Characterizing Biomarkers of Continuous Peristalsis and Bolus Transit during Oral Feeding in Infants at pH-Impedance Evaluation: Clinical and Research Implications.

OBJECTIVE: To examine the biomarkers of pharyngoesophageal swallowing during oral feeding sessions in infants undergoing pH-impedance testing and determine if swallow frequencies are distinct between oral- and partially oral-fed infants. STUDY DESIGN: One oral feeding session was performed in 40 infants during pH-impedance studies and measurements included swallowing frequency, multiple swallow rate, air and liquid swallow rates, esophageal swallow clearance time (ESCT), and gastroesophageal reflux (GER) characteristics. Linear and mixed statistical models were applied to examine the swallowing markers and outcomes. RESULTS: Infants (30.2 ± 4.4 weeks birth gestation) were evaluated at 41.2 ± 0.4 weeks postmenstrual age (PMA). Overall, 10,675 swallows were analyzed during the oral feeding sessions (19.3 ± 5.4 min per infant) and GER events were noted (2.5 ± 0.3 per study). Twenty-four-hour acid reflux index (ARI) was 9.5 ± 2.0%. Differences were noted in oral- and partially oral-fed infants for: volume consumption (p<0.01), consumption rate (p<0.01), and length of hospital stay in days (p<0.01). Infants with ARI >7% had greater frequency of swallows (p=0.01). The oral-fed group had greater ARI (12.7 ± 3.3%, p=0.05). CONCLUSIONS: Oropharyngeal swallowing regulatory characteristics decrease over the feeding duration and were different between ARI >7% vs ≤7%. Although GER is less in infants who are partially oral-fed, the neonates with increased acid exposure achieved greater oral intakes and shorter hospitalizations, despite the presence of comorbidities. Pharyngoesophageal stimulation as during consistent feeding or GER events can activate peristaltic responses and rhythms, which may be contributory to the findings.

The Irritable Infant in the Neonatal Intensive Care Unit: Risk Factors and Biomarkers of Gastroesophageal Reflux Disease.

OBJECTIVES: To determine risk factors for arching/irritability in high-risk infants and examine the significance of comorbidity and gastroesophageal reflux (GER) characteristics. STUDY DESIGN: Retrospective analysis of 24-hour pH-impedance studies of symptomatic infants in a neonatal intensive care unit (ICU) (n = 516, 30.1 ± 4.5 weeks of gestation, evaluated at 41.7 ± 3.2 weeks postmenstrual age) was conducted. Comparisons were made between infants with >72 vs ≤72 arching/irritability events per day. We characterized risk factors for arching/irritability along with clinical, pH-impedance, and outcome correlates. RESULTS: Of 39 973 arching/irritability events and 42 155 GER events, the averages per day were 77.6 ± 41.0 and 81.7 ± 48.2, respectively. Acid reflux and impedance bolus characteristics were not significantly different between infants with >72 and ≤72 arching/irritability events (P ≥ .05). The odds ratios (ORs) and 95% confidence intervals (CIs) adjusted for postmenstrual age and weight at evaluation were significant for risk factors of preterm birth (2.3 [1.2-4.4]), moderate or severe neuropathology (2.0 [1.1-3.6]), and presence of oral feeding at testing (1.57 [1.07-2.30]). CONCLUSIONS: Acid GER disease is unlikely the primary cause of arching/irritability and empiric treatment should not be used when arching/irritability is present. Prematurity and neurologic impairment may be more likely the cause of the arching/irritability. Arching/irritability may not be a concern in orally fed infants.

Global State of the Art and Science of Childhood Dysphagia: Similarities and Disparities in Burden.

Feeding/swallowing and airway protection are complex functions, essential for survival, and continue to evolve throughout the lifetime. Medical and surgical advances across the globe have improved the long-term survival of medically complex children at the cost of increasing comorbidities, including dysfunctional swallowing (dysphagia). Dysphagia is prominent in children with histories of preterm birth, neurologic and neuromuscular diagnoses, developmental delays, and aerodigestive disorders; and is associated with medical, health, and neurodevelopmental problems; and long-term socioeconomic, caregiver, health system, and social burdens. Despite these survival and population trends, data on global prevalence of childhood dysphagia and associated burdens are limited, and practice variations are common. This article reviews current global population and resource-dependent influences on current trends for children with dysphagia, disparities in the availability and access to specialized multidisciplinary care, and potential impacts on burdens. A patient example will illustrate some questions to be considered and decision-making options in relation to age and development, availability and accessibility to resources, as well as diverse cultures and family values. Precise recognition of feeding/swallowing disorders and follow-up intervention are enhanced by awareness and knowledge of global disparities in resources. Initiatives are needed, which address geographic and economic barriers to providing optimal care to children with dysphagia.

Neurodevelopmental Outcomes of Extremely Preterm Infants Fed Donor Milk or Preterm Infant Formula: A Randomized Clinical Trial.

Importance: Maternal milk feeding of extremely preterm infants during the birth hospitalization has been associated with better neurodevelopmental outcomes compared with preterm formula. For infants receiving no or minimal maternal milk, it is unknown whether donor human milk conveys similar neurodevelopmental advantages vs preterm formula. Objective: To determine if nutrient-fortified, pasteurized donor human milk improves neurodevelopmental outcomes at 22 to 26 months' corrected age compared with preterm infant formula among extremely preterm infants who received minimal maternal milk. Design, Setting, and Participants: Double-blind, randomized clinical trial conducted at 15 US academic medical centers within the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network. Infants younger than 29 weeks 0 days' gestation or with a birth weight of less than 1000 g were enrolled between September 2012 and March 2019. Intervention: Preterm formula or donor human milk feeding from randomization to 120 days of age, death, or hospital discharge. Main Outcomes and Measures: The primary outcome was the Bayley Scales of Infant and Toddler Development (BSID) cognitive score measured at 22 to 26 months' corrected age; a score of 54 (score range, 54-155; a score of ≥85 indicates no neurodevelopmental delay) was assigned to infants who died between randomization and 22 to 26 months' corrected age. The 24 secondary outcomes included BSID language and motor scores, in-hospital growth, necrotizing enterocolitis, and death. Results: Of 1965 eligible infants, 483 were randomized (239 in the donor milk group and 244 in the preterm formula group); the median gestational age was 26 weeks (IQR, 25-27 weeks), the median birth weight was 840 g (IQR, 676-986 g), and 52% were female. The birthing parent's race was self-reported as Black for 52% (247/478), White for 43% (206/478), and other for 5% (25/478). There were 54 infants who died prior to follow-up; 88% (376/429) of survivors were assessed at 22 to 26 months' corrected age. The adjusted mean BSID cognitive score was 80.7 (SD, 17.4) for the donor milk group vs 81.1 (SD, 16.7) for the preterm formula group (adjusted mean difference, -0.77 [95% CI, -3.93 to 2.39], which was not significant); the adjusted mean BSID language and motor scores also did not differ. Mortality (death prior to follow-up) was 13% (29/231) in the donor milk group vs 11% (25/233) in the preterm formula group (adjusted risk difference, -1% [95% CI, -4% to 2%]). Necrotizing enterocolitis occurred in 4.2% of infants (10/239) in the donor milk group vs 9.0% of infants (22/244) in the preterm formula group (adjusted risk difference, -5% [95% CI, -9% to -2%]). Weight gain was slower in the donor milk group (22.3 g/kg/d [95% CI, 21.3 to 23.3 g/kg/d]) compared with the preterm formula group (24.6 g/kg/d [95% CI, 23.6 to 25.6 g/kg/d]). Conclusions and Relevance: Among extremely preterm neonates fed minimal maternal milk, neurodevelopmental outcomes at 22 to 26 months' corrected age did not differ between infants fed donor milk or preterm formula. Trial Registration: ClinicalTrials.gov Identifier: NCT01534481.

Characterization of Esophageal and Sphincter Reflexes across Maturation in Dysphagic Infants with Oral Feeding Success vs Infants requiring Gastrostomy.

To test the hypothesis that esophageal and sphincteric sensory-motor reflexes are distinct across maturation in infants with dysphagia receiving gastrostomy-tube (G-tube). This is a retrospective review of 29 dysphagic infants (N = 15 study requiring gastrostomy, N = 14 age matched control achieving oral feeds) that underwent longitudinal pharyngeal-esophageal manometry at 42.3 (37-50.2) weeks postmenstrual age (PMA) and 48.9 (43.3-57.9) weeks PMA. Graded stimuli (0.1-5 mL) of varying media (air, water, and apple juice) tested esophageal peristaltic reflex, upper esophageal sphincter contractile reflex (UESCR), and lower esophageal sphincter relaxation reflex (LESRR). Comparisons were performed between study and controls and across maturation (time-1 vs time-2). Data represented as mean ± SE or OR (95% CI). Across maturation (time-1 vs time-2): Study infants did not exhibit significant differences across in peristaltic, UES, or LES reflexes (all p > 0.05). In contrast, controls exhibited increased UES resting pressure (13 ± 3 vs 17 ± 3 mmHg, p = 0.001), LES resting pressure (22 ± 3 vs 25 ± 3 mmHg, p < 0.009), LES nadir pressure (0.5 ± 1 vs 4.3 ± 1 mmHg, p = 0.001), and esophago-deglutition responses [2.5 (1.23-4.88), p = 0.04], and decreased secondary peristalsis [0.44 (0.31-0.61), p = 0.001], UESCR [0.4 (0.25-0.65), p = 0.001], LESRR [0.4 (0.24-0.75), p = 0.01], and symptoms [0.6 (0.45-0.83), p = 0.005]. Among infants with dysphagia, esophageal provocation induced peristaltic reflex, UESCR, and LESRR advance with longitudinal maturation when infants are oral-fed successfully, but not in those who received gastrostomy. Underlying mechanisms may be related to esophageal sensitivity, afferent or efferent transmission, and coordination of upstream excitation and downstream inhibition, which can be potential therapeutic targets for improving feeding capabilities after gastrostomy placement in infants with dysphagia.

Pharyngoesophageal motility reflex mechanisms in the human neonate: importance of integrative cross-systems physiology.

Swallowing is a critical function for survival and development in human neonates and requires cross-system coordination between neurological, airway, and digestive motility systems. Development of pharyngoesophageal motility is influenced by intra- and extrauterine development, pregnancy complications, and neonatal comorbidities. The primary role of these motility reflex mechanisms is to maintain aerodigestive homeostasis under basal and adaptive biological conditions including oral feeding, gastroesophageal reflux, and sleep. Failure may result in feeding difficulties, airway compromise, dysphagia, aspiration syndromes, and chronic eating difficulties requiring prolonged tube feeding. We review the integration of cross-systems physiology to describe the basis for physiological and pathophysiological neonatal aerodigestive functions.

Differentiating esophageal sensitivity phenotypes using pH-impedance in intensive care unit infants referred for gastroesophageal reflux symptoms.

BACKGROUND: To identify esophageal sensitivity phenotypes relative to acid (SAcid), bolus (SBolus), acid and bolus (SAcid+Bolus), and none (SNone) exposures in infants suspected with gastroesophageal reflux disease (GERD). METHODS: Symptomatic infants (N = 279) were evaluated for GERD at 42 (40-45) weeks postmenstrual age using 24-h pH-impedance. Symptom-associated probability (SAP) for acid and bolus components defined esophageal sensitivity: (1) SAcid as SAP ≥ 95% for acid (pH < 4), (2) SBolus as SAP ≥ 95% for bolus, (3) SAcid+Bolus as SAP ≥ 95% for acid and bolus, or (4) SNone as SAP < 95% for acid and bolus. RESULTS: Esophageal sensitivity prevalence (SAcid, SBolus, SAcid+Bolus, SNone) was 28 (10%), 94 (34%), 65 (23%), and 92 (33%), respectively. Emesis occurred more in SBolus and SAcid+Bolus vs SNone (p < 0.05). Magnitude (#/day) of cough and emesis events increased with SBolus and SAcid+Bolus vs SNone (p < 0.05). SAcid+Bolus had increased acid exposure vs SNone (p < 0.05). Distributions of feeding and breathing methods were distinct in infants with SBolus vs SNone (both, p < 0.05). Multivariate analysis revealed that arching and irritability events/day were lesser at higher PMAs (p < 0.001) and greater for infants on NCPAP (p < 0.01) with SBolus and SAcid+Bolus (p < 0.05). Coughs/day was greater at higher PMAs (p < 0.001) for infants with gavage and transitional feeding methods (p < 0.02) with SBolus and SAcid+Bolus (p < 0.05) but lesser with Trach (p < 0.001). Number of emesis events/day were greater with SBolus and SAcid+Bolus (p < 0.001). Sneezes/day decreased for infants on Trach (p = 0.02). CONCLUSIONS: Feeding and breathing methods can influence the frequency and type of aerodigestive symptoms. We differentiated esophageal sensitivity phenotypes in NICU infants referred for GERD symptoms using pH-impedance. Acid sensitivity alone was rare, which may explain poor response to acid suppressives; aerodigestive symptoms were predominantly linked with bolus spread. Magnitude of esophageal acid exposure and esophageal sensitivity to bolus spread may explain the pathophysiological basis for symptoms. IMPACT: Objective GERD diagnosis and reasons for symptoms in NICU infants remains unclear. Differentiation of esophageal sensitivities by acid and bolus components of GER reveal distinct symptom profiles, specifically the bolus component of GER significantly contributes to symptom occurrence. Acid only sensitivity to GER is rare, and acid-suppressive therapy alone may not improve symptoms in a majority of NICU infants. Magnitude of esophageal acid exposure and esophageal sensitivity to any bolus spread may explain the pathophysiological basis for symptoms. Feeding and breathing methods can influence the frequency and type of aerodigestive symptoms. GERD treatments should be individualized to the patient's GERD phenotype and likely also target the bolus component of GER.

Role of feeding strategy bundle with acid-suppressive therapy in infants with esophageal acid reflux exposure: a randomized controlled trial.

OBJECTIVE: To test the hypothesis that a feeding bundle concurrent with acid suppression is superior to acid suppression alone in improving gastroesophageal reflux disease (GERD) attributed-symptom scores and feeding outcomes in neonatal ICU infants. METHODS: Infants (N = 76) between 34 and 60 weeks' postmenstrual age with acid reflux index > 3% were randomly allocated to study (acid-suppressive therapy + feeding bundle) or conventional (acid-suppressive therapy only) arms for 4 weeks. Feeding bundle included: total fluid volume < 140 mL/kg/day, fed over 30 min in right lateral position, and supine postprandial position. Primary outcome was independent oral feeding and/or ≥6-point decrease in symptom score (I-GERQ-R). Secondary outcomes included growth (weight, length, head circumference), length of hospital stay (LOHS, days), airway (oxygen at discharge), and developmental (Bayley scores) milestones. RESULTS: Of 688 screened: 76 infants were randomized and used for the primary outcome as intent-to-treat, and secondary outcomes analyzed for 72 infants (N = 35 conventional, N = 37 study). For study vs. conventional groups, respectively: (a) 33% (95% CI, 19-49%) vs. 44% (95% CI, 28-62%), P = 0.28 achieved primary outcome success, and (b) secondary outcomes did not significantly differ (P > 0.05). CONCLUSIONS: Feeding strategy modifications concurrent with acid suppression are not superior to PPI alone in improving GERD symptoms or discharge feeding, short-term and long-term outcomes. IMPACT: Conservative feeding therapies are thought to modify GERD symptoms and its consequences. However, in this randomized controlled trial in convalescing neonatal ICU infants with GERD symptoms, when controlling for preterm or full-term birth and severity of esophageal acid reflux index, the effectiveness of acid suppression plus a feeding modification bundle (volume restriction, intra- and postprandial body positions, and prolonged feeding periods) vs. acid suppression alone, administered over a 4-week period was not superior in improving symptom scores or feeding outcomes. Restrictive feeding strategies are of no impact in modifying GERD symptoms or clinically meaningful outcomes. Further studies are needed to define true GERD and to identify effective therapies in modifying pathophysiology and outcomes. The improvement in symptoms and feeding outcomes over time irrespective of feeding modifications may suggest a maturational effect. This study justifies the use of placebo-controlled randomized clinical trial among NICU infants with objectively defined GERD.

Secretion Management in Tracheostomized Infants using Unconventional Approaches and Outcomes: A Case Series.

OBJECTIVE: This study aimed to increase the understanding of secretion management in infants with tracheostomies. In this case series, we describe objective evidence for an unconventional approach in infants refractory to conventional management techniques. STUDY DESIGN: Case study of two NICU infants utilizing high-resolution manometry was undertaken using personalized oral stimulation protocols with fruity foods. RESULTS: Oral stimulation improved infant swallowing to clear secretions and reduce the need for suctioning. CONCLUSION: Innovative oral stimulation protocols are needed to improve swallowing in high-risk infants.

Pharyngoesophageal and cardiorespiratory interactions: potential implications for premature infants at risk of clinically significant cardiorespiratory events.

The aims of this study were to 1) examine pharyngoesophageal and cardiorespiratory responses to provoking pharyngeal stimuli, and 2) to determine potential contributory factors impacting heart rate (HR) changes to provide insight into cardiorespiratory events occurring in preterm infants. Forty-eight neonates (19 females and 29 males, born at 27.7 ± 0.5 wk; mean ± SE) pending discharge on full oral feeds were studied at 38.7 ± 0.2 wk postmenstrual age using concurrent pharyngoesophageal manometry, electrocardiography, respiratory inductance plethysmography, and nasal airflow thermistor. Pharyngoesophageal and cardiorespiratory responses (prevalence, latency, and duration) were quantified upon abrupt pharyngeal water stimuli (0.1, 0.3, and 0.5 ml in triplicate). Mixed linear models and generalized estimating equations were used for comparisons between HR changes. Contributory factors included stimulus characteristics and subject characteristics. Of 338 pharyngeal stimuli administered, HR increased in 23 (7%), decreased in 108 (32%), and remained stable in 207 (61%) neonates. HR decrease resulted in repetitive swallowing, increased respiratory-rhythm disturbance, and decreased esophageal propagation rates (all, P < 0.05). HR responses were related to stimulus volume, stimulus flow rate, and extreme prematurity (all, P < 0.05). In preterm infants, HR remains stable in a majority of pharyngeal provocations. HR decrease, due to pharyngeal stimulation, is related to aberrant pharyngoesophageal motility and respiratory dysregulation and is magnified by prematurity. We infer that the observed aberrant responses across digestive, respiratory, and cardiovascular systems are related to maladaptive maturation of the parasympathetic nervous system. These aberrant responses may provide diagnostic clues for risk stratification of infants with troublesome cardiorespiratory events and swallowing difficulty. NEW & NOTEWORTHY Cardiorespiratory rhythms concurrent with pharyngeal, upper esophageal sphincter, and esophageal body responses were examined upon pharyngeal provocation in preterm-born infants who were studied at full-term maturation. Decreased heart rate (HR) was associated with extreme preterm birth and stimulus flow/volume. With HR decrease responses, aerodigestive reflex abnormalities were present, characterized by prolonged respiratory rhythm disturbance, repetitive multiple swallowing, and poor esophageal propagation. Promoting esophageal peristalsis may be a potential therapeutic target.

Mechanisms of Aerodigestive Symptoms in Infants with Varying Acid Reflux Index Determined by Esophageal Manometry.

OBJECTIVE: To test whether symptom generation in infants is related to the severity of gastroesophageal reflux disease (GERD) symptoms as determined by the Acid Reflux Index (ARI), stimulus media, and stimulus volume during provocative esophageal manometry. STUDY DESIGN: Symptomatic neonates (n = 74) born at a median of 28.9 weeks gestation (range, 23.4-39.4 weeks) were studied at a median of 41.0 weeks (range, 34.6-48.0 weeks) postmenstrual age using 24-hour pH-impedance methods to determine ARI severity, followed by provocative esophageal manometry with graded mid-esophageal infusions (0.1-5.0 mL) of air, water, and apple juice. Peristaltic reflexes and symptom characteristics were compared among ARI severity categories using linear mixed models and generalized estimating equations. RESULTS: The effects of 2635 separate esophageal stimuli on reflexes and symptoms were analyzed. Peristaltic reflexes occurred in 1880 infusions (71%), and physical, cardiorespiratory, sensory symptoms were seen in 439 infusions (17%). Symptom prevalence did not differ across the ARI severity categories (ARI <3, 18%; ARI 3-7, 17%; ARI >7, 16%; P = 1.0). Symptom and peristaltic responses increased with incremental stimulus volumes (all media, P < .001). CONCLUSIONS: Symptoms and peristaltic reflexes are manifestations of the recruitment of several neurosensory and neuromotor pathways evoked by mid-esophageal infusions. ARI severity grade plays no role in symptom generation, indicating that GERD should not be diagnosed and severity should not be assigned based on symptoms alone. An increase in symptom occurrence was noted with increasing stimulus volumes, which provided increased activation of receptors, afferents, and efferents in evoking peristaltic clearance reflexes.

Differentiation of esophageal pH-impedance characteristics classified by the mucosal integrity marker in human neonates.

BACKGROUND: In adults, distal baseline impedance (BI) is a determinant of esophageal mucosal integrity with values <900 Ω indicating inflammation. Relationships between acid gastroesophageal reflux (GER) and BI in neonates are unclear. METHODS: NICU infants (N = 198, 30.4 ± 0.3 weeks gestation) were evaluated at 43 ± 0.4 weeks postmenstrual age using 24-h pH-impedance. Ten randomly selected 1-min windows during rest from the distal impedance channel (Z6) were averaged. Chi-square, t-tests, and ANOVA were used to compare pH-impedance and symptom characteristics by BI severity (BI < 900 Ω, BI 900-2000 Ω, BI > 2000 Ω). Regression analysis was used to identify potential contributing factors of BI. RESULTS: In BI < 900 Ω: (1) pH-impedance characteristics were increased (acid reflux event frequency, duration, and severity, all P < 0.05 vs. BI > 2000 Ω), and (2) positive symptom correlations were noted with bolus (73%) and acid events (55%). Significant predictors of BI included chronological age, acid reflux index, and BPD diagnosis (all P < 0.05). CONCLUSIONS: Low BI is associated with prolonged acid exposure, delayed clearance, and greater aerodigestive symptom prevalence, likely associated with inflammation and or increased mucosal permeability. BI > 2000 Ω likely involves little or no inflammation because acid exposure is minimal. Combination of SAP, pH-impedance metrics, and BI along with the clarification of dysmotility mechanisms provides the rationale for personalized anti-reflux therapies as needed.

Pilot Study of Pharyngoesophageal Dysmotility Mechanisms in Dysphagic Infants of Diabetic Mothers.

OBJECTIVE: Swallowing difficulties are common in infants of diabetic mothers (IDM) and mechanisms are unclear. We tested the hypothesis that pharyngoesophageal motility reflexes are distinct in IDMs compared with healthy controls in a pilot study. STUDY DESIGN: Basal and adaptive pharyngoesophageal motility characteristics of 20 dysphagic IDMs and 10 controls were studied using purpose-built micromanometry system. RESULTS: During basal swallows, IDMs had lower frequency of deglutition apneas (62.5 vs. 95.4%) and longer active upper esophageal sphincter (UES) relaxation duration (0.8 ± 0.1 vs. 0.4 ± 0.1 second), whereas during adaptive swallows, IDMs had longer response latency to esophageal peristalsis onset (24.4 ± 2.1 vs. 9.7 ± 2.9 seconds) and longer lower esophageal sphincter nadir duration (28.9 ± 3.2 vs. 12.9 ± 4.6) (all p < 0.05) compared with controls. Nine in the IDM group needed gastrostomy feeding tube at hospital discharge versus none in controls. CONCLUSION: Feeding difficulties in IDMs are likely to be associated with maladapted or maldeveloped vagal neuropathy mechanisms manifesting as dysregulation of pharyngeal-airway interactions, longer active UES relaxation response, delays in the activation of esophageal contractile apparatus during peristalsis, and prolonged inhibition at the gastroesophageal junction.

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

BACKGROUND: Pharyngeal 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. METHODS: Nineteen 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. RESULTS: PhCI 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). CONCLUSIONS: PhCI 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.

Maturation Modulates Pharyngeal-Stimulus Provoked Pharyngeal and Respiratory Rhythms in Human Infants.

Pharyngeal-provocation induced aerodigestive symptoms in infants remain an enigma. Sources of pharyngeal provocation can be anterograde as with feeding, and retrograde as in gastroesophageal reflux. We determined maturational and dose-response effects of targeted pharyngeal-stimulus on frequency, stability, and magnitude of pharyngeal and respiratory waveforms during multiple pharyngeal swallowing responses in preterm-born infants when they were of full-term postmenstrual age (PMA). Eighteen infants (11 male) were studied longitudinally at 39.8 ± 4.8 weeks PMA (time-1) and 44.1 ± 5.8 weeks PMA (time-2). Infants underwent concurrent pharyngo-esophageal manometry, respiratory inductance plethysmography, and nasal airflow thermistor methods to test sensory-motor interactions between the pharynx, esophagus, and airway. Linear mixed models were used and data presented as mean ± SEM or %. Overall, responses to 250 stimuli were analyzed. Of the multiple pharyngeal swallowing responses (n = 160), with maturation (a) deglutition apnea duration decreases (p < 0.01), (b) number of pharyngeal waveform peaks and duration decreases for initial responses (p < 0.01), and subsequent responses have lesser variation and greater stability (p < 0.01). With increment in stimulus volumes we noted (a) increased prevalence (%) of pharyngeal responses (p < 0.05), (b) increased number of pharyngeal peaks (p < 0.05), yet pharyngeal frequency (Hz), variability, and stability remain unaffected (p > 0.05), and (c) respiratory changes were unaffected (p > 0.05). Initial and subsequent pharyngeal responses and respiratory rhythm interactions become more distinct with maturation. Interval oromotor experiences and volume-dependent increase in adaptive responses may be contributory. These mechanisms may be important in modulating and restoring respiratory rhythm normalcy.

Feeding Methods at Discharge Predict Long-Term Feeding and Neurodevelopmental Outcomes in Preterm Infants Referred for Gastrostomy Evaluation.

OBJECTIVE: To test the hypothesis that oral feeding at first neonatal intensive care unit discharge is associated with less neurodevelopmental impairment and better feeding milestones compared with discharge with a gastrostomy tube (G-tube). STUDY DESIGN: We studied outcomes for a retrospective cohort of 194 neonates <37 weeks' gestation referred for evaluation and management of feeding difficulties between July 2006 and July 2012. Discharge milestones, length of hospitalization, and Bayley Scales of Infant Development-Third Edition scores at 18-24 months were examined. χ2, Mann-Whitney U, or t tests and multivariable logistic regression models were used. RESULTS: A total of 60% (n = 117) of infants were discharged on oral feedings; of these, 96% remained oral-fed at 1 year. The remaining 40% (n = 77) were discharged on G-tube feedings; of these, 31 (40%) remained G-tube dependent, 17 (22%) became oral-fed, and 29 (38%) were on oral and G-tube feedings at 1 year. Infants discharged on a G-tube had lower cognitive (P <.01), communication (P = .03), and motor (P <.01) composite scores. The presence of a G-tube, younger gestation, bronchopulmonary dysplasia, or intraventricular hemorrhage was associated significantly with neurodevelopmental delay. CONCLUSIONS: For infants referred for feeding concerns, G-tube evaluations, and feeding management, the majority did not require a G-tube. Full oral feeding at first neonatal intensive care unit discharge was associated with superior feeding milestones and less long-term neurodevelopmental impairment, relative to full or partial G-tube feeding. Evaluation and feeding management before and after G-tube placement may improve long-term feeding and neurodevelopmental outcomes.

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

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.

Effects of Esophageal Acidification on Troublesome Symptoms: An Approach to Characterize True Acid GERD in Dysphagic Neonates.

To quantify and compare maximal extent (height) of acid reflux events (AREs) on symptom generation in dysphagic neonates. Dysphagic neonates (N = 53), born at 30 ± 5.3 weeks gestation, underwent 24-hour pH-impedance study for the evaluation of troublesome symptoms purported to be due to gastroesophageal reflux disease (GERD). AREs (pH < 4 for >4 s) detected by impedance (Z) were categorized by maximal extent as refluxate reaching distal (Z6, Z5), middle (Z4, Z3), or proximal (Z2, Z1) impedance channels. AREs reaching the pH sensor only were categorized as distal. Symptom correlation (%, symptom index, symptom sensitivity index, and symptom associated probability) and temporal characteristics (clearance times) of AREs were analyzed using linear mixed and GEE models comparing height categories presented as mean ± SEM, median (IQR), and OR (95% CI). Of the 2003 AREs, 1) distal extent AREs (n = 1642) had increased frequency (p < 0.05), decreased ACT (p < 0.05), and decreased acidity (p < 0.05); 2) in middle and proximal AREs, acid clearance was longer than bolus clearance, (p < 0.01); and 3) the odds of having cardiorespiratory (cough or sneeze) symptoms are increased with proximal and middle AREs (p < 0.05). Most proximal ascent of AREs into middle or proximal esophagus likely activates protective aerodigestive reflexes (peristalsis) or vigilant states to facilitate bolus and chemical clearance. Heightened esophageal sensitivity, acid neutralization delays, or clearance mechanism delays may accentuate multi-systemic troublesome symptoms.

Characterization and mechanisms of the pharyngeal swallow activated by stimulation of the esophagus.

Stimulation of the esophagus activates the pharyngeal swallow response (EPSR) in human infants and animals. The aims of this study were to characterize the stimulus and response of the EPSR and to determine the function and mechanisms generating the EPSR. Studies were conducted in 46 decerebrate cats in which pharyngeal, laryngeal, and esophageal motility was monitored using EMG, strain gauges, or manometry. The esophagus was stimulated by balloon distension or luminal fluid infusion. We found that esophageal distension increased the chance of occurrence of the EPSR, but the delay was variable. The chance of occurrence of the EPSR was related to the position, magnitude, and length of the stimulus in the esophagus. The most effective stimulus was long, strong, and situated in the cervical esophagus. Acidification of the esophagus activated pharyngeal swallows and sensitized the receptors that activate the EPSR. The EPSR was blocked by local anesthesia applied to the esophageal lumen, and electrical stimulation of the recurrent laryngeal nerve caudal to the cricoid cartilage (RLNc) activated the pharyngeal swallow response. We conclude that the EPSR is activated in a probabilistic manner. The receptors mediating the EPSR are probably mucosal slowly adapting tension receptors. The sensory neural pathway includes the RLNc and superior laryngeal nerve. We hypothesize that, because the EPSR is observed in human infants and animals, but not human adults, activation of EPSR is related to the elevated position of the larynx. In this situation, the EPSR occurs rather than secondary peristalsis to prevent supraesophageal reflux when the esophageal bolus is in the proximal esophagus.

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.