Severe traumatic brain injuries are extremely heterogeneous. At least
seven of the secondary derangements in the brain that have been identi
fied as occurring after most traumatic brain injuries also occur after
cardiac arrest. These secondary derangements include posttraumatic br
ain ischemia. In addition, traumatic brain injury causes insults not p
resent after cardiac arrest, i.e., mechanical tissue injury (including
axonal injury and hemorrhages), followed by inflammation, brain swell
ing, and brain herniation. Brain herniation, in the absence of a mass
lesion, is due to a still-to-be-clarified mix of edema and increased c
erebral blood flow and blood volume. Glutamate release immediately aft
er traumatic brain injury is proven. Late excitotoxicity needs explora
tion. Inflammation is a trigger for repair mechanisms. In the 1950s an
d 1960s, traumatic brain injury with coma was treated empirically with
prolonged moderate hypothermia and intracranial pressure monitoring a
nd control. Moderate hypothermia (30 degrees to 32 degrees C), but not
mild hypothermia, can help prevent increases in intracranial pressure
. How to achieve optimized hypothermia and rewarming without delayed b
rain herniation remains a challenge for research. Deoxyribonucleic aci
d (DNA) damage and triggering of programmed cell death (apoptosis) by
trauma de serve exploration. Rodent models of cortical contusion are b
eing used effectively to clarify the molecular and cellular responses
of brain tissue to trauma and to study axonal and dendritic injury. Ho
wever, in order to optimize therapeutic manipulations of posttraumatic
intracranial dynamics and solve the problem of brain herniation, it m
ay be necessary to use traumatic brain injury models in large animals
(e.g., the dog), with long-term intensive care. Stepwise measures to p
revent lethal brain swelling after traumatic brain injury need experim
ental exploration, based on the multifactorial mechanisms of brain swe
lling. Novel treatments have so far influenced primarily healthy tissu
e; future explorations should benefit damaged tissue in the penumbra z
ones and in remote brain regions. The prehospital arena is unexplored
territory for traumatic brain injury research.