Therapeutic hypothermia has been shown to be beneficial after ischemic and traumatic brain injury. After global brain ischemia hypothermia is currently established in therapeutic concepts, but the benefit from hypothermia in traumatic brain injury is a controversial issue. A number of protective mechanisms of hypothermia in traumatic brain injury have been detected experimentally in adults. In contrast, investigations for infant traumatic brain injury do not exist in a comparable manner. We, therefore, investigated the early changes of cerebral hemodynamics and metabolism in piglet models for brain trauma (lateral fluid percussion) and controlled increase of intracranial pressure (epidural balloon). In these models, the effects of hypothermia on cerebral hemodynamic and metabolism were investigated. Additionally, the histopathologic damage was quantified in the brain trauma model at 24 hours postinjury. The protective effects of therapeutic hypothermia notwithstanding, little is known about the influence of hypothermia on drug requirements, particularly during long-time application. A further experimental approach was used for assessing the effect of hypothermia on plasma fentanyl concentration and hepatic microsomal cytochrome P450 3A4. The chosen experimental designs were appropriate observing early hemodynamic and metabolic changes after experimental traumatic brain injury. We were able to describe reproducible posttraumatic secondary intracranial pressure increase accompanied by patterns of diffuse brain damage. Mild hypothermia has prevented this secondary intracranial pressure increase, and may improve the cerebral compliance this way. Furthermore, hypothermia may enhance the tolerance to compromised cerebral perfusion in the juvenile brains. Additionally, the pharmacokinetics of fentanyl is strongly altered by hypothermia.