Infant Pulmonary Function Testing and Phenotypes in Severe Bronchopulmonary Dysplasia.

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.

Unique Patterns of Body Composition and Anthropometric Measurements During Maturation in Neonatal Intensive Care Unit Neonates: Opportunities for Modifying Nutritional Therapy and Influencing Clinical Outcomes.

BACKGROUND: Body composition is an important predictor of long-term outcomes in neonates and may be altered by several factors. Innovative methods like air displacement plethysmography (ADP) can safely and reliably measure body composition, potentially assisting in individualization of nutrition therapy. OBJECTIVES: 1) To characterize patterns of body composition change in convalescing neonates in the neonatal intensive care unit (NICU) and examine factors leading to variation. 2) To evaluate if the time interval between 2 measurements via ADP can detect significant changes. METHODS: NICU infants underwent anthropometry and body composition measurements by ADP at 37.5±0.7 weeks (Time 1) and 41.0±0.7 weeks (Time 2) postmenstrual age. Nutrition data were recorded. Data were analyzed using paired t-tests and linear regression models, presented as mean±SE, median (IQR), or %. RESULTS: Twenty-two neonates (54% males, 32.2±0.9 weeks gestation) were evaluated with a median interval of 3.6 (2.9-4.0) weeks between studies. Mean weight and % body fat increased significantly. There was no significant difference between mean weight and mean % body fat compared with normal references. Abdominal girth increased and mid-arm circumference decreased (p<0.01). Preterm group had higher mean % body fat (10.1) than term infants (6.5), p = 0.03. CONCLUSION: Longitudinal assessment of body composition can effectively assess nutrition status of fragile NICU infants. Although, an interval of 2.9-4.0 weeks between consecutive measurements detected significant changes in body composition, more frequent measurements are needed to determine nutrition factors responsible for body composition changes.

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.

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.

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.

Feed-Thickening Practices in NICUs in the Current Era: Variability in Prescription and Implementation Patterns.

BACKGROUND: Feed-thickening for infants in the Neonatal Intensive Care Unit (NICU) is performed due to concerns of dysphagia and gastroesophageal reflux disease (GERD). No standards currently exist regarding feed-thickening prescriptions and practices and this results in variable and potentially unsafe feeding approaches. METHODS: Electronic surveys were sent to neonatal feeding therapists and providers in order to determine the prescriptions and practices currently being used for feed-thickening in the NICU. RESULTS: A total of 313 responses were collected. Results revealed the majority of providers use thickened feeds for concerns of dysphagia or GERD with some reporting they thicken expressed breast milk. Variability of thickening prescriptions was noted regarding consistencies, thickening agents, and recipes used. Reported approaches for measuring, mixing, and warming thickened feeds varied. CONCLUSION: Variability was noted in the feed-thickening prescriptions and practices performed in the NICU. Further research and standardization are required to develop thickening guidelines.

Gestational and postnatal modulation of esophageal sphincter reflexes in human premature neonates.

BACKGROUND: Effects of gestational age (GA) and postnatal maturation on upper and lower esophageal sphincter (UES and LES) reflex development remain unclear. We hypothesized very-preterm (VPT) born neonates (< 32 wk GA) have delayed maturation of UES contractile reflex (UESCR) and LES relaxation reflex (LESRR) vs. preterm (PT) born (32-37 wk GA) neonates. METHODS: Using provocative manometry, effects of 1,263 graded mid-esophageal stimuli (air, liquid) on sensory-motor characteristics of UESCR and LESRR were investigated in 24 VPT-born and 12 PT-born neonates (37.8 ± 0.6 vs. 38.9 ± 0.4 wk postmenstrual age respectively, P = 0.14). RESULTS: In response to liquid stimuli (vs. air), VPT-born neonates displayed prolonged UESCR and LESRR response latencies (P < 0.001) and prolonged UESCR and LESRR durations (P < 0.01); unlike PT-born neonates, who exhibit prolonged LESRR response latency (P < 0.01), but similar UESCR and LESRR durations (P = 0.2). Differences were noted in LESRR duration in VPT vs. PT neonates for air stimuli (P = 0.04). With liquid stimuli, increasing GA was associated with decreasing response onset latencies to UESCR and LESRR (P < 0.05), and increasing LESRR duration (P = 0.02). CONCLUSION: Using GA as categorical or continuous variable, vagus-mediated mechano-sensitive and liquid-sensitive reflex characteristics of UESCR and LESRR are distinct; LESRR differs with varying intrauterine maturation suggesting inhibitory modulation progresses with advancing maturation.

Effects of birth asphyxia on the modulation of pharyngeal provocation-induced adaptive reflexes.

Perinatal asphyxia and aerodigestive symptoms are troublesome. We tested the hypothesis that pharyngeal provocation alters proximal and distal aerodigestive reflex coordination and kinetics in infants with hypoxic ischemic encephalopathy (HIE), compared with healthy controls. Specifically, we characterized the sensory-motor properties of pharyngeal provocation-induced effects on upper esophageal sphincter (UES) and lower esophageal sphincter (LES) reflexes. Ten orally fed controls (32.0 ± 1.5 wk gestation) and 25 infants with HIE (38.1 ± 0.4 wk gestation) were evaluated at 39.7 ± 0.9 and 41.9 ± 0.6 wk postmenstrual age respectively. Pharyngo-esophageal reflexes evoked upon graded water stimuli were tested using water-perfusion micromanometry methods. Analysis included sensory-motor characteristics of pharyngeal reflexive swallow (PRS), pharyngo-UES-contractile reflex (PUCR), esophageal body-waveform kinetics, and pharyngo-LES-relaxation reflex (PLESRR). For controls vs. infants with HIE, median appearance, pulse, grimace, activity, respiration (APGAR) scores were 6 vs. 1 at 1 min (P < 0.001) and 8 vs. 3 at 5 min (P < 0.001). Upon pharyngeal- stimulation, HIE infants (vs. controls) had frequent PUCR (P = 0.01); increased UES basal tone (P = 0.03); decreased LES basal tone (P = 0.002); increased pharyngeal-waveforms per stimulus (P = 0.03); decreased frequency of LES relaxation (P = 0.003); and decreased proximal esophageal contractile amplitude (P = 0.002), with prolonged proximal esophageal contractile duration (P = 0.008). Increased tonicity and reactivity of the UES and dysregulation of LES may provide the pathophysiological basis for pooling of secretions, improper bolus clearance, and aspiration risk. Deficits in function at the nuclear or supranuclear level involving glossopharyngeal and vagal neural networks and respiratory regulatory pathways involved with aerodigestive protection may be contributory.