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1.  RESULTS OF THE MRI SUBSTUDY OF THE INTRAVENOUS MAGNESIUM EFFICACY IN STROKE (IMAGES) TRIAL 
Background and Purpose
Although magnesium is neuroprotective in animal stroke models, no clinical benefit was confirmed in the Intravenous Magnesium Efficacy in Stroke (IMAGES) trial of acute stroke patients. The Magnetic Resonance in IMAGES (MR IMAGES) substudy investigated the effects of magnesium on the imaging surrogate outcome of infarct growth.
Methods
IMAGES trial patients in participating centers were randomized to receive either intravenous magnesium or placebo within 12 hours of stroke onset. Infarct growth was defined as volume difference between baseline DWI and day 90 FLAIR lesions. Patients who died were imputed the largest infarct growth observed.
Results
Among the 90 patients included in the primary analysis, there was no difference in infarct growth (median absolute growth p=0.639; median percentage growth p=0.616; proportion with any growth p=0.212) between the 46 treated with magnesium and 44 with placebo). Infarct growth correlated with NIHSS score change from baseline to day 90. There was a trend showing baseline serum glucose correlated with infarct growth with magnesium treatment but not in the placebo group. The mismatch frequency was reduced from 73% to 47% by increasing the mismatch threshold from >20% to >100% of core volume.
Conclusions
Infarct growth, confirmed here as a surrogate for clinical progression, was similar between magnesium and placebo treatment, paralleling the main IMAGES trial clinical outcomes. Glucose was a covariate for infarct growth with magnesium treatment. A more stringent mismatch threshold to define penumbra more appropriately would have excluded half of the patients in this sub-12 hour stroke study.
doi:10.1161/STROKEAHA.108.537613
PMCID: PMC2694570  PMID: 19299636
Stroke; Magnesium; Magnetic resonance imaging; Diffusion weighted imaging; Glucose; Surrogate endpoint
2.  Thrombolysis in acute ischemic stroke: Experience from a tertiary care centre in India 
The management of acute ischemic stroke has undergone a sea of change with the introduction of intravenous thrombolysis (IVT). Current guidelines state that the window period for IVT using rTPA is 4.5 hours. The MERCI, Multi Merci, and Penumbra trials in which patients with acute ischemic stroke were treated using endovascular treatment demonstrated better recanalisation in patients having a large vessel occlusion. However, recently published data from the three large trials IMS 3, Synthesis Expansion, and MR rescue, which compared endovascular treatment with intravenous therapy, failed to demonstrate superiority of endovascular treatment over IVT. In these trials, stent retrievers were used in very few patients. We present our results from a tertiary care center in India where patients are treated using intravenous as well as endovascular modalities. Among the 53 patients with acute ischemic stroke treated between 2010 and 2012, 23 were treated with IVT and 30 with endovascular methods. Stent retriever was used in majority of the endovascular cases.
Aims:
To compare the outcomes of acute ischemic stroke patients treated with IVT versus those who were managed using endovascular therapy. To evaluate outcomes of patients with acute ischemic stroke with a large vessel occlusion in whom endovascular modalities were used and to compare them with those of patients who were treated with IVT in presence of a large vessel occlusion.
Settings and Design:
Data of patients who underwent thrombolysis at our centre was collected over a 3-year period, that is, from 2010 to 2012. Endovascular treatment was done by an interventional neurologist.
Materials and Methods:
Data of patients with acute ischemic stroke who underwent IVT or endovascular treatment at our centre between 2010 and 2012 was analyzed. Parameters included age, National Institutes of Health Stroke Scale (NIHSS) on admission, door to needle time, stroke subtype, modality of treatment, outcome based on modified Rankin Scale (mRS) Score at 90 days follow up and mortality rates at 90 days.
Statistical Analysis:
Tabulated results were analysed using INSTAT Graphpad analyser. Data were analysed using paired and unpaired t-test, Chi-square test, and Fishers test as applicable. P value was considered significant when it was <0.05.
Results:
Upon comparison of the outcomes of patients with acute ischemic stroke and large vessel disease treated with endovascular therapy with those treated with IVT, it was found that the former group had better outcomes. We also found that in spite of there being a significant difference in the NIHSS on admission and a significant difference in the door to needle time, the outcomes of patients treated using intravenous or endovascular therapy were similar. There was no statistically significant difference in mortality rates between intravenous and endovascular groups.
Conclusions:
IVT is currently the standard of care in the management of acute ischemic stroke. Endovascular treatment during the window period is reserved for those patients with contraindication to IVT. In this study, we found that patients with documented large vessel disease with no evidence of cross flow through Willisian collaterals benefit from endovascular treatment. We recommend that all patients of acute ischemic stroke, be subjected to a baseline angiogram either computed tomography (CT) or magnetic resonance imaging (MRI) to document vessel status. This will help in identifying patients who may benefit from early endovascular treatment, if they fail to improve with IVT. Further, large trials using stent retrievers are needed, to prove that endovascular treatment is superior to IVT, in presence of documented large vessel disease.
doi:10.4103/0976-3147.127867
PMCID: PMC3985351  PMID: 24741245
Endovascular thrombolysis; intravenous thrombolysis; IV thrombolysis; stent retriever; stroke
3.  The effect of magnesium supplementation on primary insomnia in elderly: A double-blind placebo-controlled clinical trial 
Background:
Nearly 50% of older adults have insomnia, with difficulty in getting to sleep, early awakening, or feeling unrefreshed on waking. With aging, several changes occur that can place one at risk for insomnia, including age-related changes in various circadian rhythms, environmental and lifestyle changes, and decreased nutrients intake, absorption, retention, and utilization. The natural N-methyl-D-aspartic acid (NMDA) antagonist and GABA agonist, Mg2+, seems to play a key role in the regulation of sleep. The objective of this study was to determine the efficacy of magnesium supplementation to improve insomnia in elderly.
Materials and Methods:
A double-blind randomized clinical trial was conducted in 46 elderly subjects, randomly allocated into the magnesium or the placebo group and received 500 mg magnesium or placebo daily for 8 weeks. Questionnaires of insomnia severity index (ISI), physical activity, and sleep log were completed at baseline and after the intervention period. Anthropometric confounding factors, daily intake of magnesium, calcium, potassium, caffeine, calories form carbohydrates, and total calorie intake, were obtained using 24-h recall for 3 days. Blood samples were taken at baseline and after the intervention period for analysis of serum magnesium, renin, melatonin, and cortisol. Statistical analyses were performed using SPSS19 and P values < 0.05 were considered as statistically significant.
Results:
No significant differences were observed in assessed variables between the two groups at the baseline. As compared to the placebo group, in the experimental group, dietary magnesium supplementation brought about statistically significant increases in sleep time (P = 0.002), sleep efficiency (P = 0.03), concentration of serum renin (P < 0.001), and melatonin (P = 0.007), and also resulted in significant decrease of ISI score (P = 0.006), sleep onset latency (P = 0.02) and serum cortisol concentration (P = 0.008). Supplementation also resulted in marginally between-group significant reduction in early morning awakening (P = 0.08) and serum magnesium concentration (P = 0.06). Although total sleep time (P = 0.37) did not show any significant between-group differences.
Conclusion:
Supplementation of magnesium appears to improve subjective measures of insomnia such as ISI score, sleep efficiency, sleep time and sleep onset latency, early morning awakening, and likewise, insomnia objective measures such as concentration of serum renin, melatonin, and serum cortisol, in elderly people.
PMCID: PMC3703169  PMID: 23853635
Dietary supplementation; elderly; insomnia; magnesium
4.  Magnesium Sulfate Only Slightly Reduces the Shivering Threshold in Humans 
British journal of anaesthesia  2005;94(6):756-762.
Background: Hypothermia may be an effective treatment for stroke or acute myocardial infarction; however, it provokes vigorous shivering, which causes potentially dangerous hemodynamic responses and prevents further hypothermia. Magnesium is an attractive antishivering agent because it is used for treatment of postoperative shivering and provides protection against ischemic injury in animal models. We tested the hypothesis that magnesium reduces the threshold (triggering core temperature) and gain of shivering without substantial sedation or muscle weakness.
Methods: We studied nine healthy male volunteers (18-40 yr) on two randomly assigned treatment days: 1) Control and 2) Magnesium (80 mg·kg-1 followed by infusion at 2 g·h-1). Lactated Ringer's solution (4°C) was infused via a central venous catheter over a period of approximately 2 hours to decrease tympanic membrane temperature ≈1.5°C·h-1. A significant and persistent increase in oxygen consumption identified the threshold. The gain of shivering was determined by the slope of oxygen consumption vs. core temperature regression. Sedation was evaluated using verbal rating score (VRS, 0-10) and bispectral index of the EEG (BIS). Peripheral muscle strength was evaluated using dynamometry and spirometry. Data were analyzed using repeated-measures ANOVA; P<0.05 was statistically significant.
Results: Magnesium reduced the shivering threshold (36.3±0.4 [mean±SD] vs. 36.6±0.3°C, P=0.040). It did not affect the gain of shivering (Control: 437±289, Magnesium: 573±370 ml·min-1·°C-1, P=0.344). The magnesium bolus did not produce significant sedation or appreciably reduce muscle strength.
Conclusions: Magnesium significantly reduced the shivering threshold; however, due to the modest absolute reduction, this finding is considered to be clinically unimportant for induction of therapeutic hypothermia.
doi:10.1093/bja/aei105
PMCID: PMC1361806  PMID: 15749735
Magnesium; Temperature; Thermoregulation; Therapeutic hypothermia; Brain protection; Cardiac protection; Shivering
5.  Can Comprehensive Stroke Centers Erase the ‘Weekend Effect’? 
Background
Prior epidemiological work has shown higher mortality in ischemic stroke patients admitted on weekends, which has been termed the ‘weekend effect’. Our aim was to assess stroke patient outcomes in order to determine the significance of the ‘weekend effect’ at 2 comprehensive stroke centers.
Methods
Consecutive stroke patients were identified using prospective databases. Patients were categorized into 4 groups: intracerebral hemorrhage (ICH group), ischemic strokes not treated with IV t-PA (intravenous tissue plasminogen activator; IS group), acute ischemic strokes treated with IV t-PA (AIS-TPA group), and transient ischemic attack (TIA group). Weekend admission was defined as the period from Friday, 17:01, to Monday, 08:59. Patients treated beyond the 3-hour window, receiving intra-arterial therapy, or enrolled in nonobservational clinical trials were excluded. Patient demographics, NIHSS scores, and admission glucose levels were examined. Adverse events, poor functional outcome (modified Rankin scale, mRS, 3–6), and mortality were compared.
Results
A total of 2,211 patients were included (1,407 site 1, 804 site 2). Thirty-six percent (800/2,211) arrived on a weekend. No significant differences were found in the ICH, IS, AIS-TPA, or TIA groups with respect to the rate of symptomatic ICH, mRS on discharge, discharge disposition, 90-day mRS, or 90-day mortality when comparing weekend and weekday groups. Using multivariate logistic regression to adjust for site, age, admission NIHSS, and blood glucose, weekend admission was not a significant independent predictive factor for in-hospital mortality in all strokes (OR = 1.10, 95% CI 0.74–1.63, p = 0.631).
Conclusions
Our results suggest that comprehensive stroke centers (CSC) may ameliorate the ‘weekend effect’ in stroke patients. These results may be due to 24/7 availability of stroke specialists, advanced neuroimaging, or ongoing training and surveillance of specialized nursing care available at CSC. While encouraging, these results require confirmation in prospective studies.
doi:10.1159/000177916
PMCID: PMC2790057  PMID: 19039213
Stroke; Weekend; Mortality; Outcomes research; Quality of healthcare
6.  Outcome and upper extremity function within 72 hours after first occasion of stroke in an unselected population at a stroke unit. A part of the SALGOT study 
BMC Neurology  2012;12:162.
Background
Reduced upper extremity function is one of the most common impairments after stroke and has previously been reported in approximately 70-80% of patients in the acute stage. Acute care for stroke has changes over the last years, with more people being admitted to a stroke unit as well as use of thrombolysis. The aim of the present study was to describe baseline characteristics, care pathway and discharge status in an unselected group of patients with first occasion of stroke who were at a stroke unit within 72 hours after stroke and also to investigate the frequency of impaired arm and hand function. A second aim was to explore factors associated with impaired upper extremity function and the impact of impairment on the patient’s outcome.
Methods
Patients over 18 years of age with first ever stroke, living in a geographical catchment area, being at the stroke unit within 72 hours after onset, with no prior upper extremity impairment were included. Baseline characteristics, arm and hand function within 72 hours, stroke outcome and care pathway in the acute phase were described, by gathering information retrospectively from the patients’ charts. Ischemic strokes were categorized according to the Bamford classification and the Trial of Org 10172 in Acute Stroke Treatment criteria.
Results
Of the 969 patients with first ever stroke who were screened, 642 patients fulfilled the inclusion criteria. According to the National Institutes of Health Stroke Scale (NIHSS), the patients had a mean score of 6.0, median 3.0, at arrival to the hospital. Ischemic stroke was most frequent in the anterior circulation (87.7%). Within 72 hours after stroke onset 48.0% of the patients had impaired arm and hand function and this was positively associated with higher age (p < 0.004), longer stay in the acute care (p < 0.001) and mortality in acute care (p < 0.001). Directly admitted to the stroke unit were 89.1% of the patients and 77.1% received hospital care on same day as stroke onset. Mean length of stay in the stroke unit was 9.9 days, 56.8% of the patients were discharged directly home from the stroke unit. Mortality within 72 hours after stroke onset was 5.0%.
Conclusion
Impaired arm and hand function is present in 48% of the patients in a non selected population with first ever stroke, estimated within 72 hours after onset. This is less than previously reported. Impaired arm and hand function early after stroke is associated with higher age, longer stay in the acute care, and higher mortality within the acute hospital care.
doi:10.1186/1471-2377-12-162
PMCID: PMC3554428  PMID: 23273107
Stroke recovery; Upper extremity; Paresis; Outcomes; Process assessment
7.  Magnesium Sulfate and Nimesulide Have Synergistic Effects on Rescuing Brain Damage after Transient Focal Ischemia 
Journal of Neurotrauma  2012;29(7):1518-1529.
Abstract
Magnesium sulfate and nimesulide are commonly used drugs with reported neuroprotective effects. Their combination as stroke treatment has the potential benefits of decreasing individual drug dosage and fewer adverse effects. This study evaluated their synergistic effects and compared a low-dose combination with individual drug alone and placebo. Sprague-Dawley rats underwent 90 min of focal ischemia with intraluminal suture occlusion of the middle cerebral artery followed by reperfusion. The rats were randomly assigned to receive one of the following treatments: placebo, magnesium sulfate (MgSO4; 45 mg/kg) intravenously immediately after the induction of middle cerebral artery occlusion, nimesulide (6 mg/kg) intraperitoneally before reperfusion, and combined therapy. Three days after the ischemia-reperfusion insult, therapeutic outcome was assessed by 2,3,5-triphenyltetrazolium chloride staining and a 28-point neurological severity scoring system. Cyclooxygenase-2, prostaglandin E2, myeloperoxidase, and caspase-3 expression after treatment were evaluated using Western blot analyses and immunohistochemical staining, followed by immunoreactive cell analysis using tissue cytometry. Only the combination treatment group showed a significant decrease in infarction volume (10.93±6.54% versus 26.43±7.08%, p<0.01), and neurological severity score (p<0.05). Low-dose MgSO4 or nimesulide showed no significant neuroprotection. There was also significant suppression of cyclooxygenase-2, prostaglandin E2, myeloperoxidase, and caspase-3 expression in the combination treatment group, suggesting that the combination of the two drugs improved the neuroprotective effects of each individual drug. MgSO4 and nimesulide have synergistic effects on ischemia-reperfusion insults. Their combination helps decrease drug dosage and adverse effects. Combined treatment strategies may help to combat stroke-induced brain damage in the future.
doi:10.1089/neu.2011.2030
PMCID: PMC3335109  PMID: 22332641
in vivo studies; ischemia; middle cerebral artery occlusion; therapeutic approach; stroke
8.  Intravenous Magnesium Infusion for the Prevention of Symptomatic Cerebral Vasospasm after Aneurysmal Subarachnoid Hemorrhage 
Objective
The study examined the difference in the incidence of symptomatic cerebral vasospasm with magnesium supplementation in aneurysmal subarachnoid hemorrhage (SAH) in a Korean population.
Methods
This retrospective analysis was performed in 157 patients diagnosed with aneurysmal SAH from January 2007 to December 2011 at a single center. Seventy patients (44.6%) received a combination treatment of nimodipine with magnesium and 87 patients (55.4%) received only nimodipine. A matched case-control study using propensity scores was conducted and 41 subjects were selected from each group. A dosage of 64 mmol/day of magnesium was administrated.
Results
The infusion of magnesium did not reduce the incidence of symptomatic cerebral vasospasm (n=7, 17.1%, p=0.29) compared with simple nimodipine injection (n=11, 26.8%). The ratios of good clinical outcome (modified Rankin scale 0-2) at 6 months were similar, being 78% in the combination treatment group and 80.5% in the nimodipine only group (p=0.79). The proportions of delayed cerebral infarction was not significantly lower in patients with combination treatment (n=2, 4.9% vs. n=3, 7.3%; p=0.64). There was no difference in the serum magnesium concentrations between the patients with symptomatic vasospasm and without vasospasm who had magnesium supplementation. No major complications associated with intravenous magnesium infusion were observed.
Conclusion
Magnesium supplementation (64 mmol/day) may not be beneficial for the reduction of the incidence of symptomatic cerebral vasospasm in patients with aneurysmal SAH.
doi:10.3340/jkns.2012.52.2.75
PMCID: PMC3467379  PMID: 23091662
Cerebral vasospasm; Subarachnoid hemorrhage; Magnesium sulfate
9.  Estimates of Outcomes Up to Ten Years after Stroke: Analysis from the Prospective South London Stroke Register 
PLoS Medicine  2011;8(5):e1001033.
Charles Wolfe and colleagues collected data from the South London Stroke Register on 3,373 first strokes registered between 1995 and 2006 and showed that between 20% and 30% of survivors have poor outcomes up to 10 years after stroke.
Background
Although stroke is acknowledged as a long-term condition, population estimates of outcomes longer term are lacking. Such estimates would be useful for planning health services and developing research that might ultimately improve outcomes. This burden of disease study provides population-based estimates of outcomes with a focus on disability, cognition, and psychological outcomes up to 10 y after initial stroke event in a multi-ethnic European population.
Methods and Findings
Data were collected from the population-based South London Stroke Register, a prospective population-based register documenting all first in a lifetime strokes since 1 January 1995 in a multi-ethnic inner city population. The outcomes assessed are reported as estimates of need and included disability (Barthel Index <15), inactivity (Frenchay Activities Index <15), cognitive impairment (Abbreviated Mental Test < 8 or Mini-Mental State Exam <24), anxiety and depression (Hospital Anxiety and Depression Scale >10), and mental and physical domain scores of the Medical Outcomes Study 12-item short form (SF-12) health survey. Estimates were stratified by age, gender, and ethnicity, and age-adjusted using the standard European population. Plots of outcome estimates over time were constructed to examine temporal trends and sociodemographic differences. Between 1995 and 2006, 3,373 first-ever strokes were registered: 20%–30% of survivors had a poor outcome over 10 y of follow-up. The highest rate of disability was observed 7 d after stroke and remained at around 110 per 1,000 stroke survivors from 3 mo to 10 y. Rates of inactivity and cognitive impairment both declined up to 1 y (280/1,000 and 180/1,000 survivors, respectively); thereafter rates of inactivity remained stable till year eight, then increased, whereas rates of cognitive impairment fluctuated till year eight, then increased. Anxiety and depression showed some fluctuation over time, with a rate of 350 and 310 per 1,000 stroke survivors, respectively. SF-12 scores showed little variation from 3 mo to 10 y after stroke. Inactivity was higher in males at all time points, and in white compared to black stroke survivors, although black survivors reported better outcomes in the SF-12 physical domain. No other major differences were observed by gender or ethnicity. Increased age was associated with higher rates of disability, inactivity, and cognitive impairment.
Conclusions
Between 20% and 30% of stroke survivors have a poor range of outcomes up to 10 y after stroke. Such epidemiological data demonstrate the sociodemographic groups that are most affected longer term and should be used to develop longer term management strategies that reduce the significant poor outcomes of this group, for whom effective interventions are currently elusive.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Every year, 15 million people have a stroke. About 5 million of these people die within a few days, and another 5 million are left disabled. Stroke occurs when the brain's blood supply is suddenly interrupted by a blood clot blocking a blood vessel in the brain (ischemic stroke, the commonest type of stroke) or by a blood vessel in the brain bursting (hemorrhagic stroke). Deprived of the oxygen normally carried to them by the blood, the brain cells near the blockage die. The symptoms of stroke depend on which part of the brain is damaged but include sudden weakness or paralysis along one side of the body, vision loss in one or both eyes, and confusion or trouble speaking or understanding speech. Anyone experiencing these symptoms should seek immediate medical attention because prompt treatment can limit the damage to the brain. Risk factors for stroke include age (three-quarters of strokes occur in people over 65 years old), high blood pressure, and heart disease.
Why Was This Study Done?
Post-stroke rehabilitation can help individuals overcome the physical disabilities caused by stroke, and drugs and behavioral counseling can reduce the risk of a second stroke. However, people can also have problems with cognition (thinking, awareness, attention, learning, judgment, and memory) after a stroke, and they can become depressed or anxious. These “outcomes” can persist for many years, but although stroke is acknowledged as a long-term condition, most existing data on stroke outcomes are limited to a year after the stroke and often focus on disability alone. Longer term, more extensive information is needed to help plan services and to help develop research to improve outcomes. In this burden of disease analysis, the researchers use follow-up data collected by the prospective South London Stroke Register (SLSR) to provide long-term population-based estimates of disability, cognition, and psychological outcomes after a first stroke. The SLSR has recorded and followed all patients of all ages in an inner area of South London after their first-ever stroke since 1995.
What Did the Researchers Do and Find?
Between 1995 and 2006, the SLSR recorded 3,373 first-ever strokes. Patients were examined within 48 hours of referral to SLSR, their stroke diagnosis was verified, and their sociodemographic characteristics (including age, gender, and ethnic origin) were recorded. Study nurses and fieldworkers then assessed the patients at three months and annually after the stroke for disability (using the Barthel Index, which measures the ability to, for example, eat unaided), inactivity (using the Frenchay Activities Index, which measures participation in social activities), and cognitive impairment (using the Abbreviated Mental Test or the Mini-Mental State Exam). Anxiety and depression and the patients' perceptions of their mental and physical capabilities were also assessed. Using preset cut-offs for each outcome, 20%–30% of stroke survivors had a poor outcome over ten years of follow-up. So, for example, 110 individuals per 1,000 population were judged disabled from three months to ten years, rates of inactivity remained constant from year one to year eight, at 280 affected individuals per 1,000 survivors, and rates of anxiety and depression fluctuated over time but affected about a third of the population. Notably, levels of inactivity were higher among men than women at all time points and were higher in white than in black stroke survivors. Finally, increased age was associated with higher rates of disability, inactivity, and cognitive impairment.
What Do These Findings Mean?
Although the accuracy of these findings may be affected by the loss of some patients to follow-up, these population-based estimates of outcome measures for survivors of a first-ever stroke for up to ten years after the event provide concrete evidence that stroke is a lifelong condition with ongoing poor outcomes. They also identify the sociodemographic groups of patients that are most affected in the longer term. Importantly, most of the measured outcomes remain relatively constant (and worse than outcomes in an age-matched non-stroke-affected population) after 3–12 months, a result that needs to be considered when planning services for stroke survivors. In other words, these findings highlight the need for health and social services to provide long-term, ongoing assessment and rehabilitation for patients for many years after a stroke.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001033.
The US National Institute of Neurological Disorders and Stroke provides information about all aspects of stroke (in English and Spanish); the US National Institute of Health SeniorHealth Web site has additional information about stroke
The Internet Stroke Center provides detailed information about stroke for patients, families, and health professionals (in English and Spanish)
The UK National Health Service Choices Web site also provides information about stroke for patients and their families
MedlinePlus has links to additional resources about stroke (in English and Spanish)
More information about the South London Stroke Register is available
doi:10.1371/journal.pmed.1001033
PMCID: PMC3096613  PMID: 21610863
10.  Inflammatory Markers and Poor Outcome after Stroke: A Prospective Cohort Study and Systematic Review of Interleukin-6 
PLoS Medicine  2009;6(9):e1000145.
In a prospective cohort study of patient outcomes following stroke, William Whiteley and colleagues find that markers of inflammatory response are associated with poor outcomes. However, addition of these markers to existing prognostic models does not improve outcome prediction.
Background
The objective of this study was to determine whether: (a) markers of acute inflammation (white cell count, glucose, interleukin-6, C-reactive protein, and fibrinogen) are associated with poor outcome after stroke and (b) the addition of markers to previously validated prognostic models improves prediction of poor outcome.
Methods and Findings
We prospectively recruited patients between 2002 and 2005. Clinicians assessed patients and drew blood for inflammatory markers. Patients were followed up by postal questionnaire for poor outcome (a score of>2 on the modified Rankin Scale) and death through the General Register Office (Scotland) at 6 mo. We performed a systematic review of the literature and meta-analysis of the association between interleukin-6 and poor outcome after stroke to place our study in the context of previous research. We recruited 844 patients; mortality data were available in 844 (100%) and functional outcome in 750 (89%). After appropriate adjustment, the odds ratios for the association of markers and poor outcome (comparing the upper and the lower third) were interleukin-6, 3.1 (95% CI: 1.9–5.0); C-reactive protein, 1.9 (95% CI: 1.2–3.1); fibrinogen, 1.5 (95% CI: 1.0–2.36); white cell count, 2.1 (95% CI: 1.3–3.4); and glucose 1.3 (95% CI: 0.8–2.1). The results for interleukin-6 were similar to other studies. However, the addition of inflammatory marker levels to validated prognostic models did not materially improve model discrimination, calibration, or reclassification for prediction of poor outcome after stroke.
Conclusions
Raised levels of markers of the acute inflammatory response after stroke are associated with poor outcomes. However, the addition of these markers to a previously validated stroke prognostic model did not improve the prediction of poor outcome. Whether inflammatory markers are useful in prediction of recurrent stroke or other vascular events is a separate question, which requires further study.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Every year, 15 million people have a stroke. In the US alone, someone has a stroke every 40 seconds and someone dies from a stroke every 3–4 minutes. Stroke occurs when the blood supply to the brain is suddenly interrupted by a blood clot blocking a blood vessel in the brain (ischemic stroke, the commonest type of stroke) or by a blood vessel in the brain bursting (hemorrhagic stroke). Deprived of the oxygen normally carried to them by the blood, the brain cells near the blockage die. The symptoms of stroke depend on which part of the brain is damaged but include sudden weakness or paralysis along one side of the body, vision loss in one or both eyes, and confusion or trouble speaking or understanding speech. Anyone experiencing these symptoms should seek medical assistance immediately because prompt treatment can limit the damage to the brain. Risk factors for stroke include age (three-quarters of strokes occur in people over 65 years old), high blood pressure, and heart disease.
Why Was This Study Done?
Many people are left with permanent disabilities after a stroke. An accurate way to predict the likely long-term outcome (prognosis) for individual patients would help clinicians manage their patients and help relatives and patients come to terms with their changed circumstances. Clinicians can get some idea of their patients' likely outcomes by assessing six simple clinical variables. These include the ability to lift both arms and awareness of the present situation. But could the inclusion of additional variables improve the predictive power of this simple prognostic model? There is some evidence that high levels in the blood of inflammatory markers (for example, interleukin-6 and C-reactive protein) are associated with poor outcomes after stroke—inflammation is the body's response to infection and to damage. In this prospective cohort study, the researchers investigate whether inflammatory markers are associated with poor outcome after stroke and whether the addition of these markers to the six-variable prognostic model improves its predictive power. Prospective cohort studies enroll a group of participants and follow their subsequent progress.
What Did the Researchers Do and Find?
The researchers recruited 844 patients who had had a stroke (mainly mild ischemic strokes) in Edinburgh. Each patient was assessed soon after the stroke by a clinician and blood was taken for the measurement of inflammatory markers. Six months after the stroke, the patient or their relatives completed a postal questionnaire that assessed their progress. Information about patient deaths was obtained from the General Register Office for Scotland. Dependency on others for the activities of daily life or dying was recorded as a poor outcome. In their statistical analysis of these data, the researchers found that raised levels of several inflammatory markers increased the likelihood of a poor outcome. For example, after allowing for age and other factors, individuals with interleukin-6 levels in the upper third of the measured range were three times as likely to have a poor outcome as patients with interleukin-6 levels in the bottom third of the range. A systematic search of the literature revealed that previous studies that had looked at the potential association between interleukin-6 levels and outcome after stroke had found similar results. Finally, the researchers found that the addition of inflammatory marker levels to the six-variable prognostic model did not substantially improve its ability to predict outcome after stroke for this cohort of patients.
What Do These Findings Mean?
These findings provide additional support for the idea that increased levels of inflammatory markers are associated with a poor outcome after stroke. However, because patients with infections were not excluded from the study, infection may be responsible for part of the observed association. Importantly, these findings also show that although the inclusion of inflammatory markers in the six variable prognostic model slightly improves its ability to predict outcome, the magnitude of this improvement is too small to warrant the use of these markers in routine practice. Whether the measurement of inflammatory markers might be useful in the prediction of recurrent stroke—at least a quarter of people who survive a stroke will have another one within 5 years—requires further study.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000145.
This study is further discussed in a PLoS Medicine Perspective by Len Kritharides
The US National Institute of Neurological Disorders and Stroke provides information about all aspects of stroke (in English and Spanish); the Know Stroke site provides educational materials about stroke prevention, treatment, and rehabilitation (in English and Spanish)
The Internet Stroke Center provides detailed information about stroke for patients, families and health professionals (in English and Spanish)
The UK National Health Service also provides information for patients and their families about stroke (in several languages)
MedlinePlus provides links to further resources and advice about stroke (in English and Spanish)
The six simple variable model for prediction of death or disability after stroke is available here: http://dcnapp1.dcn.ed.ac.uk/scope/
doi:10.1371/journal.pmed.1000145
PMCID: PMC2730573  PMID: 19901973
11.  Effects of magnesium sulfate on the clinical course and GCS of patients with a severe diffuse axonal injury 
Journal of Injury and Violence Research  2012;4(3 Suppl 1): Paper No. 70.
Abstract:
Background:
Previous studies have shown that magnesium sulfate (MgSO4) administered in a patient with a diffuse axonal injury (DAI) can serve as a useful neuroprotective agent. The present study was conducted to examine whether magnesium sulfate has a therapeutic efficacy and safety in patients with a severe diffuse axonal injury.
Methods:
Adult patients admitted within 1 hour of a closed Traumatic Brain Injury (TBI) with a severe diffuse axonal injury that met eligibility criteria were randomly selected and divided into two groups. Our treatment guidelines consisted of an initial loading dose of 50 mg/kg magnesium sulfate and then 50 mg/kg QID (quarter in die) up to 24 hours after the trauma. The outcome measures were mortality, Glasgow Coma Scale (GCS) score, and motor function scores which were assessed up to 2 months post-trauma.
Results:
Magnesium showed a significant positive effect on GCS score at 2 months post-trauma (P=0.03). Motor functioning scores of patients in the MgSO4 group were higher than those in the control group but this was not statistically significant (P equal to 0.51).
Conclusions:
Findings of the present study demonstrated that administration of magnesium sulfate following severe DAI can have neuroprotective effect.
Keywords:
Severe diffuse axonal injury, Magnesium sulfate, Outcome
PMCID: PMC3571596
12.  Docosahexaenoic acid complexed to human albumin in experimental stroke: neuroprotective efficacy with a wide therapeutic window 
Background
Docosahexaenoic acid (DHA) complexed to human serum albumin (Alb) is neuroprotective after experimental stroke. Here we tested using lower concentrations of albumin as part of the complex to achieve neuroprotection. We found that lower Alb concentrations extend the therapeutic window of protection beyond 5 h after stroke onset.
Methods
Sprague–Dawley rats were received 2 h middle cerebral artery occlusion (MCAo). The behavior was evaluated on day 1, 2, 3 and 7 after MCAo. In the dose–response study, animals were given either DHA (5mg/kg), Alb (0.63g/kg), DHA-Alb (5mg/kg + 0.32, 0.63 or 1.25 g/kg) or saline, i.v. 3 h after onset of stroke (n=6-8 per group). In the therapeutic window study, DHA-Alb (5mg/kg + 1.25g/kg) was administered i.v. at either 3, 4, 5, 6 or 7 h after onset of stroke (n=7-9 per group). Alb (1.25g/kg) was given at 3 h or 5 h and saline at 3h after onset of reperfusion. Seven days after MCAo, infarct volumes and number of GFAP, ED-1, NeuN, SMI-71 positive cells and vessels were counted.
Results
Moderate DHA-Alb doses (0.63 and 1.25 g/kg) improved neurological scores compared to albumin-treated rats on days 1, 2, 3 and 7. All DHA-Alb doses (0.32, 0.63 and 1.25 g/kg) markedly reduced cortical (by 65-70%), striatal (by 52-63%) and total infarct volumes (by 60-64%) compared to native Alb group. In the therapeutic window study DHA-Alb led to improved neurological score and significant reductions of infarct volumes (especially in the cortical or penumbral region), even when treatment was initiated as late as 7 hours after onset of MCAo.
Conclusions
The DHA-Alb complex affords high-grade neurobehavioral neuroprotection in focal cerebral ischemia, equaling or exceeding that afforded by native Alb or DHA, at considerably moderate doses. It has a broad therapeutic window extending to 7 h after stroke onset. Taken together, these finding support the potential clinical feasibility of administering DHA-Alb therapy to patients with acute ischemic stroke.
doi:10.1186/2040-7378-4-19
PMCID: PMC3540001  PMID: 22980673
Penumbra; DHA-Alb complex; Neuroprotection; Behavior; Histopathology; Focal ischemia; Experimental stroke
13.  Effects of oral magnesium supplementation on inflammatory markers in middle-aged overweight women 
Background:
This study aimed to investigate whether magnesium supplementation might affect serum magnesium, high sensitive C-reactive protein (hs-CRP), plasma fibrinogen, and interleukin 6 (IL-6) levels in healthy middle-aged overweight women. The relationships, if any, between serum magnesium and the inflammatory markers were also examined cross-sectionally in the entire participants at the beginning of the study.
Materials and Methods:
This double-blinded, placebo-controlled, randomized trial included 74 middle-aged overweight women. Participants were randomly assigned to receive either 250 mg magnesium as magnesium oxide or placebo daily for 8 weeks. Serum magnesium, hs-CRP, fibrinogen and IL-6 concentrations were measured before and after the intervention.
Results:
Serum magnesium was found to be inversely correlated with hs-CRP (rs =−0.22, P=0.05) in the entire participants at baseline. Serum hs-CRP declined significantly in both groups as compared with baseline values (median change=0.8 mg/L; PMagnesium= 0.03, PPlacebo < 0.001). Plasma fibrinogen decreased significantly, by 9%, in the magnesium group at the end of week 8 compared to baseline (P=0.001). Mean concentration of IL-6 was significantly increased in the magnesium group comparing the baseline value(P=0.001). However hs-CRP, fibrinogen and IL-6 levels at week 8 or any changes during the study were not statistically different between the two groups. Serum magnesium showed no significant changes in any groups.
Conclusions:
Serum magnesium had a significant inverse correlation with hs-CRP. In the present study, magnesium as magnesium oxide, 250 mg/day, for 8 weeks did not significantly attenuate inflammatory markers in the magnesium group as compared to the placebo.
PMCID: PMC3685774  PMID: 23798918
Magnesium; middle-aged women; overweight; IL-6; hs-CRP; systemic inflammation
14.  The efficacy of magnesium sulfate loading on microalbuminuria following SIRS: One step forward in dosing 
Backgrounds
Magnesium has been known for its antioxidative and antiinflammatory properties in many studies. In this study two dosing regimens of magnesium were compared with a placebo control group in order to investigate safety and efficacy of high doses of intravenous magnesium sulfate infusion on critically ill trauma patients. Inflammatory and oxidative factors were measured in this trial.
Methods
45 trauma patients with systemic inflammatory response syndromes (SIRS) were randomly assigned into 2 treatment and one placebo groups. The high dose group received 15 g MgSO4, low dose group received 7.5 g of MgSO4 over 4 hour infusion, and placebo group received saline alone. The initial and post magnesium sulfate injections levels of tumor necrosis factor alpha (TNF-α), total antioxidant power and lipid peroxidation were measured after 6, 18 and 36 hours. The pre-infusion along with 6 and 36 hour level of microalbuminuria were also determined.
Results
Repeated measurements illustrated that there was no significant difference in TNF-α, total antioxidant power and lipid peroxidation levels among groups during the period of analysis. The microalbuminuria at 36 hour post infusion of high dose group was lower than that of control group (p = 0.024). Patient’s mortality (28 day) was similar among all treatment groups. Both magnesium infusion groups tolerated the drug without experiencing any complications.
Conclusion
No evidence for antioxidative and antiinflammatory effects of magnesium in traumatic SIRS positive patients was found. Magnesium in high doses may be recommended for traumatic patients with SIRS status to prevent microalbuminuria.
doi:10.1186/2008-2231-20-74
PMCID: PMC3556002  PMID: 23351890
Magnesium; Microalbumin; TNF-α; Oxidative stress; Trauma; Critical care
15.  Evaluation of IScore validity in a Greek cohort of patients with type 2 diabetes 
BMC Neurology  2013;13:121.
Background
Diabetes constitutes a risk factor for stroke that also aggravates stroke prognosis. Several prognostic models have been developed for the evaluation of neurologic status, severity, short-term functional outcome and mortality of stroke patients. IScore is a novel tool recently developed in order to predict mortality rates within 30 days and 1 year after ischemic stroke and diabetes is not included in the scoring scale of IScore. The aim of the present study was to evaluate and compare IScore validity in ischemic stroke patients with and without diabetes.
Methods
This prospective study included 312 consecutive Caucasian patients with type 2 diabetes and 222 Caucasian patients without diabetes admitted for ischemic stroke in a tertiary Greek hospital. Thirty-day and 1-year IScores were individually calculated for each patient and actual mortality was monitored at the same time intervals. IScore’s predictive ability and calibration was evaluated and compared for ischemic stroke patients with and without diabetes. The performance of IScore for predicting 30 and 1-year mortality between patients with and without diabetes was assessed by determining the calibration and discrimination of the score. The area under the receiver operating characteristic curve was used to evaluate the discriminative ability of IScore for patients with and without diabetes, whereas the calibration of IScore was assessed by the Hosmer–Lemeshow goodness-of fit statistic.
Results
Baseline population characteristics and mortality rates did not differ significantly for both cohorts. IScore values were significantly higher for patients with diabetes at 30 days and 1 year after ischemic stroke and patients with diabetes presented more frequently with lacunar strokes. Based on ROC curves analysis IScore’s predictive ability for 30 day mortality was excellent, without statistically significant difference, for both cohorts. Predictive ability for 1 year mortality was also excellent for both groups with significantly better ability for patients with diabetes especially at high score values. Calibration of the model was good for both groups of patients.
Conclusions
IScore accurately predicts mortality in acute ischemic stroke Caucasian patients with and without diabetes with higher efficacy in predicting 1 year mortality in patients with diabetes especially with high scores.
doi:10.1186/1471-2377-13-121
PMCID: PMC3852226  PMID: 24041109
IScore; Stroke; Ischemic stroke; Ischemic stroke mortality; Diabetes
16.  Uncovering Treatment Burden as a Key Concept for Stroke Care: A Systematic Review of Qualitative Research 
PLoS Medicine  2013;10(6):e1001473.
In a systematic review of qualitative research, Katie Gallacher and colleagues examine the evidence related to treatment burden after stroke from the patient perspective.
Please see later in the article for the Editors' Summary
Background
Patients with chronic disease may experience complicated management plans requiring significant personal investment. This has been termed ‘treatment burden’ and has been associated with unfavourable outcomes. The aim of this systematic review is to examine the qualitative literature on treatment burden in stroke from the patient perspective.
Methods and Findings
The search strategy centred on: stroke, treatment burden, patient experience, and qualitative methods. We searched: Scopus, CINAHL, Embase, Medline, and PsycINFO. We tracked references, footnotes, and citations. Restrictions included: English language, date of publication January 2000 until February 2013. Two reviewers independently carried out the following: paper screening, data extraction, and data analysis. Data were analysed using framework synthesis, as informed by Normalization Process Theory. Sixty-nine papers were included. Treatment burden includes: (1) making sense of stroke management and planning care, (2) interacting with others, (3) enacting management strategies, and (4) reflecting on management. Health care is fragmented, with poor communication between patient and health care providers. Patients report inadequate information provision. Inpatient care is unsatisfactory, with a perceived lack of empathy from professionals and a shortage of stimulating activities on the ward. Discharge services are poorly coordinated, and accessing health and social care in the community is difficult. The study has potential limitations because it was restricted to studies published in English only and data from low-income countries were scarce.
Conclusions
Stroke management is extremely demanding for patients, and treatment burden is influenced by micro and macro organisation of health services. Knowledge deficits mean patients are ill equipped to organise their care and develop coping strategies, making adherence less likely. There is a need to transform the approach to care provision so that services are configured to prioritise patient needs rather than those of health care systems.
Systematic Review Registration
International Prospective Register of Systematic Reviews CRD42011001123
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Every year, 15 million people have a stroke. About 5 million of these people die within a few days, and another 5 million are left disabled. Stroke occurs when the blood supply of the brain is suddenly interrupted by a blood vessel in the brain being blocked by a blood clot (ischemic stroke) or bursting (hemorrhagic stroke). Deprived of the oxygen normally carried to them by the blood, the brain cells near the blockage die. The symptoms of stroke depend on which part of the brain is damaged but include sudden weakness or paralysis along one side of the body, vision loss in one or both eyes, and confusion or trouble speaking or understanding speech. Anyone experiencing these symptoms should seek immediate medical attention because prompt treatment can limit the damage to the brain. In the longer term, post-stroke rehabilitation can help individuals overcome the physical disabilities caused by stroke, and drugs that thin the blood, reduce blood pressure and reduce cholesterol (major risk factors for stroke) alongside behavioral counseling can reduce the risk of a second stroke.
Why Was This Study Done?
Treatment for, and rehabilitation from, stroke is a lengthy process that requires considerable personal investment from the patient. The term “treatment burden” describes the self-care practices that patients with stroke and other chronic diseases must perform to follow the complicated management strategies that have been developed for these conditions. Unfortunately, treatment burden can overwhelm patients. They may be unable to cope with the multiple demands placed on them by health-care providers and systems for their self-care, a situation that leads to poor adherence to therapies and poor outcomes. For example, patients may find it hard to complete all the exercises designed to help them regain full movement of their limbs after a stroke. Treatment burden has been poorly examined in relation to stroke. Here, the researchers identify and describe the treatment burden in stroke by undertaking a systematic review (a study that uses predefined criteria to identify all the literature on a given topic) of qualitative studies on the patient experience of stroke management. Qualitative studies collect non-quantitative data so, for example, a qualitative study on stroke treatment might ask people how the treatment made them feel whereas a quantitative study might compare clinical outcomes between those receiving and not receiving the treatment.
What Did the Researchers Do and Find?
The researchers identified 69 qualitative studies dealing with the experiences of stroke management of adult patients and analyzed the data in these papers using framework synthesis—an approach that divides data into thematic categories. Specifically, the researchers used a coding framework informed by normalization process theory, a sociological theory of the implementation, embedding and integration of tasks and practices; embedding is the process of making tasks and practices a routine part of everyday life and integration refers to sustaining these embedded practices. The researchers identified four main areas of treatment burden for stroke: making sense of stroke management and planning care; interacting with others, including health care professionals, family and other patients with stroke; enacting management strategies (including enduring institutional admissions, managing stroke in the community, reintegrating into society and adjusting to life after stroke); and reflecting on management to make decisions about self-care. Moreover, they identified problems in all these areas, including inadequate provision of information, poor communication with health-care providers, and unsatisfactory inpatient care.
What Do These Findings Mean?
These findings show that stroke management is extremely demanding for patients and is influenced by both the micro and macro organization of health services. At the micro organizational level, fragmented care and poor communication between patients and clinicians and between health-care providers can mean patients are ill equipped to organize their care and develop coping strategies, which makes adherence to management strategies less likely. At the macro organizational level, it can be hard for patients to obtain the practical and financial help they need to manage their stroke in the community. Overall, these findings suggest that care provision for stroke needs to be transformed so that the needs of patients rather than the needs of health-care systems are prioritized. Further work is required, however, to understand how the patient experience of treatment burden is affected by the clinical characteristics of stroke, by disability level, and by other co-existing diseases. By undertaking such work, it should be possible to generate a patient-reported outcome measure of treatment burden that, if used by policy makers and health-care providers, has the potential to improve the quality of stroke care.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001473.
The US National Institute of Neurological Disorders and Stroke provides information about all aspects of stroke (in English and Spanish); its Know Stroke site provides educational materials about stroke prevention, treatment, and rehabilitation including personal stories (in English and Spanish); the US National Institutes of Health SeniorHealth website has additional information about stroke
The Internet Stroke Center provides detailed information about stroke for patients, families, and health professionals (in English and Spanish)
The UK National Health Service Choices website also provides information about stroke for patients and their families, including personal stories
MedlinePlus has links to additional resources about stroke (in English and Spanish)
The UK not-for-profit website Healthtalkonline provides personal stories about stroke
Wikipedia provides information on the burden of treatment and on the normalization process theory (note: Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)
doi:10.1371/journal.pmed.1001473
PMCID: PMC3692487  PMID: 23824703
17.  Selected acute phase CSF factors in ischemic stroke: findings and prognostic value 
BMC Neurology  2011;11:41.
Background
Study aimed at investigation of pathogenic role and prognostic value of several selected cerebrospinal fluid acute phase factors that can reflect the severity of ischemic brain damage.
Methods
Ninety five acute ischemic stroke patients were investigated. Ischemic region visualized at the twenty fourth hour by conventional Magnetic Resonance Imaging. Stroke severity evaluated by National Institute Health Stroke Scale. One month outcome of disease was assessed by Barthel Index. Cerebrospinal fluid was taken at the sixth hour of stroke onset. CSF pro- and anti-inflammatory cytokines were studied by Enzyme Linked Immunosorbent Assay. Nitric Oxide and Lipoperoxide radical were measured by Electron Paramagnetic Resonance. CSF Nitrate levels were detected using the Griess reagent. Statistics performed by SPSS-11.0.
Results
At the sixth hour of stroke onset, cerebrospinal fluid cytokine levels were elevated in patients against controls. Severe stroke patients had increased interleukin-6 content compared to less severe strokes (P < 0.05). Cerebrospinal fluid Electron Paramagnetic Resonance signal of nitric oxide was increased in patients against controls. Severe stroke group had an elevated Electron Paramagnetic Resonance signal of lipoperoxiradical compared to less severe stroke. Cerebrospinal fluid nitrate levels in less severe stroke patients were higher than those for severe stroke and control. Positive correlation was established between the initial interleukin-6 content and ischemic lesion size as well as with National Institute Health Stroke Scale score on the seventh day. Initial interleukin-6 and nitrate levels in cerebrospinal fluid found to be significant for functional outcome of stroke at one month.
Conclusion
According to present study the cerebrospinal fluid contents of interleukin-6 and nitrates seem to be the most reliable prognostic factors in acute phase of ischemic stroke.
doi:10.1186/1471-2377-11-41
PMCID: PMC3078848  PMID: 21450100
brain; ischemia; inflammation; oxidative stress
18.  Poor outcome in primary intracerebral haemorrhage: results of a matched comparison 
Postgraduate Medical Journal  2004;80(940):89-92.
Background: Primary intracerebral haemorrhage (PICH) is associated with a poorer outcome than cerebral infarction. This study aimed to determine whether this is explained by the clinical severity of stroke.
Methods: An observational study of outcome in consecutive admissions with acute PICH and ischaemic stroke was undertaken. A nested case-control analysis, matched on a 1:2 basis for age, pre-stroke disability, early neurological impairment (Scandinavian Stroke Scale; SSS), and Oxfordshire Community Stroke Project classification was then performed. Follow up was at 30 days and at hospital discharge.
Results: Overall, 679 subjects were included in the analysis. Of these, 53 (8%) had PICH; this group had more severe initial neurological impairment (day 3 SSS 28 v 45 points, p<0.001) and a higher prevalence of total anterior circulation strokes (55% v 21%, p<0.001) than did the group admitted with ischaemic strokes. Outcomes were poorer in the PICH group, with 36% inpatient mortality and 68% of survivors having a day 30 modified Rankin Scale (MRS) of at least 3 (compared with 13% and 52%, respectively, in the ischaemic stroke group). Following matching for baseline clinical characteristics, the PICH group had a higher mortality, but this was not statistically significant; the day 30 MRS and institutionalisation rates in survivors were similar in the matched haemorrhage and infarct groups.
Conclusions: Compared with ischaemic stroke, PICH is associated with higher mortality and increased disability in survivors. The severity of clinical stroke is a major contributor to these poor outcomes; baseline characteristics, however, do not fully explain outcome differences.
doi:10.1136/pmj.2003.010967
PMCID: PMC1742919  PMID: 14970296
19.  The Effect of Intravenous Magnesium Sulfate on Laryngospasm After Elective Adenotonsillectomy Surgery in Children 
Background:
Laryngospasm is the protective reflex of tracheobronchial tree against secretions and hemorrhage. This reflex is more prevalent in adenotonsillectomy in the presence of light anesthesia, which can lead to obstruction of airway, complications, and mortality. Different methods have been studied for preventing this complication; however, none of them could reliably prevent it.
Objectives:
The objective was to assess the effect of magnesium sulfate on laryngospasm and coughing after adenotonsillectomy.
Patients and Methods:
Seventy children with three to 12 years of age and ASA classes I and II, who were candidates for adenotonsillectomy, were recruited in this randomized clinical trial. The study group received 15 mg/kg intravenous magnesium sulfate and the control group received 0.9% normal saline with the same volume, 2 minutes after tracheal intubation via intravenous infusion for 20 minutes. After removing the endotracheal tube in the recovery room, the patients were assessed at minutes zero, 15, and 30in terms of laryngospasm and coughing. The assessment was based on four-point scale of severity of these complications and saturation percentage of arterial oxygen in operating and recovery room. After collecting the data, results were analyzed with the SPSS 16 software anda P value < 0.05 was considered statistically significant.
Results:
Laryngospasm was not found in the magnesium sulfate group; however, its incidencewas5.7% in the control group. The incidence rates of coughs were 17.1% and 40% in the magnesium sulfate group and in the control group, respectively, which had no statistically significant differences.
Conclusions:
Intravenous magnesium sulfate with dose of 15 mg/kg could not prevent laryngospasm and coughing after removal of the endotracheal tube in patients undergoing adenotonsillectomy; however, it reduced coughing and laryngospasm in the magnesium sulfate group compared with the control group.
doi:10.5812/aapm.15960
PMCID: PMC3961025  PMID: 24660159
Magnesium Sulfate; Laryngospasm; Surgical Procedures, Elective; Child
20.  Late Night Activity Regarding Stroke Codes: (LuNAR strokes) 
International Journal of Stroke  2011;7(6):473-476.
Background
There is diurnal variation for cardiac arrest and sudden cardiac death. Stroke may show a similar pattern. We assessed whether strokes presenting during a particular time of day or night are more likely of vascular etiology.
Aim
To compare emergency department stroke codes arriving between 10 pm and 8 am (LuNAR strokes) vs. others (n-LuNAR strokes). The purpose was to determine if late night strokes are more likely to be true strokes or warrant acute tissue plasminogen activator evaluations.
Methods
We reviewed prospectively collected cases in the University of California, San Diego Stroke Team database gathered over a four-year period. Stroke codes at six emergency departments were classified based on arrival time. Those arriving between 10 pm and 8 am were classified as LuNAR stroke codes, the remainder were classified as ‘n-LuNAR ’. Patients were further classified as intracerebral hemorrhage, acute ischemic stroke not receiving tissue plasminogen activator, acute ischemic stroke receiving tissue plasminogen activator, transient ischemic attack, and non-stroke. Categorical outcomes were compared using Fisher’s Exact test. Continuous outcomes were compared using Wilcoxon Rank-sum test.
Results
A total of 1607 patients were included in our study, of which, 299 (19%) were LuNAR code strokes. The overall median NIHSS was five, higher in the LuNAR group (n-LuNAR 5, LuNAR 7; p=0.022). There was no overall differences in patient diagnoses between LuNAR and n-LuNAR strokes (p=0.169) or diagnosis of acute ischemic stroke receiving tissue plasminogen activator (n-LuNAR191 (14.6%), LuNAR 42 (14.0%); p=0.86). Mean arrival to CT scan time was longer during LuNAR hours (n-LuNAR 54.9±76.3 mins, LuNAR 62.5±87.7 mins; p=0.027). There was no significant difference in 90 day mortality (n-LuNAR 15.0%, LuNAR 13.2%; p=0.45)
Conclusions
Our stroke center experience showed no difference in diagnosis of acute ischemic stroke between day and night stroke codes. This similarity was further supported in similar rates of tissue plasminogen activator administration. Late night strokes may warrant a more rapid stroke specialist evaluation due to the longer time elapsed from symptom onset and the longer time to CT scan.
doi:10.1111/j.1747-4949.2011.00610.x
PMCID: PMC3319328  PMID: 21714850
acute stroke therapy; cerebral infarction; epidemiology; ischaemic stroke; rtPA; stroke teams; thrombolysis; treatment
21.  Outcome Evaluation of Intravenous Infusion of Urokinase for Acute Ischemic Stroke 
Chonnam Medical Journal  2012;48(1):52-56.
The aim of this study was to evaluate the clinical effect of a continuous infusion of urokinase in cerebral stoke patients who were late admitted over 6 hours after onset. From January to December in 2008, acute cerebral stroke patients (n=143) treated with intravenous urokinase infusion (Group I, n=93) or not (Group II, n=50) after 6 hours and within 72 hours of stroke onset were reviewed. Continuous intravenous infusion of urokinase was done for 5 days. The clinical outcome for each patient was evaluated by using the modified National Institutes of Health Stroke Scale (NIHSS) on admission and on the day of discharge. The NIHSS score was decreased at discharge compared with admission in the urokinase treatment group (Group I; from 4.8±2.2 to 3.8±1.9; p=0.002). There was an improvement in the patients who initiated urokinase treatment within 24 hours from stroke onset in Group I (from 5.1±1.9 to 3.9±1.5; p=0.04). In patients with initiated urokinase treatment within 24 hours from stroke onset, intravenous urokinase infusion could be an effective modality in acute ischemic stroke patients admitted later than 6 hours after onset.
doi:10.4068/cmj.2012.48.1.52
PMCID: PMC3341438  PMID: 22570816
Stroke; Urokinase; Brain
22.  A double-blind, placebo-controlled study of the short term effects of a spring water supplemented with magnesium bicarbonate on acid/base balance, bone metabolism and cardiovascular risk factors in postmenopausal women 
BMC Research Notes  2010;3:180.
Background
A number of health benefits including improvements in acid/base balance, bone metabolism, and cardiovascular risk factors have been attributed to the intake of magnesium rich alkaline mineral water. This study was designed to investigate the effects of the regular consumption of magnesium bicarbonate supplemented spring water on pH, biochemical parameters of bone metabolism, lipid profile and blood pressure in postmenopausal women.
Findings
In this double-blind, placebo-controlled, parallel-group, study, 67 postmenopausal women were randomised to receive between 1500 mL and 1800 mL daily of magnesium bicarbonate supplemented spring water (650 mg/L bicarbonate, 120 mg/L magnesium, pH 8.3-8.5) (supplemented water group) or spring water without supplements (control water group) over 84 days. Over this period biomarkers of bone turnover (serum parathyroid hormone (PTH), 1,25-dihydroxyvitamin D, osteocalcin, urinary telopeptides and hydroxyproline), serum lipids (total cholesterol, HDL-cholesterol, LDL-cholesterol and triglycerides), venous and urinary pH were measured together with measurements of standard biochemistry, haematology and urine examinations.
Serum magnesium concentrations and urinary pH in subjects consuming the magnesium bicarbonate supplemented water increased significantly at Day 84 compared to subjects consuming the spring water control (magnesium - p = 0.03; pH - p = 0.018). The consumption of spring water led to a trend for an increase in parathyroid hormone (PTH) concentrations while the PTH concentrations remained stable with the intake of the supplemented spring water. However there were no significant effects of magnesium bicarbonate supplementation in changes to biomarkers of bone mineral metabolism (n-telopeptides, hydroxyproline, osteocalcin and 1,25-dihydroxyvitamin D) or serum lipids or blood pressure in postmenopausal women from Day 0 to Day 84.
Conclusions
Short term regular ingestion of magnesium bicarbonate supplemented water provides a source of orally available magnesium. Long term clinical studies are required to investigate any health benefits.
Trial registration
ACTRN12609000863235
doi:10.1186/1756-0500-3-180
PMCID: PMC2908636  PMID: 20579398
23.  High Dose Magnesium Infusions Are Not Associated With Increased Pressor Requirements After Carotid Endarterectomy 
Neurosurgery  2006;58(1):71-77.
INTRODUCTION
Although magnesium provides cerebral protection in animal stroke models, magnesium therapy has significant side effects in humans. Therefore, we sought to examine the incidence of α-agonist treated hypotension in our ongoing, prospective, randomized, double-blind, placebo-controlled Phase I/IIa dose escalation study of magnesium therapy in patients undergoing carotid endarterectomy.
METHODS
Eighty patients undergoing elective carotid endarterectomy were randomly assigned to a placebo control group (n = 38) or to one of the three intravenous magnesium groups. Magnesium levels were obtained before induction, and then 15 minutes, 1 hour, 2 hours, 6 hours, 12 hours, and 24 hours after a loading dose and infusion. After surgery, a target systolic blood pressure range was chosen, and the amount and duration of phenylephrine needed to maintain that pressure was compared across treatment groups.
RESULTS
All treatment groups achieved levels significantly different from baseline at 12 and 24 hours (P < 0.01). Magnesium treatment did not significantly increase the proportion of patients requiring pressure support. For those requiring pressure support, the amount and average duration of phenylephrine required was not different between control patients and those receiving magnesium, even when the individual minimum systolic blood pressures required were subdivided on the basis of dose of magnesium administered.
CONCLUSION
There were no significant differences detected in the 1) percentage of patients requiring pressor support, 2) the duration of postoperative pressor support, or 3) the amount of phenylephrine support needed between controls and magnesium treated patients. The percentage of patients requiring pressure support depended on the minimum systolic blood pressure ordered after surgery.
PMCID: PMC1449741  PMID: 16385331
Carotid endarterectomy; Cerebral protection; Hypotension; Magnesium; Phenylephrine
24.  Effects of Edaravone on Muscle Atrophy and Locomotor Function in Patients with Ischemic Stroke 
Drugs in R&d  2012;10(3):155-163.
Background and Objective: Stroke patients with severe leg paralysis are often bedridden in the acute and subacute phase, which increases the risk of disuse muscle atrophy in the chronic phase. The evidence to date indicates that oxidative stress plays an important role in the mechanism of disuse muscle atrophy. Therefore, the aim of this study was to determine if long-term radical scavenger treatment with edaravone following an acute stroke prevents the progression of disuse muscle atrophy and improves leg locomotor function in the chronic phase.
Methods: This randomized controlled pilot study was conducted at 19 acute stroke and rehabilitation centers across Japan. Forty-seven ischemic stroke patients with at least leg motor weakness admitted within 24 hours of onset were randomly assigned to receive continuous intravenous infusions of edaravone 30 mg twice daily for 3 days (short-term group) or 10–14 days (long-term group). The primary endpoints of the study included the degree of leg disuse muscle atrophy, as measured by the percentage change from baseline in femoral muscle circumference 15 cm above the knee, and the improvement in leg locomotor function, as assessed by the maximum walking speed over 10 m, 3 months after the onset of stroke.
Results: Three-month follow-up was completed by a total of 41 patients (21 in the short-term group and 20 in the long-term group). On admission, there was no significant difference in the severity of stroke or the grade of leg paresis between the two treatment groups. The grade of disuse muscle atrophy and incidence of gait impairment 3 weeks after stroke onset were also similar between the short- and long-term groups. However, disuse muscle atrophy of the paretic and non-paretic legs was significantly less severe in the long-term versus the short-term treatment group (3.6±5.9% and 1.5±6.0% vs 8.3±5.2% and 5.7±6.4%; p<0.01 and p<0.05) 3 months after stroke onset. Additionally, the maximum walking speed over a distance of 10 m was significantly greater in the long-term group (98±67 vs 54±55 cm/sec; p<0.05).
Conclusion: Edaravone treatment for up to 14 days suppresses the progression of disuse muscle atrophy and improves leg locomotor function to a greater extent than shorter-term treatment in acute stroke patients. This suggests that the management of stroke may be improved with long-term edaravone therapy by providing myoprotective effects that ameliorate functional outcome in the chronic phase.
doi:10.2165/11586550-000000000-00000
PMCID: PMC3585769  PMID: 20945946
25.  Transient Ischemic Attack Before Nonlacunar Ischemic Stroke in the Elderly 
Background:
Several studies suggest transient ischemic attack (TIA) may be neuroprotective against ischemic stroke analogous to preinfarction angina's protection against acute myocardial infarction. However, this protective ischemic preconditioning-like effect may not be present in all ages, especially among the elderly. The purpose of this study was to determine the neuroprotective effect of TIAs (clinical equivalent of cerebral ischemic preconditioning) to neurologic damage after cerebral ischemic injury in patients over 65 years of age.
Methods:
We reviewed the medical charts of patients with ischemic stroke for presence of TIAs within 72 hours before stroke onset. Stroke severity was evaluated by the National Institutes of Health Stroke Scale and disability by a modified Rankin scale.
Results:
We evaluated 203 patients (≥65 years) with diagnosis of acute ischemic stroke and categorized them according to the presence (n = 42, 21%) or absence (n = 161, 79%) of TIAs within 72 hours of stroke onset. Patients were monitored until discharged from the hospital (length of hospital stay 14.5 ± 4.8 days). No significant differences in the National Institutes of Health Stroke Scale and modified Rankin scale scores were observed between those patients with TIAs and those without TIAs present before stroke onset at admission or discharge.
Conclusion:
These results suggest that the neuroprotective mechanism of cerebral ischemic preconditioning may not be present or functional in the elderly.
doi:10.1016/j.jstrokecerebrovasdis.2008.03.004
PMCID: PMC2676578  PMID: 18755403
Cerebral ischemic preconditioning; transient ischemic attack; elderly; stroke

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