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Improvements in the control of haemorrhage after trauma have resulted in the survival of many people who would otherwise have died from the initial loss of blood. However, the danger is not over once bleeding has been arrested and blood pressure restored. Two-thirds of patients who die following major trauma now do so as a result of causes other than exsanguination. Trauma evokes a systemic reaction that includes an acute, non-specific, immune response associated, paradoxically, with reduced resistance to infection. The result is damage to multiple organs caused by the initial cascade of inflammation aggravated by subsequent sepsis to which the body has become susceptible. This Series examines the biological mechanisms and clinical implications of the cascade of events caused by large-scale trauma that leads to multiorgan failure and death, despite the stemming of blood loss. Furthermore, the stark and robust epidemiological finding—namely, that age has a profound influence on the chances of surviving trauma irrespective of the nature and severity of the injury—will be explored. Advances in our understanding of the inflammatory response to trauma, the impact of ageing on this response, and how this information has led to new and emerging treatments aimed at combating immune dysregulation and reduced immunity after injury will also be discussed.

In a trial comparing decompressive craniectomy with medical therapy in patients with traumatic brain injury and raised intracranial pressure refractory to medical therapy, decompressive craniectomy resulted in lower mortality and higher rates of vegetative state and severe disability. After traumatic brain injury (TBI), intracranial pressure can be elevated owing to a mass effect from intracranial hematomas, contusions, diffuse brain swelling, or hydrocephalus. 1 Intracranial hypertension can lead to brain ischemia by reducing the cerebral perfusion pressure. 2 Intracranial hypertension after TBI is associated with an increased risk of death in most studies. 3 , 4 The monitoring of intracranial pressure and the administration of interventions to lower intracranial pressure are routinely used in patients with TBI, despite the lack of level 1 evidence. 5 Decompressive craniectomy is a surgical procedure in which a large section of the skull is removed and the underlying . . .

Almost all studies that have investigated the immune response to trauma have analysed blood samples acquired post-hospital admission. Thus, we know little of the immune status of patients in the immediate postinjury phase and how this might influence patient outcomes. The objective of this study was therefore to comprehensively assess the ultra-early, within 1-hour, immune response to trauma and perform an exploratory analysis of its relationship with the development of multiple organ dysfunction syndrome (MODS). The immune and inflammatory response to trauma was analysed in 89 adult trauma patients (mean age 41 years, range 18-90 years, 75 males) with a mean injury severity score (ISS) of 24 (range 9-66), from whom blood samples were acquired within 1 hour of injury (mean time to sample 42 minutes, range 17-60 minutes). Within minutes of trauma, a comprehensive leukocytosis, elevated serum pro- and anti-inflammatory cytokines, and evidence of innate cell activation that included neutrophil extracellular trap generation and elevated surface expression of toll-like receptor 2 and CD11b on monocytes and neutrophils, respectively, were observed. Features consistent with immune compromise were also detected, notably elevated numbers of immune suppressive CD16BRIGHT CD62LDIM neutrophils (82.07 x 106/l ± 18.94 control versus 1,092 x 106/l ± 165 trauma, p < 0.0005) and CD14+HLA-DRlow/- monocytes (34.96 x 106/l ± 4.48 control versus 95.72 x 106/l ± 8.0 trauma, p < 0.05) and reduced leukocyte cytokine secretion in response to lipopolysaccharide stimulation. Exploratory analysis via binary logistic regression found a potential association between absolute natural killer T (NKT) cell numbers and the subsequent development of MODS. Study limitations include the relatively small sample size and the absence of data relating to adaptive immune cell function. Our study highlighted the dynamic and complex nature of the immune response to trauma, with immune alterations consistent with both activation and suppression evident within 1 hour of injury. The relationship of these changes, especially in NKT cell numbers, to patient outcomes such as MODS warrants further investigation.

Retinal nerve fibre layer (RNFL) and ganglion cell layer (GCL) thinning occur weeks to months after traumatic brain injury (TBI), even without computed tomography (CT) findings. The patterns of RNFL and GCL loss and their relationship to TBI severity and CT findings have not been characterised. This observational study included consecutive patients assessed in hospital after TBI. All patients underwent OCT. A literature review was conducted to determine the test–retest variability of RNFL and GCL measurements. Of 135 included patients, 62 had follow up OCTs. The test–retest limit of agreement for global RNFL thickness was 4 µm. Two patients had symptomatic traumatic optic neuropathy, 17 had less severe RNFL thinning on follow up, six RNFL thickening and 31 no RNFL changes. Higher TBI severity, Marshall CT classification and lower time to first OCT after injury strongly associated with subsequent RNFL changes (p < 0.001 for all). Global RNFL thickness in patients with initial OCT < 42 days after injury declined by 1.74 µm/month with Marshall II CT findings, compared 0.05 µm/month with Marshall I, and 3.69 µm/month after severe TBI, versus 1.47 µm/month after mild. Subclinical OCT changes therefore occur after TBI, and may contribute to future multimodal TBI diagnostic and severity assessments.

Current technologies for the point-of-care diagnosis of traumatic brain injury (TBI) lack sensitivity, require specialist handling or involve complicated and costly procedures. Here, we report the development and testing of an optofluidic device for the rapid and label-free detection, via surface-enhanced Raman scattering (SERS), of picomolar concentrations of biomarkers for TBI in biofluids. The SERS-active substrate of the device consists of electrohydrodynamically fabricated submicrometre pillars covered with a plasmon-active nanometric gold layer, integrated in an optofluidic chip. We show that the device can detect N -acetylasparate in finger-prick blood samples from patients with TBI, and that the biomarker is released immediately from the central nervous system after TBI. The simplicity, sensitivity and robustness of SERS-integrated optofluidic technology might eventually help the triaging of TBI patients and assist clinical decision making at point-of-care settings. An optofluidic device rapidly detects, via surface-enhanced Raman scattering, picomolar concentrations of biomarkers for traumatic brain injury in finger-prick blood samples from patients.

Background The CRASH-3 trial hypothesised that timely tranexamic acid (TXA) treatment might reduce deaths from intracranial bleeding after traumatic brain injury (TBI). To explore the mechanism of action of TXA in TBI, we examined the timing of its effect on death. Methods The CRASH-3 trial randomised 9202 patients within 3 h of injury with a GCS score ≤ 12 or intracranial bleeding on CT scan and no significant extracranial bleeding to receive TXA or placebo. We conducted an exploratory analysis of the effects of TXA on all-cause mortality within 24 h of injury and within 28 days, excluding patients with a GCS score of 3 or bilateral unreactive pupils, stratified by severity and country income. We pool data from the CRASH-2 and CRASH-3 trials in a one-step fixed effects individual patient data meta-analysis. Results There were 7637 patients for analysis after excluding patients with a GCS score of 3 or bilateral unreactive pupils. Of 1112 deaths, 23.3% were within 24 h of injury (early deaths). The risk of early death was reduced with TXA (112 (2.9%) TXA group vs 147 (3.9%) placebo group; risk ratio [RR] RR 0.74, 95% CI 0.58–0.94). There was no evidence of heterogeneity by severity ( p  = 0.64) or country income ( p  = 0.68). The risk of death beyond 24 h of injury was similar in the TXA and placebo groups (432 (11.5%) TXA group vs 421 (11.7%) placebo group; RR 0.98, 95% CI 0.69–1.12). The risk of death at 28 days was 14.0% in the TXA group versus 15.1% in the placebo group (544 vs 568 events; RR 0.93, 95% CI 0.83–1.03). When the CRASH-2 and CRASH-3 trial data were pooled, TXA reduced early death (RR 0.78, 95% CI 0.70–0.87) and death within 28 days (RR 0.88, 95% CI 0.82–0.94). Conclusions Tranexamic acid reduces early deaths in non-moribund TBI patients regardless of TBI severity or country income. The effect of tranexamic acid in patients with isolated TBI is similar to that in polytrauma. Treatment is safe and even severely injured patients appear to benefit when treated soon after injury. Trial registration ISRCTN15088122 , registered on 19 July 2011; NCT01402882 , registered on 26 July 2011.

Mitochondrial dynamics are regulated by a complex system of proteins representing the mitochondrial quality control (MQC). MQC balances antagonistic forces of fusion and fission determining mitochondrial and cell fates. In several neurological disorders, dysfunctional mitochondria show significant changes in gene and protein expression of the MQC and contribute to the pathophysiological mechanisms of cell damage. In this study, we evaluated the main gene and protein expression involved in the MQC in rats receiving traumatic brain injury (TBI) of different severities. At 6, 24, 48 and 120 hours after mild TBI (mTBI) or severe TBI (sTBI), gene and protein expressions of fusion and fission were measured in brain tissue homogenates. Compared to intact brain controls, results showed that genes and proteins inducing fusion or fission were upregulated and downregulated, respectively, in mTBI, but downregulated and upregulated, respectively, in sTBI. In particular, OPA1, regulating inner membrane dynamics, cristae remodelling, oxidative phosphorylation, was post-translationally cleaved generating differential amounts of long and short OPA1 in mTBI and sTBI. Corroborated by data referring to citrate synthase, these results confirm the transitory (mTBI) or permanent (sTBI) mitochondrial dysfunction, enhancing MQC importance to maintain cell functions and indicating in OPA1 an attractive potential therapeutic target for TBI.

BackgroundThe mechanisms underlying the state of systemic immune suppression that develops following major trauma are poorly understood. A post-injury increase in circulating levels of prostaglandin E2 (PGE2) has been proposed as a contributory factor, yet few studies have addressed how trauma influences PGE2 biology.MethodsBlood samples from 95 traumatically-injured patients (injury severity score ≥8) were collected across the pre-hospital (≤2 hours), acute (4-12 hours) and subacute (48-72 hours) post-injury settings. Alongside ex vivo assessments of lipopolysaccharide (LPS)-induced cytokine production by monocytes, neutrophil reactive oxygen species production and phagocytosis, serum concentrations of PGE2 and its scavenger albumin were measured, and the expression of enzymes and receptors involved in PGE2 synthesis and signalling analysed. Leukocytes from trauma patients were treated with cyclooxygenase (COX) inhibitors (indomethacin or NS-398), or the protein kinase A inhibitor H89, to determine whether injury-induced immune suppression could be reversed by targeting the PGE2 pathway. The effect that trauma relevant concentrations of PGE2 had on the anti-microbial functions of neutrophils, monocytes and monocyte-derived macrophages (MDMs) from healthy controls (HC) was examined, as was the effect of PGE2 on efferocytosis. To identify factors that may trigger PGE2 production post-trauma, leukocytes from HC were treated with mitochondrial-derived damage associated molecular patterns (mtDAMPs) and COX-2 expression and PGE2 generation measured.ResultsPGE2 concentrations peaked in blood samples acquired ≤2 hours post-injury and coincided with significantly reduced levels of albumin and impaired LPS-induced cytokine production by monocytes. Significantly higher COX-2 and phospholipase A2 expression was detected in neutrophils and/or peripheral blood mononuclear cells isolated from trauma patients. Treatment of patient leukocytes with indomethacin, NS-398 or H89 enhanced LPS-induced cytokine production and neutrophil extracellular trap generation. Exposure to physiological concentrations of PGE2 suppressed the anti-microbial activity of monocytes, neutrophils and MDMs of HC, but did not influence efferocytosis. In a formyl-peptide receptor-1 dependent manner, mtDAMP treatment significantly increased COX-2 protein expression in neutrophils and monocytes, which resulted in increased PGE2 production.ConclusionsPhysiological concentrations of PGE2 suppress the anti-microbial activities of neutrophils, monocytes and MDMs. Targeting the PGE2 pathway could be a therapeutic approach by which to enhance innate immune function post-injury.

Assault is the third most common cause of traumatic brain injury (TBI), after falls and road traffic collisions. TBI can lead to multiple long-term physical, cognitive and emotional sequelae, including post-traumatic stress disorder (PTSD). Intentional violence may further compound the psychological trauma of the event, in a way that conventional outcome measures, like the Glasgow Outcome Scale (GOS), fail to capture. This study aims to examine the influence of assault on self-reported outcomes, including quality of life and symptoms of PTSD. Questionnaire were completed by 256 patients attending a TBI clinic, including Quality of Life after Brain Injury (QOLIBRI) and PTSD checklist (PCL-C). Medical records provided demographics, clinical data and aetiology of injury. Subjective outcomes were compared between assault and other causes. Of 202 patients analysed, 21% sustained TBI from assault. There was no difference in severity of injuries between assault and non-assault groups. No relationship was found between self-reported outcomes and TBI severity or GOS. The assault group scored worse in all self-reported questionnaires, with statistically significant differences for measures of PTSD and post-concussion symptoms. However, using threshold scores, the prevalence of PTSD in assaulted patients was not higher than non-assault. After adjusting for age, ethnicity and the presence of extra-cranial trauma, assault did not have a significant effect on questionnaire scores. Exploratory analysis showed that assault and road traffic accidents were associated with significantly worse outcomes compared to falls. Quality of life is significantly related to functional and psychological outcomes after TBI. Assaulted patients suffer from worse self-reported outcomes than other patients, but these differences were insignificant when adjusted for demographic factors. Intentionality behind the traumatic event is likely more important than cause alone. Differences in quality of life and other self-reported outcomes are not reflected by the Glasgow Outcome Scale. This information is useful in arranging earlier and targeted review and support.

Traumatic injury to the brain and spinal cord (neurotrauma) is a common event across populations and often causes profound and irreversible disability. Pathophysiological responses to trauma exacerbate the damage of an index injury, propagating the loss of function that the central nervous system (CNS) cannot repair after the initial event is resolved. The way in which function is lost after injury is the consequence of a complex array of mechanisms that continue in the chronic phase post-injury to prevent effective neural repair. This review summarises the events after traumatic brain injury (TBI) and spinal cord injury (SCI), comprising a description of current clinical management strategies, a summary of known cellular and molecular mechanisms of secondary damage and their role in the prevention of repair. A discussion of current and emerging approaches to promote neuroregeneration after CNS injury is presented. The barriers to promoting repair after neurotrauma are across pathways and cell types and occur on a molecular and system level. This presents a challenge to traditional molecular pharmacological approaches to targeting single molecular pathways. It is suggested that novel approaches targeting multiple mechanisms or using combinatorial therapies may yield the sought-after recovery for future patients.