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Research Overview
F Zeiler - Acute TBI Research Lab
Principal Investigator:  Frederick A. Zeiler BSc MD PhD CIP FRCSC

Overview - Area of Research

Traumatic brain injury (TBI) is one of the leading causes of death and disability within Canada and globally, with more than 50 million people per year suffering a TBI worldwide, which costs just under $540 billion CAD annually across the globe. Overall, there has been little change in mortality and morbidity associated TBI in the past four decades of TBI care. This morbidity and mortality is associated with both primary and secondary injury, with primary injury representing the structural damage to the brain at the time of the incident, and secondary injury referring to the cascade of systemic and local cellular events that lead to tissue damage within the brain. Little can be done about primary injury, aside from public awareness, policy and educational campaigns directed at the reduction in head injury incidence.  However, the mechanisms involved in secondary brain injury after TBI are amenable to therapeutic intervention, which might lead to improvements in morbidity and mortality. Secondary brain injury causes include: impaired cerebral autoregulation (CA), local/systemic inflammatory responses, metabolic derangements, and mitochondrial dysfunction, all of which are modulated by individual patient age, sex, and genetic variation. CA refers to the cerebral vessels innate ability to maintain constant cerebral blood flow (~55 mL/100gm/min) despite changes in systemic arterial pressures, ensuring adequate blood and nutrient delivery to the brain. Impaired CA has emerged as a major player in secondary brain injury after moderate/severe TBI. Recent data show that current interventions in the critical care management of TBI patients fail to correct dysfunctional CA, and may be the reason for relatively unchanged mortality rates over the last 25 years. Ischemic stroke, edema, intra-cerebral hemorrhage, metabolic failure and neuronal death are all the consequence of impaired CA after moderate and severe TBI.  Factors which drive the impairment of CA in TBI currently remain unknown. Potentially associated factors include autonomic dysfunction, cortical spreading depression, local/systemic inflammatory responses, blood-brain-barrier breakdown, neuronal excitotoxicity, local/systemic injury burden and individual genetics.  By better understanding CA changes in TBI we can improve both short and long-term patient morbidity and mortality.

The goal of Dr. Zeiler’s research program is to better understand cerebral autoregulatory (CA) dysfunction in critically ill, moderate and severe TBI patients, its drivers, and the development of therapeutic targets for prevention and treatment of dysfunction. The overriding hypothesis of the research program is that CA dysfunction post-TBI is driven by specific injury burden and host vascular response factors, which are amenable to the elucidation of specific therapeutic targets and development of therapies for prevention and treatment.

Selected Current and Upcoming Projects (NOTE: Many more ongoing and available; inquiry welcome)

1. Near Infrared Spectroscopy (NIRS) for Continuous Characterization of Cerebrovascular Reactivity in Critically Ill Traumatic Brain Injury.
a. Prospective evaluation of bilateral regional cerebral oxygen saturation and derived vascular reactivity metrics (assessed during both acute and long-term phase), in association with functional outcome metrics.  Study involves application of new spatially resolved NIRS and continuous non-invasive ABP monitoring, time-series signal analytic techniques, and multi-variate modelling.

2. Robotic Transcranial Doppler (rTCD) for Continuous Assessment of Cerebral Blood Flow and Vascular Reactivity in Critically Ill Traumatic Brain Injury.
a. Prospective evaluation of bilateral cerebral blood flow velocity and derived vascular reactivity metrics (assessed during both acute and long-term phase), in association with functional outcome metrics.  Study involves application of new cutting edge robotic TCD technology and continuous non-invasive ABP monitoring, time-series signal analytic techniques, and multi-variate modelling. Derivation of various cerebrovascular physiologic metrics will occur, including analyzing critical closing pressure and vascular time constants for cerebral vasculature.

3. In vivo multi-modal invasive assessment of cerebrovascular reactivity and regional metabolism in critically ill TBI.
a. Prospective evaluation of continuously measured intra-cranial pressure, brain tissue oxygen, and cerebral blood flow in concert with regional microdialysate sampling for metabolism.  Study will evaluate the multi-variate relationships between pressure, flow, oxygen delivery, autoregulation and metabolism using high-frequency data capture and signal analytic techniques.

4. Comprehensive multi-modal characterization of cerebrovascular reactivity in critically ill TBI.
a. Will involve application of a myriad of invasive and non-invasive cranial monitoring devices to provide continuous comprehensive characterization of cerebrovascular reactivity. Signal analytic and multi-variate statistical methodologies will be applied.

5. Evaluation of low-resolution vascular reactivity metrics derived from intra-cranial pressure: a Nordic Multi-center Collaborative.
a. New long-term ongoing initiative between U of Manitoba, Karolinska Institute and University of Helsinki. Various sub-projects exist, including but not limited to: metric validation, outcome association studies, and critical threshold derivation.

6. “CPP OPtimal” To IndividuaLize Care Of Traumatic Brain Injury Patients (CO-PILOT Study) – Canadian Traumatic Brain Injury Consortium Initiative.
a. Canadian initiative between UBC, U of Calgary, U of Manitoba and U of Montreal, aimed at characterization of CPP practices and creation of the first Canadian multi-center high-resolution ICU database for critically ill TBI patients.

7. Characterization of NIRS and rTCD continuous vasogenic slow-wave cerebral physiology in a healthy population: a reference study.
a. Prospective simultaneous application of spatially resolved NIRS and rTCD in adult healthy control population.  Will evaluate normative values for cerebral regional oxygen saturation and blood flow velocity, as well as non-invasively derived cerebrovascular reactivity metrics. Exploration of statistical signal properties and derivation of normative reference ranges will occur.

*Various other multi-center projects ongoing with the University of Cambridge (Dr. Zeiler is appointed as a guest researcher), Maastricht University, the Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI) Study (Dr. Zeiler is a collaborator and investigator), and the Genetic Associations In Neurotrauma (GAIN) international initiative (Dr. Zeiler is a collaborator and investigator). There are also ongoing local database and biobank projects for high-frequency digital physiology, microdialysis and genetics in critically ill TBI patients.

Collaborative Links

University of Cambridge, Karolinska Institute, University of Helsinki, Maastricht University, CENTER-TBI collaborative, GAIN collaborative, COPILOT collaborative, Pan Am Concussion Clinic and the Canadian Traumatic Brain Injury Research Consortium (CTRC).

Current Funding

University of Manitoba Rudy Falk Clinician-Scientist Professorship, University of Manitoba Thorlakson Chair in Surgical Research Establishment Grant, University of Manitoba VPRI Research Investment Fund and the Health Sciences Centre Foundation.

Opportunities for Students

Openings available for both MSc and PhD level students through either: A. Biomedical Engineering Program, B. Human Anatomy and Cell Sciences, or C. Department of Surgery MSc (Surgery) program.

Contact
Frederick.Zeiler@umanitoba.ca