Can rotational thromboelastometry rapidly identify theragnostic targets in isolated traumatic brain injury?

OBJECTIVE: Coagulation assessment in traumatic brain injury (TBI) typically relies upon laboratory-based standard coagulation tests (SCTs), including the activated partial thromboplastin time (aPTT), INR and platelet count. Rotational thromboelastometry (ROTEM) sigma is an alternative point-of-care assay; however, its role in isolated TBI is under-evaluated. The present study aims to assess the prognostic utility of ROTEM sigma in isolated TBI. METHODS: ROTEM sigma analysis was performed during the initial evaluation of patients presenting to the Royal Adelaide Hospital between February 2022 and 2023 with radiographically demonstrated traumatic intracranial haemorrhage and GCS ≤14. Patients with concomitant severe extracranial injury, or who received blood products or antifibrinolytic therapy prior to sample collection were excluded. RESULTS: Thirty-six patients had blood samples analysed with ROTEM, 25 of these patients were also evaluated with paired SCTs. Twenty-two per cent (8/36) of patients with isolated TBI had a hypocoaguable ROTEM profile, and this was associated with an increased incidence of head injury-related death (50% [4/8] vs 11% [3/28], P = 0.03). Median diagnostic turn-around-times were shorter for ROTEM parameters compared to SCT counterparts: EXTEM clotting time (CT) versus INR (20 vs 63 min, P < 0.01), and INTEM CT versus aPTT (21 vs 63 min, P < 0.01). EXTEM CT, FIBTEM CT and INR values had similar performance in predicting head injury-related death, area under the receiver operator curves were 0.8, 0.8 and 0.7, respectively. CONCLUSIONS: ROTEM sigma expedites the detection of clinically significant coagulopathy in isolated TBI. EXTEM and FIBTEM CT values are more rapidly attainable than INR and comparable in predicting head injury-related death.

Incidence of hydrocephalus following decompressive craniectomy for ischaemic stroke: A systematic review and meta-analysis.

OBJECTIVE: Decompressive craniectomy (DC) following malignant ischaemic stroke is a potentially life-saving procedure. Event rates of ventriculomegaly following DC performed in this setting remain poorly defined. Accordingly, we performed a systematic review to determine the incidence of hydrocephalus and the need for cerebrospinal fluid (CSF) diversion following DC for malignant stroke. METHODS: MEDLINE, EMBASE and Cochrane libraries were searched from database inception to 17 July 2021. Our search strategy consisted of "Decompressive Craniectomy", AND "Ischaemic stroke", AND "Hydrocephalus", along with synonyms. Through screening abstracts and then full texts, studies reporting on rates of ventriculomegaly following DC to treat ischaemic stroke were included for analysis. Event rates were calculated for both of these outcomes. A risk of bias assessment was performed to determine the quality of the included studies. RESULTS: From an initial 1117 articles, 12 were included following full-text screening. All were of retrospective design. The 12 included studies reported on 677 patients, with the proportion experiencing hydrocephalus/ventriculomegaly being 0.38 (95% CI: 0.24, 0.53). Ten studies incorporating 523 patients provided data on the need for permanent CSF diversion, with 0.10 (95% CI: 0.07, 0.13) requiring a shunt. The included studies were overall of high methodological quality and rigour. CONCLUSION: Though hydrocephalus is relatively common following DC in this clinical setting, only a minority of patients are deemed to require permanent CSF diversion. Clinicians should be aware of the incidence of this complication and counsel patients and families appropriately.

Evaluating the effect of post-traumatic hypoxia on the development of axonal injury following traumatic brain injury in sheep.

Damage to the axonal white matter tracts within the brain is a key cause of neurological impairment and long-term disability following traumatic brain injury (TBI). Understanding how axonal injury develops following TBI requires gyrencephalic models that undergo shear strain and tissue deformation similar to the clinical situation and investigation of the effects of post-injury insults like hypoxia. The aim of this study was to determine the effect of post-traumatic hypoxia on axonal injury and inflammation in a sheep model of TBI. Fourteen male Merino sheep were allocated to receive a single TBI via a modified humane captive bolt animal stunner, or sham surgery, followed by either a 15 min period of hypoxia or maintenance of normoxia. Head kinematics were measured in injured animals. Brains were assessed for axonal damage, microglia and astrocyte accumulation and inflammatory cytokine expression at 4 hrs following injury. Early axonal injury was characterised by calpain activation, with significantly increased SNTF immunoreactivity, a proteolytic fragment of alpha-II spectrin, but not with impaired axonal transport, as measured by amyloid precursor protein (APP) immunoreactivity. Early axonal injury was associated with an increase in GFAP levels within the CSF, but not with increases in IBA1 or GFAP+ve cells, nor in levels of TNFα, IL1ß or IL6 within the cerebrospinal fluid or white matter. No additive effect of post-injury hypoxia was noted on axonal injury or inflammation. This study provides further support that axonal injury post-TBI is driven by different pathophysiological mechanisms, and detection requires specific markers targeting multiple injury mechanisms. Treatment may also need to be tailored for injury severity and timing post-injury to target the correct injury pathway.

Haemostatic efficacy and inflammatory response of a novel beta-chitin patch in a cerebral small vessel injury model - A pilot study.

OBJECTIVE: Rapid and efficacious haemostasis is paramount in neurosurgery. Assessing the efficacy and short- and long-term safety of haemostatic agents utilised within cerebral tissue is essential. This pilot study investigates the haemostatic efficacy and long-term safety of a novel beta-chitin patch against traditionally used agents, bipolar and Floseal, within cerebral tissue. METHODS: Eighteen Merino sheep underwent standardised distal cortical vessel injury via temporal craniotomy. Sheep were randomised to receive 2 mls Floseal, 2 cm novel beta-chitin patch, or bipolar cautery to manage bleeding. All sheep underwent cerebral magnetic resonance imaging (MRI) at three months, before euthanasia and brain harvesting for histological assessment. RESULTS: Beta-chitin demonstrated a trend towards a faster mean time to haemostasis (TTH) compared to Floseal (223.3 ± 199 s v. 259.8 ± 186.4 s), albeit non-significant (p = 0.234). Radiologically, cerebrocortical necrosis (p = 0.842) and oedema (p = 0.368) were noted slightly more frequently in the beta-chitin group. Histologically, severe fibrotic (p = 0.017) and granulomatous changes at the craniotomy sites were only present in the beta-chitin group (p = 0.002). Neuronal degeneration was seen in all with Floseal, but beta-chitin showed a trend towards more severe reaction when present. Bipolar use predominantly showed an inflammatory cortical reaction with substantial microvascular proliferation, and Floseal showed worse severity and depth of subpial oedema, however no statistical significance was reached. CONCLUSION: All haemostats controlled bleeding, with beta-chitin demonstrating a non-inferior TTH compared to Floseal. However, it resulted in intense granulomatous and fibrotic changes, including degenerative neuronal reactions. More extensive studies are needed to assess these trends, to make further clinical inferences.

Effect of Pre-Management Antithrombotic Agent Use on Outcome after Traumatic Acute Subdural Hematoma in the Elderly: A Systematic Review.

Traumatic acute subdural hematomas (ASDH) are common in elderly patients (age ≥65 years) and are associated with a poorer prognosis compared with younger populations. Antithrombotic agent (ATA) use is also common in the elderly; however, the influence that pre-morbid ATA has on outcome in ASDH is poorly understood. We hypothesized that pre-morbid ATA use significantly worsens outcomes in elderly patients presenting with traumatic ASDH. English language medical literature was searched for articles relating to ATA use in the elderly with ASDH. Data were collated and appraised where possible. Analyses of study bias were performed. Twelve articles encompassing 2038 patients were included; controls were poorly described in the included studies. Pre-morbid ATA use was seen in 1042 (51.1%) patients and 18 different ATA combination therapies were identified, with coumarins being the most common single agent used. The newer direct oral anticoagulants were evaluated in only two studies. ATA use was associated with a lower presenting Glasgow Coma Scale (GCS) score but not hematoma volume on computed tomography (CT) or post-operative hematoma re-accumulation. No studies connected ATA use with patient outcomes without the presence of confounders and bias. Reversal strategies, bridging therapy, recommencement of ATA, and comparison groups were poorly described; accordingly, our hypothesis was rejected. ATA reversal methods, identification of surgical candidates, optimal surgery methods, and when or whether ATA should be recommenced following ASDH resolution remain topics of debate. This study defines our current understanding on this topic, revealing clear deficiencies in the literature with recommendations for future research.

Effects of Remote Immune Activation on Performance in the 5-Choice Serial Reaction Time Task Following Mild Traumatic Brain Injury in Adolescence.

In adult pre-clinical models, traumatic brain injury (TBI) has been shown to prime microglia, exaggerating the central inflammatory response to an acute immune challenge, worsening depressive-like behavior, and enhancing cognitive deficits. Whether this phenomenon exists following mTBI during adolescence has yet to be explored, with age at injury potentially altering the inflammatory response. Furthermore, to date, studies have predominantly examined hippocampal-dependent learning domains, although pre-frontal cortex-driven functions, including attention, motivation, and impulsivity, are significantly affected by both adolescent TBI and acute inflammatory stimuli. As such, the current study examined the effects of a single acute peripheral dose of LPS (0.33 mg/kg) given in adulthood following mTBI in mid-adolescence in male Sprague-Dawley rats on performance in the 5-choice serial reaction time task (5-CSRTT). Only previously injured animals given LPS showed an increase in omissions and reward collection latency on the 5-CSRTT, with no effect noted in sham animals given LPS. This is suggestive of impaired motivation and a prolonged central inflammatory response to LPS administration in these animals. Indeed, morphological analysis of myeloid cells within the pre-frontal cortex, via IBA1 immunohistochemistry, found that injured animals administered LPS had an increase in complexity in IBA1+ve cells, an effect that was seen to a lesser extent in sham animals. These findings suggest that there may be ongoing alterations in the effects of acute inflammatory stimuli that are driven, in part by increased reactivity of microglial cells.

Injury during adolescence leads to sex-specific executive function deficits in adulthood in a pre-clinical model of mild traumatic brain injury.

Adolescents are more likely than adults to develop chronic symptoms, such as impulsivity and difficulty concentrating, following a mild traumatic brain injury (mTBI) which may relate to disruption of pre-frontal cortex (PFC development). During adolescence the PFC is undergoing extensive remodelling, driving maturation of executive functions incorporating attention, motivation and impulse control. In part maturation of the PFC is driven by outgrowth of dopaminergic neurons to the PFC under the guidance of specific axonal targeting cues, including netrin-1. How a mTBI in adolescence may alter the expression of these axonal targeting cues, and the influence on PFC development is not yet known. As such the effects of mTBI in mid-adolescence on executive functioning in adulthood (12 weeks) were examined via the 5-choice serial reaction task in both male and female Sprague Dawley rats. Animals at p35 (n = 12-16 per group) were injured via weight drop (100 g from 0.75 m) and injury confirmed by a significant increase in righting reflex. Interestingly, while a mid-adolescence mTBI in females led to significantly higher omissions and decreased accuracy when task difficulty was high (stimulus duration 1 s), males had significantly increased premature response rate when the intertrial interval was varied. Examination of levels of TH, as a reflection of dopaminergic innervation, found no difference in either gender post-TBI in the PFC, but a significant increase in the limbic system (nucleus accumbens) in males, but not females, chronically post-TBI, suggesting an imbalance between the regions. The increase in TH was accompanied by a chronic reduction in netrin-1 within the nucleus accumbens in males only. Taken together, these results indicate that mTBI in adolescence leads to sex specific effects in different domains of PFC function in adulthood, which may relate to subtle alterations in the developmental trajectory of the mesocortical limbic pathway in males only.

Beyond the Brain: Peripheral Interactions after Traumatic Brain Injury.

Traumatic brain injury (TBI) is a leading cause of death and disability, and there are currently no pharmacological treatments known to improve patient outcomes. Unquestionably, contributing toward a lack of effective treatments is the highly complex and heterogenous nature of TBI. In this review, we highlight the recent surge of research that has demonstrated various central interactions with the periphery as a potential major contributor toward this heterogeneity and, in particular, the breadth of research from Australia. We describe the growing evidence of how extracranial factors, such as polytrauma and infection, can significantly alter TBI neuropathology. In addition, we highlight how dysregulation of the autonomic nervous system and the systemic inflammatory response induced by TBI can have profound pathophysiological effects on peripheral organs, such as the heart, lung, gastrointestinal tract, liver, kidney, spleen, and bone. Collectively, this review firmly establishes TBI as a systemic condition. Further, the central and peripheral interactions that can occur after TBI must be further explored and accounted for in the ongoing search for effective treatments.