Improvement In Neurological Outcome Research Articles

Effect of selenium on early outcomes after cardiopulmonary resuscitation : Apreliminary report from aretrospective data evaluation.

Administration of selenium, atrace element with antioxidative properties, has been shown to be beneficial in critically ill patients. In this retrospective study, we analyzed the influence of selenium treatment on the outcome of patients after cardiopulmonary resuscitation (CPR) following cardiac arrest. We retrospectively analyzed selenium plasma levels, neurological performance by Cerebral Performance Categories (CPC), and survival to discharge of 28resuscitated patients receiving selenium treatment of any cause24, 48, or 72 h after CPR. All patients received a1000 µg selenium bolus, followed by a1000 µg continuous intravenous infusion during a24 h period. Results were compared to matched controls of resuscitated patients without selenium administration within the first 72 h after CPR. There were clearly distinct time courses of selenium plasma levels between the selenium and the control groups, and between the selenium groups depending on the timepoint of selenium administration after cardiac arrest. Patients receiving selenium within the first 48 h-and especially those with selenium administration within the first 24 h after CPR-showed significantly better neurological outcome, reflected by CPC, and significantly higher survival compared to controls. This small observational study gives an indication of apossible improvement in neurological outcome and survival rate with early selenium treatment in patients after CPR.

Effect of Cord Blood Magnesium Level at Birth on Non-neurologic Neonatal Outcomes.

We examined the effects of magnesium sulfate on non-neurologic neonatal outcomes with respect to cord blood magnesium level. We conducted a secondary analysis of the Maternal-Fetal Medicine Units Beneficial Effects of Antenatal Magnesium (MFMU BEAM) trial comparing the upper and lower quintiles of cord blood magnesium level. Outcomes included cerebral palsy (CP), necrotizing enterocolitis (NEC), retinopathy of prematurity (ROP), bronchopulmonary dysplasia (BPD), and assessments of mental and motor disability. Logistic regression was used to estimate adjusted odds ratios (aORs) of each outcome, controlling for gestational age (GA), birth weight, and treatment group (TG). A total of 1,254 women of the 2,444 included in the BEAM trial had cord blood magnesium levels recorded. GA and birth weight were lower and TG was more common in the upper quintile cohort (p < 0.001). Neonates in the upper quintile were more likely to have severe NEC (OR, 2.41, 95% confidence interval [CI]: 1.11-5.24), ROP (OR, 1.65, 95% CI: 1.05-2.59), and BPD (OR, 1.70, 95% CI: 1.04-2.73). Adjustment for covariates demonstrated no difference in the NEC, ROP, and BPD rates, although there was a decrease in rates of mental disability index < 70 which was not seen in the unadjusted analysis (aOR, 0.49, 95% CI: 0.25-0.99). Higher cord blood magnesium levels do not appear to have adverse non-neurologic effects on the neonate and may demonstrate improvement in neurologic outcomes.

Association Between Neurological Outcomes Related to Aneurysmal Subarachnoid Hemorrhage and Onsite Access to Neurointerventional Radiology

An onsite access to neurointerventional radiology (NIR) may be useful for managing patients with aneurysmal subarachnoid hemorrhage (aSAH) after the aneurysm-securing procedure. We aimed to assess the association between neurological outcomes related to aSAH and onsite access to NIR service. This was a sequential period study of 47 patients with aSAH admitted consecutively during the pre-NIR period (January 2010 to June 2012) compared with 81 patients with aSAH admitted consecutively during the post-NIR period (January 2013 to June 2015) at an academic tertiary referral intensive care unit (ICU). The primary end point was the incidence of poor neurological outcome, defined as modified Rankin scale of ≥3 at 6 months from ictus. Secondary outcomes included incidence of symptomatic vasospasm (SV) and length of stay in ICU/hospital. The primary end point was observed in 18 of 47 (38%) patients during the pre-NIR period versus 25 of 81 (31%) patients during the post-NIR period (P= 0.39). The post-NIR period did not have an independent impact on neurological outcomes (adjusted odds ratio= 0.8, 95% confidence interval 0.3-2.1; P= 0.66). Of the patients who developed SV, 10 of 47 (21%) were during the pre-NIR period versus 33 of 81 (41%) during the post-NIR period (P= 0.02). The post-NIR period and higher Fisher grade were independent predictors of SV. Patients with SV had similar outcomes, but with longer stay in ICU during the post-NIR period compared with the pre-NIR period. Among patients with aSAH, the post-NIR period was associated with more frequent detection of SV, more endovascular procedures, longer hospital stay, but with no appreciable improvement in neurological outcomes either overall or in the subset of patients with SV. Australian New Zealand Clinical Trials Registry ACTRN12616000201471.

Does Erythropoietin monotherapy reduce mortality or moderate/severe disability in neonates with hypoxic ischaemic encephalopathy?

Commentary on: Malla RR, Asimi R, Teli MA, Shaheen F, Bhat MA. Erythropoietin monotherapy in perinatal asphyxia with moderate to severe encephalopathy: a randomized placebo-controlled trial. Journal of Perinatology 2017; 37: 596-601. PMID 28277490. Erythropoietin (EPO) works by a number of mechanisms that gives it neuroprotective properties including decreasing neuronal apoptosis in the acute phase and enhancing angiogenesis and neurogenesis for long-term brain healing 1. Malla et al. 2 demonstrate improved neurologic outcomes in patients treated with EPO monotherapy vs placebo when treating moderate or severe hypoxic ischaemic encephalopathy (HIE). A study carried out in China by Zhu et al. 3 comparing EPO vs placebo, also without adjunctive therapeutic hypothermia (TH), showed similar results. Importantly, these studies showed a significant improvement in neurologic outcome in patients with moderate but not severe encephalopathy. There was also no difference in mortality between the placebo and EPO groups. This differs from trials with TH, the current standard of care in most resource-rich areas, which show a similar reduction in combined mortality and morbidity, but also demonstrate a reduction in mortality [RR–0.75 (95% CI: 0.64, 0.88) [Table 1.2, reference (4)] and disability [RR–0.77 (95% CI: 0.63, 0.94) [Table 1.3, reference (4)], when stratified by moderate or severe encephalopathy (data not shown) (4). These differences could be attributed to the larger sample size of patients in the Cochrane review 4 compared to the single-center study 2 and are certainly reflected in the forest plots when looking at individual trials 4. In settings where TH is widely available, there is significant interest in the potential benefits of EPO as an adjunct therapy to TH. A phase I trial by Wu et al. 5 showed that a presumably effective dosing regimen of EPO could be safely given to neonates undergoing TH for HIE. In a phase II trial, Wu et al. 6 showed that infants treated with EPO as an adjunct to TH had less MRI brain injury and improved motor outcomes at 1 year of age. Currently, there are three phase III clinical trials underway (HEAL, PAEAN and Neurepo) comparing mortality and neurodevelopmental disability in term infants with HIE treated with EPO+ TH vs TH alone 7. These may reaffirm the safety of EPO as adjunct therapy to TH and substantiate evidence that it improves neurologic outcome. The number needed to treat (NNT) to prevent the composite measure of death or moderate or severe disability in this EPO monotherapy study was four 2, which is lower than most trials using TH alone, with an NNT of 7–9 1; however, the number of patients studied to date is far fewer. There has never been a head to head trial comparing EPO monotherapy vs TH. Given the findings of Malla et al. 2, is it an investigation worth considering given the resource intensity associated with TH compared to EPO monotherapy? Perhaps more importantly, would this ever be ethically feasible given the lack of clinical equipoise for the proven effectiveness of TH – although TH as compared to placebo has not been studied in the developing world either. Therefore, if the addition of EPO as an adjunct to TH in the current phase three trials fails to show a benefit, there may be an opportunity to ask this question again. The more challenging issue will be if adjunct EPO therapy does show incremental benefit compared to placebo, does that close the door on a head to head EPO vs TH? The use of simulation models may help to tease out some of the incremental cost-benefit challenges and potentially lay groundwork for a head to head trial. Careful consideration, however, must be given to the benefits of TH beyond neuroprotection that EPO may not offer (i.e. cardiovascular, gastrointestinal system, etc.). https://ebneo.org/2017/12/does-erythropoietin-monotherapy-reduce-mortality-or-moderatesevere-disability-in-neonates-with-hypoxic-ischemic-encephalopathy/ None. No relevant conflict of interests to declare.

Traumatic optic neuropathy: Surgical intervention improves vision and color perception

The most common cause of traumatic optic neuropathy (TON) is indirect injury to the optic nerve, which is thought to be the result of transmitted shock from an orbital impact to the intracanalicular portion of optic nerve. Direct TON can result from penetrating injury or from bony fragments in the optic canal or orbit piercing the optic nerve. Orbital hemorrhage and optic nerve sheath hematoma can also cause TON by direct compression. There may be optic nerve avulsion and transection also. Trauma to the optic nerve rarely improves vision with best of the management. The diagnosis of TON is made clinically based on history and ophthalmic signs along with neurological investigations. The management of indirect optic nerve injury is controversial. Experimental studies of optic nerve injury have employed Corticosteroid Randomization After Significant Head injury study, National Acute Spinal Cord Injury Study (NASCIS 2 and 3) and optic canal depression surgery. Most of the therapeutic regimens have been extrapolated from the NASCIS II, which showed a statistically significant improvement in neurologic outcome (motor and sensory) in a subgroup analysis of acute spinal cord injury patients receiving a methylprednisolone 30 mg/kg bolus within 8 h of injury, followed by 5.4 mg/kg/h for 23 h, but sometimes have high death rates and other complications. Based on the studies, good results can be obtained if interventions are made within 8 h of incident and observation thereafter.

Erythropoietin therapy after out-of-hospital cardiac arrest: A systematic review and meta-analysis.

AIMTo assess safety and efficacy of early erythropoietin (Epo) administration in patients with out-of-hospital cardiac arrest (OHCA).METHODSA systematic literature search was performed using PubMed, MEDLINE, EMBASE, EBSCO, CINAHL, Web of Science and Cochrane databases, of all studies published from the inception through October 10, 2016. Inclusion criteria included: (1) Adult humans with OHCA and successful sustained return of spontaneous circulation; and (2) studies including mortality/brain death, acute thrombotic events as their end points. Primary efficacy outcome was “brain death or Cerebral Performance Category (CPC) score of 5”. Secondary outcomes were “CPC score 1, and 2-4”, “overall thrombotic events” and “acute coronary stent thrombosis”.RESULTSWe analyzed a total of 606 participants (n = 276 received Epo and n = 330 with standard of care alone) who experienced OHCA enrolled in 3 clinical trials. No significant difference was observed between the Epo and no Epo group in brain death or CPC score 5 (OR = 0.77; 95%CI: 0.42-1.39), CPC score 1 (OR = 1.16, 95%CI: 0.82-1.64), and CPC score 2-4 (OR = 0.77, 95%CI: 0.44-1.36). Epo group was associated with increased thrombotic complications (OR = 2.41, 95%CI: 1.26-4.62) and acute coronary stent thrombosis (OR = 8.16, 95%CI: 1.39-47.99). No publication bias was observed.CONCLUSIONOur study demonstrates no improvement in neurological outcomes and increased incidence of thrombotic events and acute coronary stent thrombosis in OHCA patients who were treated with Epo in addition to standard therapy.

Baicalin Attenuates Blood-Brain Barrier Disruption and Hemorrhagic Transformation and Improves Neurological Outcome in Ischemic Stroke Rats with Delayed t-PA Treatment: Involvement of ONOO--MMP-9 Pathway.

Tissue plasminogen activator (t-PA) has a restrictive therapeutic window within 4.5h after ischemic stroke with the risk of hemorrhagic transformation (HT) and neurotoxicity when it is used beyond the time window. In the present study, we tested the hypothesis that baicalin, an active compound of medicinal plant, could attenuate HT in cerebral ischemia stroke with delayed t-PA treatment. Male Sprague-Dawley rats were subjected to middle cerebral artery occlusion (MCAO) for 4.5h and then continuously received t-PA infusion (10mg/kg) for 0.5h and followed by 19-h reperfusion. Baicalin (50, 100, 150mg/kg) was administrated via femoral vein at 4.5h after MCAO cerebral ischemia. Delayed t-PA infusion significantly increased the mortality rate, induced HT, blood-brain barrier (BBB) damage, and apoptotic cell death in the ischemic brains and exacerbated neurological outcomes in cerebral ischemia-reperfusion rats at 24h after MCAO cerebral ischemia. Co-treatment of baicalin significantly reduced the mortality rates, ameliorated the t-PA-mediated BBB disruption and HT. Furthermore, baicalin showed to directly scavenge peroxynitrite and inhibit MMP-9 expression and activity in the ischemic brains with the delayed t-PA treatment. Baicalin had no effect on the t-PA fibrinolytic function indicated by t-PA activity assay. Taken together, baicalin could attenuate t-PA-mediated HT and improve the outcomes of ischemic stroke treatment possibly via inhibiting peroxynitrite-mediated MMP-9 activation.

Resveratrol Attenuates Neurodegeneration and Improves Neurological Outcomes after Intracerebral Hemorrhage in Mice.

Intracerebral hemorrhage (ICH) is a devastating type of stroke with a substantial public health impact. Currently, there is no effective treatment for ICH. The purpose of the study was to evaluate whether the post-injury administration of Resveratrol confers neuroprotection in a pre-clinical model of ICH. To this end, ICH was induced in adult male CD1 mice by collagenase injection method. Resveratrol (10 mg/kg) or vehicle was administered at 30 min post-induction of ICH and the neurobehavioral outcome, neurodegeneration, cerebral edema, hematoma resolution and neuroinflammation were assessed. The Resveratrol treatment significantly attenuated acute neurological deficits, neurodegeneration and cerebral edema after ICH in comparison to vehicle treated controls. Further, Resveratrol treated mice exhibited improved hematoma resolution with a concomitant reduction in the expression of proinflammatory cytokine, IL-1β after ICH. Altogether, the data suggest the efficacy of post-injury administration of Resveratrol in improving acute neurological function after ICH.

Age-Dependent Effects of ALK5 Inhibition and Mechanism of Neuroprotection in Neonatal Hypoxic-Ischemic Brain Injury

Neonatal encephalopathy due to hypoxic-ischemic (HI) brain injury triggers a wave of neuroinflammatory events attributed to causing the progressive degeneration and functional deficits seen weeks after the initial insult. In a recent set of studies, we evaluated the therapeutic efficacy of a small molecule antagonist for ALK5 (activin-like kinase 5 ), TGF-β receptor in a rat model of moderate perinatal HI and found significant improvements in neurologic outcomes. Here, we have extended those studies to evaluate the efficacy of delayed TGF-β receptor antagonism on postnatal day (P) 6 and P9 HI rat pups with and without hypothermia. The ALK5 receptor antagonist SB505124 was administered systemically by osmotic pump beginning 3 days following HI. Extending our earlier data set that showed protection of the hippocampus in P6 pups treated with SB505124, these animals sustained less damage to their hippocampi and had improved performance on the Morris water maze (MWM) when tested on P60 versus vehicle-treated HI animals. By contrast, SB505124 did not improve sensorimotor deficits and exacerbated hippocampal and thalamic volume loss when administered 3 days after HI to P9 pups. SB505124-treated rats injured on P9 tended to perform worse than their vehicle-treated counterparts on MWM, and SB505124 treatment did not preserve hippocampal or thalamic neurons in P9 pups when combined with hypothermia. To elucidate the mechanism whereby ALK5 inhibition reduced neuronal death in the P6 HI model, we assessed levels of autophagy markers in neurons of the neocortex, hippocampus, and thalamus, and in the subcortical white matter, and found that SB505124 increased numbers of autophagosomes and levels of lipidated LC3 (light chain 3), a key protein known to mediate autophagy. Altogether, our results demonstrate that there is a dynamic switch in the CNS response to TGF-β₁ that occurs around P9 in rats where TGF-β signaling inhibition worsens functional outcomes. This response is similar to the outcome of antagonizing TGF-β signaling in adult stroke and other CNS disease models. We conclude that attenuating TGF-β₁ signaling will likely be an effective treatment for HI-related encephalopathy in moderately preterm infants, offering protection of the neocortex, hippocampus, and thalamus with enhanced cerebral autophagy contributing to the decrease in the extent of progressive neuronal cell death.

Meta-Analysis of Therapeutic Hypothermia for Traumatic Brain Injury in Adult and Pediatric Patients.

Therapeutic hypothermia has been used to attenuate the effects of traumatic brain injuries. However, the required degree of hypothermia, length of its use, and its timing are uncertain. We undertook a comprehensive meta-analysis to quantify benefits of hypothermia therapy for traumatic brain injuries in adults and children by analyzing mortality rates, neurologic outcomes, and adverse effects. Electronic databases PubMed, Google Scholar, Web of Science, Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov and manual searches of studies were conducted for relevant publications up until February 2016. Forty-one studies in adults (n = 3,109; age range, 18-81 yr) and eight studies in children (n = 454; age range, 3 mo to 18 yr) met eligibility criteria. Baseline patient characteristics, enrollment time, methodology of cooling, target temperature, duration of hypothermia, and rewarming protocols were extracted. Risk ratios with 95% CIs were calculated. Compared with adults who were kept normothermic, those who underwent therapeutic hypothermia were associated with 18% reduction in mortality (risk ratio, 0.82; 95% CI, 0.70-0.96; p = 0.01) and a 35% improvement in neurologic outcome (risk ratio, 1.35; 95% CI, 1.18-1.54; p < 0.00001). The optimal management strategy for adult patients included cooling patients to a minimum of 33°C for 72 hours, followed by spontaneous, natural rewarming. In contrast, adverse outcomes were observed in children who underwent hypothermic treatment with a 66% increase in mortality (risk ratio, 1.66; 95% CI, 1.06-2.59; p = 0.03) and a marginal deterioration of neurologic outcome (risk ratio, 0.90; 95% CI, 0.80-1.01; p = 0.06). Therapeutic hypothermia is likely a beneficial treatment following traumatic brain injuries in adults but cannot be recommended in children.

Selective Brain Hypothermia Mitigates Brain Damage and Improves Neurological Outcome after Post-Traumatic Decompressive Craniectomy in Mice.

Hypothermia and decompressive craniectomy (DC) have been considered as treatment for traumatic brain injury. The present study investigates whether selective brain hypothermia added to craniectomy could improve neurological outcome after brain trauma. Male CD-1 mice were assigned into the following groups: sham; DC; closed head injury (CHI); CHI followed by craniectomy (CHI+DC); and CHI+DC followed by focal hypothermia (CHI+DC+H). At 24 h post-trauma, animals were subjected to Neurological Severity Score (NSS) test and Beam Balance Score test. At the same time point, magnetic resonance imaging using a 9.4 Tesla scanner and subsequent volumetric evaluation of edema and contusion were performed. Thereafter, the animals were sacrificed and subjected to histopathological analysis. According to NSS, there was a significant impairment among all the groups subjected to trauma. Animals with both trauma and craniectomy performed significantly worse than animals with craniectomy alone. This deleterious effect disappeared when additional hypothermia was applied. BBS was significantly worse in the CHI and CHI+DC groups, but not in the CHI+DC+H group, compared to the sham animals. Edema and contusion volumes were significantly increased in CHI+DC animals, but not in the CHI+DC+H group, compared to the DC group. Histopathological analysis showed that neuronal loss and contusional blossoming could be attenuated by application of selective brain hypothermia. Selective brain cooling applied post-trauma and craniectomy improved neurological function and reduced structural damage and may be therefore an alternative to complication-burdened systemic hypothermia. Clinical studies are recommended in order to explore the potential of this treatment.

Posterior approaches for symptomatic metastatic spinal cord compression.

Surgical interventions for spinal metastasis are commonly performed for mechanical stabilization, pain relief, preservation of neurological function, and local tumor reduction. Although multiple surgical approaches can be used for the treatment of metastatic spinal lesions, posterior approaches are commonly performed. In this study, the role of posterior surgical procedures in the treatment of spinal metastases was reviewed, including posterior laminectomy with and without instrumentation for stabilization, transpedicular corpectomy, and costotransversectomy. A review of the literature from 1980 to 2015 was performed using Medline, as was a review of the bibliographies of articles meeting preset inclusion criteria, to identify studies on the role of these posterior approaches among adults with spinal metastasis. Thirty-four articles were ultimately analyzed, including 1 randomized controlled trial, 6 prospective cohort studies, and 27 retrospective case reports and/or series. Some of the reviewed articles had Level II evidence indicating that laminectomy with stabilization can be recommended for improvement in neurological outcome and reduction of pain in selected patients. However, the use of laminectomy alone should be carefully considered. Additionally, transpedicular corpectomy and costotransversectomy can be recommended with the expectation of improving neurological outcomes and reducing pain in properly selected patients with spinal metastases. With improvements in the treatment paradigms for patients with spinal metastasis, as well as survival, surgical therapy will continue to play an important role in the management of spinal metastasis. While this review presents a window into determining the utility of posterior approaches, future prospective studies will provide essential data to better define the roles of the various options now available to surgeons in treating spinal metastases.

Neuroprotection by Estrogen and Progesterone in Traumatic Brain Injury and Spinal Cord Injury.

In recent years there has been a growing body of clinical and laboratory evidence demonstrating the neuroprotective effects of estrogen and progesterone after traumatic brain injury (TBI) and spinal cord injury (SCI). In humans, women have been shown to have a lower incidence of morbidity and mortality after TBI compared with age-matched men. Similarly, numerous laboratory studies have demonstrated that estrogen and progesterone administration is associated with a mortality reduction, improvement in neurological outcomes, and a reduction in neuronal apoptosis after TBI and SCI. Here, we review the evidence that supports hormone-related neuroprotection and discuss possible underlying mechanisms. Estrogen and progesterone-mediated neuroprotection are thought to be related to their effects on hormone receptors, signaling systems, direct antioxidant effects, effects on astrocytes and microglia, modulation of the inflammatory response, effects on cerebral blood flow and metabolism, and effects on mediating glutamate excitotoxicity. Future laboratory research is needed to better determine the mechanisms underlying the hormones’ neuroprotective effects, which will allow for more clinical studies. Furthermore, large randomized clinical control trials are needed to better assess their role in human neurodegenerative conditions.

Nafamostat Mesilate Improves Neurological Outcome and Axonal Regeneration after Stroke in Rats.

Disability including deficiency in sensorimotor and cognition functions is a dominant consequence after stroke. Evidence suggests that serine proteases play an important role in the physiology and pathology of the brain. Previous studies reported that nafamostat mesilate (NM), a synthetic serine protease inhibitor, attenuates neuronal damage in the acute phase after stroke. However, its efficacy in the chronic phase and the mechanism underlying its beneficial effect are not fully known. Here, we have studied whether NM improves long-term functional recovery after ischemic stroke. Experimental ischemic stroke was induced by transient middle cerebral artery occlusion (tMCAO). NM treatment attenuated the brain infarct volume and the loss of body weight and improved the recovery of sensorimotor and cognitive functions. One month after tMCAO, neuronal axons and dendrites were preserved in the NM group, accompanied by increasedsynaptic proteins and structures in the ipsilateral hippocampus. The expression of brain-derived neurotrophic factor, nerve growth factor and neurotrophin-3 was increased in the contralateral sensorimotor cortex and ipsilateral hippocampus by the administration of NM. Furthermore, NM activated tyrosine receptor kinase B (TrkB), extracellular signal-regulated kinas1/2(ERK1/2) and cAMP-response element binding protein (CREB) and inhibited the activity of Cyclin-dependent Kinase 5 (Cdk5) in the contralateral sensorimotor cortex and ipsilateral hippocampus. These results demonstrated that NM treatment could improve neurological outcome and axonal regeneration, which might be correlated with down-regulating Cdk5 activity and up-regulating TrkB-ERK1/2-CREB pathway.

Recombinant human erythropoietin improves neurological outcomes in very preterm infants.

ObjectiveTo evaluate the efficacy and safety of repeated low‐dose human recombinant erythropoietin (rhEPO) in the improvement of neurological outcomes in very preterm infants.MethodsA total of 800 infants of ≤32‐week gestational age who had been in an intensive care unit within 72 hours after birth were included in the trial between January 2009 and June 2013. Preterm infants were randomly assigned to receive rhEPO (500IU/kg; n = 366) or placebo (n = 377) intravenously within 72 hours after birth and then once every other day for 2 weeks. The primary outcome was death or moderate to severe neurological disability assessed at 18 months of corrected age.ResultsDeath and moderate/severe neurological disability occurred in 91 of 338 very preterm infants (26.9%) in the placebo group and in 43 of 330 very preterm infants (13.0%) in the rhEPO treatment group (relative risk [RR] = 0.40, 95% confidence interval [CI] = 0.27–0.59, p < 0.001) at 18 months of corrected age. The rate of moderate/severe neurological disability in the rhEPO group (22 of 309, 7.1%) was significantly lower compared to the placebo group (57 of 304, 18.8%; RR = 0.32, 95% CI = 0.19–0.55, p < 0.001), and no excess adverse events were observed.InterpretationRepeated low‐dose rhEPO treatment reduced the risk of long‐term neurological disability in very preterm infants with no obvious adverse effects. Ann Neurol 2016;80:24–34

Tachycardia burden in stroke unit is associated with functional outcome after ischemic stroke.

Stroke unit care is associated with decrease in mortality and improvement in neurological outcome in patients with acute stroke. Heart rate is a commonly monitored variable in the stroke unit. However, little is known about tachycardia burden in the stroke unit and its association with outcome. To investigate the effects of tachycardia burden in the stroke unit on functional outcome in patients with acute ischemic stroke. We collected data from 246 patients with acute ischemic stroke admitted to our stroke unit between July 2013 and June 2014. Tachycardia burden was defined as duration of heart rate over 95 per minute divided by the total monitoring time, using the heart rate data sampled every 1 min. We divided the study population into quartiles of tachycardia burden and analyzed their association with poor three-month functional outcome (modified Rankin Scale score of ≥3). Among included patients (age, 67.4 ± 12.8; male, 53.7%), tachycardia burden was 0.7% (median, interquartile range [0.1-5.7%]). The patients with higher tachycardia burdens were older, more likely to have higher stroke severity, cardioembolic etiology, atrial fibrillation, fever, pneumonia, higher initial glucose level, and higher white blood cell count. As compared with the lowest quartile (<0.1%), the highest quartile of tachycardia burden (≥6.0%) was significantly associated with poor outcome (adjusted odds ratio, 5.10; 95% confidence interval, 1.38-18.90; p = 0.01) after adjustment for covariates. Patients with increased tachycardia burden during stroke unit stay have poor functional outcome. Countermeasures against worsening factors might be utilized for patients with increased tachycardia burden.

Abstract WP102: Cerebrolysin Improves Neurological Outcome in Rats After Acute Stroke: a Prospective, Randomized, Blinded, Placebo-controlled Study

Background and Purpose: Cerebrolysin is a mixture of neuropeptides and free amino acids that exert potent neuroprotective and neurorestorative properties in experimental models of stroke. We conducted a prospective, randomized, double-blind and placebo controlled dose-response study of Cerebrolysin in both male and female rats after embolic stroke. Methods: Randomization schemas were generated using nQuery3.0. Male and female Wistar rats (3-4 months) were subjected to embolic middle cerebral artery occlusion (MCAO). After confirming successful stroke with a 5 point neurological scale (Longa scale) at 3h after MCAO, ischemic rats were treated with Cerebrolysin at doses of (0.8, 2.5, 5.0, 7.5ml/kg) and saline based on the randomization schema 4h after MCAO and continued daily for a total of 10 consecutive days. The primary outcome was neurologic outcome measured by adhesive removal test, foot-fault test, and modified neurological severity score at day 28, lesion volume and mortality were secondary and safety outcomes, respectively. Results: There was a significant dose effect of Cerebrolysin on neurological functional improvement 28 day after MCAO. Cerebrolysin at a dose of ≥ 2.5ml/kg significantly (P&lt;0.001) improved neurological outcome (Mean Estimate with 95%CL): 0.8ml/kg: 6.2 (-6.0/18.4), 2.5ml/kg: -28.9 (-41.6/-16.2), 5.0ml/kg: -33.4 (-45.0/-21.7), 7.5ml/kg: -36.3 (-48.2/-24.4). Higher doses (≥2.5ml/kg) resulted in better recovery; however, differences between effective doses were not significant. Treatment with 5ml/kg reduced lesion volume (19.5±8.9%) compared with saline treated rats (27.7±11.9%, P=0.016). No treatment gender interactions were found and there were no differences on mortality rate. Conclusion: Cerebrolysin in a dose-dependent manner significantly improved neurological outcomes in ischemic rats. Cerebrolysin at a dose of 5ml/kg reduced infarct volume. Our data on Cerebrolysin efficacy demonstrate the feasibility of a preclinical study setup following a randomized, placebo controlled, and blinded design with a clinical relevant treatment scheme.

Intravenous Treatment With Coenzyme Q10 Improves Neurological Outcome and Reduces Infarct Volume After Transient Focal Brain Ischemia in Rats

Coenzyme Q10 (CoQ10) crosses the blood-brain barrier when administered intravenously and accumulates in the brain. In this study, we investigated whether CoQ10 protects against ischemia-reperfusion injury by measuring neurological function and brain infarct volumes in a rat model of transient focal cerebral ischemia. In male Wistar rats, we performed transient middle cerebral artery occlusion (tMCAO) for 60 minutes, followed by reperfusion for 24 hours or 7 days. Forty-five minutes after the onset of occlusion (or 15 minutes before reperfusion), rats received a single intravenous injection of solubilized CoQ10 (30 mg·mL(-1)·kg(-1)) or saline (2 mL/kg). Sensory and motor function scores and body weights were obtained before the rats were killed by decapitation, and brain infarct volumes were calculated using tetrazolium chloride staining. CoQ10 brain levels were measured by high-performance liquid chromatography with electrochemical detection. CoQ10 significantly improved neurological behavior and reduced weight loss up to 7 days after tMCAO (P < 0.05). Furthermore, CoQ10 reduced cerebral infarct volumes by 67% at 24 hours after tMCAO and 35% at 7 days (P < 0.05). Cerebral ischemia resulted in a significant reduction in endogenous CoQ10 in both hemispheres (P < 0.05). However, intravenous injection of solubilized CoQ10 resulted in its increase in both hemispheres at 24 hours and in the contralateral hemisphere at 7 days (P < 0.05). Our results demonstrate that CoQ10 is a robust neuroprotective agent against ischemia-reperfusion brain injury in rats, improving both functional and morphological indices of brain damage.

Low-Molecular-Weight Fucoidan Attenuates Mitochondrial Dysfunction and Improves Neurological Outcome After Traumatic Brain Injury in Aged Mice: Involvement of Sirt3.

Traumatic brain injury (TBI) is a leading cause of death and long-term disability. Fucoidan, a sulfated polysaccharide extracted from brown algae, possesses potent anti-oxidative and anti-inflammatory effects. Considering TBI happens frequently in adults, especially in aged individuals, we herein sought to define the protective effects of low-molecular-weight fucoidan (LMWF) in the aged mice. 16- to 18-month-old mice administered with LMWF (1-50mg/kg) or vehicle were subjected to TBI using a controlled cortical impact (CCI) model. LMWF at the doses of 10 and 50mg/kg significantly reduced both cortical and hippocampal lesion volume. This protection was associated with reduced neuronal apoptosis, as evidenced by TUNEL staining. Importantly, LMWF was effective even when administered up to 4h after TBI. Treatment with LMWF improved long-term neurobehavioral outcomes, including sensorimotor function, and hippocampus-associated spatial learning and memory. In addition, LMWF significantly suppressed protein carbonyl, lipid peroxidation, reactive oxygen species (ROS) generation, as well as mitochondrial dysfunction, which was evidenced by mitochondrial cytochrome c release and collapse of mitochondrial membrane potential (MMP). To evaluate the underlying molecular mechanisms, the expression of sirtuin 3 (Sirt3) was detected by RT-PCR and Western blot. The results showed that TBI significantly increased the expression of Sirt3, which was further elevated by LMWF treatment. Knockdown of Sirt3 using intracerebroventricular injection of small interfering RNA (siRNA) partially prevented the therapeutic effects of LMWF. Collectively, these findings demonstrated that LMWF exerts neuroprotection against TBI in the aged brain, which may be associated with the attenuation of mitochondrial dysfunction through Sirt3 activation.

Improved Neurological Outcome With Mild Hypothermia in Surviving Patients With Massive Cerebral Hemispheric Infarction

We conducted this randomized controlled trial to investigate the effects of therapeutic hypothermia on mortality and neurological outcome in patients with massive cerebral hemispheric infarction. Patients within 48 hours of symptom onset were randomized to either a hypothermia group or a control group. Patients in the hypothermia group were given standard medical treatment plus endovascular hypothermia with a target temperature of 33 or 34°C. Hypothermia was maintained for a minimum of 24 hours. Patients in the control group were given standard medical treatment only with a target temperature of normothermia. The primary end points were mortality and the modified Rankin Scale score at 6 months. There were 16 patients in the hypothermia group and 17 patients in the control group. At 6 months, 8 patients had died in the hypothermia group versus 7 patients in the control group (P=0.732). The main cause of death was fatal herniation caused by a pronounced rise in intracranial pressure. Seven patients (43.8%) had a modified Rankin Scale of 1 to 3 in the hypothermia group versus 4 patients (23.5%) in the control group (P=0.282). Additionally, of the survivors, patients in the hypothermia group achieved better neurological outcomes compared with those in the control group (7/8, 87.5% versus 4/10, 40.0%; P=0.066; odds ratio=10.5; 95% confidence interval, 0.9-121.4). Mild hypothermia seems to not reduce mortality in patients with massive cerebral hemispheric infarction but may improve the neurological outcome in survivors. An adequately powered multicenter randomized controlled trial seems warranted. URL: http://www.chictr.org.cn. Unique identifier: ChiCTR-TCS-12002680.