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1.  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
2.  Magnesium for neuroprotection in birth asphyxia 
Background:
Magnesium ion gates the N-methyl-D-aspartate (NMDA) receptor and may protect the brain from NMDA receptor-mediated asphyxial injury. The present study evaluated the neuroprotective role of magnesium in birth asphyxia.
Material and Methods:
Forty term neonates with severe birth asphyxia were randomized to either the study group or the control group. Neonates in the study group received magnesium sulfate in a dose of 250 mg/kg initially within half an hour of birth followed by 125 mg/kg at 24 and 48 h of birth. Cranial computed tomography (CT) scan and electroencephalography (EEG) were performed for all the babies. Denver II was used for developmental assessment at the age of 6 months.
Results:
Two babies in each group died of severe hypoxic ischemic encephalopathy. EEG abnormalities occurred in 43.75% of the cases in the control group compared with 31.25% in the study group. CT scan abnormalities were present in 62.5% of the control group compared with 37.5% of the cases in the study group. The Denver II assessment at 6 months revealed that there were five babies that were either abnormal or suspect in the control group compared with three in the study group.
Conclusion:
Magnesium is well tolerated and does appear to have beneficial effects in babies with severe asphyxia. More data is however needed and a large multicenter trial should be conducted.
doi:10.4103/1817-1745.76094
PMCID: PMC3087983  PMID: 21559152
Asphyxia; magnesium; neuroprotection
3.  A Comparative Study to Determine the Effect of Intravenous Magnesium on Postoperative Bleeding after on Pump CABG in Patients Receiving Pre-Operative Aspirin 
Indian Journal of Anaesthesia  2009;53(2):197-203.
Summary
Hypomagnesaemia is a common complication after cardiopulmonary bypass (CPB) and predisposes to the development of cardiac arrhythmias. Previous studies showed that intravenous magnesium reduces the incidence of postoperative cardiac arrhythmias but it also inhibits platelet function. Our aim was to compare the postoperative blood loss in patients not receiving magnesium after CPB with the group who received magnesium and to compare the requirement of blood, fresh frozen plasma (FFP) and platelets within 24 hours after surgery. This prospective randomized controlled study was conducted in 80 adult patients on oral aspirin undergoing elective CABG requiring CPB. Group A patients had not received magnesium infusion after recovery from CPB. Group B patients received magnesium infusion after recovery from CPB. Postoperative bleeding was assessed in both the groups. All the data were statistically analyzed. There was a insignificant increase in 24 hours postoperative drainage in magnesium recipient group compared to control group (p>0.05). Requirements of blood and blood products to maintain haematocrit and coagulation profile revealed insignificant (p > 0.05). Increase in requirement of PRC, FFP and platelets in magnesium recipient patients than the control group. Incidence of atrial fibrillation (Gr A 2.5%, Gr B 2.5%) and atrial extrasystoles (Gr A 2.5%, Gr B 10%) revealed comparable (p > 0.05) between the groups, but incidence of ventricular arrhythmias were significantly (p<0.05) high in the patients of Gr A(17.5%) than Gr B(5%). To conclude, magnesium may be administered to patients who continue pre-operative aspirin to undergo on-pump CABG surgery.
PMCID: PMC2900106  PMID: 20640123
Aspirin; Magnesium; CPB; CABG; Postoperative bleeding
4.  The Impact of Magnesium Sulfate Therapy on Angiogenic Factors in Preeclampsia 
Pregnancy hypertension  2012;2(1):16-21.
Objective
The objective was to evaluate whether intravenous magnesium sulfate (magnesium) alters levels of angiogenic factors in women with preeclampsia.
Study Design
This was a prospective cohort study comparing women with preeclampsia treated with magnesium for seizure prophylaxis to those who were not. Serum levels of angiogenic factors, soluble fms-like tyrosine kinase 1, soluble endoglin and placental growth factor, were measured at the time of diagnosis and approximately 24 hours later. Secondary analysis compared women receiving magnesium for preeclampsia to women receiving magnesium for preterm labor. Analysis of covariance was used to compare levels at 24 hours, adjusting for levels at enrollment and potential confounders.
Results
Angiogenic factor levels did not differ between preeclampsia groups with and without magnesium or between preeclampsia and preterm labor groups treated with magnesium (all P > 0.05).
Conclusion
Magnesium likely decreases seizure risk in preeclampsia by a mechanism other than altering angiogenic factor levels.
doi:10.1016/j.preghy.2011.08.118
PMCID: PMC3254114  PMID: 22247820
angiogenic factors; magnesium sulfate; preeclampsia; pregnancy; toxemia
5.  Retrospective study of Heparin Administration for Ischemic Stroke when there is an IV-tPA Contraindication 
Background:
The majority of patients presenting with an ischemic stroke arrive after the 3-4.5 h time window allowed for intravenous tissue plasminogen activator (IV tPA) administration. Most of the literature on heparin use in acute ischemic stroke does not describe dose-adjusted intravenous unfractionated heparin (IV UFH) without bolus, a common method of administration. This study was designed to test whether an anticoagulation regimen of intravenous dose-adjusted UFH with no bolus, in patients with a contraindication to IV TPA, administered within 24 h of an acute ischemic stroke could be effective and safe.
Methods:
We conducted a retrospective study of 273 patients over two consecutive years with acute ischemic stroke, who were outside the window for IV tPA. All patients had imaging studies on admission. The primary outcome measure of the study was to evaluate the safety of dose-adjusted IV UFH use in the setting of acute stroke. We looked at duration of heparin infusion, average partial thromboplastin time (PTT) value, and the incidence of new hemorrhagic events.
Results:
A total of 273 patients met the inclusion criteria. These patients received heparin infusion within 24 h of symptom onset. The duration of intravenous heparin infusion ranged from 1 to 18 days with a mean of 4 days. Mean PTT value was 72.4. Hemorrhagic complications occurred in 26 patients (9.5%), and included 12 asymptomatic petechial or hemorrhagic conversion (4.3%), 2 symptomatic intracranial hemorrhages (0.7%), 5 gastrointestinal bleeds (2 requiring transfusion and interventions), 2 patients experienced benign hematuria, 4 patients with groin hematomas, and one neck hematoma.
Conclusion:
This study suggests that intravenous dose-adjusted UFH with no bolus can be administered to patients with acute ischemic stroke with relative safety.
doi:10.4103/2152-7806.132032
PMCID: PMC4078448  PMID: 24991465
Anticoagulation; hemorrhagic complications; heparin; intravenous tissue plasminogen activator; stroke
6.  The effect of acute magnesium loading on the maximal exercise performance of stable chronic obstructive pulmonary disease patients 
Clinics  2012;67(6):615-621.
OBJECTIVE:
The potential influence of magnesium on exercise performance is a subject of increasing interest. Magnesium has been shown to have bronchodilatatory properties in asthma and chronic obstructive pulmonary disease patients. The aim of this study was to investigate the effects of acute magnesium IV loading on the aerobic exercise performance of stable chronic obstructive pulmonary disease patients.
METHODS:
Twenty male chronic obstructive pulmonary disease patients (66.2±8.3 years old, FEV1: 49.3±19.8%) received an IV infusion of 2 g of either magnesium sulfate or saline on two randomly assigned occasions approximately two days apart. Spirometry was performed both before and 45 minutes after the infusions. A symptom-limited incremental maximal cardiopulmonary test was performed on a cycle ergometer at approximately 100 minutes after the end of the infusion. ClinicalTrials.gov: NCT00500864
RESULTS:
Magnesium infusion was associated with significant reductions in the functional residual capacity (-0.41 l) and residual volume (-0.47 l), the mean arterial blood pressure (-5.6 mmHg) and the cardiac double product (-734.8 mmHg.bpm) at rest. Magnesium treatment led to significant increases in the maximal load reached (+8 w) and the respiratory exchange ratio (0.06) at peak exercise. The subgroup of patients who showed increases in the work load equal to or greater than 5 w also exhibited significantly greater improvements in inspiratory capacity (0.29 l).
CONCLUSIONS:
The acute IV loading of magnesium promotes a reduction in static lung hyperinflation and improves the exercise performance in stable chronic obstructive pulmonary disease patients. Improvements in respiratory mechanics appear to be responsible for the latter finding.
doi:10.6061/clinics/2012(06)12
PMCID: PMC3370314  PMID: 22760901
Pulmonary Disease; Chronic Obstructive; Magnesium; Cardiopulmonary Exercise Test; Spirometry; Blood Pressure; Circulatory and Respiratory Physiology
7.  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
8.  Neuroprotective Effects of Erythropoietin in Acute Ischemic Stroke 
International Journal of Preventive Medicine  2013;4(Suppl 2):S306-S312.
Background:
Ischemic brain strokes consisttwo-thirdsof strokesand their complications bear a lot of disability for patient and society. In this study, we seek for effect of Erythropoietin on ischemic brain stroke's outcomes according to National Institutes of Health Stroke Scale (NIHSS) changes.
Methods:
This study is a RCT (randomized clinical trial). All patients with focal neurologic deficit with primary suspicion of brain stroke undergone neuroimaging evaluations. After confirmation of new ischemic brain stroke, the patients with inclusion criteria’srandomized into two groups of cases and controls.
NIHSS was defined for each patient and all patients received a routine treatment protocol. Erythropoietin 16,000 IU as a bolus intravenous dose was given to case patients as soon as neuroimaging study confirmed new ischemic stroke and continued as 8000 IU each 12 h up to total dose of 56,000 IU during 3 days. Patients re-evaluated at days 14 and 28 and NIHSS was assessed by another neurologist blinded to patient's group. Finally, NIHSS changes of both groups compared with each other's.
Results:
Evaluations revealed that in days14 and 28 during follow-up, Erythropoietin was effective in NIHSS (P= 0.0001). This effect was of value in level of consciousness Commands (P= 0.024), facial palsy (P= 0.003), motor arm (P= 0.0001), motor leg (P= 0.0001), sensory (P= 0.009), and best language (P= 0.023).
Conclusions:
Administration of high-dose erythropoietin in first 24 h can be effective on reduction of ischemic stroke complication. A larger scale clinical trial is warranted.
PMCID: PMC3678237  PMID: 23776743
Erythropoietin; national institutes of health stroke scale; neuroprotection; stroke
9.  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
10.  A Randomized, Controlled Trial of Magnesium Sulfate for the Prevention of Cerebral Palsy 
The New England journal of medicine  2008;359(9):895-905.
BACKGROUND
Research suggests that fetal exposure to magnesium sulfate before preterm birth might reduce the risk of cerebral palsy.
METHODS
In this multicenter, placebo-controlled, double-blind trial, we randomly assigned women at imminent risk for delivery between 24 and 31 weeks of gestation to receive magnesium sulfate, administered intravenously as a 6-g bolus followed by a constant infusion of 2 g per hour, or matching placebo. The primary outcome was the composite of stillbirth or infant death by 1 year of corrected age or moderate or severe cerebral palsy at or beyond 2 years of corrected age.
RESULTS
A total of 2241 women underwent randomization. The baseline characteristics were similar in the two groups. Follow-up was achieved for 95.6% of the children. The rate of the primary outcome was not significantly different in the magnesium sulfate group and the placebo group (11.3% and 11.7%, respectively; relative risk, 0.97; 95% confidence interval [CI], 0.77 to 1.23). However, in a prespecified secondary analysis, moderate or severe cerebral palsy occurred significantly less frequently in the magnesium sulfate group (1.9% vs. 3.5%; relative risk, 0.55; 95% CI, 0.32 to 0.95). The risk of death did not differ significantly between the groups (9.5% vs. 8.5%; relative risk, 1.12; 95% CI, 0.85 to 1.47). No woman had a life-threatening event.
CONCLUSIONS
Fetal exposure to magnesium sulfate before anticipated early preterm delivery did not reduce the combined risk of moderate or severe cerebral palsy or death, although the rate of cerebral palsy was reduced among survivors. (ClinicalTrials.gov number, NCT00014989.)
doi:10.1056/NEJMoa0801187
PMCID: PMC2803083  PMID: 18753646
11.  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
12.  Magnesium: Potential Roles in Neurovascular Disease 
Objective: Magnesium therapy has been studied extensively in pre-clinical and clinical trials in multiple organ systems. Cerebrovascular diseases may benefit from its neuroprotective properties. This review summarizes current studies of magnesium in a wide range of neurovascular diseases.
Methods: We searched relevant terms in the National Library of Medicine PubMed database and selected research including basic science, translational reports, meta-analyses, and clinical studies.
Results: Studies examining magnesium administration in ischemic stroke have failed to show any benefit in clinical outcome. Data on magnesium for intracerebral hemorrhage (ICH) are limited. Preliminary investigations in subarachnoid hemorrhage (SAH) were promising, but definitive studies did not reveal differences in clinical outcome between magnesium and placebo-treated groups. Studies examining magnesium administration in global ischemia following cardiac arrest suggest a trend toward improved clinical outcome. The strongest evidence for clinically relevant neuroprotection following magnesium administration derives from studies of pre-term infants and patients undergoing cardiac bypass and carotid endarterectomy procedures. Magnesium was found to have an excellent safety profile across all investigations.
Conclusion: Magnesium is easy to administer and possesses a favorable safety profile. Its utility as a neuroprotectant in cardiac surgery, carotid endarterectomy, and pre-term infant hypoxia remain promising. Value as a therapeutic agent in ischemic stroke, ICH, and SAH is unclear and appears to be limited by late administration. Ongoing clinical trials assessing magnesium administration in the first hours following symptom onset may help clarify the role of magnesium therapy in these disease processes.
doi:10.3389/fneur.2014.00052
PMCID: PMC3995053  PMID: 24782823
magnesium; neuroprotection; intracerebral hemorrhage; subarachnoid hemorrhage; all cerebrovascular disease/stroke
13.  Effects of preoperative magnesium therapy on arrhythmias and myocardial ischemia during off-pump coronary surgery 
Annals of Thoracic Medicine  2009;4(3):137-139.
BACKGROUND:
Heart manipulation during off-pump coronary artery bypass surgery may cause hemodynamic instability, and temporary coronary arterial occlusion may lead to myocardial ischemia. To reduce this, perioperative β-blocking agents or calcium antagonists can be administrated. The effects of perioperative administration of magnesium on myocardial function were studied in patients undergoing coronary artery bypass grafting.
OBJECTIVE:
The aim of the study was to evaluate the effects of preoperative magnesium administration on perioperative hemodynamia, ventricular arrhythmias and myocardial protection.
MATERIALS AND METHODS:
We reviewed 2 groups of patients undergoing off-pump coronary artery bypass surgery – 24 patients (control group) that had not received preoperative intravenous infusion of magnesium and 23 patients (treatment group) that had received preoperative intravenous magnesium sulfate.
RESULTS:
The results demonstrated that it had reduced the heart rate, changes of ST segments, the need of β-blocking agents and the use of intra-operative intra-aortic balloon pump and the inotropic usage.
CONCLUSION:
This treatment may provide hemodynamic optimization during off-pump coronary artery bypass.
doi:10.4103/1817-1737.53355
PMCID: PMC2714568  PMID: 19641645
Ischemia and arrhythmia; magnesium effects; off-pump coronary surgery
14.  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
15.  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
16.  Stroke Outcomes in Thai Elderly Patients Treated with and without Intravenous Thrombolysis 
Neurology International  2013;5(3):e15.
Higher mortality was found in very old patients with acute ischemic stroke treated with intravenous recombinant tissue-plasminogen activator (rtPA) as compared to younger patients. The benefit of thrombolytic treatment in this particular subgroup is still a subject of debate. The purpose of this study was to compare stroke outcomes in Thai patients aged over 70 years treated with and without intravenous rtPA. This was a retrospective review of sequential cases and was not a randomized controlled study. One-hundred and five patients with acute ischemic stroke aged over 70 years who were treated with intravenous rtPA and 105 patients without rtPA treatment (control group) were included in the study. Patients’ base-line characteristics and study outcomes of interest were compared. There were significant differences in the base-line characteristics of the two groups. However, for the subgroup of patients aged over 80 years, these characteristics were similar. Those who were treated with intravenous rtPA had a higher rate of favorable outcomes (40% vs 16%; P=0.137) and a lower rate of mortality (22% vs 44%; P=0.128) than patients who did not receive rtPA treatment. In well-matched subgroups of patients aged over 80 years, our retrospective review revealed there was a trend of a higher rate of favorable outcome and lower mortality in patients receiving rtPA treatment. More study is needed to further confirm the suggested benefit of thrombolysis in Asian octogenarian acute stroke patients.
doi:10.4081/ni.2013.e15
PMCID: PMC3794450  PMID: 24147212
thrombolysis; stroke; aging; Asian; Thai
17.  Role of magnesium sulfate in aneurysmal subarachnoid hemorrhage management: A meta-analysis of controlled clinical trials 
Asian Journal of Neurosurgery  2011;6(1):26-31.
Background:
There has been longstanding controversy over the use of magnesium sulfate infusion in the medical management of aneurysmal subarachnoid hemorrhage (SAH). Several clinical trials evaluating the beneficial effects of magnesium on cerebral vasospasm and their poor outcome have been published. However, results from the majority of these studies have been inconclusive. This meta-analysis was performed to evaluate the effectiveness of magnesium on patient outcomes after aneurysmal SAH.
Materials and Methods:
PubMed and the Cochrane library were searched for controlled clinical trials assessing the efficacy of magnesium sulfate infusion after aneurysmal SAH. Eight studies consisting of 936 patients were included.
Results:
There was a decreased risk of poor outcome at 3–6 months after SAH in magnesium treatment groups when compared to placebo [0.78 (95% CI 0.66–0.93)]. Poor outcome was defined as severe disability, persistent vegetative state, or death, as measured by the Glasgow outcome scale (GOS), extended Glasgow outcome scale (GOSE) or modified Rankin scale (mRS). The risk of mortality after SAH was unaffected by magnesium treatment [RR 0.68 (95% CI 0.58–1.27)].
Conclusion:
Magnesium sulfate infusion decreases risk of poor outcome after aneurysmal SAH. Current studies in the literature do not suggest a role for magnesium sulfate in mortality reduction after SAH.
doi:10.4103/1793-5482.85632
PMCID: PMC3205548  PMID: 22059101
Cerebral vasospasm; delayed cerebral ischemia; magnesium sulfate; subarachnoid hemorrhage
18.  Effect of clonidine and magnesium sulphate on anaesthetic consumption, haemodynamics and postoperative recovery: A comparative study 
Indian Journal of Anaesthesia  2010;54(2):137-141.
This randomised, placebo-controlled, double-blind study was designed to assess the effect of intravenous clonidine and magnesium sulphate on intraoperative haemodynamics, anaesthetic consumption and postoperative recovery. Seventy five patients undergoing elective upper limb orthopaedic surgery were randomised into three groups. Group C received clonidine 3 μg/kg as a bolus before induction and 1μg/kg/hour by infusion intraopertively. Group M received magnesium sulphate 30 mg/kg as a bolus before induction and 10 mg/kg/hour by infusion. Group P received same volume of isotonic saline. Anaesthesia was induced and maintained with fentanyl citrate and propofol. Muscular relaxation was achieved by vecuronium bromide. Induction time, recovery time and consumption of propofol as well as fentanyl citrate were recorded. Induction of anaesthesia was rapid with both clonidine and magnesium sulphate. Time of bispectral index (BIS) to reach 60 was significantly lower in Group C and Group M (P < 0.0001). Requirements of propofol and fentanyl were significantly less in Group C and Group M (P < 0.001). Postoperative recovery was slower in Group M compared with other two groups (P < 0.001). Perioperative use of both clonidine and magnesium sulphate significantly reduced the consumption of propofol and fentanyl citrate. Magnesium sulphate caused a delayed recovery.
doi:10.4103/0019-5049.63659
PMCID: PMC2900737  PMID: 20661352
Anaesthetic consumption; bispectral index; clonidine; magnesium sulphate
19.  Early Anticipation of Candidacy for Intra-Arterial Reperfusion Therapy Based on Baseline Clinical Stroke Subtypes: Comparison with Multiparametric MRI Taken within 4.5 Hours from Stroke Onset 
Background
The decision to proceed with intra-arterial (IA) reperfusion therapy is typically made late in the course of in-hospital treatment for acute ischemic stroke. Early anticipation of candidacy for IA reperfusion therapy based on clinical stroke subtypes would be useful for guiding stroke management. The aim of this study was to investigate the relationship between the clinical Oxfordshire Community Stroke Project (OCSP) classification and MRI results taken within a 4.5-hour time window from stroke onset, with the hypothesis that the persistence of major arterial occlusion and extended ischemic penumbra, key criteria for proceeding with IA reperfusion therapy, would be distinctive between the clinical stroke subtypes.
Methods
A total of 161 patients with acute ischemic stroke in the anterior circulation were included in this study. All patients were treated with intravenous alteplase, and MRI scans were performed following alteplase initiation. Prior to treatment, the patients were categorized, based on the OCSP classification scheme, as having total anterior circulation infarcts (TACI), partial anterior circulation infarcts (PACI), or lacunar infarcts (LACI). The relationship between OCSP subtypes, MRI parameters, and clinical variables was analyzed.
Results
Overall, 40/161 patients (24.8%) were candidates for IA rescue reperfusion. With respect to the classification, 30/69 TACI (43.5%), 6/33 PACI (18.2%), and 4/59 LACI patients (6.8%) were candidates (p < 0.001). Major arterial occlusion was found in 56/161 patients (34.8%), and 46/69 TACI (66.7%), 6/33 PACI (18.2%), and 4/59 LACI patients (6.8%) had a major arterial occlusion (p < 0.001). A perfusion-diffusion mismatch greater than 20% was found in 85/161 patients (52.8%). More specifically, 40/69 TACI (58.0%), 25/33 PACI (75.8%), and 20/59 LACI patients (33.9%) had a perfusion-diffusion mismatch (p < 0.001). However, in terms of the total area of mismatch, 66.0% of patients with ASPECTSDWI-PWI ≥2 (Alberta Stroke Program Early CT Score) were classified as TACI patients (p < 0.001) and of the patients with ASPECTSDWI-PWI ≥3, 74.3% were classified as TACI patients (p < 0.001). Relative to candidates for IA rescue reperfusion, the clinical TACI group showed 75.0% sensitivity, 67.8% specificity, a positive predictive value of 43.5%, and a negative predictive value of 89.1%.
Conclusions
In this study, patients classified as having clinical TACI were significantly more likely to be candidates for IA rescue reperfusion. Additionally, they incurred a higher incidence of persistent major arterial occlusion and had a penumbra area that was significantly larger than normal. Therefore, clinical OCSP can be used as an ‘early warning system’ for IA reperfusion candidacy, which can allow for advanced preparation of IA therapy and theoretically shorten treatment time and reduce infarction.
doi:10.1159/000353130
PMCID: PMC3711001  PMID: 23885261
Acute stroke; Thrombolysis; Clinical stroke syndromes; Oxfordshire Community Stroke Project classification; MRI

20.  Evaluation of single epidural bolus dose of magnesium as an adjuvant to epidural fentanyl for postoperative analgesia: A prospective, randomized, double-blind study 
Saudi Journal of Anaesthesia  2012;6(3):273-278.
Objective:
Magnesium has been used as an adjuvant by various routes, including intravenous, intrathecal, and epidural in different dosage regimens. The effect of single bolus dose of magnesium as an adjuvant to fentanyl for postoperative analgesia has not been studied. This prospective randomized controlled trial was done to evaluate the efficacy of single bolus administration of magnesium epidurally as an adjuvant to epidural fentanyl for postoperative analgesia in patients undergoing total hip replacement under combined spinal epidural anesthesia.
Methods:
Sixty patients received combined spinal–epidural anesthesia with 2 mL of 0.5% hyperbaric bupivacaine intrathecally. After the surgery, patients were randomized into Group F [epidural fentanyl (1 μg/kg) in 10 mL saline] and Group FM [epidural magnesium (75 mg) along with fentanyl (1 μg/kg) in 10 mL saline]. Supplementary analgesia was provided by 50 mg intravenous tramadol if Verbal Rating Score (VRS) >4. Patient's first analgesic requirement and duration of analgesia were recorded.
Results:
The duration of analgesia was significantly longer for Group FM, 340±28.8 min, compared with Group F, 164±17.1 min (P=0.001). The frequency of rescue analgesics required in 24-h postoperative period in Group FM (2.3±0.5) was significantly less than that in Group F (4.3±0.5) (P=0.001). VRS was significantly lower in Group FM up to 4 h in the postoperative period (P=0.001). Bromage scale was statistically insignificant at all points of time.
Conclusions:
The administration of magnesium (75 mg) as an adjuvant to epidural fentanyl (1 μg/ kg) for postoperative analgesia results in significantly lower VRS with prolonged duration of analgesia as compared with epidural fentanyl (1 μg/kg) alone. Concomitant administration of magnesium also reduces the requirement of breakthrough analgesics with no increased incidence of side effects.
doi:10.4103/1658-354X.101221
PMCID: PMC3498668  PMID: 23162403
Epidural; magnesium; N-methyl-d-aspartate receptor; post operative pain; rescue analgesia
21.  Magnesium Sulfate for Severe Acute Asthma in Children 
Magnesium is an abundant intracellular cation that has been used for years in the treatment of hyper-tension and seizures associated with eclampsia of pregnancy as well as used as a tocolytic agent.1 Over sixty years ago, Haury showed that magnesium sulfate (MgSO4) could produce bronchodilation in asthmatics.2 However, interest in magnesium sulfate as a potential therapy for acute asthma surfaced in the late 1980s following a series of studies demonstrating that magnesium produced dose-dependent bronchodilation. The precise mechanism by which magnesium produces smooth muscle relaxation is not known, but it is thought to act by enhancing calcium uptake in the sarcoplasmic reticulum3 and/or as a calcium antagonist.4 In addition, magnesium is a cofactor regulating a number of enzymatic and cellular activities in the body, including adenyl cyclase and sodium-potassium ATP-ase, potentially enhancing the effects of β2-agonists.5 Other potential beneficial mechanisms in asthma include inhibition of acetylcholine release from cholinergic nerves6 and reduction of histamine release from mast cells.7
It is not clear whether magnesium acts as a functional antagonist to bronchoconstriction like the β2-agonists and theophylline or a specific antagonist like anticholinergics and antihistamines. Studies showing attenuation of the bronchoconstriction from histamine and methacholine would suggest functional antagonism.8,9 Some suggest that the response to intravenous magnesium sulfate is dependent upon achieving serum magnesium concentrations of 4–6 mg/dL (1.6–2.4 mmol/L).10 These values are similar to those that are employed to achieve tocolysis (4–8 mg/dL) and about one half those associated with severe toxicity of respiratory failure, cardiac arrhythmias and death (12–15 mg/ dL).1 It should be pointed out that studies have not reported lower magnesium concentrations in asthmatics than controls although one study reported correlation with bronchial hyperresponsiveness and intracellular magnesium concentrations in asthmatics. 11–13 Thus, it is unlikely that the bronchodilator response to magnesium is a result of restoring normal homeostasis but most likely a function of its direct antagonistic effects on intracellular calcium activity.
doi:10.5863/1551-6776-8.1.40
PMCID: PMC3469115  PMID: 23300395
magnesium; asthma
22.  Un-witnessed Stroke: Impact of Different Onset Times on Eligibility into Stroke 
Background
Patients with un-witnessed stroke represent over 25% of all strokes. Clinical trials enrolling patients with un-witnessed stroke onset have conservatively used ‘last known normal’ (LKN) as the time of stroke onset. We explored the impact of alternative methods of selecting onset time in un-witnessed strokes on eligibility into an acute stroke therapeutic trial using a representative sample of acute stroke subjects.
Methods
We analyzed data on 641 consecutive patients with suspected stroke presenting to our hospital from January 2007 to July 2008. Time of onset was calculated by three methods: (1) LKN, (2) first known abnormal (FKA), (3) midpoint between LKN and FKA. Subjects with incomplete data or a non-ischemic stroke final diagnosis were excluded. Rates of trial eligibility based on different onset times were compared for several inclusion time windows.
Results
Onset time was known in 440 subjects (69%). Of the remaining 201 patients with un-witnessed onset, 114 (57%) were ‘wake-up’ strokes. Among un-witnessed stroke subjects, eligibility increased from 18% using LKN to 57% using FKA at 4.5 hours and 42% to 81% at 9 hours (p<0.001), respectively. Overall enrollment eligibility for the full cohort increased from 36% to 48% at 4.5 hours and 61% to 73% at 9 hours (p<0.001), respectively.
Conclusion
Given potential advantages in safety evaluation and the historical inadequate enrollment rates in acute stroke trials, alternative onset time definitions, perhaps in combination with advanced neuroimaging methods (e.g. FLAIR-DWI mismatch), should be considered for early-phase trials.
doi:10.1016/j.jstrokecerebrovasdis.2011.08.004
PMCID: PMC3718254  PMID: 21917477
stroke; trials; time; onset; enrollment
23.  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
24.  Safety of intravenous administration of hydrogen-enriched fluid in patients with acute cerebral ischemia: initial clinical studies 
Medical Gas Research  2013;3:13.
Background
Most of the results regarding hydrogen (H2) therapy for acute cerebral ischemia are derived from in vitro studies and animal experiments, with only a few obtained from human trials with a limited number of subjects. Thus, there is a paucity of information regarding both the beneficial therapeutic effects as well as the side effects of H2 on acute cerebral ischemia in humans. We designed a pilot study to investigate single dose intravenous H2-administration in combination with edaravone, aiming to provide an initial estimate of the possible risks and benefits in select patients presenting with acute ischemic stroke.
Methods
An open-label, prospective, non-randomized study of intravenous H2-administration was performed in 38 patients hospitalized for acute ischemic stroke. All patients received an H2-enriched intravenous solution in addition to edaravone immediately after the diagnosis of acute ischemic stroke. Acute stroke patients within 3 h of onset received intravenous tissue plasminogen activator (t-PA) (0.6 mg/kg) treatment, and patients receiving t-PA had to commence the administration of the H2-enriched intravenous solution and edaravone before or at the same time as the t-PA was infused.
Results
Complications were observed in 2 patients (5.3%), which consisted of diarrhea in 1 patient (2.6%) and cardiac failure in 1 patient (2.6%). No deterioration in laboratory tests, urinary tests, ECG, or chest X-ray radiograms occurred in any patient in this study. In all patients, the mean National Institutes of Health Stroke Scale (NIHSS) scores at baseline, and 7, 30, and 90 d after admission were 8.2 ± 7.5, 5.6 ± 7.1, 4.9 ± 6.5, and 4.5 ± 6.3, respectively. The early recanalization was identified in 4 of 11 patients (36.4%) who received intravenous t-PA administration. Hemorrhagic transformation was observed in 2 patients (18.2%). None of the patients in this study that were treated with t-PA developed symptomatic intracranial hemorrhage.
Conclusions
Data from the current study indicate that an H2-enriched intravenous solution is safe for patients with acute cerebral infarction, including patients treated with t-PA.
doi:10.1186/2045-9912-3-13
PMCID: PMC3694409  PMID: 23799921
Acute ischemic stroke; Edaravone; Free radical scavenger; Hydrogen; Reactive oxygen species; Safety; Tissue plasminogen activator
25.  Early and intermediate prognosis of intravenous thrombolytic therapy in acute ischemic stroke subtypes according to the causative classification of stroke system 
Objectives: Intravenous thrombolytic therapy has established acceptable results in treating ischemic stroke. However, there is little information on treatment outcome especially in different subtypes. The aim of current study was to evaluate early and intermediate prognosis in intravenous thrombolytic therapy for acute ischemic stroke subtypes.
Methodology: Forty eligible patients (57.5% male with mean age of 63.18±13.49 years) with definite ischemic stroke who were admitted to emergency department of Imam Reza University Hospital, in the first 180 minutes after occurrence received recombinant tissue plasminogen activator. All investigation findings were recorded and stroke subtypes were determined according to the Causative Classification of Stroke System. Stroke severity forms including modified Rankin Scale (mRS) and National Institutes of Health Stroke Scale (NIHSS) scores were recorded for all patients in first, seven and 90 days after stroke and disease outcome was evaluated.
Results: The etiology of stroke was large artery atherosclerosis in 20%, cardio-aortic embolism in 45%, small artery occlusion in 17.5% and undetermined causes in 17.5%. NIHSS and mRS scores were significantly improved during time (P < 0.001 in both cases). Three months mortality rate was 25%. Among the etiologies, patients with small artery occlusion and then cardio-aortic embolism had lower NIHSS score at arrival (P = 0.04). Caplan-meier analysis showed that age, sex and symptom to needle time could predict disease outcome.
Conclusion: Intravenous thrombolytic therapy is accompanied by good early and intermediate outcome in most patients with ischemic stroke. Small artery occlusion subtype had less disease severity and higher improvement.
doi:10.12669/pjms.291.2897
PMCID: PMC3809211  PMID: 24353536
Ischemic stroke; Thrombolytic therapy; Etiology; Outcome; Ischemic Stroke Subtypes

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