasia (BPD).Methods:Manometry signatures of cough were recognized in 16 premature infants with BPD undergoing concurrent esophageal manometry, respiratory inductance plethysmography, and nasal air flow measurements. Pretussive and post-tussive pharyngo-esophageal motility changes were analyzed. Mechanisms associated with cough and mechanisms that restored respiratory and esophageal normalcy were analyzed.Results:We analyzed 312 cough events during 88 cough clusters; 97% were associated with recognizable manometric patterns. Initial mechanisms related with coughing included nonpropagating swallow (59%), upper esophageal sphincter (UES) reflex contraction (18%), and lower esophageal sphincter (LES) relaxation (14%). UES and LES dysfunction was present in 69% of nonpropagating swallow-associated cough clusters. Mechanisms restoring post-tussive normalcy included primary peristalsis (84%), secondary peristalsis (8%), and none recognized (8%). UES contraction reflex was associated with cough clusters more frequently in infants on nasal continuous positive airway pressure (NCPAP) (OR = 9.13, 95% CI = 1.88–44.24).Conclusion:Cough clusters in infants with BPD had identifiable etiologies associated with esophageal events; common initial mechanisms were of upper aerodigestive origin, while common clearing mechanisms were peristaltic reflexes.

Somatic stimulation causes frontoparietal cortical changes in neonates: a functional near-infrared spectroscopy study.

Abstract. Palmar and plantar grasp are the foremost primitive neonatal reflexes and functions. Persistence of these reflexes in infancy is a sign of evolving cerebral palsy. Our aims were to establish measurement feasibility in a clinical setting and to characterize changes in oxyhemoglobin (HbO) and deoxyhemoglobin (HbD) concentration in the bilateral frontoparietal cortex in unsedated neonates at the crib-side using functional near-infrared spectroscopy (fNIRS). We hypothesized that bilateral concentration changes will occur upon somatic central and peripheral somatic stimulation. Thirteen preterm neonates (five males) underwent time 1, and six (two males) returned for time 2 (mean PMA=41.6 and 47.0 weeks, respectively). Signals from a total of 162 somatic stimuli responses were measured. Response amplitude, duration, and latency were log-transformed and compared between palmar, plantar, and oromotor stimuli using linear mixed models, adjusted for cap, electroencephalogram abnormality, time (1 versus 2), and Sarnat score, if necessary. The oromotor stimulus resulted in a 50% greater response than the palmar or plantar stimuli for HbO left and right hemisphere duration (p<0.0001). There were no other statistically significant differences between stimuli for any other outcome (p>0.05). Utilizing fNIRS in conjunction with occupational and physical therapy maneuvers is efficacious to study modifiable and restorative neurophysiological mechanisms.

The physiologic coupling of sucking and swallowing coordination provides a unique process for neonatal survival

Although the coordination of sucking and swallowing is critical for successful oral intake in neonates, the mechanisms that facilitate this coordination are not well understood. This investigation sought to clarify the mechanisms that facilitate this coordination, by comparing sucks that were coordinated with swallows and sucks that were completed in isolation.

Infant Pulmonary Function Testing and Phenotypes in Severe Bronchopulmonary Dysplasia

Using iPFT data, this study demonstrates 3 distinct phenotypes in sBPD, with the unexpected finding that 9% had exclusively restrictive disease. BACKGROUND: The definition of severe bronchopulmonary dysplasia (sBPD) is based on respiratory support needs. The management of a patient with sBPD remains empirical and is highly variable among providers. Our objective in this study was to test the hypothesis that infant pulmonary function testing (iPFT) would reveal distinct phenotypes in patients with established sBPD during the initial NICU stay. METHODS: A prospective cohort study with data prospectively collected on infants with sBPD from May 1, 2003, to June 30, 2016. iPFT data were used to classify the patients as obstructive, restrictive, or mixed. RESULTS: The median gestational age at birth was 25 weeks (interquartile range [IQR], 24–27 weeks) and the median birth weight was 707 g (IQR, 581–925 g). At the time of iPFT, the median postmenstrual age was 52 weeks (IQR, 45–63 weeks), and the median weight was 4.4 kg (IQR, 3.7–6.0 kg). There were 56 (51%) patients with obstructive, 44 (40%) with mixed, and 10 (9%) with restrictive phenotypes. Moderate or severe obstruction was seen in 86% of the obstructive group and 78% of the mixed group. Of the restrictive patients, 70% had moderate and 30% had mild restriction. Bronchodilator response was seen in 74% of obstructive, 63% of mixed, and 25% of restrictive patients. CONCLUSIONS: Our findings reveal that sBPD as it is currently defined includes distinct phenotypes. Future researchers of diagnostic approaches to this population should consider the development of bedside tests to define phenotypes, and researchers in future therapeutic trials should consider the use of pulmonary function phenotyping in patient recruitment.

Defining pharyngeal contractile integral during high-resolution manometry in neonates: a neuromotor marker of pharyngeal vigor

BackgroundPharyngeal contractility is critical for safe bolus propulsion. Pharyngeal contractile vigor can be measured by Pharyngeal Contractile Integral (PhCI): product of mean pharyngeal contractile amplitude, length, and duration. We characterized PhCI in neonates and examined the hypothesis that PhCI differs with mode of stimulation.MethodsNineteen neonates born at 38.6 (34–41) weeks gestation were evaluated at 42.9 (40.4–44.0) weeks postmenstrual age using high-resolution manometry (HRM). PhCI was calculated using: (a) Conventional and (b) Automated Swallow Detection algorithm (ASDA) methods. Contractility metrics of all pharyngeal regions were examined using mixed statistical models during spontaneous and adaptive state (pharyngeal and oral stimulus) swallowing.ResultsPhCI of oral stimuli swallows were distinct from pharyngeal stimuli and spontaneous swallows (P < 0.05). Correlation between conventional and ASDA methods was high (P < 0.001). PhCI increased with swallows for pharyngeal stimulation (P < 0.05) but remained stable for swallows with oral stimulation. PhCI differed between proximal and distal pharynx (P < 0.001).ConclusionsPhCI is a novel reliable metric capable of distinguishing (1) proximal and distal pharyngeal activity, (2) effects of oral and pharyngeal stimulation, and (3) effects of prolonged stimulation. Changes in pharyngeal contractility with maturation, disease, and therapies can be examined with PhCI.

338 Maturation and Stimulus-Volumes Modulate Pharyngeal Provocation Induced Pharyngeal Rhythms in Human Premature Infants

Introduction: Human disease models can help to better understand the pathophysiology and systematically characterize its consequences. Upper esophageal sphincter (UES) dysphagia is a common sequela of a number of disorders including CVA, reflux disease and aging. Intrinsic disorders of the UES such as fibrosis and inflammation can result in its diminished distensibility and restrict its opening causing dysphagia. Aim: To characterize the pharyngeal and UES deglutitive pressure phenomena in an experimentally induced restricted UES model in humans. Methods: We studied 15 patients (8 male, age 65±11 years) with various supraesophageal reflux symptoms. To induce UES restriction, we used a handmade simple device comprised of two components that could be comfortably worn around the neck: an elastic band and a cushion (5 X 3 X 2.5 CM). The cushion was placed horizontally at the center of the cricoid cartilage. By adjusting the elastic band, we selectively applied 0, 20, 30, 40 mmHg pressure perpendicular to the cricoid laryngeal structure inducing equivalent resistance against UES opening. In this model, the UES, in addition to relaxation, has to overcome the externally imparted pressure to open. Deglutitive pharyngeal and UES pressure phenomena were determined using high-resolution manometry, which recorded from entire pharynx, UES and proximal esophagus. We tested dry, 5 and 10ml swallows x 3. Results: Application of the external pressure band increased the length of the UES high pressure zone from 2.5 cm without the band to 3.1, 3.5 and 3.7 cm for 20, 30, 40mmHg cricoid restrictive pressure, respectively (p<0.05). Increased restrictive pressure against UES resulted in a significant increase in hypopharyngeal intra-bolus pressure (IBP) during all swallowed volumes (figure). Similarly, increased UES restrictive pressure resulted in increased UES nadir deglutitive relaxation pressure for all swallowed volumes (table, p<0.05). Swallowed volume had no effect on pharyngeal peak pressure, duration or velocity. None of these were affected by restrictive external UES pressures. Deglutitive velopharygeal pressure progressively increased with increased swallowed volume (p<0.05). These pressures were also not affected by UES restrictive external pressure. Conclusions: Acute experimental restriction of UES opening by external cricoid pressure in humans manifests the pressure characteristics of increased resistance to UES trans-sphincteric flow observed in disorders that are accompanied by reduced UES opening. These pressure characteristics include increased hypopharyngeal intra-bolus as well as nadir deglutitive UES relaxation pressures. This model can potentially be helpful in better understanding of UES pathophysiology. The effect of external cricoid (UES restrictive) pressure on UES nadir pressure

Sa1453 Mechanisms of Origin and Resolution of Cough Reflex in Human Neonates

BACKGROUND: Cough and swallowing are important protective mechanisms that maintain the integrity of the aero-digestive tract across the age spectrum. Premature neonates commonly experience swallowing and breathing problems. Consequently, anterograde or retrograde aspiration is a frequent concern in neonates with chronic lung disease such as bronchopulmonary dysplasia (BPD). AIMS: Our aims were to define the cough-initiating and subsequent post-tussive mechanisms that restore aero-digestive normalcy (defined as return of respiratory rhythm to baseline along with esophageal quiescence) in human premature infants suffering from BPD. METHODS: Ten premature neonates (born at 25.5 ± 0.6 wks gestation, studied at 42.2 ± 1.2 wks post-menstrual age), diagnosed with BPD underwent concurrent pharyngo-esophageal manometry, respiratory inductance plethysmography (using Respitrace) and nasal air flow (using thermistor) methods to determine the relationships between esophageal motility and respiratory phases using a specially designed manometric catheter with upper and lower esophageal sphincter (UES and LES) sleeves and 5 recording pressure ports from pharynx, proximal-, middle-, and distalesophagus, and stomach. Cough was recognized as forceful exhalation preceded by deep inhalation on the respiratory waveforms along with audible cough marked during the study. The dynamic characteristics were analyzed preceding and following cough events defined by manometry and Respitrace. RESULTS: 1) Cough initiating mechanisms during 59 cough episodes are shown (Table). 2) Post-tussive mechanisms that restored aero-digestive normalcy were primary peristalsis in 81.4% (48/59), secondary peristalsis in 15.3 % (9/59), and not recognizable in 3.4 % (2/59). CONCLUSIONS: 1) In premature neonates with BPD, non-propagating swallows and UES contractile reflexes are the dominant reasons for the origin of the cough reflex, indicating the majority of cough events have upper aero-digestive origins. 2) Primary peristalsis is the most important clearance mechanism for post-tussive restoration of respiratory normalcy and pharyngo-esophageal quiescence. 3) These phenomena underscore the importance of postnatal development of esophagus-airway reciprocal communications mediated by Glossopharyngeal and Vagal nerves in human premature neonates with BPD. *Supported by PPG-PO1 DK 068051 Mechanisms triggering cough in neonates.