The effect of concomitant peripheral injury on traumatic brain injury pathobiology and outcome

Abstract

Background: Traumatic injuries are physical insults to the body that are prevalent worldwide. Many individuals involved in accidents suffer injuries affecting a number of extremities and organs, otherwise known as multitrauma or polytrauma. Traumatic brain injury is one of the most serious forms of the trauma-induced injuries and is a leading cause of death and long-term disability. Despite over dozens of phase III clinical trials, there are currently no specific treatments known to improve traumatic brain injury outcomes. These failures are in part due to our still poor understanding of the heterogeneous and evolving pathophysiology of traumatic brain injury and how factors such as concomitant extracranial injuries can impact these processes.

Main body: Here, we review the available clinical and pre-clinical studies that have investigated the possible impact of concomitant injuries on traumatic brain injury pathobiology and outcomes. We then list the pathophysiological processes that may interact and affect outcomes and discuss promising areas for future research. Taken together, many of the clinical multitrauma/polytrauma studies discussed in this review suggest that concomitant peripheral injuries may increase the risk of mortality and functional deficits following traumatic brain injury, particularly when severe extracranial injuries are combined with mild to moderate brain injury. In addition, recent animal studies have provided strong evidence that concomitant injuries may increase both peripheral and central inflammatory responses and that structural and functional deficits associated with traumatic brain injury may be exacerbated in multiply injured animals.

Conclusions: The findings of this review suggest that concomitant extracranial injuries are capable of modifying the outcomes and pathobiology of traumatic brain injury, in particular neuroinflammation. Though additional studies are needed to further identify the factors and mechanisms involved in central and peripheral injury interactions following multitrauma and polytrauma, concomitant injuries should be recognized and accounted for in future pre-clinical and clinical traumatic brain injury studies.

Keywords: Animal model; Bone fracture; Clinical; Concussion; Cytokines; Inflammation; Multitrauma; Polytrauma; Traumatic brain injury.

Fig. 1

Possible pathways through which extracranial injury may alter TBI pathobiology. Secondary injury processes of TBI include neuroinflammation, excitotoxicity, metabolic disturbances, apoptosis, ischemia, oxidative stress, and BBB disruption. The neuroinflammatory response of TBI is characterized by microglial and astrocyte activation, leukocyte infiltration and elevated levels of pro-inflammatory cytokines. For multitrauma/polytrauma patients, there is potential for the systemic effects of significant extracranial injuries to impact upon secondary injury pathways of TBI, and in particular the neuroinflammatory response. Possible extracranial trauma-induced influences on TBI include elevated circulating inflammatory cytokines, growth factors, reactive oxygen species, and for the patient with bone fracture, potential influence of fat emboli and mobilized mesenchymal stem cells. Polytrauma may produce the added risk of central influences of sepsis, SIRS and hemorrhagic shock