Severe traumatic brain injury remains a major health-care problem worldwide. Although major progress has been made in understanding of the pathophysiology of this injury, this has not yet led to substantial improvements in outcome. In this report, we address present knowledge and its limitations, research innovations, and clinical implications. Improved outcomes for patients with severe traumatic brain injury could result from progress in pharmacological and other treatments, neural repair and regeneration, optimisation of surgical indications and techniques, and combination and individually targeted treatments. Expanded classification of traumatic brain injury and innovations in research design will underpin these advances. We are optimistic that further gains in outcome for patients with severe traumatic brain injury will be achieved in the next decade.
Introduction
Traumatic brain injury is a major global health problem. Country-based estimates of incidence range from 108 to 332 new cases admitted to hospital per 100 000 population per year.1 On average, 39% of patients with severe traumatic brain injury die from their injury, and 60% have an unfavourable outcome on the Glasgow Outcome Scale (appendix p 2). The incidence of traumatic brain injury is rising in low-income and middle-income countries because of increased transport-related injuries,2 and young men (who are over-represented in transport, work, and recreational injuries) are particularly affected. In most countries, ageing populations have given rise to a new cohort—elderly people—who sustain substantial traumatic brain injuries from fairly low-impact falls.1 Furthermore, blast injury to the brain, which has distinctive pathological changes, treatment, and prognosis, is common in civilians and military personnel who are exposed to improvised explosive devices and suicide terrorist attacks.3
Key messages
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Incidence of traumatic brain injury is increasing worldwide and overall mortality rates have only slightly improved since 1990. The weighted average mortality for severe traumatic brain injury is 39%, and for unfavourable outcome on the Glasgow Outcome Scale is 60%.
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The randomised trial of early decompressive craniectomy for diffuse brain injury noted worse outcomes after surgery than with medical treatment. Further trials are needed. Steroids are not indicated after traumatic brain injury, except in cases of anterior pituitary insufficiency. Induced hypothermia and hyperoxia need further assessment in clinical trials.
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Promising drug candidates are erythropoietin, statins, ciclosporin-A, tranexamic acid, and progesterone.
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Multimodal monitoring, including cerebral oximetry and microdialysis, needs further assessment to determine if it leads to improved outcomes.
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The IMPACT and MRC-CRASH online prediction models are valuable for clinical practice and research. Promising new biomarkers are glial fibrillary acidic protein and ubiquitin carboxy-terminal hydrolase L1.
Survivors of severe traumatic brain injury have a low life expectancy, dying 3·2 times faster than the general population.4 Furthermore, survivors face prolonged care and rehabilitation, and have consequent long-term physical, cognitive, and psychological disorders that affect their independence, relationships, and employment. In 2007, a conservative estimate of lifetime costs per case of severe traumatic brain injury was US$396 331, with costs for disability and lost productivity ($330 827) outweighing those for medical care and rehabilitation ($65 504).5
Mortality and functional outcomes, and resulting long-term dependence and disability, are determined by the initial injury and subsequent treatment. However, an audit6 of 774 patients treated at an urban, level 1 trauma centre between 2006 and 2008 showed only 17% compliance with Brain Trauma Foundation guidelines for craniotomy, intracranial pressure monitoring, and reversal of coagulopathy. Adherence to clinical practice guidelines for traumatic brain injury, such as those of the Brain Trauma Foundation, are likely to reduce mortality, optimise clinical outcomes, and create substantial economic savings by reducing costs of medical care, rehabilitation, and lost productivity.5 Survival after severe traumatic brain injury was three times higher in a regionalised trauma system in which patients with serious head injury were transferred to neurosurgical centres, than in a less organised system in which fewer patients were treated in specialist centres.7
In this report, which is aimed especially at surgeons and other clinicians who care for patients with acute traumatic brain injury, we summarise advances in the understanding of severe traumatic brain injury and recovery, and give an update of clinical interventions in the crucial early stages of care.
Section snippets
Classification
Although modern approaches to disease classification use anatomical, physiological, metabolic, immunological, and genetic attributes, traumatic brain injury remains largely classified on the basis of clinical signs. With the Glasgow Coma Scale, patients are divided into crude categories of mild, moderate, and severe injury. These categories not only fail to identify the heterogeneity and complexity of severe injuries, but also minimise the real burden of mild traumatic brain injury. This issue
Pathophysiology
Traumatic brain injury has a dynamic pathophysiology that evolves in time (figure). The mechanism consists of the primary injury, followed by a combination of systemic derangements (hypoxia, hypotension, hypercarbia) and local events, which together cause secondary brain injury. Changes to the cerebral environment involve a complex interplay between cellular and molecular processes, in which glutamate-driven excitotoxic effects, oxidative stress, inflammation, ion imbalance, and metabolic
Pre-hospital
Despite the potential benefits of early intervention, few pre-hospital treatment options have proved effective. In nine randomised controlled trials and one cohort study of pre-hospital fluid treatment in patients with traumatic brain injury,15 hypertonic crystalloids and colloid solutions were not more effective than was isotonic saline. Results from observational studies16 of pre-hospital endotracheal intubation have been conflicting. Poor outcomes in intubated patients were probably due to
Monitoring of the injured brain
Continuous intensive-care monitoring of patients with severe traumatic brain injury provides information to help prevent and treat secondary cerebral ischaemia. Monitoring of intracranial pressure is standard practice for severe traumatic brain injury in most neurosurgical centres. Guidelines66 from the Brain Trauma Foundation detail indications for such monitoring alongside supporting evidence. However, the first randomised trial67 to test the effectiveness of treatment based on intracranial
Outcomes and their prediction
Comparison and prediction of outcomes in traumatic brain injury is challenging because of heterogeneity within the patient population, substantial differences in baseline prognostic risk, and the complexity of outcomes. Seemingly, mortality after traumatic brain injury has decreased and outcome has improved. Mortality rates of 10–15% noted in selected trials are compared with historial cohorts, such as the US Traumatic Coma Databank, which reported a mortality rate of 39% in 1984–87 (appendix p
Implications for research
Disappointingly, discoveries in the laboratory have translated into few new treatments for traumatic brain injury in human beings. Strategies for addressing this failure have been identified,108 including more research in larger animals, such as pigs and sheep with gyriform brains, rather than in rodents, whose brains are small and lissencephalic.108 CNS drugs take about 18 years to go from the laboratory bench to the patient, and spend on average 8·1 years in human testing.109 The cost of
Conclusion
The outcome of severe traumatic brain injury is dependent on delivery of high-quality care by a well-integrated multidisciplinary team of health professionals. Further improvements will probably result from precise classification, innovations in trial design, implementation of comparative effectiveness research, selection of patients who are likely to benefit from particular interventions, and individualised treatment in intensive-care units based on multimodal monitoring. Preclinical
Search strategy and selection criteria
We searched Medline, evidence-based medicine reviews, Cochrane Central Register of Controlled Trials, CENTRAL, and Embase from Jan 1, 2006, to Nov 28, 2011, using the core terms “brain injuries”, “craniocerebral trauma” and “traumatic brain injury” and keywords for the following topics: monitoring, decompressive craniectomy, haematoma evacuation, steroids, antifibrinolytics, therapeutic hypothermia, hyperoxia, stem cells, outcomes, predictors of outcome, and novel predictors of outcome. All
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Xuefu Zhuyu decoction (XFZYD) is a traditional Chinese herbal formula known for its ability to eliminate blood stasis and improve blood circulation, providing neuroprotection against severe traumatic brain injury (sTBI). However, the underlying mechanism is still unclear.
We aim to investigate the neuroprotective effects of XFZYD in sTBI from a novel mechanistic perspective of miRNA-mRNA. Additionally, we sought to elucidate a potential specific mechanism by integrating transcriptomics, bioinformatics, and conducting both in vitro and in vivo experiments.
The sTBI rat model was established, and the rats were treated with XFZYD for 14 days. The neuroprotective effects of XFZYD were evaluated using a modified neurological severity score, hematoxylin and eosin staining, as well as Nissl staining. The anti-inflammatory effects of XFZYD were explored using quantitative real-time PCR (qRT-PCR), Western blot analysis, and immunofluorescence. Next, miRNA sequencing of the hippocampus was performed to determine which miRNAs were differentially expressed. Subsequently, qRT-PCR was used to validate the differentially expressed miRNAs. Target core mRNAs were determined using various methods, including miRNA prediction targets, mRNA sequencing, miRNA-mRNA network, and protein-protein interaction (PPI) analysis. The miRNA/mRNA regulatory axis were verified through qRT-PCR or Western blot analysis. Finally, morphological changes in the neural synapses were observed using transmission electron microscopy and immunofluorescence.
XFZYD exhibited significant neuroprotective and anti-inflammatory effects on subacute sTBI rats' hippocampus. The analyses of miRNA/mRNA sequences combined with the PPI network revealed that the therapeutic effects of XFZYD on sTBI were associated with the regulation of the rno-miR-191a-5p/BDNF axis. Subsequently, qRT-PCR and Western blot analysis confirmed XFZYD reversed the decrease of BDNF and TrkB in the hippocampus caused by sTBI. Additionally, XFZYD treatment potentially increased the number of synaptic connections, and the expression of the synapse-related protein PSD95, axon-related protein GAP43 and neuron-specific protein TUBB3.
XFZYD exerts neuroprotective effects by promoting hippocampal synaptic remodeling and improving cognition during the subacute phase of sTBI through downregulating of rno-miR-191a-5p/BDNF axis, further activating BDNF-TrkB signaling.
Globally, severe lower limb injuries (SLLIs) are the predominant cause of long-term injury related disability and poor functional outcomes. Chronic pain is a major source of this morbidity, but the magnitude of the contribution is not clearly understood. The aim of this systematic review and meta-analysis was to determine the prevalence of chronic pain following SLLIs in civilian and military patients.
This systematic review was prospectively registered with The International Prospective Register of Systematic Reviews (PROSPERO) with study ID CRD42022313615. A systematic literature search (Medline, Embase, Ovid, and Web of Science) was performed to identify original studies that reported chronic pain outcomes for adults who underwent surgical treatment for SLLIs in a civilian or military setting. Risk of bias in included studies was assessed using the ROBINS-E tool, and quality assessment was reported at study level using the Newcastle–Ottawa Scale, and at outcome-level using the GRADE framework. Absolute (proportional) and relative (odds ratio) outcome measures were calculated and pooled using a random effects model.
Forty-three studies reporting the outcomes of 5601 patients were included. Estimated overall prevalence of pain was 63 % (CI 55–70 %). The prevalence of chronic pain in amputees (64 % (CI 55–73 %)) was similar to those who underwent limb salvage (56 % (CI 44–67 %)). The prevalence of chronic pain in civilian populations was 70 % (CI 63–77 %) compared to military populations (51 % (CI 35–66 %)). In amputees, the prevalence of residual limb pain was similar to phantom limb pain (OR 1.06 [0.64–1.78], p = 0.81, I2 = 92 %).
Most people who sustain a SLLI will suffer from chronic pain. Healthcare systems must continue to research interventions that can reduce the incidence and severity of long-term pain and ensure adequate resources are allocated for this common and debilitating complication.
Traumatic brain injury (TBI) is a major public health challenge. Up to 90 % of TBIs are on the mild spectrum of TBI (mTBI), where diagnosis is a major challenge. Majority of studies in this field have been conducted on human subjects, which inherently suffer from the lack of appropriate control group, selection bias, and individual differences in patients. To overcome these limitations, animal studies have been used as an alternative approach to provide deeper insights into the underlying mechanism related to the injury. Therefore our aim is to investigate various quantitative imaging biomarkers acquired from T1-W and diffusion tensor imaging (DTI) sequences to provide more information about the microstructural changes in the brain after mTBI. We then use this to generate subject-specific finite element models of the brain and examine how the changes in the brain material properties reflected in MR images affects strain distribution patterns on a subsequent head hit. Our study revealed a decrease in FA and an increase in diffusivity indices (MD, AD, RD) in the white matter tracts of the brain. This finding may represent the axonal damage, demyelination and gliosis after mild TBI, which have been shown in other animal and human studies. Moreover, our FE analysis showed that microstructural changes in the brain after mTBI might have weakened the structural integrity of the brain as the subsequent head hit led to wider and more severe brain deformations.
Animal models have been used to investigate biomechanical and pathophysiological aspects of mild traumatic brain injuries in the past. Still, most of them used small animals such as rats and mice. These models provided valuable insight into the pathophysiology of mTBI, but their findings have limitations due to their inherent differences to human brains. We have developed a large animal model of mTBI with sheep brains by combining advanced MRI and finite element analysis as they mimic the human brain better. To the best of our knowledge, this study is the first mTBI neuroimaging study conducted on large animal brains to investigate the diffusional changes in the white matter tracts after mTBI. Our FE analysis revealed that such microstructural changes resulted in tissue softening as the extent of brain deformation increased on a subsequent head hit, indicating increased brain vulnerability after head impacts.
The severity of inevitable neurological deficits and long-term psychiatric disorders in the aftermath of traumatic brain injury is influenced by pre-injury biological factors. Herein, we investigated the therapeutic effect of chitosan lactate on neurological and psychiatric aberrations inflicted by circadian disruption (CD) and controlled-cortical impact (CCI) injury in mice. Firstly, CD was developed in mice by altering sporadic day-night cycles for 2 weeks. Then, CCI surgery was performed using a stereotaxic ImpactOne device. Mice subjected to CCI displayed a significant disruption of motor coordination at 1-, 3- and 5-days post-injury (DPI) in the rotarod test. These animals showed anxiety- and depression-like behaviors in the elevated plus maze and forced-swim test at 14 and 15 DPI, respectively. Notably, mice subjected to CD + CCI exhibited severe cognitive impairment in Y-maze and novel object recognition tasks. The compromised neurological, psychiatric, and cognitive functions were mitigated in chitosan-treated mice (1 and 3 mg/mL). Immunohistochemistry and real-time PCR assay results revealed the magnified responses of prima facie biomarkers like glial-fibrillary acidic protein and ionized calcium-binding adaptor molecule 1 in the pericontusional brain region of the CD + CCI group, indicating aggravated inflammation. We also noted the depleted levels of brain-derived neurotrophic factor and augmented expression of toll-like receptor 4 (TLR4)-leucine-rich-containing family pyrin domain-containing 3 (NLRP3) signaling [apoptosis-associated-speck-like protein (ASC), caspase-1, and interleukin 1-β] in the pericontusional area of CD + CCI group. CCI-induced changes in the astrocyte-glia and aggravated immune responses were ameliorated in chitosan-treated mice. These results suggest that the neuroprotective effect of chitosan in CCI-induced brain injury may be mediated by inhibition of the TLR4-NLRP3 axis.
Traumatic brain injury (TBI) strongly correlates with neurodegenerative disease. However, it remains unclear which neurodegenerative mechanisms are intrinsic to the brain and which strategies most potently mitigate these processes. We developed a high-intensity ultrasound platform to inflict mechanical injury to induced pluripotent stem cell (iPSC)-derived cortical organoids. Mechanically injured organoids elicit classic hallmarks of TBI, including neuronal death, tau phosphorylation, and TDP-43 nuclear egress. We found that deep-layer neurons were particularly vulnerable to injury and that TDP-43 proteinopathy promotes cell death. Injured organoids derived from C9ORF72 amyotrophic lateral sclerosis/frontotemporal dementia (ALS/FTD) patients displayed exacerbated TDP-43 dysfunction. Using genome-wide CRISPR interference screening, we identified a mechanosensory channel, KCNJ2, whose inhibition potently mitigated neurodegenerative processes in vitro and in vivo, including in C9ORF72 ALS/FTD organoids. Thus, targeting KCNJ2 may reduce acute neuronal death after brain injury, and we present a scalable, genetically flexible cerebral organoid model that may enable the identification of additional modifiers of mechanical stress.
Traumatic brain injuries (TBIs) are a significant cause of morbidity and mortality in the United States. but have a disproportionate impact on patients based on gender. This systematic review and meta-analysis aim to compare gender differences in clinical outcomes between male and female adult trauma patients with moderate and severe TBI.
Studies assessing gender differences in outcomes following TBIs on PubMed, Google Scholar, EMBASE, and ProQuest were searched. Meta-analysis was performed for outcomes including in-hospital mortality, hospital length of stay, intensive care unit length of stay, and Glasgow outcome scale (GOS) at 6 mo.
Eight studies were included for analysis with 26,408 female and 63,393 male patients. Meta-analysis demonstrated that males had a significantly lower risk of mortality than females (RR: 0.88; 95% CI 0.78, 0.99; P = 0.0001). Females had a shorter hospital length of stay (mean difference −1.4 d; 95% CI - 1.6 d, −1.2 d). No significant differences were identified in intensive care unit length of stay (mean difference −3.0 d; 95% CI -7.0 d, 1.1 d; P = 0.94) or GOS at 6 mo (mean difference 0.2 d; 95% CI -0.9 d, 1.4 d; P = 1).
Compared to male patients, female patients with moderate and severe TBI had a significantly higher in-hospital mortality risk. There were no significant differences in long-term outcomes between genders based on GOS at 6 mo. These findings warrant further investigation into the etiology of these gender disparities and their impact on additional clinical outcome measures.