This thesis explores physiological changes occurring after acute brain injury.
The first two chapters focus on traumatic brain injury (TBI), a significant cause
of disability and death worldwide. I discuss the evidence behind current
management of secondary brain injury with emphasis on partial brain oxygen
tension (PbtO2) and intracranial pressure (ICP). The second chapter describes
a subgroup analysis of the effect of hypothermia on ICP and PbtO2 in 17
patients enrolled to the Eurotherm3235 trial. There was a mean decrease in
ICP of 4.1 mmHg (n=9, p<0.02) and a mean decrease in PbtO2 (7.8 ± 3.1
mmHg (p < 0.05) in the hypothermia group that was not present in controls.
The findings support previous studies in demonstrating a decrease in ICP with
hypothermia. Decreased PbtO2 could partially explain worse outcomes seen in
the hypothermia group in the Eurotherm3235 trial. Further analysis of PbtO2
and ICP guided treatment is needed.
The third chapter focuses on delayed cerebral ischaemia (DCI) after
aneurysmal subarachnoid haemorrhage (aSAH), another form of acute brain
injury that causes significant morbidity and mortality. I include a background of
alpha-calcitonin gene-related peptide (αCGRP), a potential treatment of DCI,
along with results from a systematic review and meta-analysis of nine
experimental models investigating αCGRP. The meta-analysis demonstrates
a 40.8 ± 8.2% increase in cerebral vessel diameter in those animals treated
with αCGRP compared with controls (p < 0.0005, 95% CI 23.7 to 57.9).
Neurobehavioural scores were reported in four publications and showed a
Physiological responses to brain tissue hypoxia and blood flow after acute brain injury
standardised mean difference of 1.31 in favour of αCGRP (CI -0.49 to 3.12). I
conclude that αCGRP reduces cerebral vessel narrowing seen after SAH in
animal studies but note that there is insufficient evidence to determine its effect
on functional outcomes. A review of previous trials of αCGRP administration
in humans is included, in addition to an original retrospective analysis of CSF
concentrations of αCGRP in humans. Enzyme-linked immunosorbent assay of
CSF (n = 22) was unable to detect αCGRP in any sample, which contrasts with
previous studies and was likely secondary to study methodology. Finally, I
summarise by discussing a protocol I designed for a dose-toxicity study
involving the intraventricular administration of αCGRP to patients with aSAH
and provide some recommendations for future research. This protocol was
based upon the systematic review and was submitted to the Medical Research
Council’s DPFS funding stream during the PhD