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| Name | Class |
|---|---|
| BC Children's Hospital Research Institute | OTHER |
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Very preterm infants in the neonatal intensive care unit (NICU) need lifesaving medical procedures which can be stressful and affect brain development. Calmer was invented to mimic key parts of parental holding (touch, heartbeat sounds and breathing motion) to help reduce stress if parents cannot be there to hold their infant. Using specialized brain scans done at full term, we will gather initial information in 22 infants born 3-4 months early to compare brain development in infants who receive Calmer at least 3 hours each day (+ regular NICU care) over 2-3 weeks with infants who have regular NICU care.
Very preterm infants (< 32 weeks gestational age [GA]) experience developmentally unexpected, repeated stress as part of lifesaving care in the NICU during a period of considerable brain maturation and growth. Exposure to early-life stress alters brain maturation resulting in long-term changes in neurodevelopment. Parental skin-to-skin care (SSC) can mitigate stress; however, parents are not always available. Calmer, a patented, therapeutic medical device, was invented to simulate aspects of SSC (skin-like surface, breathing motion, heartbeat sounds) with rates of the latter two individualized for each infant. In a randomized trial, Calmer has been shown to stabilize brain blood flow during a single, routine blood test. Most recently, we found that very preterm infants who received Calmer treatment for 3 continuous weeks had 25% greater head growth compared to controls. However, we do not know if/how Calmer treatment affects brain development in very preterm infants.
Objectives: We will gather pilot data for a larger trial to examine differences in brain structural and functional development in very preterm infants who receive Calmer treatment for 2-3 consecutive weeks compared to controls.
Methods: 22 infants born 26-30 weeks GA admitted to BC Women's Hospital NICU will be randomized to either control (n=11) or treatment groups (n=11; Calmer for 2-3 continuous weeks, 3 hours/day minimum treatment). Infants from both groups will undergo feed and bundle MRI scans at term-equivalent age using high resolution volumetric, diffusion and resting-state functional MRI to explore group differences in whole-brain volumes and structural and functional connectivity. Images will be processed using existing quantitative neonatal imaging analysis pipelines in the Selvanathan and Weber labs at BC Children's Hospital Research Institute. Analyses will include: measures of trial feasibility and description of brain differences between groups.
Significance: Ultimately, Calmer may support healthy brain maturation optimizing the neurodevelopment of vulnerable infants in Canada and beyond.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Calmer | Experimental | Infants in the Calmer group will have a Calmer* placed and left in their incubators for a minimum of 2 and maximum of 3 weeks and will receive treatment for a minimum cumulative total of 3 hours/day (i.e. time can be discontinuous). Each day, after the infant's parent rests for 10 minutes, the research and/or bedside nurse will record the heart and respiratory rates for a 2-minute period (or taken by the caregiver themselves after training by research/NICU staff). The 1-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 values can be adjusted over the day as parents wish. *Calmer, a patented, therapeutic bed that mimics key aspects of skin-to-skin care (SSC) to reduce stress in preterm infants. Calmer fits into NICU incubators and delivers 3 key SSC stimuli: touch, breathing motion, and heartbeat sounds (rates individualized to each infant based on their parents' HR/RR). |
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| Control | No Intervention | Infants in the Control group will receive standard NICU care, including parent SSC. |
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Calmer | Device | Calmer, a unique, patented, therapeutic bed that mimics key aspects of SSC that reduce stress in preterm infants. Calmer fits into NICU incubators and cribs, and delivers 3 key SSC stimuli: touch, breathing motion, and heartbeat sounds; the rates of the latter 2 stimuli are individualized to each infant based on their parents' breathing and heart rates. Calmer is designed to provide complementary care only when parents are not able to give SSC. It is not meant nor designed to replace human SSC, so will never be tested as such a replacement. Instead, Calmer was invented to enhance and optimize brain development in preterm infants by reducing stress during the NICU stay, when parents/caregivers are not available for SSC. Our ultimate goal is to enable use of Calmer from an infant's admission to discharge, only during those times when caregivers are not available. |
| Measure | Description | Time Frame |
|---|---|---|
| Brain Volumes | Anatomical analysis: Anatomical images (T2w) will be manually inspected for quality control. Images with very poor tissue contrast or motion artefacts will be rejected. T2w images will be bias-field corrected using ANTs N4ITK. The images will then be skull-stripped and segmented using the dHCP anatomical pipeline to calculate total and sub-regional brain volumes. | When each participant reaches 40 weeks post-conceptual age and return for their MRI scan |
| Brain Functional Connectivity | Resting state fMRI analysis: Fieldmaps will be generated using the dual-echo EPI and magnitude scan. The dHCP functional pipeline will be implemented to achieve distortion-correction and motion-correction, register the functional image to the corresponding T2w structural image, generate a transform matrix from functional space to the 40-week T2w template; and we will perform temporal high-pass filtering (150 s high-pass cutoff) and independent component analysis (ICA) denoising using ICA FIX. Scans with a mean FD > 1 mm will be excluded. The dHCP functional pipeline will then be run on all subjects using the study-specific training file. Spatial smoothing of 5 mm will be applied using FSL's SUSAN and grand mean intensity normalization will be computed. Functional connectivity measures will be computed using the CONN toolbox. | When each participant reaches 40 weeks post-conceptual age |
| Brain Fractional Anisotropy | Diffusion tensor imaging analysis: The dHCP neonatal dMRI data processing pipeline will be used to pre-process the diffusion weighted images. Briefly, opposite phase b0 images are used to estimate the off-resonance field that is then used in the simultaneous correction of motion artefacts, susceptibility-induced and eddy current distortions. Data will then be super-resolved and, after pre-processing is complete, local diffusion and microstructural models are fitted in every voxel and averaged to calculate mean fractional anisotropy. | When participants reach term-equivalent age |
| Measure | Description | Time Frame |
|---|---|---|
| Clinical weight measures | Weight: infant weight in kilograms captured when enrolled in the study (i.e. baseline T1) and end of experimental phase (2-3 weeks later; T2) We will use the weight measure to determine changes between baseline and the end of treatment. | From the start of study treatment (or enrolment if Control group) to 2-3 weeks later, at the end of intervention exposure. |
| Measure | Description | Time Frame |
|---|---|---|
| Trial feasibility | Consent rate: overall average consent rate of infants/month | 2 years from the start of the study |
| Trial feasibility | Protocol delivery: % of on/off protocol infants |
Inclusion Criteria:
Exclusion Criteria: Infants who have
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| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| Manon Ranger, PhD | Contact | 604-827-1382 | manon.ranger@ubc.ca |
| Name | Affiliation | Role |
|---|---|---|
| Manon Ranger, PhD | University of British Columbia | Principal Investigator |
| Liisa Holsti, PhD | University of British Columbia | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| BC Women's Hospital & Health Centre | Vancouver | British Columbia | V6H 3N1 | Canada |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 31041426 | Result | Holsti L, MacLean K, Oberlander T, Synnes A, Brant R. Calmer: a robot for managing acute pain effectively in preterm infants in the neonatal intensive care unit. Pain Rep. 2019 Mar 14;4(2):e727. doi: 10.1097/PR9.0000000000000727. eCollection 2019 Mar-Apr. | |
| 33490850 | Result | Ranger M, Albert A, MacLean K, Holsti L. Cerebral hemodynamic response to a therapeutic bed for procedural pain management in preterm infants in the NICU: a randomized controlled trial. Pain Rep. 2021 Jan 12;6(1):e890. doi: 10.1097/PR9.0000000000000890. eCollection 2021 Jan-Feb. |
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As part of this study, participants' de-identified research data may be shared in a public database when the research is published. Sharing this deidentified data helps make research more transparent and allows others to double-check the results. It also means that other researchers can use the data for different studies in the future, beyond the scope of this current study. The exact details have not been decided yet.
When the research findings are published.
We have not decided on these details.
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| ID | Term |
|---|---|
| D047928 | Premature Birth |
| ID | Term |
|---|---|
| D007752 | Obstetric Labor, Premature |
| D007744 | Obstetric Labor Complications |
| D011248 | Pregnancy Complications |
| D005261 | Female Urogenital Diseases and Pregnancy Complications |
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We will conduct a single-site, single-blind, two-group (treatment and control), randomized pilot trial and determine the feasibility of our study design. We will also gather preliminary data of Calmer's effect on infant structural and functional brain development to inform a larger trial.
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| Head growth measures | Head circumference: infant head circumference in centimetres (occipito-frontal circumference) captured when enrolled in the study (i.e. baseline T1) and end of experimental phase (2-3 weeks later; T2). We will use the head circumference measures to determine changes between baseline and the end of treatment. | From the start of study treatment (or enrolment if Control group) to 2-3 weeks later, at the end of intervention exposure. |
| 2 years from the start of the study |
| Trial feasibility | Outcome measures: % of infants with complete primary outcome data | 2 years from the start of the study |
| Trial feasibility | Rate/nature of safety issues | 2 years from the start of the study |
| D000091642 | Urogenital Diseases |