Background
Perinatal stroke occurs between 20 weeks gestation and 28 days postnatal life and is the leading cause of unilateral cerebral palsy [
1] with an estimated incidence of 1 in 1600–3000 live births. Perinatal stroke may result in life-long motor impairments [
1‐
4]. For example, the children typically have limitations with walking, which results in abnormal loading of the joints, premature musculoskeletal problems, reduced physical activity, and participation [
5,
6]. Further, the sequelae from perinatal stroke can have a profound impact on family well-being [
7].
Recent evidence indicates active interventions improve function [
8], while passive interventions, such as bracing and botulinum toxin A injections, provide only short-term gains with unknown or suboptimal longer-term outcomes [
9‐
11]. Early, intensive rehabilitation for the upper extremity has gained acceptance, but active rehabilitation for the lower extremity remains infrequent with little standardization between therapists and centres [
12].
Our preliminary efficacy trial indicated that the ELEVATE (Engaging the Lower Extremity Via Active Therapy Early) intervention resulted in significantly greater improvements in gross motor function compared to a control group receiving usual care [
13]. Children less than three years old with perinatal stroke tolerated one hour of intensive lower extremity activity, four days/week for twelve weeks.
Sufficient intensity of neurological rehabilitation is important [
14], but it is often neither feasible nor cost-effective for physical therapists to administer high-intensity training for a prolonged period. Achieving this intensity is often better achieved by children’s parents or guardians, especially with very young children [
15,
16]. Involvement of the family is essential for enhancing child outcomes [
17], but there are limited reports of parents’ experiences with conducting home rehabilitation programs, especially as partners in therapy [
18]. Furthermore, while family centered care advocates for parent-clinician partnerships, clinicians are cautioned against ‘downloading’ professionally driven interventions to families [
19]. This study is a concurrent mixed methods design; the qualitative study will explore the parents’ perspectives of the intervention and their experiences as a partner in rehabilitation.
The purpose of this trial is to evaluate the effectiveness of early, intensive rehabilitation delivered using a parent-therapist partnership model for children with perinatal stroke. The trial was designed in collaboration with parents and therapists to build on our findings in the laboratory and determine if the intervention is effective in a real-world setting. We hypothesize that, as compared to a control group receiving usual care, young children with perinatal stroke and unilateral cerebral palsy (CP) who receive intensive lower extremity training delivered in a parent-therapist partnership will demonstrate greater improvement in gross motor function.
Outcomes
Primary outcome measure
Gross motor function
The Gross Motor Function Measure-66 (GMFM-66) is the primary outcome measure, a criterion-referenced observational measure for assessing gross motor function in children with CP [
24]. It has been validated for children > 0.5 years old and is a gold standard for measuring gross motor function in children with CP [
25]. The assessing therapists will be pediatric physical therapists from the community trained by study personnel to administer the GMFM-66 and are masked to the child’s group assignment. All parents will be informed not to disclose the child’s group assignment to the assessing therapist. All assessments will be videotaped for reference. The GMFM-66 will be administered twice at baseline and monthly thereafter, for a total of 14 measurements per child. The two measures at baseline will be averaged to provide a more reliable estimate.
Secondary outcome measures
Quality of life
Quality of life of the participants and their parents will be quantified at entry to the study, and again every 3 months using the Pediatric Quality of Life Inventory™, module for cerebral palsy (PedsQL CP) [
26]. The PedsQL CP will be administered via online self-report through REDCap, or over the phone if respondents require assistance. The PedsQL is reliable and sensitive [
26] and has been used extensively for this population. The children in this study are too young to self-report, so a parent proxy will be used. The scales in the CP module used are those recommended for children up to four years old [
26]. The PedsQL also has a 36-item scale to measure the impact of a child’s health condition on the family, called Family Impact Module (PedsQL FIM). The scale has been widely used for parents of children with chronic health conditions, including perinatal stroke [
7]. Three scores will result from this module, which reflect the parents’ health-related quality of life, family functioning and a total score.
Resource use and costing
Costs related to lower extremity therapy as well as resources used for treatment and management of the child’s cerebral palsy will be included over the study period, similar to a previously reported protocol [
27]. The child will be the unit of analysis and utilization incurred by the participant, caregivers and/or the healthcare system will be assigned to the child for analysis. The Resource Use Questionnaire (RUQ) is a tool validated for use in participants with neurodevelopmental disabilities [
28,
29] and will be used to collect information regarding resource use and out-of-pocket costs (e.g. physical or occupational therapy, materials and equipment, child-focussed recreation activities, etc.).
The RUQ will be administered at baseline, six months, the end of the one year study period and at the four-year-old follow up. The total cost per participant per month will be calculated and used in extrapolation. For the healthcare system perspective, costs will include physical or occupational therapy, child-focused recreation activities and additional services related to the child’s care paid for by the public healthcare system. For the societal perspective, costs will include all costs for the healthcare system perspective as well as parent lost productivity and parent out-of-pocket costs. For analysis using the societal perspective, a human capital approach [
30] will be used to monetize lost caregiver productivity. Parent reports on the RUQ will include out-of-pocket costs for additional services, child-focused recreation activities, and materials and equipment. Lost productivity and out-of-pocket costs will be summed for the family of each participant to obtain total lost productivity and out of pocket costs for each participant over the study period.
The cost of the ELEVATE intervention will be estimated from the compensation to therapists including training, administration of the ELEVATE intervention and the cost of any materials and supplies associated with the intervention.
Participation
The Young Children's Participation and Environment Measure (YC-PEM) will be used to assess participation in three settings: home, daycare/preschool, and the community [
31]. This questionnaire, completed by a parent or caregiver, was developed for children aged 0–5 years. The YC-PEM will be administered at baseline and every three months throughout the twelve-month study period and may be administered over the phone with research staff or via online self-report through REDCap.
Spasticity
We will use a newly developed device for measuring spasticity called the Portable Spasticity Assessment Device (PSAD, Nordic Neurostim, Denmark) [
32,
33] to determine if the intervention reduces contracture or spasticity at the ankle, as seen in other active therapies for the lower extremities [
32,
34]. Ankle joint range of motion, mechanical resistance caused by contracture and reflex-mediated spasticity can be measured using this device. We focus on the ankle, since this is the lower extremity joint very commonly affected by spasticity and is often the target of passive approaches including botulinum toxin, serial casting and orthoses [
35]. Contracture, defined here as increased stiffness in joint movement cause by changes in intrinsic soft-tissue properties, will be reflected by the torque during slow stretch without any muscle activity. Spasticity will be indicated by the joint angle at which reflex EMG is generated in a fast stretch, similar to the angle of catch in the Tardieu Scale. This measure will be used at two study sites, because we only have two devices.
Reporting of co-interventions
During the six-month control period for the Waitlist-control Group and the follow-up period for both groups, parents will be asked to report any rehabilitation for their child’s lower extremity including the nature, duration and frequency. This will provide clarity on usual care, and the variations between sites.
Sample size
The effect size on the primary outcome measure is estimated at 0.91, based on data from a cohort of children trained by their parents in our preliminary efficacy trial, as this is the more conservative estimate compared to the 1.67 effect size of children trained by a physical therapist. Twenty children per group are required to achieve statistical power of 0.8 and significance of 0.05. To account for cluster randomization with an estimated intra-cluster correlation coefficient of 0.02, a design effect of 1.4 is considered, which results in a total sample size of 56.
Data management and analysis
Data will be entered in REDCap and analyzed at the primary study site. The primary time point of interest is at six months (Fig.
2), so change scores from baseline to six months will be compared between the ELEVATE intervention and control groups. Multiple linear regression models may be developed to assess the effect of variables (e.g. age at time of intervention) for each outcome. We will assess model fit and provide estimates with 95% confidence intervals.
Cost-effectiveness analysis (CEA)
In the CEA, the ratio of the difference in mean cost between the ELEVATE and Waitlist-control groups to the difference in effectiveness scores (change in GMFM-66) between groups will be used to estimate an incremental cost-effectiveness ratio (ICER) from the publicly funded healthcare payer and societal perspectives. The mean effectiveness for each group will be compared using patient level regression. We will use Ordinary least squares (OLS) to assess the difference in effectiveness and the difference in cost between groups. We will control for a set of covariates including study site, age and baseline GMFM-66 scores. The mean cost per participant for each group will also be compared using participant-level regression. A bootstrapped analysis will be conducted for the CEA and results presented on a cost-effectiveness acceptable curve (CEAC).
Trial monitoring
The trial is overseen by Health Canada because the PSAD is approved for investigational testing. The trial is monitored by the Quality Management in Clinical Research unit at the University of Alberta. The Research Ethics Board 3, University of Alberta, approved this study and the researchers are responsible for reporting protocol amendments and adverse events. Annual ethics renewals of the protocol are monitored by this Board.
Discussion
Perinatal stroke results in life-long consequences for children and families. By intervening early, limited health care resources can be directed to children at an age when the effects are potentially largest. This study engages parents as partners so they become familiar with the principles of the approach. We anticipate that parent involvement will facilitate longer-term outcomes that will potentially enhance child motor development beyond the study period. We hypothesize that early improvements in gross motor function will enhance child outcomes and improve child and family quality of life. In addition, economic benefits may extend beyond our study period, for example, by delaying or avoiding the need for orthoses and botulinum toxin A injections, which we aim to capture at the four-year-old follow-up. Understanding parents’ experiences with the parent-therapist partnership model will allow for refinement of this approach to rehabilitation and more effective translation to clinical settings. Finally, partnering with key knowledge users, including families and pediatric clinicians, aims to bring about faster and more seamless adoption of the intervention if the results demonstrate effectiveness.
Acknowledgements
Biostatistics and REDCap access have been supported by the Women and Children’s Health Research Institute. We thank Donna Livingstone, PT, Rhina Delgado, OT, Catherine Bangel, Erin Coffin, and Simone Hunter, PT, for contributing to the design of this study.
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