Glutamate is the principal excitatory neurotransmitter in the brain, responsible for activating neurons and facilitating processes including learning, memory and synaptic plasticity. Under normal conditions, glutamate is carefully regulated within synapses and rapidly cleared after use. However, when brain cells are deprived of oxygen, as occurs during cardiac arrest and hypoxic-ischaemic brain injury (HIBI), this regulation breaks down.
During and after cardiac arrest, oxygen-starved neurons lose the ability to maintain their membrane potential and begin releasing massive quantities of glutamate into the surrounding tissue. This excitotoxic glutamate cascade over-activates neighbouring neurons through receptors including NMDA and AMPA receptors, triggering an influx of calcium ions into cells. Excessive intracellular calcium activates enzymes that damage cell membranes, mitochondria and DNA, contributing to secondary neuronal death in the hours and days following the initial injury. This secondary injury phase is the target of post-arrest neuroprotective strategies such as targeted temperature management (TTM).
The glutamate excitotoxicity model helps explain why some brain damage after cardiac arrest continues to evolve even after the heart has been restarted. It also underpins research into potential neuroprotective drugs that block NMDA receptors or limit calcium influx, though no such treatment has yet translated successfully into routine clinical practice. Maintaining normal blood glucose, avoiding fever, and controlling seizures (which cause further glutamate release) are all current strategies that limit ongoing excitotoxic damage.
Understanding that secondary brain injury after cardiac arrest is partly driven by a biochemical cascade rather than simply by the initial event is important for families. It explains why neurological assessment in the intensive care unit is carefully deferred for at least 72 hours after rewarming from targeted temperature management, as the brain continues to evolve and early prognostic assessments can be misleading.
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