Physiotherapy - Theses
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ItemSystematic investigation of early-phase trial designs for upper limb therapy post-stroke( 2022)A lack of early-phase trials to systematically investigate dose and target population during intervention development is a likely reason for non-pharmacological stroke recovery trials falling short of the outcomes expected by researchers and clinicians and needed by people living with stroke. The overall objective of the work presented in this thesis was to systematically investigate dose, target population and decision-logic of early-phase trial designs in non-pharmacological stroke recovery. To achieve the objective, Study 1 developed the tools required to appraise early-phase trials of preclinical and clinical non-pharmacological stroke recovery motor interventions and embedded them in an accompanying protocol for a systematic scoping review. Study 2 executed the systematic scoping review and demonstrated a lack of published and high-quality preclinical and clinical early-phase stroke recovery motor trials that explicitly aimed to investigate dose. Study 3 established a lack of Phase I stroke trials that were registered or funded. Collectively, these studies resulted in original contributions in the form of (a) a systematic discovery pipeline tool, (b) an Early Phase Research Quality Checklist, and (c) an understanding that systematic early-phase research is rarely completed. The above findings provided an essential basis for in-depth investigation of the adaption of early-phase trial designs for application to the domain of clinical non-pharmacological stroke recovery motor interventions. As a part of this investigation, Study 3 developed a decision support tool to guide the design of Phase I non-pharmacological trials that can escalate more than one dose dimension. Study 4 utilised the decision support tool to guide the design and implementation of a multidimensional Phase I dose-ranging trial of an upper limb motor intervention delivered early post-stroke. This trial is ongoing, with the current tolerable dose being three 15-minute upper limb sessions per day. Finally, Study 5 investigated the impact of target population selection on the generalisability of upper limb motor trials conducted early post-stroke. Participant sampling was found to be a complex process that needs to be adequately reported and systematically undertaken to ensure an appropriate balance between internal and external validity. Overall, these studies have resulted in the original contributions in the form of: (d) a Phase I decision support tool, (e) confirmation that a multidimensional Phase I dose-ranging trial is feasible to implement, (f) confirmation that the current tolerable dose range is higher than usual care upper limb therapy provided early post-stroke in Australia, (g) an understanding that a lack of reporting in trials is impacting generalisability, and (h) an understanding that broadening eligibility criteria alone is unlikely to improve generalisability. Collectively, these contributions have enriched early-phase stroke recovery research by identifying barriers to its completion and providing solutions to support its uptake and quality. The completed research provides a sound basis for ongoing work to demonstrate the benefits of embedding intervention development through a systematic discovery pipeline approach within the confines of intervention complexity and the heterogeneous context of stroke. Adopting a systematic approach to intervention development via early-phase trials is achievable and likely a crucial step in bringing the field closer to identifying practice-changing interventions.
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ItemCritical Illness Survivorship: Rehabilitation and Recovery( 2021)Survivors of critical illness can experience significant physical disability during their recovery, delaying return to activities of daily living, all negatively impacting their health-related quality of life. Level one evidence supports the implementation of physical rehabilitation programs to address these short term sequalae. However, recent large randomized controlled trials measuring longer term physical function and health-related quality of life do not report sustained improvement. To better understand this phenomenon, investigations into the role of patient characteristics in responsiveness to physical rehabilitation and critical illness recovery is an emerging research area and is the focus of this thesis. The first study of this thesis is a narrative review, where 12 randomized controlled trials with conflicting results for the beneficial effects of physical rehabilitation on the physical function, health-related quality of life and health care utilization outcomes of critically ill adults were identified from a comprehensive and systematic literature search. Through critical evaluation of these randomized controlled trials and additionally relevant studies, a theoretical construct was developed for the research of this thesis and to advance the field. In brief, the core components of the theoretical construct are in searching for the responder; investigation into potential modifiers of physical rehabilitation outcomes (including patient characteristics); tailoring rehabilitation interventions to address known physical impairments; and deciphering the prime time for responsiveness to these interventions based on patients biological and physiological recovery. Lastly, the conclusion that more research is needed on the optimal prescription parameters of physical rehabilitation programs to guide clinical practice with consideration to facilitators and barriers to implementation of the intervention is reached. The second study is a systematic review examining the association between indicators of social and economic position within society (socioeconomic position) and health outcomes following critical illness. Ten studies were included in this systematic review, with a strong focus on mortality despite survivorship being the identified challenge for critical care in the 21st century. The higher mortality rates and poorer health-related quality of life reported for critically ill adults with a lower socioeconomic position signal that a social gradient exists in critical care. This may indicate a clinical subgroup that would derive benefit from multimodal and interdisciplinary interventions to potentially alter their recovery trajectory. For the third and final study a systematic review and an individual participant data meta-analysis of randomized controlled trials was performed to examine the interaction between the treatment group (intervention vs control) and patient characteristics (comorbidity, age, sex and illness severity) for the performance-based physical function (at hospital discharge, three and six months) and health-related quality of life (at three, six and 12 months) outcomes of critically ill adults. From the four randomized controlled trials included, totaling a combined sample size of over 800 participants, comorbidity modified the effect of physical rehabilitation for the health-related quality of life instrument (Physical Component Summary score of the 12-item and 36-item Short Form Health Surveys). Specifically, the Physical Component Summary scores were higher (better) for multimorbid patients (defined as Functional Comorbidity Index score >=2) who were allocated to the intervention group at the three and six but not 12 month follow up time points. We hypothesize that this study has implications for future trial design, where a stratified approach (Functional Comorbidity Index <=1 and >=2) may reduce sample size calculations. We recommend that clinicians prioritize the provision of a structured individualized physical rehabilitation program to multimorbid patients as a subgroup that derives significant benefit from this intervention. In conclusion, the findings of this thesis navigate the path forward for rehabilitation research in critical care. This area, both in research and clinical practice, has previously been plagued by the heterogeneity of the patient population. The identification of a target group of critically ill patients (multimorbid, Functional Comorbidity Index score >= 2) provides direction clinically and for future investigations into the effects of physical rehabilitation. Ultimately leading to the progression of the field to provide patients with the right intervention at the right time in their recovery trajectory to improve their outcomes following critical illness.