The puzzle of neuronal death and life: is mannitol the right drug for the treatment of brain oedema associated with ischaemic stroke?

Brain oedema is a major factor contributing to the poor outcome of subjects with acute ischaemic stroke but the use of mannitol and other hyperosmolar agents in this setting is controversial and hardly debated. Recent data have demonstrated that mannitol at concentrations which may be achieved in clinical conditions and hyperosmotic stress itself can activate the process of apoptotic cell death. This could have important clinical implications as apoptosis is involved in the more gradual loss of neurons in the penumbra zone surrounding the core of ischaemic stroke where neurons die immediately from oxygen starvation. Mannitol has the potential to activate inflammatory mediators, induce oxidant stress and produce rebound cell swelling and, through these mechanisms, can further aggravate the neuronal injury due to ischaemia. Furthermore, apoptosis in ischaemic areas closely parallels the timing of brain oedema and this suggests that a cause-effect relationship links the two phenomena rather than simply a temporal correlation. On this basis, it is crucial that emergency-physicians critically rethink the management strategy of brain oedema associated with ischaemic stroke.