Association of time to craniectomy with survival in patients with severe combat-related brain injury.

OBJECTIVEIn combat and austere environments, evacuation to a location with neurosurgery capability is challenging. A planning target in terms of time to neurosurgery is paramount to inform prepositioning of neurosurgical and transport resources to support a population at risk. This study sought to examine the association of wait time to craniectomy with mortality in patients with severe combat-related brain injury who received decompressive craniectomy.METHODSPatients with combat-related brain injury sustained between 2005 and 2015 who underwent craniectomy at deployed surgical facilities were identified from the Department of Defense Trauma Registry and Joint Trauma System Role 2 Registry. Eligible patients survived transport to a hospital capable of diagnosing the need for craniectomy and performing surgery. Statistical analyses included unadjusted comparisons of postoperative mortality by elapsed time from injury to start of craniectomy, and Cox proportional hazards modeling adjusting for potential confounders. Time from injury to craniectomy was divided into quintiles, and explored in Cox models as a binary variable comparing early versus delayed craniectomy with cutoffs determined by the maximum value of each quintile (quintile 1 vs 2-5, quintiles 1-2 vs 3-5, etc.). Covariates included location of the facility at which the craniectomy was performed (limited-resource role 2 facility vs neurosurgically capable role 3 facility), use of head CT scan, US military status, age, head Abbreviated Injury Scale score, Injury Severity Score, and injury year. To reduce immortal time bias, time from injury to hospital arrival was included as a covariate, entry into the survival analysis cohort was defined as hospital arrival time, and early versus delayed craniectomy was modeled as a time-dependent covariate. Follow-up for survival ended at death, hospital discharge, or hospital day 16, whichever occurred first.RESULTSOf 486 patients identified as having undergone craniectomy, 213 (44%) had complete date/time values. Unadjusted postoperative mortality was 23% for quintile 1 (n = 43, time from injury to start of craniectomy 30-152 minutes); 7% for quintile 2 (n = 42, 154-210 minutes); 7% for quintile 3 (n = 43, 212-320 minutes); 19% for quintile 4 (n = 42, 325-639 minutes); and 14% for quintile 5 (n = 43, 665-3885 minutes). In Cox models adjusted for potential confounders and immortal time bias, postoperative mortality was significantly lower when time to craniectomy was within 5.33 hours of injury (quintiles 1-3) relative to longer delays (quintiles 4-5), with an adjusted hazard ratio of 0.28, 95% CI 0.10-0.76 (p = 0.012).CONCLUSIONSPostoperative mortality was significantly lower when craniectomy was initiated within 5.33 hours of injury. Further research to optimize craniectomy timing and mitigate delays is needed. Functional outcomes should also be evaluated.

Military Deployment May Increase the Risk for Traumatic Brain Injury Following Deployment.

OBJECTIVE: To compare rates of traumatic brain injury (TBI) diagnosis before and after overseas military deployment. DESIGN: We conducted a retrospective examination of a cohort of 119 353 active duty US military service members (Army, Navy, Air Force, and Marines) whose first lifetime overseas deployment began at any time between January 1, 2011, and December 31, 2011, and lasted at least for 30 days. For this cohort, TBI diagnoses were examined during the 76 weeks prior to deployment, during deployment, and 76 weeks following the end of deployment. MAIN MEASURES: 4-week rates of TBI diagnosis. RESULTS: The risk of being diagnosed with TBI within 4 weeks after returning from deployment was 8.4 times higher than the average risk before deployment. The risk gradually decreased thereafter up to 40 weeks postdeployment. However, during the 41 to 76 weeks following deployment, risk stabilized but remained on average 1.7 times higher than before deployment. CONCLUSION: An increased rate of TBI diagnosis following deployment was identified, which may be partly due to delayed diagnosis of TBIs that occurred while service members were deployed. Also, the increased rate may partly be due to riskier behaviors of service members following deployment that results in an increased occurrence of TBIs.

Revisiting therapeutic hypothermia for severe traumatic brain injury... again.

Improved understanding of the molecular mechanisms of secondary brain injury has informed the optimum depth and duration of cooling and led to increased clinical interest in the therapeutic moderate hypothermia for severe traumatic brain injury over the past two decades. Although several large multi-center clinical trials have not found a treatment effect, multiple single-center trials have, and a recent meta-analysis by Crossley and colleagues now finds that the cumulative findings of those single-center trials dilute the multi-center trial results and show an overall reduction in mortality and poor outcomes associated with cooling. The need for consistent support of key physiologic parameters during cooling is emphasized by this finding.

Biofluid, Imaging, Physiological, and Functional Biomarkers of Mild Traumatic Brain Injury and Subconcussive Head Impacts.

Post-concussive symptoms are frequently reported by individuals who sustain mild traumatic brain injuries (mTBIs) and subconcussive head impacts, even when evidence of intracranial pathology is lacking. Current strategies used to evaluate head injuries, which primarily rely on self-report, have a limited ability to predict the incidence, severity, and duration of post-concussive symptoms that will develop in an individual patient. In addition, these self-report measures have little association with the underlying mechanisms of pathology that may contribute to persisting symptoms, impeding advancement in precision treatment for TBI. Emerging evidence suggests that biofluid, imaging, physiological, and functional biomarkers associated with mTBI and subconcussive head impacts may address these shortcomings by providing more objective measures of injury severity and underlying pathology. Interest in the use of biomarker data has rapidly accelerated, which is reflected by the recent efforts of organizations such as the National Institute of Neurological Disorders and Stroke and the National Academies of Sciences, Engineering, and Medicine to prioritize the collection of biomarker data during TBI characterization in acute-care settings. Thus, this review aims to describe recent progress in the identification and development of biomarkers of mTBI and subconcussive head impacts and to discuss important considerations for the implementation of these biomarkers in clinical practice.

Committee on Surgical Combat Casualty Care position statement: Neurosurgical capability for the optimal management of traumatic brain injury during deployed operations.

BACKGROUND: Experiences over the last three decades of war have demonstrated a high incidence of traumatic brain injury (TBI) resulting in a persistent need for a neurosurgical capability within the deployed theater of operations. Despite this, no doctrinal requirement for a deployed neurosurgical capability exists. Through an iterative process, the Joint Trauma System Committee on Surgical Combat Casualty Care (CoSCCC) developed a position statement to inform medical and nonmedical military leaders about the risks of the lack of a specialized neurosurgical capability. METHODS: The need for deployed neurosurgical capability position statement was identified during the spring 2021 CoSCCC meeting. A triservice working group of experienced forward-deployed caregivers developed a preliminary statement. An extensive iterative review process was then conducted to ensure that the intended messaging was clear to senior medical leaders and operational commanders. To provide additional context and a civilian perspective, statement commentaries were solicited from civilian clinical experts including a recently retired military trauma surgeon boarded in neurocritical care, a trauma surgeon instrumental in developing the Brain Injury Guidelines, a practicing neurosurgeon with world-renowned expertise in TBI, and the chair of the Committee on Trauma. RESULTS: After multiple revisions, the position statement was finalized, and approved by the CoSCCC membership in February 2023. Challenges identified include (1) military neurosurgeon attrition, (2) the lack of a doctrinal neurosurgical capabilities requirement during deployed combat operations, and (3) the need for neurosurgical telemedicine capability and in-theater computed tomography scans to triage TBI casualties requiring neurosurgical care. CONCLUSION: Challenges identified regarding neurosurgical capabilities within the deployed trauma system include military neurosurgeon attrition and the lack of a doctrinal requirement for neurosurgical capability during deployed combat operations. To mitigate risk to the force in a future peer-peer conflict, several evidence-based recommendations are made. The solicited civilian commentaries strengthen these recommendations by putting them into the context of civilian TBI management. This neurosurgical capabilities position statement is intended to be a forcing function and a communication tool to inform operational commanders and military medical leaders on the use of these teams on current and future battlefields. LEVEL OF EVIDENCE: Prognostic and Epidemiological; Level V.

Effects of non-neurological complications on traumatic brain injury outcome.

Traumatic brain injury (TBI) affects over 1.5 million Americans annually and consumes a significant amount of healthcare dollars. Identification of complications and factors that impact recovery from TBI is important in improving outcome and allocating appropriate resources. Understanding the role of non-neurologic complications such as sepsis, acute kidney injury, and respiratory problems on TBI outcome and mortality is critical.

Military Traumatic Brain Injury: The History, Impact, and Future.

This review examines how lessons learned from United States military conflicts, beginning with the United States Civil War through the engagements in Iraq and Afghanistan, have shaped current traumatic brain injury (TBI) care in the United States military, influenced congressional mandates and directives, and led to best practices in caring for the warfighter. Prior to the most recent war, emphasis was placed on improving the surgical and medical care of service members (SM) with severe and especially penetrating brain injuries. However, during the Iraq and Afghanistan conflicts, also known as the Global War on Terrorism (GWOT), blast injury from improvised explosive devices most often caused mild TBI (mTBI), an injury that was not always recognized and was labelled the "signature wound" of the GWOT. This has led to extensive research on objective diagnostic technologies for mTBI, the association of mTBI with post-traumatic stress disorder (PTSD), and the long term consequences of mTBI. Here we summarize the key findings and most important advances from those efforts, and discuss the way forward regarding future military conflicts.

Military TBI-What civilian primary care providers should know.

In June 2019, the Department of Veterans Affairs (VA) launched the VA Mission Act, which expanded veterans' health-care access to the private sector. Since civilian primary care providers may see more veterans in their practice, it will be important to understand the unique experiences, comorbidities, and culture of this population in order to provide optimal care. Military service members (SMs) are at an increased risk for traumatic brain injury (TBI), and comorbidities, such as post traumatic stress disorder (PTSD), increasing the likelihood of prolonged symptoms. Military training and repetitive low-level blast exposure may cause symptoms similar to TBI or increase long-term negative effects in SMs. Military culture often has a strong influence in this population. Those who serve in the military identify with military values and have a strong team mentality, which places emphasis on the mission above all else, not accepting defeat, and not ever leaving a fellow SM behind. These values can impact the way a SM/veteran seeks care and/or communicates with his or her health-care provider. Taking a detailed history to understand how these factors apply, as well as screening for mental health comorbidities, are recommended. Understanding the military cultural influences can assist in promoting a stronger therapeutic alliance and encourage more open communication. Ultimately, it is the trusting and respectful relationship between the SM/veteran and the provider that will determine the most effective treatment and result in the most effective resolution of TBI and comorbid symptoms.

The Prehospital Evaluation and Care of Moderate/Severe TBI in the Austere Environment.

Increased resource constraints secondary to a smaller medical footprint, prolonged evacuation times, or overwhelming casualty volumes all increase the challenges of effective management of traumatic brain injury (TBI) in the austere environment. Prehospital providers are responsible for the battlefield recognition and initial management of TBI. As such, targeted education is critical to efficient injury recognition, promoting both provider readiness and improved patient outcomes. When austere conditions limit or prevent definitive treatment, a comprehensive understanding of TBI pathophysiology can help inform acute care and enhance prevention of secondary brain injury. Field deployable, noninvasive TBI assessment and monitoring devices are urgently needed and are currently undergoing clinical evaluation. Evidence shows that the assessment, monitoring, and treatment in the first few hours and days after injury should focus on the preservation of cerebral perfusion and oxygenation. For cases where medical management is inadequate (eg, evidence of an enlarging intracranial hematoma), guidelines have been developed for the performance of cranial surgery by nonneurosurgeons. TBI management in the austere environment will continue to be a challenge, but research focused on improving evidence-based monitoring and therapeutic interventions can help to mitigate some of these challenges and improve patient outcomes.

Contemporary management of traumatic intracranial hypertension: is there a role for therapeutic hypothermia?

OBJECTIVE: Intracranial hypertension (ICH) remains the single most difficult therapeutic challenge for the acute management of severe traumatic brain injury (TBI). We reviewed the published trials of therapeutic moderate hypothermia to determine its effect on ICH and compared its efficacy to other commonly used therapies for ICH. METHODS: A PubMed database search was done using various combinations of the search terms "brain injury," "therapeutic hypothermia," "intracranial hypertension," "barbiturates," "mannitol," "hypertonic saline," "hyperventilation," "decompressive craniectomy," and "CSF drainage." RESULTS: We identified 11 prospective randomized clinical TBI trials comparing hypothermia vs. normothermia treatment for which intracranial pressure (ICP) data was provided, and 6 prospective cohort studies that provided ICP data before and during hypothermia treatment. In addition, we identified 37 clinical TBI studies of lumbar CSF drainage, mannitol, hyperventilation, barbiturates, hypertonic saline, and decompressive craniectomy that provided pre- and posttreatment ICP data. Hypothermia was at least as effective as the traditional therapies for ICH (hyperventilation, mannitol, and barbiturates), but was less effective than hypertonic saline, lumbar CSF drainage, and decompressive craniectomy. Ultimately, however, therapeutic hypothermia does appear to have a favorable risk/benefit profile. CONCLUSION: Therapeutic moderate hypothermia is as effective, or more effective, than most other treatments for ICH. If used for 2-3 days or less there is no evidence that it causes clinically significant adverse events. The lack of consistent evidence that hypothermia improves long-term neurologic outcome should not preclude consideration of its use for the primary treatment of ICH since no other ICP therapy is held to this standard.

Traumatic brain injury research priorities: the Conemaugh International Brain Injury Symposium.

In 2005, an international symposium was convened with over 100 neuroscientists from 13 countries and major research centers to review current research in traumatic brain injury (TBI) and develop a consensus document on research issues and priorities. Four levels of TBI research were the focus of the discussion: basic science, acute care, post-acute neurorehabilitation, and improving quality of life (QOL). Each working group or committee was charged with reviewing current research, discussion and prioritizing future research directions, identifying critical issues that impede research in brain injury, and establishing a research agenda that will drive research over the next five years, leading to significantly improved outcomes and QOL for individuals suffering brain injuries. This symposium was organized at the request of the Congressional Brain Injury Task Force, to follow up on the National Institutes of Health Consensus Conference on TBI as mandated by the TBI ACT of 1996. The goal was to review what progress had been made since the National Institutes of Health (NIH) Consensus Conference, and also to follow up on the 1990's Decade of the Brain Project. The major purpose of the symposium was to provide recommendations to the U.S. Congress on a priority basis for research, treatment, and training in TBI over the next five years.

MRI in Management of Mild TBI/Concussion in the Deployed Setting.

Magnetic resonance imaging (MRI) has specific limitations in theater and has unique requirements for its safe use with patients which require additional technician training and strict adherence to MRI-specific safety protocols. Neuroimaging is recommended for the evaluation of service members with clinical red flags new onset or persistent or worsening symptoms, and individuals whose recovery is not progressing as anticipated. This article is a brief discussion of when MRI is appropriate.

Sex and genetic associations with cerebrospinal fluid dopamine and metabolite production after severe traumatic brain injury.

OBJECT: Dopamine (DA) pathways have been implicated in cognitive deficits after traumatic brain injury (TBI). Both sex and the dopamine transporter (DAT) 3' variable number of tandem repeat polymorphism have been associated with differences in DAT protein density, and DAT protein affects both presynaptic DA release, through reverse transport, and DA reuptake. Catecholamines and associated metabolites are subject to autooxidation, resulting in the formation of reactive oxygen species that may contribute to subsequent oxidative injury. The purpose of this study was to determine associations between factors that affect DAT expression and cerebrospinal fluid (CSF) DA and metabolite levels after severe TBI. METHODS: Sixty-three patients with severe TBI (Glasgow Coma Scale score < or = 8) were evaluated. The patients' genotypes were obtained using previously banked samples of CSF, and serial CSF samples (416 samples) were used to evaluate DA and metabolite levels. High-performance liquid chromatography was used to determine CSF levels of DA, 3,4-dihydroxyphenylacetic acid (DOPAC), and homovanillic acid (HVA) during the first 5 days after injury. Mixed-effects multivariate regression modeling revealed that patients with the DAT 10/10 genotype had higher CSF DA levels than patients with either the DAT 9/9 or DAT 9/10 genotypes (p = 0.009). Females with the DAT 10/10 genotype had higher CSF DA levels than females with the DAT 9/9 or DAT 9/10 genotypes, and sex was associated with higher DOPAC levels (p = 0.004). Inotrope administration also contributed to higher DA levels (p = 0.002). CONCLUSIONS: In addition to systemic administration of DA, inherent factors such as sex and DAT genotype affect post-TBI CSF DA and DA metabolite levels, a phenomenon that may modulate susceptibility to DA-mediated oxidative injury.

The Benefits and Risks of Energy Drinks in Young Adults and Military Service Members.

INTRODUCTION: Energy drinks (EDs) have become an integral part of the young adult, athletic, and military culture. Many athletes are convinced that EDs enhance performance, and service members as well as college students frequently use EDs as stimulants to counter sleep deprivation, or to improve academic performance. However, concerns have been raised by some military leaders about potential adverse effects of EDs. MATERIALS AND METHODS: A needs assessment survey of a convenience sample of military health care providers was conducted and identified EDs as a top knowledge need for those providers working in the area of traumatic brain injury (TBI). The instrument demonstrated high interitem consistency (Cronbach's α > .80). To further explore the state of knowledge on EDs, and to prompt further discussion of ED use and how it may related to military treatment protocols and supporting educational products, we conducted a literature review of English language publications listed in the National Library of Medicine using the search term "energy drinks" and published during the last 5 years to determine what is known about EDs in terms of their potential benefits and health risks. RESULTS: The active ingredients in most EDs are caffeine, and to a lesser extent taurine and sugars. Several reports suggest that the combination of these ingredients is more active than the caffeine alone. Despite the positive attributes of EDs, there are increasing reports of serious and potentially life-threatening side effects. Most recently there also has been a dramatic increase in the use of ED/alcohol combination drinks, and there are preliminary studies that suggest important adverse effects with this combination. A 2013 National Institutes of Health expert workshop concluded that more clinical studies are needed to clearly define the health risks associated with ED use. CONCLUSION: The needs assessment points to a desire for more ED knowledge of health providers working with TBI patients. A few key themes emerged from the exploratory literature review that can be taken into consideration when educating health providers and delivering knowledge-based resources. Adverse effects of EDs are most closely associated with the dose of caffeine consumed. In general, the combination of ED with alcohol should be avoided because the ED can mask the level of intoxication, and the combination may be associated with increased risk-taking behavior. Overall, the risks and benefits of EDs remain controversial and good-quality long-term clinical trials are needed to inform policymaking, regulation, and the development of prevention and treatment resources.

Increased phosphorylation of protein kinase B and related substrates after traumatic brain injury in humans and rats.

Activation of protein kinase B (PKB, also known as Akt) by phosphorylation at serine-473 and threonine-308 promotes cell survival in multiple in vitro and in vivo models where neuronal death is seen, including traumatic brain injury (TBI); however, whether PKB is activated in humans after TBI was heretofore unknown. Activated PKB inhibits apoptogenic factors and is involved in the regulation of several transcription factors. Accordingly, we examined phosphorylation of the PKB signaling pathway in humans as well as rats after TBI using phosphospecific antibodies. Increased phosphorylation of PKB and PKB substrates was detected in injured brain from both humans and rats. In humans, increased phosphorylation of the PKB signaling pathway-related proteins Bad and forkhead transcription factor (FKHR) was detected in patients with TBI versus controls. In rats, increased phosphorylation of FKHR, inhibitor of kappaBalpha, and cyclic adenosine monophosphate responsive element binding protein (CREB) was detected after TBI versus controls. The deoxyribonucleic acid-binding activity of CREB was also enhanced after TBI in rats. Increased phosphorylation of PKB and PKB substrates was identified in neurons and other cell types by immunohistochemistry in both humans and rats. These data show increased phosphorylation of PKB, PKB substrates, and related proteins after both experimental and clinical TBI, suggesting either activation of the PKB signaling pathway or reduced phosphatase activity in both species.

Proteolysis consistent with activation of caspase-7 after severe traumatic brain injury in humans.

The expression and proteolysis of caspase family proteins are involved in the initiation and execution of apoptosis, which has been reported to occur in human and experimental traumatic brain injury (TBI). Caspase-3, -6, and -7 belong to the group of executioner caspases, which are cleaved and activated at the late, irreversible stage of apoptosis. Our previous studies demonstrated roles for caspase-1, -3, and -8 in humans after severe TBI. Here we report expression of caspase-7 mRNA and protein in humans after TBI (n = 16) and control brain-bank tissue (n = 6). Semiquantitative reverse transcription polymerase chain reaction showed no differences between caspase-7 mRNA in TBI patients versus controls (73 +/- 24 vs. 85 +/- 56 relative optical density [ROD], respectively). In contrast, Western blot analysis showed increased pro-caspase-7 in TBI patients versus controls (214 +/- 30 vs. 1 +/- 1 ROD, respectively), as well as an increase in the approximately 20 kD proteolytic fragment in TBI patients versus controls (86 +/- 13 vs. 22 +/- 12 ROD, respectively), consistent with activation of caspase-7 after TBI in humans. Immunohistochemical analysis showed that cells expressing caspase-7 included astrocytes and neurons and possibly other glial cell types and infiltrated inflammatory cells. These data show that caspase-7 and its cleavage product are increased in human brain after TBI in many central nervous system, as well as noncentral nervous system, cell types. Thus, caspase-7 may play a role in the glial and inflammatory responses, and possibly neuronal death, after TBI in humans.

Early Glasgow Outcome Scale scores predict long-term functional outcome in patients with severe traumatic brain injury.

Patients sustaining severe traumatic brain injury (TBI) have variable long-term outcomes. We examined the association between Glasgow Outcome Scale (GOS) assessed at 3 months and long-term outcomes at 12 months after TBI. We studied 159 patients with severe, closed traumatic brain injuries (Glasgow Coma Scale [GCS]

Caspase-8 expression and proteolysis in human brain after severe head injury.

Programmed cell death involves a complex and interrelated cascade of cysteine proteases termed caspases that are synthesized as inactive zymogens, which are proteolytically processed to active enzymes. Caspase-8 is an initiator caspase that becomes activated when Fas death receptor-Fas ligand (FasL) coupling on the cell surface leads to coalescence of a "death complex" perpetuating the programmed cell death cascade. In this study, brain tissue samples removed from adult patients during the surgical management of severe intracranial hypertension after traumatic brain injury (TBI; n=17) were compared with postmortem control brain tissue samples (n=6). Caspase-8 mRNA was measured by semiquantitative reverse transcription and polymerase chain reaction, and caspase-8 protein was examined by Western blot and immunocytochemistry. Fas and FasL were also examined using Western blot. Caspase-8 mRNA and protein were increased in TBI patients vs. controls, and caspase-8 protein was predominately expressed in neurons. Proteolysis of caspase-8 to 20-kDa fragments was seen only in TBI patients. Fas was also increased after TBI vs. control and was associated with relative levels of caspase-8, supporting formation of a death complex. These data identify additional steps in the programmed cell death cascade involving Fas death receptors and caspase-8 after TBI in humans.

Traumatic brain injury in the US military: epidemiology and key clinical and research programs.

Traumatic brain injury (TBI), and particularly concussion, is a major concern for the U.S. Military because of the associated short term disability, long term cognitive and pain symptoms suffered by some, and risk of prolonged or permanent neurologic injury if the Service member incurs a second TBI before full recovery from the first. Concussions were seen more often during the recent conflicts in Afghanistan and Iraq than in prior conflicts, such as the Vietnam War, because of the use of improvised explosive devices that typically caused non-penetrating closed head injury. Since 2000 more than 300,000 Service members were diagnosed with TBI, of which more than 80 % were concussions. Improved TBI screening tools also have identified a higher than expected incidence of concussions occurring in garrison. In this review we summarize current epidemiologic data for TBI in the Military, and describe contemporary Military procedures and strategies for TBI prevention, identification, evaluation, and acute and chronic care. Key TBI clinical research priorities and programs are described, and innovative organizational plans to address future TBI needs are summarized.

The effects of admission alcohol level on cerebral blood flow and outcomes after severe traumatic brain injury.

This study examined the relationship between admission serum alcohol level (ETOH) and cerebral blood flow (CBF) and outcomes in the adult traumatic brain injured (TBI) population. We hypothesized that individuals with ETOH > 100 mg/dL will have decreased blood flow on admission and poorer outcomes. Eighty subjects, age 16-65, with severe TBI (Glasgow Coma Score [GCS] 100 mg/dL at the time of admission after a TBI were associated with a decrease in global CBF. Elevated serum ETOH level at time of injury did not, however, impact outcomes.