Ikram, Adeel
(2024)
Musculoskeletal function and phenotyping in frail older patients having hip surgery following fracture.
PhD thesis, University of Nottingham.
Abstract
A hip fracture is a catastrophic injury to an elderly individual with a significant impact individually, on the family, and for health care services. Despite optimisation of medical comorbidities, effective skilled anaesthesia, and early surgery, the patient important outcomes of mobility, independence, and mortality have not improved. With an aging population comes increasing frailty, and those who are frail have the worst outcomes. However, frailty in existing literature has been difficult to quantify. Multiple methods have been used to ascertain and classify frailty status, utilising two different schools of thought: cumulative deficits and phenotype models. Frailty is the ability for an individual to bounce back from illness or injury. It is not known why those who are frail have the worst outcomes and what biological processes occur which underpin these poor outcomes in these individuals.
This study describes and explains the effect of frailty on post-operative outcomes following hip fracture surgery. It evaluates local muscle gene expression using Vastus Lateralis muscle in both the non-injured and injured limb of a range of frail individuals to explain the underpinning biological process of frailty. Lastly it investigates the systemic inflammation secondary to trauma, and how this impacts mortality within this cohort.
The first experimental chapter examined the subjective and objective measures of muscle function and performance. It showed that there are significant differences between the extreme ends of the spectrum of frailty, those with a greater frailty had a poorer health related quality of life both at day 7 and day 90, mobility, institutionalisation, and mortality. Patients with severe frailty, clinical frailty scale score of 7, do not improve in mobility outcomes from day 7 post-surgery. Timed up and go test provides a useful binary measure to predict discharge home in patients who are admitted from their own home. The second experimental chapter identifies significant differentially expressed genes in the Vastus Lateralis muscles when comparing the fractured leg with the non-fractured leg. It also demonstrates no significant difference in gene expression in the non-fractured leg when stratifying for frailty scores. However, in the fractured leg there is a significant difference in gene expression when comparing higher frailty states to lower frailty states. Key mechanisms of inhibition of apoptosis and cell death are reduced as frailty increases, and increased protein catabolism increases with increasing frailty. This highlights key mechanisms which may be potential targets to improve outcomes and prevent frailty. The third experimental chapter identifies the systemic inflammatory markers present at the time of hip fracture surgery and their relationship with 6-month mortality. Two biomarkers FGF-23 and IL-15RA are significantly raised and correlated with renal function which, are predictive of 6-month mortality. This highlights potential treatment targets for reducing inflammation and the role of optimisation of renal function in the peri and post operative management of hip fracture.
This study is uniquely placed amongst the existing literature for a myriad of reasons. It is the first study to investigate gene expression in the vastus lateralis muscle in the non-fractured leg and fractured leg of the same participants. It is also the first study to investigate gene expression in a range of frail patients identifying mechanisms which potentially underpin frailty and poor outcomes following hip fracture surgery. It is also the first study to investigate and evaluate a range of inflammatory markers using proteomic analysis and their relationship with 6-month mortality. The identification of novel biomarkers, cellular functions and objective assessments now paves the way for further research in determining novel therapeutic agents and rehabilitation strategies to not only further improve outcomes for hip fracture surgery but is translatable to reduce the impact of frailty on homeostatic reserve of elderly patients.
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