Abstract Severe traumatic brain injury (TBI) often initiates a systemic inflammatory response syndrome (SIRS), which can potentially culminate into multi-organ dysfunction (MOD). A central player in this cascade is endotheliopathy, caused by perturbations in homeostatic mechanisms governed by endothelial cells due to injury-induced coagulopathy, heightened sympathoadrenal response, complement activation, and pro-inflammatory cytokine release. Unique to TBI is the potential disruption of the blood-brain barrier (BBB), which may expose neuronal antigens to the peripheral immune system and permit neuroinflammatory mediators to enter systemic circulation, propagating endotheliopathy systemically. This review aims to provide comprehensive insights into the “ neuro-endothelial axis ” underlying endothelial dysfunction following TBI, identify potential diagnostic and prognostic biomarkers, and explore therapeutic strategies targeting these interactions, with the ultimate goal of improving patient outcomes following severe TBI.
ABSTRACT Injuries lead to an early systemic inflammatory state with innate immune system activation. Neutrophil extracellular traps (NETs) are a complex of chromatin and proteins released from the activated neutrophils. Although initially described as a response to bacterial infections, NETs have also been identified in the sterile postinjury inflammatory state. Peptidylarginine deiminases (PADs) are a group of isoenzymes that catalyze the conversion of arginine to citrulline, termed citrullination or deimination. PAD2 and PAD4 have been demonstrated to play a role in NET formation through citrullinated histone 3. PAD2 and PAD4 have a variety of substrates with variable organ distribution. Preclinical and clinical studies have evaluated the role of PADs and NETs in major trauma, hemorrhage, burns, and traumatic brain injury. Neutrophil extracellular trap formation and PAD activation have been shown to contribute to the postinjury inflammatory state leading to a detrimental effect on organ systems. This review describes our current understanding of the role of PAD and NET formation following injury and burn. This is a new field of study, and the emerging data appear promising for the future development of targeted biomarkers and therapies in trauma.
BACKGROUND Hemorrhage and traumatic brain injury (TBI) are the leading causes of death in trauma. Future military conflicts are likely to be in austere environments, where prolonged damage-control resuscitation (p-DCR) may be required for 72 hours before evacuation. Previous studies showed that early administration of fresh frozen plasma (FFP) during p-DCR can significantly decrease the volume of resuscitation required in models of hemorrhagic shock and also provide neuroprotection after TBI. In the current study, we hypothesized that the addition of FFP to p-DCR would decrease the resuscitation requirements and improve neurological outcomes in a large animal model of combined hemorrhagic shock and TBI. METHODS Yorkshire swine (40–45 kg; n = 10) were subjected to TBI (controlled cortical impact) and 40% blood volume hemorrhage. After 2 hours of shock, they were randomized to either: (1) p-DCR–normal saline or (2) p-DCR–FFP (250 mL). Prolonged damage-control resuscitation targeted a systolic blood pressure of 90% of baseline, in line with Tactical Combat Casualty Care principles. At 72 hours, animals were transfused 1 U of packed red blood cells, simulating evacuation to higher echelons of care. Brain lesion size, physiologic parameters, resuscitation fluid requirements, and neurological severity score were used to compare the clinical outcomes. RESULTS The p-DCR–FFP group required significantly less total volume (4,540.0 ± 151.7 mL vs. 974.0 ± 167.0 mL, p < 0.01) of resuscitation to maintain the target systolic blood pressure. Fresh frozen plasma–treated animals had significantly reduced brain lesion size (4,517.0 ± 180.0 mm 3 vs. 2,477.0 ± 1,191.0 mm 3 , p < 0.01) and showed significantly decreased functional neurologic impairment. CONCLUSION In this exploratory study, treatment with FFP decreased resuscitation requirements, reduced brain lesion size, and improved neurological outcomes when added to prolonged DCR in a porcine model of combined hemorrhagic shock and TBI.
Prolonged Casualty Care (PCC) is a military adaptation aimed at providing pre-hospital care in austere settings when evacuation is delayed or even impossible. Current lack of standardized medical equipment and size/weight restrictions of military packs during dismounted operations hinder effective PCC. We sought to design a standardized, practical, and effective prolonged field care kit (PFAK) to enable widespread implementation of PCC.
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