Thermoregulate, autoregulate and ventilate: brain-directed critical care for pediatric cardiac arrest.

PURPOSE OF REVIEW: Cardiac arrest in childhood is associated with a high risk for mortality and poor long-term functional outcome. This review discusses the current evidence for neuroprotective therapies and goals for postarrest care in the context of the pathophysiology of hypoxic-ischemic injury, modalities for neurologic prognostication in these children and potential future monitoring paradigms for maximizing cerebral perfusion in the postarrest period. RECENT FINDINGS: The recent publication of the in-hospital and out-of-hospital Therapeutic Hypothermia After Cardiac Arrest trials demonstrated a lack of statistically significant benefit for the use of postarrest therapeutic hypothermia. As a result, targeted normothermic temperature management has become standard of care. Continuous electroencephalographic monitoring during the acute postarrest period provides useful additional data for neurologic prognostication, in addition to its value for detection of seizures. Ongoing research into noninvasive monitoring of cerebrovascular autoregulation has the potential to individualize blood pressure goals in the postarrest period, maximizing cerebral perfusion in these patients. SUMMARY: Therapeutic strategies after cardiac arrest seek to maximize cerebral perfusion while mitigating the effects of secondary brain injury and loss of autoregulation. Future research into new monitoring strategies and better long-term outcome measures may allow more precise targeting of therapies to these goals.

Methylmalonic and propionic acidemias: clinical management update.

PURPOSE OF REVIEW: Recent clinical studies and management guidelines for the treatment of the organic acidopathies methylmalonic acidemia (MMA) and propionic acidemia address the scope of interventions to maximize health and quality of life. Unfortunately, these disorders continue to cause significant morbidity and mortality due to acute and chronic systemic and end-organ injury. RECENT FINDINGS: Dietary management with medical foods has been a mainstay of therapy for decades, yet well controlled patients can manifest growth, development, cardiac, ophthalmological, renal, and neurological complications. Patients with organic acidopathies suffer metabolic brain injury that targets specific regions of the basal ganglia in a distinctive pattern, and these injuries may occur even with optimal management during metabolic stress. Liver transplantation has improved quality of life and metabolic stability, yet transplantation in this population does not entirely prevent brain injury or the development of optic neuropathy and cardiac disease. SUMMARY: Management guidelines should identify necessary screening for patients with methylmalonic acidemia and propionic acidemia, and improve anticipatory management of progressive end-organ disease. Liver transplantation improves overall metabolic control, but injury to nonregenerative tissues may not be mitigated. Continued use of medical foods in these patients requires prospective studies to demonstrate evidence of benefit in a controlled manner.

Is Heading in Youth Soccer Dangerous Play?

BACKGROUND: Soccer is among the most popular youth sports with over 3 million youth players registered in the U.S. Soccer is unique in that players intentionally use their head to strike the ball, leading to concerns that heading could cause acute or chronic brain injury, especially in the immature brains of children. METHODS: Pub Med search without date restriction was conducted in November 2014 and August 2015 using the terms soccer and concussion, heading and concussion, and youth soccer and concussion. 310 articles were identified and reviewed for applicable content specifically relating to youth athletes, heading, and/or acute or chronic brain injury from soccer. RESULTS: Soccer is a low-risk sport for catastrophic head injury, but concussions are relatively common and heading often plays a role. At all levels of play, concussions are more likely to occur in the act of heading than with other facets of the game. While concussion from heading the ball without other contact to the head appears rare in adult players, some data suggests children are more susceptible to concussion from heading primarily in game situations. Contributing factors include biomechanical forces, less developed technique, and the immature brain's susceptibility to injury. CONCLUSIONS: There is no evidence that heading in youth soccer causes any permanent brain injury and there is limited evidence that heading in youth soccer can cause concussion. A reasonable approach based on U.S. Youth Soccer recommendations is to teach heading after age 10 in controlled settings, and heading in games should be delayed until skill acquisition and physical maturity allow the youth player to head correctly with confidence.

Determining brain fitness to fight: Has the time come?

Professional boxing is associated with a risk of chronic neurological injury, with up to 20-50% of former boxers exhibiting symptoms of chronic brain injury. Chronic traumatic brain injury encompasses a spectrum of disorders that are associated with long-term consequences of brain injury and remains the most difficult safety challenge in modern-day boxing. Despite these concerns, traditional guidelines used for return to sport participation after concussion are inconsistently applied in boxing. Furthermore, few athletic commissions require either formal consultation with a neurological specialist (i.e. neurologist, neurosurgeon, or neuropsychologist) or formal neuropsychological testing prior to return to fight. In order to protect the health of boxers and maintain the long-term viability of a sport associated with exposure to repetitive head trauma, we propose a set of specific requirements for brain safety that all state athletic commissions would implement.

Ice Hockey Summit II: zero tolerance for head hits and fighting.

OBJECTIVE: To present currently known basic science and on-ice influences of sport-related concussion (SRC) in hockey, building on the Ice Hockey Summit I action plan (2011) to reduce SRC. METHODS: The prior summit proceedings included an action plan intended to reduce SRC. As such, the proceedings from Summit I served as a point of departure, for the science and discussion held during Summit II (Mayo Clinic, Rochester MN, October 2013). Summit II focused on (1) Basic Science of Concussions in Ice Hockey: Taking Science Forward; (2) Acute and Chronic Concussion Care: Making a Difference; (3) Preventing Concussions via Behavior, Rules, Education and Measuring Effectiveness; (4) Updates in Equipment: their Relationship to Industry Standards; and (5) Policies and Plans at State, National and Federal Levels to reduce SRC. Action strategies derived from the presentations and discussion described in these sectors were subsequently voted on for purposes of prioritization. The following proceedings include knowledge and research shared by invited faculty, many of whom are health care providers and clinical investigators. RESULTS: The Summit II evidence-based action plan emphasizes the rapidly evolving scientific content of hockey SRC. It includes the most highly prioritized strategies voted on for implementation to decrease concussion. CONCLUSIONS: The highest priority action items identified from the Summit includes the following: (1) eliminate head hits from all levels of ice hockey, (2) change body-checking policies, and (3) eliminate fighting in all amateur and professional hockey.

Rugby contact and collisions--clinical challenges of a global game.

Rugby Union (rugby) is a sport that evolved from and resembles other forms of football but is unique in many respects and presents distinctive clinical challenges. This article discusses those aspects of rugby that are different from other sports and those injuries that have specific significance to the game as a result of it being a global collision sport with an increasing focus on serious injury prevention. Injury screening and intervention programs, neck injuries, rugby's contribution to evolving concussion protocols, contact and travel-related illnesses, and rugby's drug intervention protocols are discussed.

The National Football League and chronic traumatic encephalopathy: legal implications.

The growing awareness of chronic traumatic encephalopathy (CTE) has the potential to change the public perception and on-field rules of the National Football League (NFL). More than 3,000 ex-NFL players or their relatives are engaged in litigation alleging that the NFL failed to acknowledge and address the neuropsychiatric risks associated with brain injuries that result from playing in the NFL. This article explores the intersection between the medical and legal aspects of CTE in the NFL from a forensic psychiatry perspective.

New pharmacological approaches in infants with hypoxic-ischemic encephalopathy.

New knowledge of the pathophysiology and evolution of hypoxic-ischemic brain injuries has made feasible interventions to improve clinical outcomes for newborns surviving birth asphyxia. Brain injury following hypoxic-ischemic insult is a complex process evolving over hours to days, which provides a unique window of opportunity for neuroprotective treatment interventions. The specific pathologic processes preceding the onset of irreversible cerebral injury appear to be a combination of several mechanisms that are variable according to the severity and duration of the insult and to biochemical modifications in the brain. Advances in neuroimaging, brain monitoring techniques, and tissue biomarkers have improved the ability to diagnose, monitor, and care for newborn infants with neonatal encephalopathy, as well as to predict their outcome. The role of oxidative stress in newborn morbidity with respect to the higher risk of free radical damage in these babies is growing. However, challenges remain in early identification of infants at risk for neonatal encephalopathy, determination of timing and extent of hypoxic-ischemic brain injury, as well as optimal management and treatment duration. Potential neuroprotective strategies targeting different pathways leading to neuronal cell death in response to hypoxic-ischemic insult have been investigated: hypothermia, erythropoietin, iminobiotin, deferioxamine, magnesium, allopurinol, xenon, melatonin and statins. Hypothermia is currently the only recognized beneficial therapy. However, many infants still develop significant adverse outcomes. It is becoming evident that the association of moderate hypothermia with neuroprotective drugs may enhance the outcome. By virtue of their pleiotropic effects without toxic effects, melatonin and statins may act at different levels of the multiple mechanisms responsible for the progression of the neurodegenerative process and represent promising neuroprotectants, alone or as additional adjunctive therapy, for reducing brain injury and its long-term sequelae in infants. More clinical studies are needed to clarify the role of these potential neuroprotective drugs.

Huanglian-Jie-Du-Tang extract protects against chronic brain injury after focal cerebral ischemia via hypoxia-inducible-factor-1α-regulated vascular endothelial growth factor signaling in mice.

Huanglian-Jie-Du-Tang (HJDT) is a traditional Chinese herbal formula which is widely used clinically. In this study, we investigated the effects of an aqueous (HJDTaq) and an ethanolic (HJDTet) extract of HJDT on chronic brain injury after focal cerebral ischemia in mice. The ischemia was induced by occlusion of the right middle cerebral artery for 30 min. HJDTaq (4 g/kg) and HJDTet (200, 400, 800 mg/kg) were orally administered for 21 d from day 7 before ischemia to day 14 after ischemia. The survival rate decreased to less than 50% at 35 d after ischemia. HJDTet at 400 mg/kg increased the survival rate. HJDTaq (4 g/kg) and HJDTet (400, 800 mg/kg) significantly attenuated the neurological dysfunction, brain atrophy and infarct volume after ischemia. There were few cells positive for CD31, hypoxia-inducible-factor-1α (HIF-1α), vascular endothelial growth factor (VEGF) and Flk-1 in the sham control. After ischemia, the number increased. HJDTaq (4 g/kg) and HJDTet (400 or 800 mg/kg) further increased the numbers of CD31, HIF-1α, VEGF and Flk-1-positive cells in the ischemic hemisphere. We conclude that HJDTaq and HJDTet have neuroprotective effects on chronic brain injury after focal cerebral ischemia and lead to accelerated angiogenesis by HIF-1α-regulated VEGF signaling.

Postconditioning by mild hypoxic exposures reduces rat brain injury caused by severe hypoxia.

A potent neuroprotective effect of ischemic postconditioning has previously been described using cerebral artery occlusion but this is not a practical therapeutic option. The present study has been performed to determine whether postconditioning by mild episodes of hypobaric hypoxia (hypoxic postconditioning, HP) can reduce post-hypoxic brain injury in rats. Male Wistar rats were submitted to severe hypobaric hypoxia (180 Torr, 3 h) followed by HP (360 Torr, 2 h, 3 trials spaced at 24 h) starting either 3h (early HP) or 24 h (delayed HP) after severe hypoxia. The structural and functional brain injury was assessed by a complex of histological techniques, behavioral methods, and by testing the functions of the hypothalamic-pituitary-adrenal axis (HPA). It was found that early and delayed HP considerably attenuated post-hypoxic injury, reducing pyknosis, hyperchromatosis, and interstitial brain edema, as well as the rates of neuronal loss in hippocampus and neocortex. Delayed HP produced prominent anxiolytic effect on rat behavior, preventing development of post-hypoxic anxiety. Both modes of HP had beneficial effect on the functioning of HPA, but only delayed HP normalized completely the baseline HPA activity and its reactivity to stress. The results obtained demonstrate that postconditioning by using repetitive episodes of mild hypobaric hypoxia may provide a powerful neuroprotective procedure that can be easily adopted for clinical practice and recommended as a research tool for identification of endogenous mechanisms involved in post-ischemic neuroprotection.

Prevention of neonatal oxygen-induced brain damage by reduction of intrinsic apoptosis.

Within the last decade, it became clear that oxygen contributes to the pathogenesis of neonatal brain damage, leading to neurocognitive impairment of prematurely born infants in later life. Recently, we have identified a critical role for receptor-mediated neuronal apoptosis in the immature rodent brain. However, the contribution of the intrinsic apoptotic pathway accompanied by activation of caspase-2 under hyperoxic conditions in the neonatal brain still remains elusive. Inhibition of caspases appears a promising strategy for neuroprotection. In order to assess the influence of specific caspases on the developing brain, we applied a recently developed pentapeptide-based group II caspase inhibitor (5-(2,6-difluoro-phenoxy)-3(R,S)-(2(S)-(2(S)-(3-methoxycarbonyl-2(S)-(3-methyl-2(S)-((quinoline-2-carbonyl)-amino)-butyrylamino)propionylamino)3-methylbutyrylamino)propionylamino)-4-oxo-pentanoic acid methyl ester; TRP601). Here, we report that elevated oxygen (hyperoxia) triggers a marked increase in active caspase-2 expression, resulting in an initiation of the intrinsic apoptotic pathway with upregulation of key proteins, namely, cytochrome c, apoptosis protease-activating factor-1, and the caspase-independent protein apoptosis-inducing factor, whereas BH3-interacting domain death agonist and the anti-apoptotic protein B-cell lymphoma-2 are downregulated. These results coincide with an upregulation of caspase-3 activity and marked neurodegeneration. However, single treatment with TRP601 at the beginning of hyperoxia reversed the detrimental effects in this model. Hyperoxia-mediated neurodegeneration is supported by intrinsic apoptosis, suggesting that the development of highly selective caspase inhibitors will represent a potential useful therapeutic strategy in prematurely born infants.

Montelukast, a cysteinyl leukotriene receptor-1 antagonist, attenuates chronic brain injury after focal cerebral ischaemia in mice and rats.

OBJECTIVES: Previously we demonstrated the neuroprotective effect of montelukast, a cysteinyl leukotriene receptor-1 (CysLT(1) ) antagonist, on acute brain injury after focal cerebral ischaemia in mice. In this study, we have determined its effect on chronic brain injury after focal cerebral ischaemia in mice and rats. METHODS: After transient focal cerebral ischaemia was induced by middle cerebral artery occlusion, montelukast was intraperitoneally injected in mice or orally administered to rats for five days. Behavioural dysfunction, brain infarct volume, brain atrophy and neuron loss were determined to evaluate brain lesions. KEY FINDINGS: Montelukast (0.1 mg/kg) attenuated behavioural dysfunction, brain infarct volume, brain atrophy and neuron loss in mice, which was similar to pranlukast, another CysLT(1) receptor antagonist. Oral montelukast (0.5 mg/kg) was effective in rats and was more effective than edaravone, a free radical scavenger. CONCLUSION: Montelukast protected mice and rats against chronic brain injury after focal cerebral ischaemia, supporting the therapeutic potential of CysLT(1) receptor antagonists.

Sports concussion and the risk of chronic neurological impairment.

Intense recent media focus on long-term outcomes from sports concussion has highlighted concerns on both cognitive deterioration and mental health issues, such as depression and suicide. At this time, the scientific evidence to support these views is limited, with only a handful of cases thus far reported. Based on the literature on this topic that extends back over 50 years, it is clear that only a small percentage of athletes suffer such sequelae presumably due to recurrent concussive or subconcussive head impacts. At this stage, determining which athletes are at future risk is not possible; however, following existing concussion guidelines (eg, Zurich guidelines) is likely to be the safest option based on current evidence.

Future advances and areas of future focus in the treatment of sport-related concussion.

The occurrence and management of sports concussion provokes more debate and concern than virtually all other sports injuries combined. In the past 3 decades, clinicians have gone from mostly anecdotal strategies to an international consensus-based approach and the early evolution of evidence-based practice. There is increasing engagement by mainstream neuroscientists in this field, which had previously been dominated by sports team physicians. However, the interchange has largely taken place in the media rather than through scientific journals. Legislators have proposed regulatory measures that restrict medical management of concussion in ways that apply to no other medical condition. This paper examines some of the key areas that are likely to be the focus of research in the next few years.

A screening, prevention, and restoration model for saving the injured brain in intensive care unit survivors.

We face a profound and emerging public health problem in the form of acute and chronic brain dysfunction. This affects both young and elderly intensive care unit survivors and is altering the landscape of society. Two-thirds of intensive care unit patients develop delirium, and this is associated with longer stays, increased costs, and excess mortality. In addition, over half of intensive care unit survivors suffer a dementia-like illness that impacts their physical and cognitive functional abilities and which appears to be related to the duration of their intensive care unit delirium. A new paradigm of how intensivists handle the brain is required. We propose a three-step approach to address this emerging epidemic, which includes Screening, Prevention, and Restoration of brain function (SPR). Screening combines risk factor identification and delirium assessment using validated instruments. Prevention of acute and chronic brain dysfunction requires implementation of a core model of care that combines evidence-based practices: awakening and breathing, coordination with target-based sedation, delirium monitoring, and exercise/early mobility (ABCDE). Restoration introduces strategies of ongoing screening and treatment for intensive care unit survivors at high risk of ongoing brain dysfunction. This practical system applying many evidence-based concepts incorporates personalized medicine, systems-based practice, and continuing research and development toward improving acute and chronic cognitive outcomes.