Infant Development, Poor Feeding, Vagus Nerve Stimulation
Conditions
Brief summary
Oromotor dysfunction and poor feeding is common after premature birth and hypoxic ischemic encephalopathy (HIE). Pairing vagus nerve stimulation (VNS) with motor activity accelerates functional improvements after stroke. This study is designed to investigate whether transcutaneous auricular VNS (taVNS) paired with oromotor rehabilitation is tolerable, safe, and facilitates motor learning in infants who have failed oral feeding.
Detailed description
Feeding difficulty is the primary reason for delayed hospital discharge from the neonatal intensive care unit (NICU), with increased hospital costs and a negative impact on neurodevelopment. Occupational or speech therapists typically start oral stimulation programs early, then feed infants by mouth (PO) daily to encourage safe feeding while learning this motor skill. Even after weeks or months of rehabilitation with therapists, many infants need a gastrostomy tube (G-tube) surgically placed for adequate nutrition. With improved survival rates of more critically ill neonates, the national rate of G-tube placement has doubled from 2000-2012. Difficulty learning the motor sequence for oral feeding may be due to brain injury from infection, ischemia, and dysmaturity. In these infants, the normal integrative connectivity that occurs after birth between the cortex, basal ganglia, and brainstem may be disturbed, resulting in poor coordination and failure to learn the complex motor task of feeding, when it should be a normal reflex. Therapies that facilitate motor learning and enhance feeding skills would have a significant impact for infants who fail feeding rehabilitation. In neonates with brain dysmaturity or overt brain injury, neuromodulation of abnormal circuits may positively boost neuronal connectivity and enhance neuroplasticity. Vagus nerve stimulation (VNS) paired with motor activity facilitates cortical reorganization and neurogenesis, and improves motor function in animal stroke models. A noninvasive form of VNS, transcutaneous auricular VNS (taVNS), targets the auricular branch of the vagus nerve to activate vagal afferent and efferent networks. In adult patients with limb impairment after brain injury, pairing taVNS with motor activation is safe, enhances plasticity and improves functional motor recovery. This work in adult humans extends and supports the animal evidence that pairing VNS with a motor or behavioral intervention restores brain function. The study investigators applied the model of taVNS paired with a motor behavior to infants in the NICU in a prospective, open-label trial exploring the use of once and twice daily taVNS-paired rehabilitation training to enhance oral feeding in infants who are failing oral feeds and slated to receive a G-tube. After obtaining informed consent, MRIs are obtained before starting treatment, and at end of 2-3 week treatment period. In a subset of 10 patients the study investigators also obtain modified barium swallows prior to and after the treatment period, with taVNS on and off during swallowing. Daily feeding volumes as well as the slope of change of po feeding volumes are recorded before and after starting taVNS.
Interventions
DEVICEtranscutaneous auricular vagus nerve stimulation
Microcurrent stimulation delivered to the left tragus, with stimulation 'on' during sucking from a bottle, and 'off' at rest during bottle feeding
Sponsors
National Institute of General Medical Sciences (NIGMS)
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Medical University of South Carolina
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
SINGLE (Outcomes Assessor)
Masking description
Co-investigators analyzing diffusion MRI data were blinded to the timing of the MRI scans (pre- and post-treatment) and dose of taVNS.
Intervention model description
The study investigators delivered taVNS once or twice a day during a bottle feed for 2 weeks. Stimulation was paired with nutritive sucking and swallowing, and was paused during rest or burping. If PO feeds had not progressed after 2 weeks of taVNS treatment, the parents and the clinical team made decisions about timing of G-tube placement. If substantial progress in po feeds was made during the treatment period, but the infant was not quite to full oral feeds, the clinical team and parents could elect to continue for 1-2 weeks.
Eligibility
Sex/Gender
ALL
Age
3 Weeks to 5 Months
Healthy volunteers
No
Inclusion criteria
* Infants must be clinically stable, on minimal respiratory support (nasal cannula, or room air), are not restricted for attempting every feed by mouth, and are currently failing oral feeding such that the clinical team is broaching gastrostomy tube (G-tube) placement with the parents. The infant will be greater than or equal to 39weeks gestation at enrollment and either 1. Premature at birth and attempting oral feeds for at least 3 weeks or 2. Infants who are neart-term or term at birth, with significant medical issues that have precluded oral feeding, such as hypoxic ischemic encephalopathy (HIE), and attempting oral feeds for at least 2 weeks.
Exclusion criteria
* Unstable infants or those requiring positive pressure respiratory support. * Infants \<38weeks gestation at enrollment. * Major unrepaired congenital anomalies or anomalies that limit feeding volumes * Cardiomyopathy * Repeated episodes of autonomic instability (apnea or bradycardia) which are not self resolving
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Infants Who Took All Feeds by Mouth (Responders) | 3 weeks | Number of infants who maintained full daily PO intake for 4 days (\>120 ml/kg/day) and gained weight adequate for discharge (\>20 g/day) were classified as 'Responders'. |
| ml/kg/d Increase Over 7d During taVNS | 7 days | The change in ml/kg/d of oral feeds over the 7 days during taVNS-paired feeds |
| Neuroplasticity as Measured by the Change in White Matter Tract Integrity Via Fractional Anisotropy | change from baseline to week 3 | changes in radial kurtosis diffusion in Corticospinal tracts at the cerebellar peduncles assessed per week of treatment, change from baseline to week 3 reported. Kurtosis is a dimensionless summary statistic that quantifies the amount of non-Gaussianity within the tissue on a scale from 0 to infinity. Higher values indicate greater complexity in the white matter tract. The scale has no title other than diffusion kurtosis. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Episodes of Bradycardia | 3 weeks, during taVNS sessions | bradycardic episodes = heart rate \<80 beats per minute for 5 seconds |
| Number of Treatment Sessions With Sustained Increase in 'Neonatal and Infant Pain Scale' (NIPS) Scores During taVNS | 30min treatment session | Number of treatment sessions with sustained increase of 3 points in Neonatal and Infant Pain Scale (NIPS) scores from before to during taVNS: NIPS recorded at before, midway, and at the end of each treatment session. NIPS scores range from 0 (no discomfort) to 7 (maximum discomfort). An increase of 3 points on the NIPS scale indicates more discomfort with stimulation. |
Countries
United States
Participant flow
Recruitment details
Neonatal intensive Care Unit
Participants by arm
| Arm | Count |
|---|---|
| taVNS Once Daily taVNS paired with bottle feeding once daily for 2-3 weeks
Infants born preterm or near term/term HIE infants who failed to make progress in PO volumes, and were clinically determined to require a G-tube due to failure to achieve oral feeds sufficient for discharge from the hospital. | 14 |
| taVNS Twice Daily taVNS paired with bottle feeding twice daily for 2-3 weeks
Infants born preterm or near term/term HIE infants who failed to make progress in PO volumes, and were clinically determined to require a G-tube due to failure to achieve oral feeds sufficient for discharge from the hospital. | 21 |
| Total | 35 |
Baseline characteristics
| Characteristic | taVNS Once Daily | Total | taVNS Twice Daily |
|---|---|---|---|
| Age, Continuous | 44 post menstrual age in months ofgestation STANDARD_DEVIATION 4.8 | 42.8 post menstrual age in months ofgestation STANDARD_DEVIATION 3.8 | 42.1 post menstrual age in months ofgestation STANDARD_DEVIATION 2.8 |
| change in ml/kg/d po | -0.6 ml/kg/d consumed orally (po) STANDARD_DEVIATION 4.8 | -0.23 ml/kg/d consumed orally (po) STANDARD_DEVIATION 4.1 | 0.03 ml/kg/d consumed orally (po) STANDARD_DEVIATION 3.6 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 2 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 13 Participants | 33 Participants | 20 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 7 Participants | 17 Participants | 10 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 7 Participants | 18 Participants | 11 Participants |
| Sex: Female, Male Female | 9 Participants | 19 Participants | 10 Participants |
| Sex: Female, Male Male | 5 Participants | 16 Participants | 11 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 14 | 1 / 21 |
| other Total, other adverse events | 0 / 14 | 0 / 21 |
| serious Total, serious adverse events | 0 / 14 | 0 / 21 |
Outcome results
Primary
ml/kg/d Increase Over 7d During taVNS
The change in ml/kg/d of oral feeds over the 7 days during taVNS-paired feeds
Time frame: 7 days
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| taVNS Once Daily | ml/kg/d Increase Over 7d During taVNS | 3.9 ml/kg/d increase over 7d | Standard Deviation 4.2 |
| taVNS Twice Daily | ml/kg/d Increase Over 7d During taVNS | 6.0 ml/kg/d increase over 7d | Standard Deviation 4.16 |
Primary
Neuroplasticity as Measured by the Change in White Matter Tract Integrity Via Fractional Anisotropy
changes in radial kurtosis diffusion in Corticospinal tracts at the cerebellar peduncles assessed per week of treatment, change from baseline to week 3 reported. Kurtosis is a dimensionless summary statistic that quantifies the amount of non-Gaussianity within the tissue on a scale from 0 to infinity. Higher values indicate greater complexity in the white matter tract. The scale has no title other than diffusion kurtosis.
Time frame: change from baseline to week 3
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| taVNS Once Daily | Neuroplasticity as Measured by the Change in White Matter Tract Integrity Via Fractional Anisotropy | 0.07 kurtosis units on a scale | Standard Deviation 0.02 |
| taVNS Twice Daily | Neuroplasticity as Measured by the Change in White Matter Tract Integrity Via Fractional Anisotropy | 0.02 kurtosis units on a scale | Standard Deviation 0.02 |
Primary
Number of Infants Who Took All Feeds by Mouth (Responders)
Number of infants who maintained full daily PO intake for 4 days (\>120 ml/kg/day) and gained weight adequate for discharge (\>20 g/day) were classified as 'Responders'.
Time frame: 3 weeks
Population: Responders who achieved full oral feeds and weight gain adequate for discharge
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| taVNS Once Daily | Number of Infants Who Took All Feeds by Mouth (Responders) | 8 Participants |
| taVNS Twice Daily | Number of Infants Who Took All Feeds by Mouth (Responders) | 11 Participants |
Secondary
Number of Episodes of Bradycardia
bradycardic episodes = heart rate \<80 beats per minute for 5 seconds
Time frame: 3 weeks, during taVNS sessions
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| taVNS Once Daily | Number of Episodes of Bradycardia | 1 bradycardic events |
| taVNS Twice Daily | Number of Episodes of Bradycardia | 0 bradycardic events |
Secondary
Number of Treatment Sessions With Sustained Increase in 'Neonatal and Infant Pain Scale' (NIPS) Scores During taVNS
Number of treatment sessions with sustained increase of 3 points in Neonatal and Infant Pain Scale (NIPS) scores from before to during taVNS: NIPS recorded at before, midway, and at the end of each treatment session. NIPS scores range from 0 (no discomfort) to 7 (maximum discomfort). An increase of 3 points on the NIPS scale indicates more discomfort with stimulation.
Time frame: 30min treatment session
Population: total number of treatment sessions for all participants
| Arm | Measure | Value (COUNT_OF_UNITS) |
|---|---|---|
| taVNS Once Daily | Number of Treatment Sessions With Sustained Increase in 'Neonatal and Infant Pain Scale' (NIPS) Scores During taVNS | 3 treatment sessions |
| taVNS Twice Daily | Number of Treatment Sessions With Sustained Increase in 'Neonatal and Infant Pain Scale' (NIPS) Scores During taVNS | 0 treatment sessions |