A UK Interventional Trial in Premature Infants With Apnea of Prematurity Using a Simple, Non-invasive Vibratory Device to Study the Effectiveness in Supporting Breathing and General Stability

Study Overview
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Brief Summary
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Purpose of Study: Apnoea of Prematurity (AOP) is common, affecting the majority of infants born <34 weeks gestational age (GA). Apnea is accompanied by intermittent hypoxia (IH), which contributes to multiple pathologies, including retinopathy of prematurity (ROP), sympathetic ganglia injury, impaired pancreatic islet cell and bone development, and neurodevelopmental disabilities. Standard of care for AOP/IH includes prone positioning, positive pressure ventilation, and caffeine therapy. The objective of this device is to provide an adjunct to current AoP treatment to support breathing in premature infants by using a simple, non-invasive vibratory device placed over limb proprioceptor fibers, an intervention using the principle that limb movements facilitate breathing. Methods Used: Premature infants (27+6 - 34+6 weeks GA) with clinical confirmed weeks with diagnosis of Apnoea of Prematurity. Caffeine therapy was not a reason for exclusion. Small vibration devices were placed on one hand and one foot and activated in a 6 hour ON/OFF sequence for a total of 24 hours. Heart rate, respiratory rate, oxygen saturation (SpO2), and breathing pauses were continuously collected.

Detailed Description
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Aim: To study the effect of (WAVE Device) limb proprioceptive stimulation using a vibratory device on AoP events, intermittent hypoxic episodes (SpO2≤85%) and bradycardias(≤100bpm) in a premature infant with confirmed clinical diagnosis of apnea of prematurity (AoP). The objective of the WAVE device is to provide an adjunct to current care to provide support in apnea of prematurity (AOP). Recurrent apnea and accompanying resultant intermittent hypoxic (IH) episodes are significant concerns commonly encountered in premature infants, and optimal management is a challenge to neonatologists. AoP is defined as >20s breathing pause OR breathing pause of 10-20sec with clinical signs of Bradycardia (≤100bpm) and/or desaturation (≤85% SpO2) in infants born less than 37 weeks of gestation. When these pauses are longer (> 20s), they are frequently prolonged by obstructed inspiratory efforts, most likely secondary to loss of upper airway tonic activity. In extremely low birth weight (ELBW) infants, the incidence of IH progressively increases over the first 4 weeks of postnatal life, followed by a plateau and subsequent decline between 6-8 weeks. The incidence of AOP correlates inversely with gestational age and birth weight. Nearly all infants born <29 weeks gestation or <1,000 g, 54% at 30 to 31 weeks, 15% at 32 to 33 weeks, and 7% at 34 to 35 weeks gestation exhibit AOP (2). Both animal and human evidence show that immature or impaired respiratory control and the resultant IH exposure contribute to a variety of pathophysiologic issues via pro-inflammatory and/or pro-oxidant cascade as well as cellular mechanisms, e.g., apoptosis, leading to acute and chronic morbidities (e.g. retinopathy of prematurity, altered growth and cardiovascular regulation, disrupting zinc homeostasis which hampers insulin production and there by predisposing to diabetes in later life, cerebellar injuries and neurodevelopmental disabilities). Current standard of care for AOP includes prone positioning, continuous positive airway pressure (CPAP) or nasal intermittent positive pressure ventilation (NIPPV) to prevent pharyngeal collapse and alveolar atelectasis, and methylxanthine therapy (caffeine, theophylline), which is the mainstay of treatment of central apnea. Apart from prone positioning, none of these interventions are optimal for early development. CPAP masks will distort the bony facial structure in early development, and methylxanthine interventions pose serious questions of neural development interactions.

Official Title
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WAVE Trial in Premature Infants With Apnea of Prematurity Using a Simple, Non-invasive Vibratory Device to Study the Effectiveness in Supporting Breathing and General Stability

Conditions
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Apnea of Newborn, Hypoxia Neonatal, Bradycardia Neonatal

Intervention / Treatment
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* Device: WAVE device


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Written informed consent Gestational age > 27+6weeks, < 34+1 weeks Diagnosis of apnoea of prematurity (AOP) on clinical observations (atleast 4 AoP episodes and atleast one ABD event (equal and less 85% SpO2)- define clearly). Caffeine treatment will not be an exclusion. If babies are on caffeine they need on maintenance dose for atleats 48 hours. (72hours after first dose of caffeine (Infant must be on maintenance dose) During screening baby must demonstrate >4 AoP/1 ABD events Minimum 48 hours after extubation. Exclusion Criteria: Inotropes Infants with major congenital anomalies/malformations which will influence central nervous system and long-term outcomes in these infants, such as cardiac anomalies (except for Patent Ductus Arteriosus or Ventricular Septal Defect) or major neurological malformations, like meningoencephalocele, holoprosencephaly Neonates who have apnoea from airway issues like laryngomalacia or tracheomalacia. Neonates with a history of hypoxic-ischemic encephalopathy or Grade IV intraventricular haemorrhage Infants that are currently intubated and invasive ventilation Congenital skin malformations, skin conditions due to recurrent illness (microcirculation concerns). Patients being treated for sepsis.

Ages Eligible for Study
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Minimum Age: 28 Weeks
Maximum Age: 35 Weeks

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: Sequential Assignment In the same subject there were 2 periods: OFF cycles (6 hours x 2): 'No intervention' period (no vibrations) - two 6 hour epochs - total of 12 hours of 'No intervention' ON cycles (6hours x 2). Experimental period (with vibrations) - two 6 hour epochs - total of 12 hours of 'vibration intervention' In the same subjects cardio-respiratory parameters will be continuously monitored through the 24 hour treatment period of 4 cycles- heart rate, respiratory rate and oxygen saturation were compared during the experimental period (vibration) and during the no intervention period (no vibration).
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Treatment starting with an on ON cycle<br>The treatment will start ON cycle for 6 hours, followed by OFF cycle for 6 hours, followed by OFF cycle for 6 hours and finished with ON cycle for 6 hours. | Device: WAVE device<br>* WAVE applies a transcutaneous vibration to the soles of the foot and palms of the hand to elicit nerve signalling from pressure and other limb proprioceptor sensors to pontine, cerebellar, and medullary brain areas that coordinate limb movement and reflexively activate brain areas controlling breathing. The WAVE device is a battery-operated product to reduce the episodes of Apnoea of Prematurity by vibratory stimulation to the hand and foot.<br>* Other names: kinesthetic stimulation;|
| Other: Treatment starting with an on OFF cycle<br>The treatment will start OFF cycle for 6 hours, followed by ON cycle for 6 hours, followed by OFF cycle for 6 hours and finished with ON cycle for 6 hours. | Device: WAVE device<br>* WAVE applies a transcutaneous vibration to the soles of the foot and palms of the hand to elicit nerve signalling from pressure and other limb proprioceptor sensors to pontine, cerebellar, and medullary brain areas that coordinate limb movement and reflexively activate brain areas controlling breathing. The WAVE device is a battery-operated product to reduce the episodes of Apnoea of Prematurity by vibratory stimulation to the hand and foot.<br>* Other names: kinesthetic stimulation;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Compare the cumulative burden of AoP with or without WAVE stimulation | The primary objective is to compare the cumulative duration of breathing pauses related to Apnoea of Prematurity (AoP) between periods of presence and absence of tactile vibratory device stimulation as adjunct to standard care. | 24 hours | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Compare the number of AoP events. | To compare the number of AoP events between periods of presence and absence of tactile vibratory device stimulation adjunct to standard of care. | 24 hours | 
| Compare the number of desaturations (SpO2<86%) events | To compare the number of desaturations (SpO2<86%) events between periods of presence and absence of tactile vibratory device stimulation adjunct to standard of care. | 24 hours | 
| Compare the cumulative depth of desaturations. | To compare the cumulative depth of desaturations (SpO2<86%) between periods of presence and absence of tactile vibratory device stimulation adjunct to standard of care. | 24 hours | 
| Compare the cumulative duration of desaturations (SpO2<86%) events. | To compare the cumulative duration of desaturations (SpO2<86%) between periods of presence and absence of tactile vibratory device stimulation adjunct to standard of care. | 24 hours | 
| Compare the number of bradycardia events. | To compare the number of bradycardia events between periods of presence and absence of tactile vibratory device stimulation adjunct to standard of care. | 24 hours | 
| Compare the cumulative depth of bradycardia events. | To compare the cumulative depth of bradycardia events between periods of presence and absence of tactile vibratory device stimulation adjunct to standard of care. | 24 hours | 
| Compare the cumulative duration of bradycardia events. | To compare the cumulative duration of bradycardia events between periods of presence and absence of tactile vibratory device stimulation adjunct to standard of care. | 24 hours | 
| Nursing assessment scores -NPASS scoring system (6). | To compare NPASS scores (6) between periods of presence and absence of tactile vibratory device stimulation adjunct to standard of care. | 24 hours | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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cardio-respiratory stability, neonate, premature infant, proprioceptive stimulation, Apnoea of Prematurity, Medical Device