Mechanisms of Cerebral Autoregulation in Traumatic Brain Injury
While the last 30 years of research into the characterisation and dynamics of cerebral autoregulatory (CA) impairment has vastly improved understanding of this detrimental secondary injury process in traumatic brain injury (TBI), there are still unknowns before we can target autoregulatory disturbance in the neurocritical care unit. This thesis addresses two aspects of these unknowns: 1) CA in the previously uncharacterised paediatric TBI (pTBI) population, and 2) the underlying biochemical mechanisms of CA disturbance following adult TBI. There is a paucity of paediatric-specific data regarding the pressure reactivity index (PRx), with existing data limited to small or retrospective single centre studies. Studying Trends in AutoRegulation in Severe Head Injury in Paediatrics (STARSHIP) is the first multicentre prospective trial and aimed to characterise PRx in 135 children with pTBI. Firstly, I investigate the duration and magnitude of PRx disturbance following pTBI, and its association with outcome at 12 months post ictus. I demonstrate the potential clinical benefit of PRx monitoring in children, while showing that continuous measurement in the days following injury is worthwhile (Chapter 3). Next, I consider the applications of PRx monitoring in children, with the identification of the lower limit of autoregulation (LLA) in pTBI. I compare these findings to the cerebral perfusion guidelines suggested by the Brain Trauma Foundation and suggest possible clinical implications following the characterisation of this important index in children (Chapter 4). I then turn to adult TBI, where PRx is well understood and widely used. While we understand that PRx can advise treatment following TBI, we are currently unable to treat CA disturbance. To do so, researchers would need to understand the molecular basis of CA disturbance following brain injury. Guided by a literature review of candidate markers of CBF control following brain injury (Chapter 1), a large screen of 177 structural and inflammatory proteins in plasma samples from patients enrolled in a single centre Phase II randomised control trial was explored. After adjusting for intervention, this analysis explores patients with time-linked high frequency neuromonitoring and protein data. Using unsupervised and supervised dimensionality reduction techniques, I show that proteins relating to vascular inflammation are associated with deranged PRx and intracranial pressure following brain injury. Notably, proteins of the complement cascade emerged as key candidates (Chapter 5). As a natural next step of investigation, complement biomarkers were quantified and characterized in the blood of 64 TBI patients across acute (first week) and long-term (days 42, 180, and 365) phases post-injury. This included markers from the initiation, effector, and downstream pathways of the cascade, and provides a novel characterisation of this complex pathway in human TBI (Chapter 6). Next, I place complement in context of other secondary cascades, namely the larger neuroinflammatory process, and CA in this cohort. Despite limitations due to small patient numbers, findings mirror that of the initial screen, reinforcing the link between complement activation and disturbed intracranial dynamics following adult TBI (Chapter 7). Overall, Part 2 lays the foundation of this neurochemical/pressure exploration and identifies key findings that will inform a prospective investigation of the investigation between vascular inflammation and disturbed pressure dynamics following TBI. In conclusion, this thesis demonstrates that CA impairment is an important and detrimental secondary injury cascade across the age range of the TBI population (Part 1) and aims to provide preliminary evidence-based insights into vascular inflammation as a mechanistic link underlying CA disturbance following adult TBI (Part 2).
Traumatic brain injury, Cerebral autoregulation, Neuroinflammation, Paediatric brain injury, Critical care, Pressure reactivity
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