Electronic Thesis and Dissertation Repository

Thesis Format

Integrated Article

Degree

Doctor of Philosophy

Program

Medical Biophysics

Supervisor

Ellis, Christopher

2nd Supervisor

McIntyre, Christopher

Co-Supervisor

Abstract

Critically ill patients of all ages suffer from high burden of neurocognitive impairment during (i.e. delirium) and following (i.e. long term cognitive impairment) critical illness that is associated with worse patient and healthy system outcomes. Ischemia has emerged as a plausible mechanism given the high prevalence of hypotension and shock, ischemic injury on neuroimaging, and impairment of cerebral autoregulation in these patients. However, the burden of ischemic insults during critical illness and mechanisms responsible for these insults are poorly described. Furthermore, while baseline impairment in cerebrovascular function can render patients more vulnerable to ischemia, such baseline functional assessments in patients with high risk of critical illness have not been considered. Finally, the operational limitations of existing cognitive batteries preclude routine linkage of ischemic insults and baseline impairment in cerebrovascular function with neurocognitive outcomes. In this work we carried out three studies to address these knowledge gaps. In the first study, we showed that critically ill patients with respiratory failure or shock experience deviations in cerebral blood flow velocity consistent with ischemia or hyperemia for 17-24% of the observation time. These deviations occurred irrespective of the state of cerebral autoregulation and were not explained by concurrent changes in blood pressure or CO2. These deviations represent a plausible ischemic insult that may explain high prevalence of ischemic injury in previous neuroimaging and histopathologic studies, and warrants further research to understand the underlying mechanism and link with neurocognitive outcomes. In the second study, we showed that hemodialysis patients have baseline impairment in cerebrovascular function prior to onset of critical illness, which may render them more vulnerable to ischemic injury during critical illness as a result of perturbation in cerebral blood flow shown in our first study. In our third study, we optimized an existing comprehensive web-based cognitive battery for monitoring cognitive outcomes in ICU patients, which should enable future linkage of ischemic insults and baseline impairment in cerebrovascular function from our first two studies with neurocognitive outcomes, as well enable routine clinical monitoring of cognitive recovery in ICU survivors.

Summary for Lay Audience

Patients who are admitted to the intensive care units (ICU) often suffer from neurocognitive impairment both during and following their critical illness. During ICU stay, this neurocognitive impairment known as delirium is associated with increased risk of dying and prolongs the time that the patient stays on the ventilator and in hospital. Following discharge, many patients suffer from long-term cognitive impairment that can slow patient recovery and return to work and puts a huge burden on caregivers and society. Low brain blood flow during ICU stay is one potential mechanism that may be responsible for these neurocognitive impairments. However, the burden of low brain blood flow and responsible mechanisms are not well described. Furthermore, some patients may have impairment in the function of the brain blood vessels prior to ICU admission, which can make them more vulnerable to developing brain injury during critical illness. Finally, current cognitive tests that assess neurocognitive impairment are complex, expensive and take a long time, which makes it challenging to study the relationship between low brain blood flow and brain blood vessel function with neurocognitive impairment. In our first study, we showed that patients who are admitted to the ICU with low blood pressure or breathing failure spend up to one quarter of the time with low brain blood flow that is not counteracted by brain protective mechanisms. This may explain why many ICU patients develop brain injury and neurocognitive impairment. In the second study, we showed that dialysis patients have impaired baseline function of brain blood vessels prior to critical illness. This impairment can make them more vulnerable to brain injury during critical illness as a result of low brain blood flow that we showed in the first study. In the third study, we optimized an existing comprehensive web-based cognitive battery for monitoring neurocognitive outcomes in ICU patients. This tool will enable future studies of the relationship between low brain blood flow and brain blood vessel function with neurocognitive impairment, and routine clinical monitoring of cognitive recovery in ICU survivors.

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