Neural Networks

Commentary: Pediatric Neuroprotection ^{_{By Robert Tasker, MD}}

^{VOXEL-BASED MORPHOMETRY of children with severe head injuries. Distribution of blue shows where white matter has been lost in children who suffered brain swelling and focal hemorrhage.} 

The jury is still out on the most effective neuroprotective strategies for pediatric patients. Questions still linger as to appropriate emphasis for these strategies—either limiting early, acute, secondary processes that contribute in the brain injury cascade, or facilitating rehabilitation by promoting cortical plasticity after the event. Can we reverse the sequence leading to cell death in a neuron once it has been initiated? If we could, will that neuron perform as it originally did?

In the last 20 years, over 150 clinical trials have investigated more than 50 different neuroprotective approaches, yet none have resulted in bench-to-bedside translation of promising preclinical findings. We have learned, though, that maintenance of cerebral homeostasis appears the most important available strategy for limiting variability, even if it means expanding the space to accommodate swelling. Neurocritical care is about optimizing homeostasis in a variety of acute brain conditions, such as brain perfusion in the ischemic penumbra of an acute stroke.

Metabolic Patterns of the Injured Brain

We now know that the injured brain is under metabolic crisis. Cerebral microdialysis in the severely head-injured shows three metabolic patterns. The first is classical cerebral ischemia, which is characterized by reduced microdialysis pyruvate and increased lactate leading to increased lactate-to-pyruvate ratio (also in association with depressed brain tissue oxygen level). This state is a result of overt lack of oxygen and glucose in mitochondria.

A second pattern is cerebral metabolic perturbation, which occurs when brain tissue oxygen is normal. In this state, a reduction in pyruvate is the sole change that results in a rise in lactateto- pyruvate ratio. It could reflect limited glucose supply or impairment in the glycolytic pathway.

A third pattern is raised lactate-to-pyruvate ratio, reflecting raised lactate and normal pyruvate, which is typically found in regions of the brain surrounding focal infarcts or contusions. Such hyperglycolysis is marked by increased metabolism relative to utilization and, post-trauma, it represents an uncoupling between predominantly glycolytic and oxidative metabolism. The importance of these patterns is demonstrated in a recent study of adults six months after severe head injury. Chronic brain atrophy with loss of white matter is regionally specific and associated with earlier, acute regional reductions in oxidative brain metabolism in the absence of irreversible ischemia at the time of receiving neurocritical care.

Questions for the Future

A key area for study for neurocritical care is uncovering the most appropriate clinical approaches to feeding the young brain. The importance and incidence of cerebral metabolic and glycolytic problems in critically ill children is as yet unknown, since microdialysis and brain tissue oxygen probe monitoring are rarely undertaken in children. Potential brain metabolic substrates for future study are acetoacetate, 3-hydroxybutyrate and acetone.

We are also committed to new, non-invasive monitoring instruments to provide us with descriptors and measurements of brain physiology. Children’s is introducing several new modalities in a unique, coordinated neurocritical care program: doppler studies of the cerebral circulation to examine vasomotor reactivity, near infrared spectroscopy (NIRS) to study tissue oxygenation, combined arterial pressure waveform and electrocardiogram analysis to study vascular coherence and baroreceptor function and magnetic resonance imaging.

Ultimately, these modern clinical tools will answer basic and all-too-relevant questions about injury in the young brain. Children’s is taking a unique approach to pediatric critical care by building a new 3 Tesla magnetic resonance imaging suite next to our medical and surgical intensive care unit. We will be able to bring together our understanding of acute physiology and our expertise in brain imaging. Our hope is that we will move the field forward—really seeing into the brain and being able to target what matters, when it counts.