Neurocritical care management supported by multimodal brain monitoring after acute brain injury.

OBJECTIVE: To evaluate the association between different intensive care units and levels of brain monitoring with outcomes in acute brain injury. METHODS: Patients with traumatic brain injury and subarachnoid hemorrhage admitted to intensive care units were included. Neurocritical care unit management was compared to general intensive care unit management. Patients managed with multimodal brain monitoring and optimal cerebral perfusion pressure were compared with general management patients. A good outcome was defined as a Glasgow outcome scale score of 4 or 5. RESULTS: Among 389 patients, 237 were admitted to the neurocritical care unit, and 152 were admitted to the general intensive care unit. Neurocritical care unit management patients had a lower risk of poor outcome (OR = 0.228). A subgroup of 69 patients with multimodal brain monitoring (G1) was compared with the remaining patients (G2). In the G1 and G2 groups, 59% versus 23% of patients, respectively, had a good outcome at intensive care unit discharge; 64% versus 31% had a good outcome at 28 days; 76% versus 50% had a good outcome at 3 months (p < 0.001); and 77% versus 58% had a good outcome at 6 months (p = 0.005). When outcomes were adjusted by SAPS II severity score, using good outcome as the dependent variable, the results were as follows: for G1 compared to G2, the OR was 4.607 at intensive care unit discharge (p < 0.001), 4.22 at 28 days (p = 0.001), 3.250 at 3 months (p = 0.001) and 2.529 at 6 months (p = 0.006). Patients with optimal cerebral perfusion pressure management (n = 127) had a better outcome at all points of evaluation. Mortality for those patients was significantly lower at 28 days (p = 0.001), 3 months (p < 0.001) and 6 months (p = 0.001). CONCLUSION: Multimodal brain monitoring with autoregulation and neurocritical care unit management were associated with better outcomes and should be considered after severe acute brain injury.

Therapeutic advances for treating memory impairments in perinatal brain injuries with implications for cerebral palsy: a systematic review and meta-analysis of preclinical studies.

Cerebral palsy (CP) is a neurodevelopmental disorder caused by damage to the immature brain. CP is considered the main cause of physical disability in childhood. Studies have shown that memory function and emotional behaviour are significantly impaired in CP. Current thought is that interventions for neuromotor damaged play a prominent role, but neglects the memory acquisition problems that affect the functioning and quality of life of these children. This systematic review aims to map and analyse pre-clinical interventions used to treat memory formation problems resulting from CP. For this, a search was carried out in the Pubmed, Web of Science, Scopus and Lilacs databases. Then, eligibility, extraction date and evaluation of the methodological quality of the studies were determined. 52 studies were included in this review, and 27 were included in a meta-analysis. Assessing memory performance as a primary outcome, and structural and biochemical changes in the hippocampus as a secondary outcome. CP models were reported to be induced by hypoxia-ischemia, oxygen deprivation and liposaccharide (LPS) exposure, resulting in impairments in the formation of short-term and long-term memory in adult life. A reduction in escape latency and dwell time were observed in the target quadrant as well as an increase in the time needed for the rodents to find the platform in the Morris Water Maze (MWM). Brain injuries during the perinatal period are considered an insult that negatively impacts hippocampus maturation and causes impairment in memory formation in adult life. Some studies reported that regions of the hippocampus such as the dentate gyrus and cornu ammonis 1 were impaired in CP, noting an increase in oxidative stress enzymes and pro-inflammatory cytokines, associated with a reduction in BDNF and neurogenesis levels. These were reported to cause a reduction in the number of neurons and the volume of the hippocampus, in addition to an increase in astrogliosis and apoptosis of neurons and difficulties in forming new memories similar to those that occur in children with CP. Interventions that reduced neuroinflammation and the presence of free radicals were highlighted as a therapy for the memory disturbance present in CP. Preclinical studies registered treatments with oxygen interventions, resveratrol and erythropoietin, which were able to reduce the damage to the hippocampus and promote improvements in memory and behaviour. In the meta-analysis of selected studies, we observed favorable results, through effect size, for the use of oxygen interventions (SDM -6.83 95% CI [-7.91, -5.75], Z = 12.38, p = 0.03; I2 = 71%), erythropoietin (SDM -3.16 95% CI [-4.27, -2.05], Z = 5.58, p = 0.002; I2 = 82%) and resveratrol (SDM -2.42 95% CI [-3.19, - 1.66], Z = 6.21, p = 0.01; I2 = 77%), stimulating plastic responses in the hippocampus and facilitating the memory formation, with these presenting positive effects in general (SDM -2.84 95% CI [-3.10, -2.59], Z = 22.00; p < 0.00001; I2 = 92.9%). These studies demonstrate possible avenues of intervention for memory alterations in experimental models of early brain injuries, highlighting promising interventions that can facilitate the maturation of the hippocampus and memory formation and, consequently, minimize functional problems that arise during development.

Peritoneal dialysis and acute kidney injury in acute brain injury patients.

Acute kidney injury (AKI) is a heterogeneous syndrome with multiple etiologies. It occurs frequently in the neurocritical intensive care unit and is associated with greater morbidity and mortality. In this scenario, AKI alters the kidney-brain axis, exposing patients who receive habitual dialytic management to greater injury. Various therapies have been designed to mitigate this risk. Priority has been placed by KDIGO guidelines on the use of continuous over intermittent acute kidney replacement therapies (AKRT). On this background, continuous therapies have a pathophysiological rationale in patients with acute brain injury. A low-efficiency therapy such as PD and CRRT could achieve optimal clearance control and potentially reduce the risk of secondary brain injury. Therefore, this work will review the evidence on peritoneal dialysis as a continuous AKRT in neurocritical patients, describing its benefits and risks so it may be considered as an option when deciding among available therapeutic options.

Astragaloside IV alleviates stroke-triggered early brain injury by modulating neuroinflammation and ferroptosis via the Nrf2/HO-1 signaling pathway

Purpose: Stroke is an acute cerebrovascular disease. Astragaloside IV (AS-IV) is an active ingredient extracted from Astragalus membranaceus with an established therapeutic effect on central nervous system diseases. This study examined the neuroprotective properties and possible mechanisms of AS-IV in stroke-triggered early brain injury (EBI) in a rat transient middle cerebral artery occlusion (MCAO) model. Methods: The neurological scores and brain water content were analyzed. 2,3,5-triphenyl tetrazolium chloride (TTC) staining was utilized to determine the infarct volume, neuroinflammatory cytokine levels, and ferroptosis-related genes and proteins, and neuronal damage and molecular mechanisms were evaluated by terminal deoxynucleotidyl transferase dutp nickend labeling (TUNEL) staining, western blotting, and real-time polymerase chain reaction. Results: AS-IV administration decreased the infarct volume, brain edema, neurological deficits, and inflammatory cytokines TNF-α, interleukin-1ß (IL-1ß), IL-6, and NF-κB, increased the levels of SLC7A11 and glutathione peroxidase 4 (GPX4), decreased lipid reactive oxygen species (ROS) levels, and prevented neuronal ferroptosis. Meanwhile, AS-IV triggered the Nrf2/HO-1 signaling pathway and alleviated ferroptosis due to the induction of stroke. Conclusion: Hence, the findings of this research illustrate that AS-IV administration can improve delayed ischemic neurological deficits and decrease neuronal death by modulating nuroinflammation and ferroptosis via the Nrf2/HO-1 signaling pathway.

Hypoglycemia in Infants with Hypoxic-Ischemic Encephalopathy Is Associated with Additional Brain Injury and Worse Neurodevelopmental Outcome.

OBJECTIVE: To determine the incidence of hypoglycemia among infants with hypoxic-ischemic encephalopathy (HIE) who received therapeutic hypothermia, and to assess whether infants with hypoglycemia had more brain injury on magnetic resonance imaging (MRI) or differences in neurodevelopmental outcome. STUDY DESIGN: Single-center, retrospective cohort study including infants cooled for HIE. Hypoglycemia (blood glucose <36.0 mg/dL <2 hours and <46.8 mg/dL ≥2 hours after birth) was analyzed in the period before brain MRI. Brain injury was graded using a validated score. Motor and neurocognitive outcomes were assessed at 2 years for all survivors, and 5.5 years for a subset who had reached this age. RESULTS: Of 223 infants analyzed, 79 (35.4%) had hypoglycemia. MRI was performed in 187 infants. Infants with hypoglycemia (n = 65) had higher brain injury scores (P = .018). After adjustment for HIE severity, hypoglycemia remained associated with higher injury scores (3.6 points higher; 95% CI, 0.8-6.4). Hyperglycemia did not affect MRI scores. In survivors at 2 years (n = 154) and 5.5 years (n = 102), a univariable analysis showed lower 2-year motor scores and lower motor and cognitive scores at preschool age in infants with hypoglycemia. After adjustment for HIE severity, infants with hypoglycemia had 9 points lower IQs (P = .023) and higher odds of adverse outcomes at preschool age (3.6; 95% CI, 1.4-9.0). CONCLUSIONS: More than one-third of infants cooled for HIE had hypoglycemia. These infants had a higher degree of brain injury on MRI and lower cognitive function at preschool age. Strategies to avoid hypoglycemia should be optimized in this setting.

Ulinastatin alleviates early brain injury after traumatic brain injury by inhibiting oxidative stress and apoptosis

Purpose: Traumatic brain injury (TBI) remains a major public health problem and cause of death. Ulinastatin (UTI), a serine protease inhibitor, has been reported to have an anti-inflammatory effect and play a role in immunoregulation and organ protection by reducing reactive oxygen species (ROS) production, oxidative stress and inflammation. However, the neuroprotective of UTI in TBI has not been confirmed. Therefore, this study aimed to investigate the neuroprotection and potential molecular mechanisms of UTI in TBI-induced EBI in a C57BL/6 mouse model. Methods: The neurological score and brain water content were evaluated. Enzyme-linked immunosorbent assay was used to detect neuroinflammatory cytokine levels, ROS and malondialdehyde detection to evaluate oxidative stress levels, and TUNEL staining and western blotting to examine neuronal damages and their related mechanisms. Results: Treatment with UTI markedly increased the neurological score; alleviated brain oedema; decreased the inflammatory cytokine tumour necrosis factor a, interleukin-1ß (IL-1ß), IL-6 and nuclear factor kappa B (NF-kB) levels; inhibited oxidative stress; decreased caspase-3 and Bax protein expressions; and increased the Bcl-2 levels, indicating that UTI-mediated inhibition of neuroinflammation, oxidative stress and apoptosis ameliorated neuronal death after TBI. The neuroprotective capacity of UTI is partly dependent on the TLR4/NF-kB/p65 signalling pathway. Conclusions: Therefore, this study reveals that UTI improves neurological outcomes in mice and reduces neuronal death by protecting against neural neuroinflammation, oxidative stress and apoptosis.

Creatine Supplementation and Brain Health.

There is a robust and compelling body of evidence supporting the ergogenic and therapeutic role of creatine supplementation in muscle. Beyond these well-described effects and mechanisms, there is literature to suggest that creatine may also be beneficial to brain health (e.g., cognitive processing, brain function, and recovery from trauma). This is a growing field of research, and the purpose of this short review is to provide an update on the effects of creatine supplementation on brain health in humans. There is a potential for creatine supplementation to improve cognitive processing, especially in conditions characterized by brain creatine deficits, which could be induced by acute stressors (e.g., exercise, sleep deprivation) or chronic, pathologic conditions (e.g., creatine synthesis enzyme deficiencies, mild traumatic brain injury, aging, Alzheimer's disease, depression). Despite this, the optimal creatine protocol able to increase brain creatine levels is still to be determined. Similarly, supplementation studies concomitantly assessing brain creatine and cognitive function are needed. Collectively, data available are promising and future research in the area is warranted.

Effects of bone marrow mononuclear cells on induction of axonal sprouting in cortico-cortical and cortico-striatal pathways in an animal model of cortical ablation.

OBJECTIVES: Many therapies have been proposed in order to investigate the mechanisms of neural repair associated with neurological diseases, including bone marrow mononuclear cells (BMMC) transplantation. However, there is evidence that some encephalic injuries are less responsive to neural repair, such as, for example, cortical ablation. On the other hand, some models of cortical ablation have shown functional recovery after BMMC transplantation. Thus, it is relevant to expand the knowledge of BMMC transplantation-induced neuroplasticity in animal models, considering a promising approach for the rehabilitation of patients with neurological diseases. Using an experimental model of cerebral cortex ablation in adult male Wistar rats, which is known to be poorly responsive to neuroplasticity, the aim of this study was to investigate the effects of BMMC on axonal sprouting in cortico-cortical and cortico-striatal pathways synaptic fields. An anterograde neurotracer was used to evaluate the distribution of axonal fibres. RESULTS: The results showed that BMMC were not able to significantly induce axonal sprouting in the evaluated synaptic fields. Our results reinforced the idea that cortical ablation may be less responsive to neuroplasticity and the beneficial effects of BMMC therapy depend on the particularities of a neural microenvironment intrinsic to a given cortical lesion.

Sepsis: developing new alternatives to reduce neuroinflammation and attenuate brain injury.

Sepsis occurs when a systemic infection induces an uncontrolled inflammatory response that results in generalized organ dysfunction. The exacerbated peripheral inflammation can induce, in turn, neuroinflammation which may result in severe impairment of the central nervous system (CNS). Indeed, the ensuing blood-brain barrier disruption associated with sepsis promotes glial activation and starts a storm of proinflammatory cytokines in the CNS that leads to brain dysfunction in sepsis survivors. Endotoxic shock induced in mice by peripheral injection of lipopolysaccharides closely resembles the peripheral and central inflammation observed in sepsis. In this review, we provide an overview of the neuroinflammatory features in sepsis and of recent progress toward the development of new anti-neuroinflammatory therapies seeking to reduce mortality and morbidity in sepsis survivors.

Healing of brain lesions in sheep recovered from amprolium-induced polioencephalomalacia / Cicatrização das lesões cerebrais em ovinos recuperados de polioencefalomalacia induzida por amprólio

To evaluate the outcome of acute lesions in the brains of sheep that completely clinically recover from acute polioencephalomalacia (PEM), ten sheep were used in this experiment. Eight of those sheep received varying doses of amprolium to induce PEM. Four sheep were treated intramuscularly with 40mg/kg/body weight with thiamine to allow recovery and four sheep were left untreated. Two control sheep did not receive either amprolium or thiamine and were kept along with the other eight sheep for the duration of the experiment. Except for the two drugs, the diet and water source were the same for the ten sheep. Two sheep receiving high daily doses of amprolium and one sheep receiving a lower dose had acute deaths and developed acute brain lesions consisting of neuronal laminar cortical necrosis (red neurons), edema, reactive astrocytes, swollen endothelial cells and gitter cells infiltration. Four sheep that recovered from lower doses of amprolium-induced PEM after being treated with thiamine and another one that recovered spontaneously were euthanatized six months after clinical recovery and had gross changes consisting of segmental absence of cortical tissue. Histologically these segmental cortex-deprived areas corresponded to quasi-empty spaces where only vessels and gitter cells existed. No changes were seen in the brains of the two control sheep.(AU)

Para avaliar a evolução das lesões agudas no cérebro de ovinos que se recuperam clinicamente de polioencefalomalacia aguda (PEM), dez ovinos foram usados neste experimento. Oito desses ovinos receberam doses variáveis de amprólio para induzir PEM. Quatro ovinos foram tratados intramuscularmente com 40mg/kg/peso corporal de tiamina para permitir a recuperação, e outros quatro ficaram sem tratamento. Dois ovinos controles não receberam amprólio nem tiamina e foram mantidos com os outros oito ovinos durante a duração do experimento. Exceto pelas duas drogas, a dieta e a fonte de água eram as mesmas para os dez ovinos. Dois ovinos que receberam doses diárias altas de amprólio, e um que recebeu doses menores, tiveram mortes agudas e desenvolveram lesões cerebrais constituídas por necrose neuronal laminar cortical (neurônios vermelhos), edema, tumefação de células endoteliais, astrócitos reativos, tumefação de células endoteliais e infiltração por células gitter. Quatro ovinos que se recuperam da PEM induzida por amprólio, após tratamento com tiamina, e outro que se recuperou espontaneamente, permaneceram clinicamente normais e foram submetidos a eutanásia seis meses após a recuperação clínica. Na necropsia, apresentavam alterações macroscópicas caracterizadas por ausência segmentar de tecido corticocerebral. Histologicamente, essas áreas privadas de tecido cortical consistiam de espaços praticamente vazios onde apenas vasos e células gitter eram vistos. Não foram encontradas alterações no encéfalo das duas ovelhas controle.(AU)

Healing of brain lesions in sheep recovered from amprolium-induced polioencephalomalacia / Cicatrização das lesões cerebrais em ovinos recuperados de polioencefalomalacia induzida por amprólio

To evaluate the outcome of acute lesions in the brains of sheep that completely clinically recover from acute polioencephalomalacia (PEM), ten sheep were used in this experiment. Eight of those sheep received varying doses of amprolium to induce PEM. Four sheep were treated intramuscularly with 40mg/kg/body weight with thiamine to allow recovery and four sheep were left untreated. Two control sheep did not receive either amprolium or thiamine and were kept along with the other eight sheep for the duration of the experiment. Except for the two drugs, the diet and water source were the same for the ten sheep. Two sheep receiving high daily doses of amprolium and one sheep receiving a lower dose had acute deaths and developed acute brain lesions consisting of neuronal laminar cortical necrosis (red neurons), edema, reactive astrocytes, swollen endothelial cells and gitter cells infiltration. Four sheep that recovered from lower doses of amprolium-induced PEM after being treated with thiamine and another one that recovered spontaneously were euthanatized six months after clinical recovery and had gross changes consisting of segmental absence of cortical tissue. Histologically these segmental cortex-deprived areas corresponded to quasi-empty spaces where only vessels and gitter cells existed. No changes were seen in the brains of the two control sheep.(AU)

Para avaliar a evolução das lesões agudas no cérebro de ovinos que se recuperam clinicamente de polioencefalomalacia aguda (PEM), dez ovinos foram usados neste experimento. Oito desses ovinos receberam doses variáveis de amprólio para induzir PEM. Quatro ovinos foram tratados intramuscularmente com 40mg/kg/peso corporal de tiamina para permitir a recuperação, e outros quatro ficaram sem tratamento. Dois ovinos controles não receberam amprólio nem tiamina e foram mantidos com os outros oito ovinos durante a duração do experimento. Exceto pelas duas drogas, a dieta e a fonte de água eram as mesmas para os dez ovinos. Dois ovinos que receberam doses diárias altas de amprólio, e um que recebeu doses menores, tiveram mortes agudas e desenvolveram lesões cerebrais constituídas por necrose neuronal laminar cortical (neurônios vermelhos), edema, tumefação de células endoteliais, astrócitos reativos, tumefação de células endoteliais e infiltração por células gitter. Quatro ovinos que se recuperam da PEM induzida por amprólio, após tratamento com tiamina, e outro que se recuperou espontaneamente, permaneceram clinicamente normais e foram submetidos a eutanásia seis meses após a recuperação clínica. Na necropsia, apresentavam alterações macroscópicas caracterizadas por ausência segmentar de tecido corticocerebral. Histologicamente, essas áreas privadas de tecido cortical consistiam de espaços praticamente vazios onde apenas vasos e células gitter eram vistos. Não foram encontradas alterações no encéfalo das duas ovelhas controle.(AU)

Cortical Spreading Depression and Ischemia in Neurocritical Patients.

Spreading depolarization in cerebral cortex is associated with swelling of neurons, distortion of dendritic spines, massive ion translocation with a large change of the slow electrical potential, and silencing of brain electrical activity. The term spreading depression represents a wave of spontaneous activity of the electrocorticogram that propagates through contiguous cerebral gray matter at a characteristic velocity. Spreading depression is a consequence of cortical spreading depolarization. Therefore, spreading depolarization is not always accompanied by spreading depression and the terms are not synonymous.

Acute Perinatal Sentinel Events, Neonatal Brain Injury Pattern, and Outcome of Infants Undergoing a Trial of Hypothermia for Neonatal Hypoxic-Ischemic Encephalopathy.

Infants with perinatal sentinel events in the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network Hypothermia for Encephalopathy Trial had more basal ganglia and thalamus lesions on brain magnetic resonance imaging but similar neurodevelopmental outcomes at 18 months of age than infants without perinatal sentinel events. Outcomes correlated with the neonatal magnetic resonance imaging findings. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00005772.

Immunomodulation after ischemic stroke: potential mechanisms and implications for therapy.

Brain injuries are often associated with intensive care admissions, and carry high morbidity and mortality rates. Ischemic stroke is one of the most frequent causes of injury to the central nervous system. It is now increasingly clear that human stroke causes multi-organ systemic disease. Brain inflammation may lead to opposing local and systemic effects. Suppression of systemic immunity by the nervous system could protect the brain from additional inflammatory damage; however, it may increase the susceptibility to infection. Pneumonia and urinary tract infection are the most common complications occurring in patients after stroke. The mechanisms involved in lung-brain interactions are still unknown, but some studies have suggested that inhibition of the cholinergic anti-inflammatory pathway and release of glucocorticoids, catecholamines, and damage-associated molecular patterns (DAMPs) are among the pathophysiological mechanisms involved in communication from the ischemic brain to the lungs after stroke. This review describes the modifications in local and systemic immunity that occur after stroke, outlines mechanisms of stroke-induced immunosuppression and their role in pneumonia, and highlights potential therapeutic targets to reduce post-stroke complications. Despite significant advances towards a better understanding of the pathophysiology of ischemic stroke-induced immunosuppression and stroke-associated pneumonia (SAP) in recent years, many unanswered questions remain. The true incidence and outcomes of SAP, especially in intensive care unit settings, have yet to be determined, as has the full extent of stroke-induced immunosuppression and its clinical implications.

Mild hypothermia attenuates post-resuscitation brain injury through a V-ATPase mechanism in a rat model of cardiac arrest.

Although therapeutic hypothermia is an effective treatment for post-resuscitation brain injury after cardiac arrest (CA), the underlying mechanism remains unclear. Vacuolar H(+)-ATPase (V-ATPase) plays a key role in cellular adaption to a hypoxic environment. This study sought to evaluate the effect of mild hypothermia on V-ATPase and its involvement in neuroprotection after CA. Male Sprague-Dawley rats were subjected to a 6-min CA, resuscitated successfully, and then assigned to either the normothermia (NT) group or the hypothermia (HT) group. Rats were further divided into 2 subgroups based on the time of euthanasia, either 3 or 24 h after CA (NT-3 h, HT-3 h; NT-24 h, HT-24 h). Mild hypothermia was induced following CA and maintained at 33°C for 2 h. Neurologic deficit scores were used to determine the status of neurological function. Brain specimens were analyzed by TUNEL assay, western blotting, and immunohistochemistry. V-ATPase activity was estimated by subtracting total ATP hydrolysis from the bafilomycin-sensitive activity. Mild hypothermia improved the neurological outcome (HT-24 h: 34.3 ± 16.4 vs NT-24 h: 50.3 ± 17.4) and significantly decreased neurocyte apoptosis 24 h after resuscitation. Mild hypothermia significantly increased V0a1 compared to NT-3 h; V0a1 expression was associated with a decrease in the cleaved caspase 3 expression. These findings suggested that mild hypothermia inhibits CA-induced apoptosis in the hippocampus, which may be associated with reduced V-ATPase impairment. These data provide new insights into the protective effects of hypothermia in vivo.