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Thesis Format

Integrated Article

Degree

Doctor of Philosophy

Program

Medical Biophysics

Supervisor

Keith St. Lawrence

2nd Supervisor

Mamadou Diop

Co-Supervisor

Abstract

Premature birth, defined as a gestational period less than 37 weeks, occurs in 8% of infants born in Canada. These births are associated with a higher risk of developing neurological complications. Infants born with very low birth weights (VLBW, < 1500 g) experience cognitive or behavioural deficits at a rate of 40-50%, while a further 5-10% develop major disorders such as cerebral palsy. The likelihood of injury increases with a shorter gestational period and/or a lower birthweight. Intraventricular hemorrhaging (IVH) occurs in 20-25% of VLBW infants, characterized by bleeding in the germinal matrix and surrounding white matter. This highly vascularized region is particularly susceptible to bleeds due to underdeveloped cerebrovascular structures. Severe IVH causes an inflammatory response and subsequent obstruction of cerebrospinal fluid (CSF) drainage, resulting in enlargement of the brain’s ventricles, referred to as post-hemorrhagic ventricular dilatation (PHVD). PHVD increases intracranial pressure and can result in compression/damage of brain tissue.

Diagnosis of IVH and PHVD is regularly performed using cranial ultrasound. Clinicians can visually assess and grade hemorrhaging/ventricle dilatation. Ultrasound, however, is limited in its ability to continuously monitor and only detects irreversible damage. NNeMo (Neonatal NeuroMonitor) is a hybrid optical device combining diffuse correlation (DCS) and near-infrared spectroscopy (NIRS) to simultaneous monitor cerebral blood flow (CBF) and metabolism at the bedside. DCS analyzes light scatter from red blood cells to infer their motion and calculate CBF while NIRS exploits light absorption properties to quantify changes in oxidized cytochrome c oxidase (oxCCO), a direct marker of energy metabolism. System validation was presented in a piglet model of neonatal hypoxia-ischemia. Clinical translation of NNeMo was demonstrated in PHVD infants during ventricular taps (i.e., CSF drainage). Changes in perfusion and metabolism are presented in premature infants at high risk of IVH within the first 72 hours of life. Lastly, NNeMo was translated to the cardiac operating room, in patients undergoing surgery with cardiopulmonary bypass, to observe metabolic response to large intraoperative changes in CBF. Optical measures of perfusion and metabolism show potential to act as prognostic markers of injury and could aid clinicians in patient management before significant damage persists.

Summary for Lay Audience

A full-term pregnancy is approximately 40 weeks in duration. Infants born within 37 weeks are defined as premature and often experience inadequate brain growth and underdeveloped cerebrovascular structures, which are necessary to maintain an adequate supply of blood and oxygen to the brain. As a result, premature infants are at a higher risk of developing a brain injury, which further increases with a shorter gestational period or a lower weight at birth. A common injury is intraventricular hemorrhaging (IVH), which describes bleeding in and around the ventricles of the brain. IVH has been found to occur in up to 25% of infants weighing less than 1500 g at birth and 45% in those less than 1000 g, with most cases appearing within the first 48 hours of life. Furthermore, severe cases of IVH can result in improper draining of cerebrospinal fluid (CSF) from the brain’s ventricles. This leads to increased intracranial pressure and ventricle volume, described as post-hemorrhagic ventricular dilatation (PHVD), which can compress brain tissue and result in long-term cognitive deficit.

In today’s neonatal intensive care unit (NICU), brain monitoring is limited to infrequent imaging using cranial ultrasound. While ultrasound can accurately diagnose bleeding/ventricle enlargement, it cannot continuously monitor and can only image damage that has already occurred. This dissertation explores the use of biomedical optics to monitor potential physiological markers of brain injury before significant damage occurs. NNeMo (Neonatal NeuroMonitor) is a non-invasive optical device developed to continuously monitor cerebral blood flow (CBF) and metabolism at the bedside. This was achieved by combining diffuse correlation spectroscopy to characterize CBF with broadband near-infrared spectroscopy to monitor cerebral metabolism. NNeMo demonstrated changes in CBF and metabolism prior to the onset of brain injury in an animal model. The system was translated to the NICU to monitor PHVD infants during CSF drainage and preterms at risk of IVH soon after birth. Lastly, the relationship between CBF and metabolism as indicators of potential injury was investigated in patients undergoing cardiac surgery with cardiopulmonary bypass. Real-time monitoring of cerebral perfusion and metabolism has potential to aid in patient management and improve clinical outcome.

Creative Commons License

Creative Commons Attribution 4.0 License
This work is licensed under a Creative Commons Attribution 4.0 License.

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