Setting Of Acute Brain Injury Research Articles

The State of the Field of Pediatric Multimodality Neuromonitoring.

The use of multimodal neuromonitoring in pediatrics is in its infancy relative to adult neurocritical care. Multimodal neuromonitoring encompasses the amalgamation of information from multiple individual neuromonitoring devices to gain a more comprehensive understanding of the condition of the brain. It allows for adaptation to the changing state of the brain throughout various stages of injury with potential to individualize and optimize therapies. Here we provide an overview of multimodal neuromonitoring in pediatric neurocritical care and its potential application in the future. Multimodal neuromonitoring devices are key to the process of multimodal neuromonitoring, allowing for visualization of data trends over time and ideally improving the ability of clinicians to identify patterns and find meaning in the immense volume of data now encountered in the care of critically ill patients at the bedside. Clinical use in pediatrics requires more study to determine best practices and impact on patient outcomes. Potential uses include guidance for targets of physiological parameters in the setting of acute brain injury, neuroprotection for patients at high risk for brain injury, and neuroprognostication. Implementing multimodal neuromonitoring in pediatric patients involves interprofessional collaboration with the development of a simultaneous comprehensive program to support the use of multimodal neuromonitoring while maintaining the fundamental principles of the delivery of neurocritical care at the bedside. The possible benefits of multimodal neuromonitoring are immense and have great potential to advance the field of pediatric neurocritical care and the health of critically ill children.

What Does Coma Mean? Implications for Shared Decision Making in Acute Brain Injury

Insufficient attention has been devoted to shared decision-making (SDM) in the setting of acute brain injury (ABI). Communication occupies a central role that has been highlighted in recent research on SDM with brain injured patients, with respect to "the impact of specific clinician words and expressions". In this investigation, we seek to understand lay public understandings of the term "coma." Qualitative analysis of lay interpretations of the term "cComa" using modified open coding of a free-text response question at the end of a survey exploring public attitudes in the context of hypothetical ABI. Respondents (n= 511) were drawn from a convenience sample using Amazon Mechanical Turk. This analysis focuses on respondents' free-text responses to the question: "When doctors say a patient is in a coma, what does that mean?" We analyzed 206 unique responses in order to derive emergent lay conceptualizations of coma. The following 4 themes emerged in how respondents understood coma: (1) State descriptive. (2) Marker of injury severity. (3) As in distinction (or lack thereof) from brain death or sleep. (4) Covert consciousness. For each concept, we discuss its salient elements and offer representative quotes. This study provides preliminary qualitative evidence of lay public understandings of the neurologic term "coma". These findings can have implications for surrogate/family-clinician communications. While a physician may intend "coma" to convey a technical description, a family member or surrogate may interpret it as a very different activity (e.g., prognostication, emotional signaling), setting the stage for miscommunication.

Adrenergic inhibition facilitates normalization of extracellular potassium after cortical spreading depolarization

Cortical spreading depolarization (CSD) is a propagating wave of tissue depolarization characterized by a large increase of extracellular potassium concentration and prolonged subsequent electrical silencing of neurons. Waves of CSD arise spontaneously in various acute neurological settings, including migraine aura and ischemic stroke. Recently, we have reported that pan-inhibition of adrenergic receptors (AdRs) facilitates the normalization of extracellular potassium after acute photothrombotic stroke in mice. Here, we have extended that mechanistic study to ask whether AdR antagonists also modify the dynamics of KCl-induced CSD and post-CSD recovery in vivo. Spontaneous neural activity and KCl-induced CSD were visualized by cortex-wide transcranial Ca2+ imaging in G-CaMP7 transgenic mice. AdR antagonism decreased the recurrence of CSD waves and accelerated the post-CSD recovery of neural activity. Two-photon imaging revealed that astrocytes exhibited aberrant Ca2+ signaling after passage of the CSD wave. This astrocytic Ca2+ activity was diminished by the AdR antagonists. Furthermore, AdR pan-antagonism facilitated the normalization of the extracellular potassium level after CSD, which paralleled the recovery of neural activity. These observations add support to the proposal that neuroprotective effects of AdR pan-antagonism arise from accelerated normalization of extracellular K+ levels in the setting of acute brain injury.

Peritoneal Dialysis in the Setting of Acute Brain Injury, an Underappreciated Modality

Peritoneal Dialysis in the Setting of Acute Brain Injury, an Underappreciated Modality

Evidence-Based Management of External Ventricular Drains

The optimal management of external ventricular drains (EVD) in the setting of acute brain injury remains controversial. Therefore, we sought to determine whether there are optimal management approaches based on the current evidence. We identified 2 recent retrospective studies on the management of EVDs after subarachnoid hemorrhage (SAH) which showed conflicting results. A multicenter survey revealed discordance between existing evidence from randomized trials and actual practice. A prospective study in a post-traumatic brain injury (TBI) population demonstrated the benefit of EVDs but did not determine the optimal management of the EVD itself. The recent CLEAR trials have suggested that specific positioning of the EVD in the setting of intracerebral hemorrhage with intraventricular hemorrhage may be a promising approach to improve blood clearance. Evidence on the optimal management of EVDs remains limited. Additional multicenter prospective studies are critically needed to guide approaches to the management of the EVD.

Diagnostic Potential of Neural Exosome Cargo as Biomarkers for Acute Brain Injury.

ObjectiveNeuronal exosomes purified from peripheral blood samples have been proposed as diagnostic tool in the setting of acute brain injury but never tested clinically. We hypothesized that exosome protein biomarkers would change over time following acute hypoxic brain injury and would predict response to therapy.MethodsSynaptopodin (SYNPO), an actin‐associated protein present in postsynaptic spines, was evaluated as a potential biomarker as well as: synaptophysin, neuron‐specific enolase, and mitochondrial cytochrome c oxidase. A secondary analysis was performed on neonatal samples collected at 8, 10, and 14 h after the initiation of therapeutic‐controlled hypothermia for acute hypoxic–ischemic encephalopathy (n = 14). Neuronal exosomes were purified from serum and protein levels were quantified using standard ELISA methods. The primary study outcomes were length of stay (LOS), discharge on seizure medication (DCMED), and composite neuroimaging score (NIS).ResultsThe slope of change in neuronal exosome SYNPO between 8 and 14 h appeared to be the most promising biomarker for all three clinical study outcomes. SYNPO was highly correlated with LOS (−0.91, P < 0.001). SYNPO increased in 6/8 without DCMED and was worse or neutral in 5/5 with DCMED (P = 0.02). All four neonates with an abnormal NIS had neutral or decreasing SYNPO (P = 0.055). Other candidate biomarkers were not associated with outcomes.InterpretationThis report provides the first clinical evidence that neural exosomes turn over rapidly enough in the peripheral circulation to be used as a “troponin‐like” test following acute brain injury. Optimal sampling and biomarkers likely vary with type of brain injury.

Role of Interleukin-10 in Acute Brain Injuries.

Interleukin-10 (IL-10) is an important anti-inflammatory cytokine expressed in response to brain injury, where it facilitates the resolution of inflammatory cascades, which if prolonged causes secondary brain damage. Here, we comprehensively review the current knowledge regarding the role of IL-10 in modulating outcomes following acute brain injury, including traumatic brain injury (TBI) and the various stroke subtypes. The vascular endothelium is closely tied to the pathophysiology of these neurological disorders and research has demonstrated clear vascular endothelial protective properties for IL-10. In vitro and in vivo models of ischemic stroke have convincingly directly and indirectly shown IL-10-mediated neuroprotection; although clinically, the role of IL-10 in predicting risk and outcomes is less clear. Comparatively, conclusive studies investigating the contribution of IL-10 in subarachnoid hemorrhage are lacking. Weak indirect evidence supporting the protective role of IL-10 in preclinical models of intracerebral hemorrhage exists; however, in the limited number of clinical studies, higher IL-10 levels seen post-ictus have been associated with worse outcomes. Similarly, preclinical TBI models have suggested a neuroprotective role for IL-10; although, controversy exists among the several clinical studies. In summary, while IL-10 is consistently elevated following acute brain injury, the effect of IL-10 appears to be pathology dependent, and preclinical and clinical studies often paradoxically yield opposite results. The pronounced and potent effects of IL-10 in the resolution of inflammation and inconsistency in the literature regarding the contribution of IL-10 in the setting of acute brain injury warrant further rigorously controlled and targeted investigation.

Partial Brain Tissue Oxygen Levels Predict Arrhythmia and Prognosis in Patients With Brain Injury.

The objective of this study was to examine the clinical determinants of incidence and prognosis of arrhythmias in the setting of acute brain injury. Acute brain injury is known to cause electrocardiographic abnormalities and cardiac arrhythmias. The relation between partial brain tissue oxygen (PBTO) and intracranial pressure (ICP) with arrhythmia incidence and prognosis remains unknown. Consecutive patients with acute brain injury and intracranial bleed admitted to the neurosurgical intensive care unit were enrolled in the study. Baseline characteristics [demographics, medical history, etiology of brain injury, Glasgow Coma Scale (GCS) score, blood pressure, and respiratory rate] were documented. Patient's telemetry recordings were reviewed for daily mean heart rates and arrhythmias. If arrhythmia was noted, PBTO levels at the beginning of arrhythmia, ICP, brain tissue temperature, and outcomes were recorded. A total of 106 subjects (53% men, age 39 ± 18 years, 65 traumatic and 41 nontraumatic brain injuries) were studied. Overall, 62% of subjects developed a total of 241 arrhythmia episodes. Ventricular arrhythmias were associated with significantly higher daily mean heart rates, low PBTO levels, and low GCS scores, whereas atrial arrhythmias were associated with lower daily mean heart rates, normal PBTO levels, and higher GCS and ICP. Three or more episodes of arrhythmia predicted worse outcomes, including mortality (P = 0.001). In patients with acute brain injury, poor PBTO levels are associated with higher incidence of ventricular tachyarrhythmias. In contrast, atrial tachyarrhythmias occur in patients with normal PBTO levels and higher ICP. Incidence of ventricular arrhythmia in those with poor PBTO is associated with increased mortality.

Timing Is Everything in Protecting the Heart and Lungs in a “Sympathetic Storm”

Timing Is Everything in Protecting the Heart and Lungs in a “Sympathetic Storm”

Anaemia on Admission is Associated with More Severe Intracerebral Haemorrhage and Worse Outcomes

Lower haemoglobin levels may impair cerebral oxygen delivery and threaten tissue viability in the setting of acute brain injury. Few studies have examined the association between haemoglobin levels and outcomes after spontaneous intracerebral haemorrhage. We evaluated whether anaemia on admission was associated with greater intracerebral haemorrhage severity and worse outcome. Consecutive patients with spontaneous intracerebral haemorrhage were analyzed from the Registry of the Canadian Stroke Network. Admission haemoglobin was related to stroke severity (using the Canadian Neurological Scale), modified Rankin score at discharge, and one-year mortality. Adjustment was made for potential confounders including age, gender, medical history, warfarin use, glucose, creatinine, blood pressure, and intraventricular haemorrhage. Two thousand four hundred six patients with intracerebral haemorrhage were studied of whom 23% had anaemia (haemoglobin <120 g/l) on admission, including 4% with haemoglobin <100 g/l. Patients with anaemia were more likely to have severe neurological deficits at presentation [haemoglobin ≤ 100 g/l, adjusted odds ratio 4.04 (95% confidence interval 2.39, 6.84); haemoglobin 101-120 g/l, adjusted odds ratio 1.93 (95% confidence interval 1.43, 2.59), both P < 0.0001]. In nonanticoagulated patients, severe anaemia was also associated with poor outcome (modified Rankin score 4-6) at discharge [haemoglobin ≤ 100 g/l, adjusted odds ratio 2.42 (95% confidence interval 1.07-5.47), P = 0.034] and increased mortality at one-year [haemoglobin ≤ 100 g/l, adjusted hazard ratio 1.73 (95% confidence interval 1.22-2.45), P = 0.002]. Anaemia on admission is associated with greater intracerebral haemorrhage severity and worse outcomes. The utility of transfusion remains unclear in this setting.

Lacosamide Improves Outcome in a Murine Model of Traumatic Brain Injury

Use of antiepileptic drugs (AED's) is common in the neurocritical care setting. However, there remains a great deal of controversy regarding the optimal agent. Studies associating the prophylactic use of AED's with poor outcomes are heavily biased by the prevalent use of phenytoin, an agent highly associated with deleterious effects. In the current study, we evaluate lacosamide for neuroprotective properties in a murine model of closed head injury. Mice were subjected to moderate closed head injury using a pneumatic impactor, and then treated with either low-dose (6 mg/kg) or high-dose (30 mg/kg) lacosamide or vehicle at 30 min post-injury, and twice daily for 3 days after injury. Motor and cognitive functional assessments were performed following injury using rotarod and Morris Water Maze, respectively. Neuronal injury and microglial activation were measured by flourojade-B, NeuN, and F4/80 staining at 1 and 7 days post-injury. Timm's staining was also performed to assess lacosamide effects on mossy fiber axonal sprouting. To evaluate possible mechanisms of lacosamide effects on the inflammatory response to injury, an RNA expression array was used to evaluate for alterations in differential gene expression patterns in injured mice following lacosamide or vehicle treatments. High-dose lacosamide was associated with improved functional outcome on both the rotarod and Morris Water Maze. High-dose lacosamide was also associated with a reduction of neuronal injury at 24 h post-injury. However, the reduction in neuronal loss observed early did not result in greater neuronal density at 31 days post-injury based on unbiased stereology of NeuN staining. High-dose lacosamide was also associated with a significant reduction in microglial activation at 7 days post-injury. The therapeutic effects of lacosamide are associated with a delay in injury-related changes in RNA expression of a subset of inflammatory mediator genes typically seen at 24 h post-injury. Administration of lacosamide improves functional performance, and reduces histological evidence of acute neuronal injury and neuroinflammation in a murine model of closed head injury. Lacosamide effects appear to be mediated via a reduction or delay in the acute inflammatory response to injury. Prior clinical and animal studies have found antiepileptic treatment following injury to be detrimental, though these studies are biased by the common use of older medications such as phenytoin. Our current results as well as prior work on levetiracetam suggest the newer AED's may be beneficial in the setting of acute brain injury.

Cerebral Autoregulation and Acute Ischemic Stroke

Cerebral autoregulation tightly controls blood flow to the brain by coupling cerebral metabolic demand to cerebral perfusion. In the setting of acute brain injury, such as that caused by ischemic stroke, the continued precise control of cerebral blood flow (CBF) is vital to prevent further injury. Chronic as well as acute elevations in blood pressure are frequently associated with stroke, therefore, understanding the physiological response of the brain to the treatment of hypertension is clinically important. Physiological data obtained in patients with acute ischemic stroke provide no clear evidence that there are alterations in the intrinsic autoregulatory capacity of cerebral blood vessels, except perhaps in infarcted tissue. While it is likely safe to modestly reduce blood pressure by 10-15 mm Hg in most patients with acute ischemic stroke, to date, there are no controlled trial data to indicate that reducing blood pressure is beneficial. There may be subgroups, such as those with persistent large vessel occlusion, large infarcts with edema causing increased intracranial pressure or local mass effect, or chronic hypertension, in which blood pressure reduction may lead to impaired cerebral perfusion in noninfarcted tissue.

Statins Improve Outcome in Murine Models of Intracranial Hemorrhage and Traumatic Brain Injury: A Translational Approach

Traumatic brain injury (TBI) and intracerebral hemorrhage (ICH) are leading causes of neurological mortality and disability in the U.S. However, therapeutic options are limited and clinical management remains largely supportive. HMG-CoA reductase inhibitors (statins) have pleiotropic mechanisms of action in the setting of acute brain injury, and have been demonstrated to improve outcomes in preclinical models of ICH and TBI. To facilitate translation to clinical practice, we now characterize the optimal statin and dosing paradigm in murine models of ICH and TBI. In a preclinical model of TBI, mice received vehicle, simvastatin, and rosuvastatin at doses of 1 mg/kg and 5 mg/kg for 5 days after the impact. Immunohistochemistry, differential gene expression, and functional outcomes (rotarod and Morris water maze testing) were assessed to gauge treatment response. Following TBI, administration of rosuvastatin 1 mg/kg was associated with the greatest improvement in functional outcomes. Rosuvastatin treatment was associated with histological evidence of reduced neuronal degeneration at 24 h post-TBI, reduced microgliosis at day 7 post-TBI, and preserved neuronal density in the CA3 region at 35 days post-injury. Administration of rosuvastatin following TBI was also associated with downregulation of inflammatory gene expression in the brain. Following ICH, treatment with simvastatin 1 mg/kg was associated with the greatest improvement in functional outcomes, an effect that was independent of hemorrhage volume. Clinically relevant models of acute brain injury may be used to define variables such as optimal statin and dosing paradigms to facilitate the rational design of pilot clinical trials.

Incidence of retinal hemorrhages in abusive head trauma: Comparison of cases of perpetrator confession, identifiable perpetrator without confession and no identifiable perpetrator

Purpose: Retinal hemorrhages (RH) are a cardinal feature of abusive head trauma (AHT) where characteristic hemorrhages in the setting of acute brain injury should be considered nonaccidental trauma until proven otherwise. We compared retinal hemorrhages of those cases where a perpetrator confessed to the act to those where a perpetrator was identified through other means. We also analyzed cases where a single perpetrator could not be identified.

Evaluation and management of retinal hemorrhages in infants with and without abusive head trauma

Extensive intraocular hemorrhage in young infants in the setting of acute brain injury and in the absence of a history of severe accidental trauma or underlying medical cause must be considered to be nonaccidental injury until otherwise proven. In the absence of any obvious explanation, the presence of any retinal hemorrhage should raise the possibility of abusive head trauma in the differential diagnosis and perhaps lead to such testing as skeletal radiography and neuroimaging, consultation with a child abuse specialist, as well as workup for other relevant systemic conditions. Physicians who treat infants and children are mandated to report suspected child abuse to child welfare agencies for investigation, and ophthalmologists who encounter children with ophthalmic manifestations of abuse need to ensure that the proper steps are taken to protect their patients from the potential for further harm. Ascertainment of abusive head trauma is critical to prevent a potentially fatal recurrence.

The role of interleukin-1 in neuroinflammation and Alzheimer disease: an evolving perspective

Elevation of the proinflammatory cytokine Interleukin-1 (IL-1) is an integral part of the local tissue reaction to central nervous system (CNS) insult. The discovery of increased IL-1 levels in patients following acute injury and in chronic neurodegenerative disease laid the foundation for two decades of research that has provided important details regarding IL-1's biology and function in the CNS. IL-1 elevation is now recognized as a critical component of the brain's patterned response to insults, termed neuroinflammation, and of leukocyte recruitment to the CNS. These processes are believed to underlie IL-1's function in the setting of acute brain injury, where it has been ascribed potential roles in repair as well as in exacerbation of damage. Explorations of IL-1's role in chronic neurodegenerative disease have mainly focused on Alzheimer disease (AD), where indirect evidence has implicated it in disease pathogenesis. However, recent observations in animal models challenge earlier assumptions that IL-1 elevation and resulting neuroinflammatory processes play a purely detrimental role in AD, and prompt a need for new characterizations of IL-1 function. Potentially adaptive functions of IL-1 elevation in AD warrant further mechanistic studies, and provide evidence that enhancement of these effects may help to alleviate the pathologic burden of disease.

A Prospective, Observational Clinical Trial of Fever Reduction to Reduce Systemic Oxygen Consumption in the Setting of Acute Brain Injury

Fever after acute brain injury appears to be a detrimental factor, associated with impaired neurological outcomes. This study assessed physiological changes in systemic oxygen consumption (VO2) during cutaneous cooling after severe brain injury. This prospective, observational, clinical study evaluated ten, critically ill, brain-injured patients requiring mechanical ventilation with a core body temperature of greater or equal to 38 degrees C. Febrile patients failing to defervesce after acetaminophen underwent indirect calorimetry for a 1-hour baseline period followed by a 4 h cooling period. The Arctic Sun(R) Temperature Management System (Medivance) directed core temperature to a goal of 36 degrees C. The patients had a mean age of 32 years (95% CI 23, 40), Glasgow Coma Scale of 6 (95% CI 5,7), and APACHE 2 score of 19 (95% CI 15, 22), with 8 of 10 patients suffering traumatic brain injuries. The baseline 1-h core temperature was significantly reduced from 38.6 degrees +/- 0.9 to 36.3 degrees +/- 1.2 degrees C (P < 0.0001) over 4 h. Two cohorts were identified based upon the presence or absence of shivering. Within the non-shivering cohort, systemic VO2 was significantly reduced from 415 +/- 123 to 308 +/- 115 ml/min (-27 +/- 18%) (P < 0.05). In contrast, those with shivering showed no significant reduction in VO2, despite significantly decreasing core temperature. The overall percentage change of VCO2 correlated with VO2 (r (2) = 0.91). Fever reduction in acute brain injury appears to significantly reduce systemic VO2, but is highly dependent on shivering control.

Tissue plasminogen activator

Tissue-type plasminogen activator (tPA) is a serine protease that cleaves plasminogen into active plasmin. In plasma, the primary function of plasmin is the digestion of fibrin, and therefore, tPA is used as a thrombolytic agent for acute treatment of ischemic stroke. However, apart from its fibrinolytic action, tPA is widely distributed in the CNS1 and involved in mechanisms of synaptic regulation, synaptic plasticity, and neural injury.2,3 These extravascular effects of tPA have to be taken into account when treating patients with ischemic stroke with this agent because there is experimental evidence that tPA administered parenterally has access to both normal and injured brain parenchyma.4,5 Therefore, there is considerable interest in developing drugs that may neutralize the neurotoxic extravascular effects of tPA. Neuroserpin is a serine protease inhibitor that specifically inhibits the actions of tPA in the CNS.6 The interactions between tPA and neuroserpin may be important not only in the setting of acute injury but also in neurodegenerative disorders. Mutations of the neuroserpin gene are linked to familial encephalopathy with neuroserpin inclusion bodies (FENIB),7,8 and neuroserpin has a protective effect on a genetic mouse model of motor neuron disease.9 The focus of this review is on the effects of tPA on synaptic transmission and plasticity, its potentially deleterious effects in the setting of acute brain injury, and the genetic disorders where tPA–neuroserpin interactions may have a pathogenic role. Several reviews comprehensively cover these topics.2,3,6,8 Tissue-type plasminogen activator is widely expressed in neurons and glial cells of the human CNS, including the neocortex, hippocampus, hypothalamus, thalamus, cerebellum, pontine nuclei, medulla, and sympathetic ganglia.1 There is in vitro evidence that tPA is released from neurons and glial cells and has a major role in synaptic plasticity3 (figure and table). Tissue plasminogen activator is …

Levetiracetam use in critically ill patients

Levetiracetam (LEV) is used in the setting of acute brain injury for seizure treatment or prophylaxis but its safety and efficacy in this setting is unknown. We retrospectively analyzed the patterns of use and safety/efficacy of LEV in 379 patients treated in the neuroscience intensive care unit (NSICU). We extracted from the charts clinical data including diagnosis, AED therapy before and during stay in the NSICU, complications of treatment, length of stay, and clinical outcomes (improvement, Glasgow Coma Scale, and death). We analyzed the data using binary and ordered (multi-category) logistic regression. Overall, our findings are that phenytoin used prior to the NSICU admission was frequently replaced with LEV monotherapy (P < 0.001). Patients treated with LEV monotherapy when compared to other AEDs had lower complication rates and shorter NSICU stays. Older patients and patients with brain tumors or strokes were preferentially treated with LEV for prevention and/or management of seizures (all P < or = 0.014). The results of this study suggest that LEV is a frequently used AED in the setting of acute brain injury and that it may be a desirable alternative to phenytoin. Prospective studies evaluating the long-term safety, efficacy and outcomes of LEV in this setting are indicated.