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Preterm infant receiving PULSED NTrainer stimulation during gavage feeding in the neonatal intensive care unit, with a nasogastric tube placed through the left nares (not visible); pneumatic stimulus control signals and output through the pacifier nipple are shown in the left panel: (a) voltage-controller gate signal, (b) intraluminal pressure (inside) the nipple, and (c) mechanical displacement at the nipple cylinder wall (Photo courtesy of Innara Health, Inc., Olathe, Kansas USA).
Source publication
Background
Despite numerous medical advances in the care of at-risk preterm neonates, oral feeding still represents one of the first and most advanced neurological challenges facing this delicate population. Objective, quantitative, and noninvasive assessment tools, as well as neurotherapeutic strategies, are greatly needed in order to improve feed...
Context in source publication
Context 1
... NTrainer PULSED orocutaneous stimulus consists of a series of 6-cycle bursts that are delivered by a servo-controlled pneumatic amplifier (NTrainer System) to the lumen of a standard silicone pacifier (eg, WeeSoothie or Soothie). These pneumatic bursts are frequency modulated (FM) from 2.8 to 1.6 Hz across the 6-cycle structure, with a 2-second pause period between bursts (Figure 2). Individual pressure cycles have a 31 millisecond (ms) rise or fall time to ensure salient stimulus spectra with significant energy from DC-16 Hz [56]. ...
Citations
... Each infant was randomized to receive either the PULSED NTrainer (n=62) or Sham (n=55) intervention. Infants assigned to the PULSED NTrainer group received a progressive dose of the pulsatile orocutaneous stimulation (37). Beginning at 30 weeks' PMA, these infants received 2 weeks of low-dose PULSED NTrainer stimulation (2×3-minute blocks) with a 1-minute stimulus 'off-period' between the stimulation blocks. ...
... The NTrainer PULSED orocutaneous stimulus consisted of a series of 6-cycle bursts which were delivered by a servocontrolled pneumatic amplifier (NTrainer System TM ) to create rapid pressure changes within the lumen of a silicone pacifier (e.g., WeeSoothie, or regular Soothie) used in our NICUs ( Figure 1). These pneumatic bursts were FM from 2.8 to 1.6 Hz across the 6-cycle structure with a 2-second pause period between bursts (25,37). A total of 34 bursts were presented in each 3-minute block. ...
... Knowledge of those features of the NNS which are relatively invariant vs. other features which are modifiable by experience will likewise inform more effective treatment strategies in this fragile population. Two major lines of ongoing research in our laboratories and NICUs are exploring predictors of feeding readiness, including gene transcriptomics of putative feeding circuits (10,37,56,57), and motor control of ororhythmic pattern formation during NNS (37). For example, hierarchical cluster and feature analyses of NNS force dynamics have shown promise as a predictor of feeding readiness in EPIs (31). ...
Background
Non-nutritive suck (NNS) is used to promote ororhythmic patterning and assess oral feeding readiness in preterm infants in the neonatal intensive care unit (NICU). While time domain measures of NNS are available in real time at cribside, our understanding of suck pattern generation in the frequency domain is limited. The aim of this study is to model the development of NNS in the frequency domain using Fourier and machine learning (ML) techniques in extremely preterm infants (EPIs).
Methods
A total of 117 EPIs were randomized to a pulsed or sham orocutaneous intervention during tube feedings 3 times/day for 4 weeks, beginning at 30 weeks post-menstrual age (PMA). Infants were assessed 3 times/week for NNS dynamics until they attained 100% oral feeding or NICU discharge. Digitized NNS signals were processed in the frequency domain using two transforms, including the Welch power spectral density (PSD) method, and the Yule-Walker PSD method. Data analysis proceeded in two stages. Stage 1: ML longitudinal cluster analysis was conducted to identify groups (classes) of infants, each showing a unique pattern of change in Welch and Yule-Walker calculations during the interventions. Stage 2: linear mixed modeling (LMM) was performed for the Welch and Yule-Walker dependent variables to examine the effects of gestationally-aged (GA), PMA, sex (male, female), patient type [respiratory distress syndrome (RDS), bronchopulmonary dysplasia (BPD)], treatment (NTrainer, Sham), intervention phase [1, 2, 3], cluster class, and phase-by-class interaction.
Results
ML of Welch PSD method and Yule-Walker PSD method measures revealed three membership classes of NNS growth patterns. The dependent measures peak_Hz, PSD amplitude, and area under the curve (AUC) are highly dependent on PMA, but show little relation to respiratory status (RDS, BPD) or somatosensory intervention. Thus, neural regulation of NNS in the frequency domain is significantly different for each identified cluster (classes A, B, C) during this developmental period.
Conclusions
Efforts to increase our knowledge of the evolution of the suck central pattern generator (sCPG) in preterm infants, including NNS rhythmogenesis will help us better understand the observed phenotypes of NNS production in both the frequency and time domains. Knowledge of those features of the NNS which are relatively invariant vs. other features which are modifiable by experience will likewise inform more effective treatment strategies in this fragile population.
... (1) stable vital signs, (2) The Sham intervention was administered using the Soothie Ⓡ during tube feedings over the same schedule and data collection was handled in the exact same way as the NTrainer Ⓡ intervention. During Sham, the pacifier was not pressurized and modulated (Barlow et al., 2017 ...
... In addition to receiving one of two orocutaneous interventions, EPI's were assessed 3 times/week (Monday/Wednesday/Friday) for their NNS performance. The NTrainer Ⓡ System was used in "assessment mode" to record the oral compression dynamics of NNS for 3 minutes followed immediately by a tube feeding not related with the intervention condition (Barlow et al., 2017). ...
... swallowing and respiration (Barlow et al., 2018; Poore et al., 2008b). Infants who experience oromotor dyscoordination while in the NICU are at a greater risk for serious challenges during their stay in the NICU as well as following discharge (Estep et al., 2008; Mercado et al. 2001).Those infants who continue to demonstrate poor oromotor dyscoordination into early childhood are also at an increased risk of exhibiting significant delays in feeding, babbling, and speechlanguage production(Barlow et al., 2017; Barlow et al., 2011). Therefore, there is a significant need for objective assessment tools and interventions to determine when initiation of intervention and identification of infants who will positively respond to orocutaneous stimulation treatment as data are limited(Barlow et al., 2017;Poore et al., 2008b). ...
The development of non-nutritive suck (NNS) burst dynamics in preterm infants reflects the integrity of the brain and is used clinically to assess feeding readiness and orofacial motor development (Mizuno and Ueda, 2005). The application of NNS analytics in the present report represents one outcome measurement set that is part of an ongoing clinical trial involving extremely preterm infants (EPI’s,[GA]) randomized to receive either pulsed orocutaneous stimulation therapeutics or a sham (blind pacifier), in conjunction with salivary sampling twice weekly to map gene expression of key proteins involved in neural development and molecular sensing of feeding related pathways in the brain (NIH R01 HD086088, Barlow - PI). This trial is entering its fourth year of preterm enrollment at neonatal intensive care units (NICU) in the United States, including Lincoln, NE; Boston, MA; and San Jose, CA). A fourth NICU, located in Los Angeles, California, joined this trial in December 2018. The present report aims to characterize the evolution of the NNS burst through implementation of a new automated Python software platform known as NeoNNS (Liao et al., 2019) that was developed in the Communication Neuroscience Laboratories at the University of Nebraska - Lincoln. NeoNNS was designed to handle large data sets sampled at multiple NICUs using batch processing to automatically perform NNS burst discrimination among cohorts of EPI’s stratified into one of two groups based on GA. The present report is an interim analysis designed to quantify NNS burst formation in EPI’s using the spatiotemporal index (STI) calculation as a function of sex, respiratory diagnosis (bronchopulmonary dysplasia (BPD) and respiratory distress syndrome (RDS)), orosensory treatment, and postmenstrual age (PMA) using a repeated measures design. Linear Mixed Modeling (LMM) was utilized to calculate dependent variable STI on a sample of 817 NNS compression pressure waveforms sampled from 42 EPI participants. Main effects for Sex (p=.7263) and respiratory diagnosis [RDS, BPD] (p=.2128) were not significant. There was a marginally significant Treatment effect (p In spite of the small sample size for this interim analysis of NNS burst pattern formation, these findings support the hypothesis that an automated quantitative measure of NNS burst variance in medically fragile EPI’s is strongly dependent on postmenstrual age, and can provide clinicians with an objective method for charting the progression of ororhythmic motor pattern formation as infants progress in the NICU towards independent oral feeding. Faculty Mentor: Steven M. Barlow
... Despite the daunting task of conducting such large trials, progress is forthcoming. Large, multi-center trials funded by the NIH are currently underway exploring the clinical utility of both known and unknown neonatal salivary biomarkers (11). The Salivary Profiling in Infants Treated for Suspected Sepsis (SPITSS) Trial is serially quantifying and validating six salivary biomarkers (CRP, procalcitonin, interleukins [IL]-1ß, 6, 8, and TNF-α) in 4,000 infants across the United States (US) treated for a suspected infection. ...
... Salivary protein cytokine profiles will be correlated to clinical outcomes to determine if a salivary diagnostic panel can more rapidly and accurately discriminate between an infected and non-infected neonate compared to traditional biomarkers (e.g., blood culture) to reduce unnecessary antibiotic exposure. In a separate trial, a salivary diagnostic panel coined NOuRISH (Neonatal Oral Feeding-readiness In Salivary High-throughput diagnostics) composed of five novel mRNA biomarkers (NPY2R, AMPK, PLXNA1, NPHP4, and WNT3) related to oral feeding maturation is being tested in extremely premature neonates across several US hospitals (11,12) (Figure 1). As data emerge from these trials and others, it is crucial to recognize that standardized approaches to saliva collection, processing, and analyses are mandated for proper interpretation. ...
Non-invasive techniques to monitor and diagnose neonates, particularly those born prematurely, are a long-sought out goal of Newborn Medicine. In recent years, technical advances, combined with increased assay sensitivity, have permitted the high-throughput analysis of multiple biomarkers simultaneously from a single sample source. Multiplexed transcriptomic and proteomic platforms, along with more comprehensive assays such as RNASeq, allow for interrogation of ongoing physiology and pathology in unprecedented ways. In the fragile neonatal population, saliva is an ideal biofluid to assess clinical status serially and offers many advantages over more invasively obtained blood samples. Importantly, saliva samples are amenable to analysis on emerging proteomic and transcriptomic platforms, even at quantitatively limited volumes. However, biomarker targets are often degraded in human saliva, and as a mixed source biofluid containing both human and microbial targets, saliva presents unique challenges for the investigator. Here, we provide insight into technical considerations and protocol optimizations developed in our laboratory to quantify and discover neonatal salivary biomarkers with improved reproducibility and reliability. We will detail insights learned from years of experimentation on neonatal saliva within our laboratory ranging from salivary collection techniques to processing to downstream analyses, highlighting the need for consistency in approach and a global understanding of both the potential benefits and limitations of neonatal salivary biomarker analyses. Importantly, we will highlight the need for robust and stringent research in this population to provide the field with standardized approaches and workflows to impact neonatal care successfully.
... Oral feeding percentages were calculated using the nursing clinical bedside flow sheet and were defined as the amount of volume taken by mouth (termed per os, or PO) divided by the total fluid intake either provided via intravenous fluids or via an indwelling nasogastric tube (Barlow et al., 2017;Poore, Zimmerman, Barlow, Wang, & Gu, 2008;. Full oral feeding was achieved when an infant was able to take their minimum required volume orally without the use of a nasogastric tube for supplementation for greater than 24 hr. ...
Purpose
Successful oral feeding and speech emergence are dependent upon the coordination of shared oral muscles and facial nerves. We aimed to determine if the speech-associated genes, forkhead box P2 (FOXP2) , contactin-associated protein-like 2 (CNTNAP2 ), glutamate receptor, ionotropic, N-methyl D-aspartate 2A (GRIN2A) , and neurexin 1, were detectable in neonatal saliva and could predict feeding outcomes in premature newborns.
Method
In this prospective, observational, preliminary study, saliva collected from 51 premature infants (gestational ages: 30–34 6/7 weeks) at different stages of oral feeding development underwent gene expression analysis. Binary (+/–) expression profiles were explored and examined in relation to days to achieve full oral feeds.
Results
GRIN2A and neurexin 1 rarely amplified in neonatal saliva and were not informative. Infants who amplified FOXP2 but not CNTNAP2 at the start of oral feeds achieved oral feeding success 3.20 (95% CI [−2.5, 8.9]) days sooner than other gene combinations.
Conclusions
FOXP2 and CNTNAP2 may be informative in predicting oral feeding outcomes in newborns. Salivary analysis at the start of oral feeding trials may inform feeding outcomes in this population and warrants further investigation.
... 40 The platform is composed of five genes representative of hunger signaling, sensory integration and facial development and is the basis for an ongoing National Institutes of Health randomized controlled clinical trial. 41 If successful, the platform holds great promise for improving feeding outcomes by identifying infants with specific developmental delays that would allow for targeted therapies specific to that neonate in order to improve short-and long-term outcomes. Such interventions would include increased skin-to-skin in infants lagging in sensory integration, implementation of training devices such as the NTrainer in infants with a delayed nutritive suck progression pattern, or closer long-term monitoring for infants with disrupted hypothalamic signaling affecting hunger and satiety signaling pathways who may be at risk for failure to thrive in the first months of life ( Figure 1). ...
Dara Azuma,1 Jill L Maron2 1Division of Neonatal-Perinatal Medicine, Tufts Medical Center, Boston, MA, USA; 2Mother Infant Research Institute, Tufts Medical Center, Boston, MA, USACorrespondence: Jill L MaronMother Infant Research Institute, Tufts Medical Center, 800 Washington Street, Boston, MA 02111 Tel +1-617-636-0766Fax +1-617-636-1469Email jmaron@tuftsmedicalcenter.orgAbstract: Oral feeding competency is a milestone most infants must achieve prior to discharge. It is a developmentally complex task that requires integration of multiple sensory inputs, central nervous system maturation, motor coordination, and respiratory stability. While ensuring safety during oral feeding is important to reduce morbidities, we must optimize developmental windows to expedite feeding maturation. Currently, many of the assessments and therapies related to oral feeding skills focus solely on nutritive and non-nutritive sucking. Yet, this essential reflex is only one component of oral feeding. Specific challenges faced by individual newborns are often unique, and delays in development in any one of the many systems involved in oral feeding can lead to prolonged oral feeding maturation. Expanding the field to go beyond targeting oral motor skills to consider all aspects of feeding maturity, inclusive of sensory integration and hunger signaling, is needed to advance care. As technology continues to develop at a rapid pace, the field must compare the efficacy of these clinical and technologic assessments and therapies. In this review, we will address the complexity of neonatal feeding, review assessment tools and interventions for feeding safety and developmental readiness, and propose an individualized, multi-faceted approach to oral feeding evaluation and intervention.Keywords: oral feeding, neonate, prematurity
... It helps them achieve the normal milestone of independent oral feeding and shortens LOS. A better understanding of how GA, chronological age and lung disease interact with the genetic control of feeding development can further improve our ability to effectively utilize different feeding entrainments in clinical practice [76]. ...
Objective
To evaluate the effect of patterned, frequency-modulated oro-somatosensory stimulation on time to full oral feeds in preterm infants born 26–30 weeks gestation.
Study design
This is a multicenter randomized controlled trial. The experimental group (n = 109) received patterned, frequency-modulated oral stimulation via the NTrainer system through a pulsatile pacifier and the control group (n = 101) received a non-pulsatile pacifier. Intent-to-treat analysis (n = 210) was performed to compare the experimental and control groups and the outcomes were analyzed using generalized estimating equations. Time-to-event analyses for time to reach full oral feeds and length of hospital stay were conducted using Cox proportional hazards models.
Results
The experimental group had reduction in time to full oral feeds compared to the control group (-4.1 days, HR 1.37 (1.03, 1.82) p = 0.03). In the 29–30 weeks subgroup, infants in the experimental group had a significant reduction in time to discharge (-10 days, HR 1.87 (1.23, 2.84) p < 0.01). This difference was not observed in the 26–28 weeks subgroup. There was no difference in growth, mortality or morbidities between the two groups.
Conclusions
Patterned, frequency-modulated oro-somatosensory stimulation improves feeding development in premature infants and reduces their length of hospitalization.
Trial registration
ClinicalTrials.gov NCT01158391
... Improvements in device designs and increased accessibility and testing of feeding readiness and feeding performance in newborns in the NICU translate to a proliferation of suck data to be analyzed for clinical and/or research purposes [26,30,31]. us, a need exists for an efficient software processing and analysis platform for automated extraction of salient NNS features in the time and frequency domains across treatment sessions, including advanced data analytics to support randomized multicenter clinical trials involving large numbers of preterm infants and repeated-measures acquisition of ororhythmic activity [32]. ...
... is section briefly describes the computational methods and analysis parameters implemented in NeoNNS. e algorithms, notations, and parameter specifications for time-and frequency-domain analysis routines described herein are based on previous research in preterm suck development [1,4,5,8,10,15,30,32,36,37]. ...
Background and Objective: The emergence of the nonnutritive suck (NNS) pattern in preterm infants reflects the integrity of the brain and is used by clinicians in the neonatal intensive care unit (NICU) to assess feeding readiness and oromotor development. A critical need exists for an integrated software platform that provides NNS signal preprocessing, adaptive waveform discrimination, feature detection, and batch processing of big data sets across multiple NICU sites. Thus, the goal was to develop and describe a cross-platform graphical user interface (GUI) and terminal application known as NeoNNS for single and batch file time series and frequency-domain analyses of NNS compression pressure waveforms using analysis parameters derived from previous research on NNS dynamics. Methods. NeoNNS was implemented with Python and the Tkinter GUI package. The NNS signal-processing pipeline included a low-pass filter, asymmetric regression baseline correction, NNS peak detection, and NNS burst classification. Data visualizations and parametric analyses included time- and frequency-domain view, NNS spatiotemporal index view, and feature cluster analysis to model oral feeding readiness. Results. 568 suck assessment files sampled from 30 extremely preterm infants were processed in the batch mode (
... The remaining 19 studies were included in this review: 15 randomized, 1 quasi-randomized, and 3 crossover randomized controlled trials. 5,7,[30][31][32][33][34][35][36][37][38][39][40][41][42][43][44][45][46] The methodological quality of the selected studies was evaluated as reported in Table 1 . All studies had risk of bias in at least 1 of the 4 items. ...
Background:
Premature birth is associated with feeding difficulties due to inadequate coordination of sucking, swallowing, and breathing. Nonnutritive sucking (NNS) and oral stimulation interventions may be effective for oral feeding promotion, but the mechanisms of the intervention effects need further clarifications.
Purpose:
We reviewed preterm infant intervention studies with quantitative outcomes of sucking performance to summarize the evidence of the effect of interventions on specific components of sucking.
Methods:
PubMed, CINAHL, MEDLINE, EMBASE, and PSYCOLIST databases were searched for English language publications through August 2017. Studies were selected if they involved preterm infants, tested experimental interventions to improve sucking or oral feeding skills, and included outcome as an objective measure of sucking performance. Specific Medical Subject Headings (MeSH) terms were utilized.
Results:
Nineteen studies were included in this review: 15 randomized, 1 quasi-randomized, and 3 crossover randomized controlled trials. Intervention types were grouped into 6 categories (i) NNS, (ii) NNS with auditory reinforcement, (iii) sensorimotor stimulation, (iv) oral support, (v) combined training, and (vi) nutritive sucking. Efficiency parameters were positively influenced by most types of interventions, though appear to be less affected by trainings based on NNS alone.
Implications for practice:
These findings may be useful in the clinical care of infants requiring support to achieve efficient sucking skills through NNS and oral stimulation interventions.
Implications for research:
Further studies including quantitative measures of sucking performance outcome measures are needed in order to best understand the needs and provide more tailored interventions to preterm infants.
... These results suggest that the physiological stability of infants can be improved by using the gravity method of feeding when infants are in the lateral position. The need for such noninvasive strategies for optimizing feeding in preterm infants has also been highlighted elsewhere [15,16]. Although decreasing critical cardiorespiratory alarms is a desirable goal in its right, research on extremely preterm infants has also shown an association between hypoxemic episodes and increased risk of late death or disability at 18 months of age [17]. ...
Background:
Many preterm infants require enteral feeding as they cannot coordinate sucking, swallowing, and breathing. In enteral feeding, milk feeds are delivered through a small feeding tube passed via the nose or mouth into the stomach. Intermittent milk feeds may either be administered using a syringe to gently push milk into the infant's stomach (push feed) or milk can be poured into a syringe attached to the tube and allowed to drip in by gravity (gravity feed). This practice of enteral feeding is common in neonatal intensive care units. There is, however, no evidence in the literature to recommend the use of one method of feeding over the other.
Objective:
The aim of this study was to investigate which of the two methods of feeding is physiologically better tolerated by infants, as measured by the incidence of critical cardiorespiratory alarms during and immediately after feeding.
Methods:
We conducted a prospectively designed observational study with records of all feeding episodes in infants of gestational age less than 30 weeks at birth and with a minimum enteral intake of 100 mL/kg/day. In total, 2140 enteral feeding episodes were noted from 25 infants over 308 infant-days with records for several characteristics of the infants (eg, gestational age), feeding (eg, the position of infants), and of nursing-care events before feeding (eg, diapering). Logistic regression with mixed effects was used to model cardiorespiratory alarms for the push and gravity methods of feeding.
Results:
After adjustments were made for all confounding variables, the position of infants was found to be statistically significant in changing the outcome of critical alarms for the two methods of feeding (P=.02). For infants in the lateral position, push feeds led to 40% more instances of one or more critical cardiorespiratory alarms in comparison with the gravity method. Both methods of feeding created a statistically comparable number of alarms for infants in the prone position.
Conclusions:
This study provides objective data that may assist in optimizing enteral feeding protocols for premature infants. The incidence of critical cardiorespiratory alarms for infants in the lateral position can be lowered by the use of gravity instead of push feeding. No differences were observed between the two types of feeding when infants were in the prone position.
... A randomised controlled trial (sample size 180 extremely preterm infants) to determine whether pulsed orocutaneous intervention simultaneous with feeding will accelerate time to full oral feeds (ClinicalTrials.gov NCT02696343) is underway [44]. A randomised factorial experiment (sample size 530 moderate-late preterm infants) is investigating whether the simpler approach of providing smell and taste before all tube feeds will have a similar effect, as well as mitigating the increased fat mass seen by term-corrected age in preterm infants [45,46] (Australia and New Zealand Clinical Trials Registry ACTRN12616001199404). ...
Olfaction and gustation are critical for the enjoyment of food but also have important metabolic roles, initiating the cephalic phase response that sets in train secretion of hormones important for metabolism and digestion before any food is actually ingested. Smell and taste receptors are functional in the fetus and there is evidence for antenatal learning of odours. Despite enteral nutrition and metabolism being major issues in the care of very preterm infants, often little consideration is given to the potential role of smell and taste in supporting these processes, or in the role they may have in encoding hypothalamic circuitry in a way that promotes healthy metabolism in the post‑neonatal period. This review will discuss the evidence for the role of smell and taste in the newborn infant.
