Creating a Calmer NICU: Optimizing Growth and Brain Development in Preterm Infants

Study Overview
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Brief Summary
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Infants born preterm can spend months in the neonatal intensive care unit (NICU) where they experience stressful but essential procedures. Untreated stress is associated with altered brain development. Skin-to-skin holding (SSH) is one of the most effective behavioral strategies for mitigating preterm infant stress and improving brain maturation. However, parents may not be always available to provide SSH; some infants cannot be held for long periods for medical reasons. To address this problem, investigators designed Calmer, a patented, prototype therapy bed, for reducing stress in preterm infants. Calmer fits into NICU incubators and provides simultaneously an artificial skin surface, heartbeat sounds and breathing motion, mimicking aspects of SSH; the latter 2 features are individualized for each infant based on their parents' recordings. The 1st randomized controlled trial (RCT) in 58 preterm babies showed that during a routine blood test: Calmer lowered infant behavioral and heart stress responses and stabilized brain blood flow no differently than facilitated tucking; infants could be cared for safely on Calmer up to 6 hours in 1 day; Calmer was well accepted by mothers and staff. The goal now is to determine the efficacy of Calmer use over 3 weeks to support optimal physical growth and brain development in preterm infants. A 2-group (treatment, control) pilot RCT to test the implementation of an increased dose of Calmer exposure over 3 continuous weeks is proposed. 20 infants born between 26-30 weeks gestational age in the NICU will be randomized to receive either Calmer, for a minimum of 3 hours in total/day for 3 continuous weeks, or to 3 weeks of standard NICU care. Research questions: Trial feasibility Q1. Is it feasible to enrol 30 infants, complete a 3-week treatment period, and measure growth outcomes in preterm infants (26-30 weeks GA) in the NICU in a pilot RCT of daily Calmer treatment versus standard NICU care to inform a larger, definitive RCT? Infant outcomes Q2a. Are there differences in physical growth markers (daily weight gain, head circumference, body length) between preterm infants who receive Calmer and those who receive standard NICU care measured before (baseline) and after 3-weeks of daily Calmer exposure? Q2b. Are there differences in brain activity markers, as measured by cerebral electrical (EEG) signaling, between preterm infants who receive Calmer and those who receive standard NICU care, measured during 2 resting/sleeping state and routine diaper change sessions (baseline and post 3-weeks of daily Calmer exposure)?

Detailed Description
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Pilot trial implementation targets: Targets for success would be that the informed consent rate will be at least 40%, 30 patients will be enrolled in 24 months, 95% of infants will receive the 3 hour minimum treatment, and patient assessment completion rate will be at least 85%. The results of this pilot trial will be used to inform the design of a larger RCT. The results of this pilot trial will allow to assess patient accrual, protocol adherence, and to monitor the completeness and quality of the outcome data. If implementation targets are met, an application for further funding to use this protocol in a larger, multisite, non-inferiority trial comparing SSH + Calmer to SSH alone will be put forth.

Official Title
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Creating a CALMER NICU: Pilot Testing a Robot for Optimizing Growth and Brain Development in Preterm Infants in the NICU

Conditions
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Prematurity

Intervention / Treatment
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* Device: Calmer


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Preterm infants admitted to the neonatal intensive care unit (NICU) at the British Columbia (BC) Women's Hospital born at 26-30 completed weeks gestational age (GA). GA is determined accurately using early gestation ultrasonogram (standard of care in BC), or calculated using the last menstrual period; Infants who are on continuous positive airway pressure or are ventilated; At least one parent/caregiver must speak sufficient English to provide consent Exclusion Criteria: Infants who have congenital anomalies, small for GA (per medical admission history), or have a history of maternal abuse of controlled drugs and substances; - Infants with an ongoing infection at the time of enrolment; Infants that have pre-existing cardiovascular instability defined by shock/hypotension/need for cardiovascular drugs Infants receiving paralytic drugs; Infants that have major neurological injury (e.g. hypoxic ischemic encephalopathy, hemorrhage/stroke); Infants who are beyond the 30th completed week GA (30 weeks + 6 days) at enrolment.

Ages Eligible for Study
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Minimum Age: 26 Weeks
Maximum Age: 30 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: Parallel Assignment
Interventional Model Description: Single-site, single-blind, two-group (treatment and control), randomized pilot trial
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| No Intervention: Control<br>Standard Neonatal Intensive Care Unit (NICU) care | |
| Experimental: Calmer<br>Calmer placed and left in infant incubator for the 3-week study period. Calmer treatment provided for minimum total of 3 hours/day (can be discontinuous). | Device: Calmer<br>* Once randomized, infants in the Calmer group will receive treatment for a minimum cumulative total of 3 hours/day during periods when the infant may be too ill to be held or when parents do not wish to hold their infant or are not present. Calmer does not replicate a parent's contact and so the minimum exposure has been tripled. No upper limit of Calmer use will be set. Each day, the research and/or bedside nurse will record the heart and respiratory rates for a two-minute period. The one-minute average will be used to program Calmer for each infant that day to better simulate day-to-day changes in infant-parent contact. The Neonatal Intensive Care Unit (NICU) research nurse will also train the parents/caregivers to self-measure their resting heart and breathing rates so that if they are away from the NICU for more than one day, these values can be sent to the research/ bedside nurse by phone.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Trial feasibility: Consent rates | Overall average consent rate of infants/month | 36 months | 
| Trial feasibility: Protocol delivery rate | Percent of on/off protocol infants for the trial period | 36 months | 
| Trial feasibility: Complete outcome measures | Percent of infants with complete clinical primary and secondary outcome measures | 36 months | 
| Trial feasibility: Safety issues | Rate of safety issues identified | 36 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Brain activity at rest and during stress event (routine diaper change) | EEG measure during 2 single sessions (at enrollment; at end of the 3-week). EEG assessments for  60 min when the infants are at rest in their incubator (undisturbed during quiet/active sleep) while laying on the Calmer device turned off (if experimental group, otherwise incubator as standard). EEG measurements will be taken in 4 phases: Baseline A: 15-minute Sleep + Calmer device OFF (Pre) Baseline B: 15-minute Sleep + Calmer device ON Stressful event: Diaper change (standardized) + Calmer device ON Recovery: 15-minute Sleep + Calmer device ON We will conduct brain activity EEG measurements using a 64-channel HydroCel Geodesic Sensor Net specifically designed to suit the very small heads and fragile skin of preterm infants (EGI, Eugene, OR). We will have synchronized bedside video recordings and code stress behaviours using the NICU standard pain assessment tool. | 3 weeks | 
| Weight gain | The change in average infant weight gain between Calmer and control groups in grams/day (g/d) will be measured on the day before the start of the treatment (baseline), at the mid-way point ( day 11), and at the end of the 3-week period, then divided by the number of treatment days. Sex and gestational age (GA) age-specific percentiles for the measures will be calculated using the Fenton Growth charts. Changes in weight percentiles between baseline and end of treatment will then be calculated. | 3 weeks | 
| Nutritional status | Measures of daily feeding and nutritional data will include: method of feeding (intravenous, nasogastric, oral-gastric, oral), type (total parenteral nutrition, breastmilk (mother's or donor), formula, additives (Human milk fortifier, lipids), frequency/timing and method (breast/bottle) of transition from tube to oral feeds at transfer/discharge. | 3 weeks | 
| Head circumference | Baseline, mid-point and end-of-treatment measures of head circumference in cm (occipito-frontal circumference [OCP]) will be reported. Sex and GA age-specific percentiles for the measures will be calculated using the Fenton Growth charts. Changes in OFC percentiles between baseline and end of treatment will then be calculated. | 3 weeks | 
| Body length | Baseline, mid-point and end-of-treatment measures of body length in cm will be reported. Sex and GA age-specific percentiles for the measures will be calculated using the Fenton Growth charts. Changes in body length percentiles between baseline and end of treatment wil then be calculated. | 3 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Prematurity, Robotic device, Skin-to-skin holding, Stress, Brain activity, EEG, Neonatal intensive care, Growth