Characterization of a new rat model of experimental combined neurotrauma

Traumatic brain injury (TBI) is present in two-thirds of patients with multiple injuries and in one-third combined with injuries of the extremities. Studies on interactive effects between central and peripheral injuries are scarce due to the absence of clinically relevant models. To meet the demand for "more-hit" models, an experimental model of combined neurotrauma (CNT) incorporating a standardized TBI via lateral fluid percussion (LFP) together with a peripheral bone fracture, i.e., tibia fracture, is introduced. Sprague-Dawley rats were randomized to four experimental groups: controls (n = 10), animals with TBI (n = 30), animals with tibia fracture (n = 30), and animals with CNT (n = 30). Morphological aspects of brain and bone injury were analyzed via standard histopathological procedures and x-ray. Trauma-induced neuromotor dysfunction was assessed using a standardized neuroscore. For interactive effects between injuries, we studied the extent and temporal pattern of circulating interleukin 6 (IL-6) levels via immunoassay and callus formation at fracture sites by means of microradiography. LFP produced an ipsilateral lesion with cortical contusion, hemorrhage, mass shift, and neuronal cell loss (adjacent cortex and hippocampus CA-2/-3), along with contralateral neuromotor dysfunction. X-rays confirmed complete fractures in the middle of the bone shaft. The type of injury (P < 0.001) and time (P = 0.022) were significantly associated with increased IL-6 levels. CNT produced the highest IL-6 plasma levels with a maximum peak at 6 h after trauma (P < 0.001). Similarly, callus formation at fracture sites in CNT was significantly increased versus fracture only (P < 0,01). The CNT model mimics a variety of clinically relevant features known from human multiple injury, including TBI, and offers novel approaches for investigation of interactive mechanisms and therapeutic approaches.