Citicoline in the treatment of acute ischaemic stroke: an international, randomised, multicentre, placebo-controlled study (ICTUS trial) The effect of magnesium sulfate on maternal and fetal blood flow in pregnancy‐induced hypertension Stroke Treatment Academic Industry Roundtable (STAIR) Recommendations for Maximizing the Use of Intravenous Thrombolytics and Expanding Treatment Options With Intra-arterial and Neuroprotective Therapies Dose optimization of intravenous magnesium sulfate after acute stroke. The Cochrane Collaboration’s tool for assessing risk of bias in randomised trials Intravenous Administration of Magnesium Sulfate in Acute Stroke: A Randomized Double-blind Study Differential Effect of Baseline Computed Tomographic Angiography Collaterals on Clinical Outcome in Patients Enrolled in the Interventional Management of Stroke III Trial Early stroke treatment associated with better outcome: the ninds rt-pa stroke study NXY-059 for the treatment of acute ischemic stroke. High Dose Deferoxamine in Intracerebral Hemorrhage (Hi-Def) Trial: Rationale, Design, and Methods The effect of magnesium sulfate on maternal retinal blood flow in preeclampsia: a randomized placebo-controlled study. Magnesium for acute stroke (Intravenous Magnesium Efficacy in Stroke trial): randomised controlled trial. Thrombectomy for Stroke at 6 to 16 Hours with Selection by Perfusion Imaging
BACKGROUND Citicoline is approved in some countries for the treatment of acute ischaemic stroke . The drug has shown some evidence of efficacy in a pooled analysis . We sought to confirm the efficacy of citicoline in a larger trial . METHODS We undertook a r and omised , placebo-controlled , sequential trial in patients with moderate-to-severe acute ischaemic stroke admitted at university hospitals in Germany , Portugal , and Spain . Using a central ised minimisation process , patients were r and omly assigned in a 1:1 ratio to receive citicoline or placebo within 24 h after the onset of symptoms ( 1000 mg every 12 h intravenously during the first 3 days and orally thereafter for a total of 6 weeks [ 2 × 500 mg oral tablets given every 12 h ] ) . All study participants were masked . The primary outcome was recovery at 90 days measured by a global test combining three measures of success : National Institutes of Health Stroke Scale ≤1 , modified Rankin score ≤1 , and Barthel Index ≥95 . Safety endpoints included symptomatic intracranial haemorrhage in patients treated with recombinant tissue plasminogen activator , neurological deterioration , and mortality . This trial is registered , NCT00331890 . RESULTS 2298 patients were enrolled into the study from Nov 26 , 2006 , to Oct 27 , 2011 . 37 centres in Spain , 11 in Portugal , and 11 in Germany recruited patients . Of the 2298 patients who gave informed consent and underwent r and omisation , 1148 were assigned to citicoline and 1150 to placebo . The trial was stopped for futility at the third interim analysis on the basis of complete data from 2078 patients . The final r and omised analysis was based on data for 2298 patients : 1148 in citicoline group and 1150 in  placebo group . Global recovery was similar in both groups ( odds ratio 1·03 , 95 % CI 0·86 - 1·25 ; p=0·364 ) . No significant differences were reported in the safety variables nor in the rate of adverse events . INTERPRETATION Under the circumstances of the ICTUS trial , citicoline is not efficacious in the treatment of moderate-to-severe acute ischaemic stroke . FUNDING Ferrer Grupo The purpose of this study was to evaluate the effects of magnesium sulfate on maternal and fetal blood flow in pregnancy‐induced hypertension . Twelve patients with pregnancy‐induced hypertension were prospect ively studied with transcranial pulsed Doppler and transabdominal color flow Doppler before and after infusion of a 6 gram intravenous loading dose of magnesium sulfate . The maternal vessels studied included the middle cerebral , common carotid , and internal carotid arteries . The fetal vessels studied included the middle cerebral , renal , and umbilical arteries . In addition the maternal circulation in the placental base plate was imaged . The results of this descriptive study suggest that a 6 gram loading dose of magnesium sulfate  significantly vasodilates the vascular bed distal to the maternal middle cerebral artery , and increases blood velocity in this distribution . There was no significant change in pulsatility index or blood velocity in the central large vessels of the head and neck . There were no acute effects noted in the fetal or placental vessels evaluated Background and Purpose — The goal of the Stroke Treatment Academic Industry Roundtable ( STAIR ) meetings is to advance the development of acute and restorative stroke therapies . Summary of Review — At the STAIR VII recommendations for strategies to maximize the use of intravenous thrombolytics through targeting public education , and the refinement of current treatment exclusion criteria were proposed . Increased utilization of mechanical devices for intra-arterial recanalization can be achieved by obtaining more definitive evidence of efficacy in r and omized clinical trials , identification of patient characteristics associated with treatment efficacy , optimization of technical approaches , clarification of effective time windows , and development of approaches to limit complications . Neuroprotective strategies remain viable ; recommendations for further study of these agents include an emphasis on rapid administration , consideration of the systemic effects of ischemic stroke , prevention of complications associated with early reperfusion , a focus on agents with multiple mechanisms of action , and consideration of possible interactions between neuroprotective and thrombolytic therapies . Conclusions — Extending intravenous thrombolysis to a broader patient population , clarifying the risk and benefits of intra-arterial reperfusion therapies , and further development of neuroprotective therapies were the key recommendations from STAIR VII BACKGROUND AND PURPOSE Parenterally administered MgSO4 is neuroprotective in st and ard animal models of focal cerebral ischemia and in many other paradigms of brain injury . Previous small clinical trials in stroke patients have explored the safety and tolerability of different infusion regimens . This study was undertaken to optimize the regimen for a multicenter trial . METHODS Within 24 hours of the onset of clinical ly diagnosed stroke , patients were r and omized to receive placebo or one of three intravenous MgSO4 infusions : a loading infusion of 8 , 12 , or 16 mmol , followed by 65 mmol over 24 hours . Cardiovascular parameters , serum magnesium concentrations , and blood glucose concentrations were determined . Outcome at 30 and 90 days was recorded . RESULTS Twenty-five patients were recruited and treated at a mean time of 20 hours after stroke . No tolerability problems were identified . No effects of magnesium on heart rate , blood pressure , or blood glucose were evident . Serum magnesium concentrations rose to target levels most rapidly in the highest loading infusion group and were maintained in all groups for at least 24 hours . CONCLUSIONS MgSO4 infusions that rapidly elevate the serum magnesium concentration to potentially therapeutic levels are well tolerated and have no major hemodynamic effects in patients with acute stroke . The 16-mmol loading infusion achieved target serum concentrations most rapidly and has been chosen for further trials Flaws in the design , conduct , analysis , and reporting of r and omised trials can cause the effect of an intervention to be underestimated or overestimated . The Cochrane Collaboration ’s tool for assessing risk of bias aims to make the process clearer and more A r and omized , placebo-controlled , double-blind study was performed as a pilot study to examine the benefit of the administration of magnesium sulfate given intravenously as a protective substance during the first 24 hours following a stroke . Patients who had cortical infa rct ion in the middle cerebral artery territory with moderate to severe neurologic deficits lasting for more than 15 minutes with onset less than 24 hours were included . The patients were treated with magnesium sulfate or placebo for 5 days and examined by a blinded investigator . Patients had follow-up for 30 days . The primary efficacy variable was the proportion of patients reaching mild to moderate neurologic deficit on the Orgogozo scale ( 80 points ) and relative functional independence on the Barthel index ( 60 points ) . Orgogozo scale and Mathew scale values were obtained on admission and days 2 , 4 , 8 , and 30 after stroke . Barthel activities of daily living index and Rankin disability score were obtained on day 30 . Forty-one patients ( 22 given treatment and 19 given placebo )  demonstrated significant beneficial effects on the Orgogozo scale ( 84 ± 11 vs. 64 ± 10 , p < 0.0001 ) and ( 83 ± 14 vs. 70 ± 15 , p < 0.009 ) , respectively . At the end of 1-month follow-up , the Barthel ADL index was nonsignificantly higher and the Rankin disability score was marginally significantly lower in the magnesium-treated group ( 84 ± 26 vs. 71.8 ± 26 , p < 0.143 ) than in control subjects ( 2.3 ± 1.1 vs. 3 ± 1.3 , p < 0.077 ) . Intravenous magnesium sulfate had significant positive effect on the outcome in patients with acute stroke . Further studies on a larger scale are needed to confirm these findings Background and Purpose — In the Interventional Management of Stroke ( IMS ) III trial , we sought to demonstrate evidence of a differential treatment effect of endovascular treatment of acute ischemic stroke compared with intravenous tissue-type plasminogen activator , according to baseline collateral status measured using computed tomographic angiography . Methods — Of 656 patients enrolled in Interventional Management of Stroke III trial , 306 had baseline computed tomographic angiography .  Of these , 185 patients had M1 middle cerebral artery ± intracranial internal carotid artery occlusion , where baseline collateral status could be measured . Collateral status was assessed by consensus using 3 different ordinal scales and categorized as good , intermediate , and poor . Multivariable modeling was used to assess the effect of collateral status and treatment type on clinical outcome by modified Rankin Scale ( mRS 0–2 , mRS 0–1 , and the ordinal mRS ) . Results — Of 185 patients , 126 r and omized to endovascular therapy ( 87.6 % recanalized , 41.3 % 90-day mRS 0–2 ) and 59 to intravenous tissue-type plasminogen activator only ( 60.5 % recanalized , 30.5 % 90-day mRS 0–2 ) . In multivariable modeling , collateral status was a significant predictor of all clinical outcomes ( P<0.05 ) . Maximal benefit with endovascular treatment across all clinical outcomes was seen in patients with intermediate collaterals , some benefit in patients with good collaterals , and none in patients with poor collaterals , although small sample size limited the power of the analysis to show a statistically significant interaction between collateral status and treatment type ( P>0.05 ) . Conclusion — Using data from a large r and omized controlled trial ( IMS III ) , we show that baseline computed tomographic angiography collaterals are a robust determinant of final clinical outcome and could be used to select patients for endovascular therapy . Clinical Trial Registration — URL : http://www . clinical trials.gov/ct2/show/. Unique identifier : 0020NCT00359424 Background The National Institute of Neurological Disorders and Stroke ( NINDS ) rt-PA Stroke Study showed a similar percentage of intracranial hemorrhage and good outcome in patients 3 months after stroke treatment given 0 to 90 minutes and 91 to 180 minutes after stroke onset . At 24 hours after stroke onset more patients treated 0 to 90 compared to 91 to 180 minutes after stroke onset had improved by four or more points on the NIH Stroke Scale ( NIHSS ) . The authors performed further analyses to characterize the relationship of  onset-to-treatment time ( OTT ) to outcome at 3 months , early improvement at 24 hours , and intracranial hemorrhage within 36 hours . Methods Univariate analyses identified potentially confounding variables associated with OTT that could mask an OTT – treatment interaction . Tests for OTT – treatment interactions adjusting for potential masking confounders were performed . An OTT – treatment interaction was considered significant if p ≤ 0.10 , implying that treatment effectiveness was related to OTT . Results For 24-hour improvement , there were no masking confounders identified and there was an OTT – treatment interaction ( p = 0.08 ) . For 3-month favorable outcome , the NIHSS met criteria for a masking confounder . After adjusting for NIHSS as a covariate , an OTT – treatment interaction was detected ( p = 0.09 ) : the adjusted OR ( 95 % CI ) for a favorable 3-month outcome associated with recombinant tissue-type plasminogen activator ( rt-PA ) was 2.11 ( 1.33 to 3.35 ) in the 0 to 90 minute stratum and 1.69 ( 1.09 to 2.62 ) in the 91 to 180 minute stratum . In the group treated with rt-PA , after adjusting for baseline NIHSS , an effect of OTT on the occurrence of intracranial hemorrhage was not detected . Conclusions If the NINDS rt-PA Stroke Trial treatment protocol is followed , this analysis suggests that patients treated 0 to 90 minutes from stroke onset with rt-PA have an increased odds of improvement at 24 hours and favorable 3-month outcome compared to patients treated later than 90 minutes . No effect of OTT on intracranial hemorrhage was detected within the group treated with rt-PA , possibly due to low power BACKGROUND The free-radical-trapping agent NXY-059 showed promise as a neuroprotectant in the Stroke-Acute Ischemic NXY Treatment I ( SAINT I ) trial , reducing disability when given to patients who had acute ischemic stroke . We sought confirmation of efficacy in a second , larger trial . METHODS We enrolled 3306 patients with acute ischemic stroke in a r and omized , double-blind trial to receive a 72-hour infusion of intravenous NXY-059 or placebo within 6 hours after the onset of stroke symptoms . Our primary end point was the distribution of disability scores on the modified Rankin scale at 90 days . We examined scores on neurologic and activities-of-daily-living scales as secondary end points . We also tested the hypothesis that NXY-059 would reduce alteplase-related intracranial hemorrhages . RESULTS The efficacy analysis was based on 3195 patients . Prognostic factors were well balanced between the treatment groups . Mortality was equal in the two groups , and adverse-event rates were similar . The distribution of scores on the modified Rankin scale did not differ between the group treated with NXY-059 ( 1588 patients ) and the placebo group ( 1607 patients ; P=0.33 by the Cochran-Mantel-Haenszel test ; odds ratio for limiting disability , 0.94 ; 95 % confidence interval [ CI ] , 0.83 to 1.06 ) . Analysis of categorized scores on the modified Rankin scale confirmed the lack of benefit : the odds ratio for trichotomization into modified Rankin scale scores of 0 to 1 versus 2 to 3 versus 4 to 6 was 0.92 ( 95 % CI , 0.80 to 1.06 ) . There was no evidence of efficacy for any of the secondary end points . Among patients treated with alteplase , there was no difference between the NXY-059 group and the placebo group in the frequency of symptomatic or asymptomatic hemorrhage . CONCLUSIONS NXY-059 is ineffective for the treatment of acute ischemic stroke within 6 hours after the onset of symptoms . ( Clinical Trials.gov number , NCT00061022 [ Clinical Trials.gov ] . Background Hemoglobin degradation products , in particular iron , have been implicated in secondary neuronal injury following intracerebral hemorrhage ( ICH ) . The iron chelator Deferoxamine Mesylate ( DFO ) exerts diverse neuroprotective effects , reduces perihematoma edema ( PHE ) and neuronal damage , and improves functional recovery after experimental ICH . We hypothesize that treatment with DFO could minimize neuronal injury and improve outcome in ICH patients . As a prelude to test this hypothesis , we conducted a Phase I , open-label study to determine the tolerability , safety , and maximum tolerated dose ( MTD ) of DFO in patients with ICH . Intravenous infusions of DFO in doses up to 62 mg/kg/day ( up to a maximum of 6000 mg/day ) were well-tolerated and did not seem to increase serious adverse events ( SAEs ) or mortality . We have initiated a multi-center , double-blind , r and omized , placebo-controlled , Phase II clinical trial ( High Dose Deferoxamine [ HI-DEF ] in Intracerebral Hemorrhage ) to determine if it is futile to move DFO forward to Phase III efficacy evaluation . Methods We will r and omize 324 subjects with spontaneous ICH to either DFO at 62 mg/kg/day ( up to a maximum daily dose of 6000 mg/day ) or saline placebo , given by intravenous infusion for 5 consecutive days . Treatment will be initiated within 24 hours after ICH symptom onset . All subjects will be followed for 3 months and will receive st and ard of care therapy while participating in the study . At 3 months , the proportion of DFO-treated subjects with a good clinical outcome , assessed by modified Rankin Scale , will be compared to the placebo proportion in a futility analysis . Conclusions The Hi-Def trial is expected to advance our underst and ing of the pathopgysiology of secondary neuronal injury in ICH and will provide a crucial “ Go/No Go ” signal as to whether a Phase III trial to investigate the efficacy of DFO is warranted OBJECTIVES Our purpose was to determine the effect of a 6 gm intravenous bolus of magnesium sulfate on maternal retinal blood flow velocity waveforms in patients with preeclampsia . STUDY DESIGN Twenty-two patients were r and omized to two groups and were studied with color flow Doppler before and immediately after infusion of either 6 gm of magnesium sulfate or placebo . The central retinal and posterior ciliary arteries were studied . RESULTS Magnesium sulfate significantly reduced the pulsatility index ( p < 0.005 ) in both vessels ( change in pulsatility index = 0.26 + /- 0.23 for central retinal and -0.22 + /- 0.15 for posterior ciliary ) when compared with placebo ( change in pulsatility index = 0.02 + /- 0.10 for central retinal and -0.03 + /- 0.09 for posterior ciliary ) . CONCLUSIONS These data suggest that magnesium sulfate  dilates the vessels distal to the central retinal and posterior ciliary arteries . Changes in pulsatility index in the retinal arteries may be indicative of similar changes in other cerebral vessels BACKGROUND Magnesium is neuroprotective in animal models of stroke , and findings of small clinical pilot trials suggest potential benefit in people . We aim ed to test whether intravenous magnesium sulphate , given within 12 h of stroke onset , reduces death or disability at 90 days . METHODS 2589 patients were r and omised within 12h of acute stroke to receive 16 mmol MgSO4 intravenously over 15 min and then 65 mmol over 24 h , or matching placebo . Primary outcome was a global endpoint statistic expressed as the common odds ratio for death or disability at day 90 . Secondary outcomes were mortality and death or disability , variously defined as Barthel score less than 95 , Barthel score less than 60 , and modified Rankin scale more than 1 . Predefined subgroup analyses were for the primary endpoint in patients in whom treatment commenced within 6 h versus after 6 h , ischaemic versus non-ischaemic strokes , and cortical stroke syndromes versus non-cortical strokes . Intention-to-treat and efficacy analyses were done . FINDINGS The efficacy data set included 2386 patients . Primary outcome was not improved by magnesium ( odds ratio 0.95 , 95 % CI 0.80 - 1.13 , p=0.59 ) . Mortality was slightly higher in the magnesium-treated group than in the placebo group ( hazard ratio 1.18 , 95 % CI 0.97 - 1.42 , p=0.098 ) . Secondary outcomes did not show any treatment effect . Planned subgroup analyses showed benefit of magnesium in non-cortical strokes ( p=0.011 ) whereas greater benefit had been expected in the cortical group . INTERPRETATION Magnesium given within 12 h of acute stroke does not reduce the chances of death or disability significantly , although it may be of benefit in lacunar strokes Background Thrombectomy is currently recommended for eligible patients with stroke who are treated within 6 hours after the onset of symptoms . Methods We conducted a multicenter , r and omized , open‐label trial , with blinded outcome assessment , of  thrombectomy in patients 6 to 16 hours after they were last known to be well and who had remaining ischemic brain tissue that was not yet infa rct ed . Patients with proximal middle‐cerebral‐artery or internal‐carotid‐artery occlusion , an initial infa rct size of less than 70 ml , and a ratio of the volume of ischemic tissue on perfusion imaging to infa rct volume of 1.8 or more were r and omly assigned to endovascular therapy ( thrombectomy ) plus st and ard medical therapy ( endovascular‐therapy group ) or st and ard medical therapy alone ( medical‐therapy group ) . The primary outcome was the ordinal score on the modified Rankin scale ( range , 0 to 6 , with higher scores indicating greater disability ) at day 90 . Results The trial was conducted at 38 U.S. centers and terminated early for efficacy after 182 patients had undergone r and omization ( 92 to the endovascular‐therapy group and 90 to the medical‐therapy group ) . Endovascular therapy plus medical therapy , as compared with medical therapy alone , was associated with a favorable shift in the distribution of functional outcomes on the modified Rankin scale at 90 days ( odds ratio , 2.77 ; P<0.001 ) and a higher percentage of patients who were functionally independent , defined as a score on the modified Rankin scale of 0 to 2 ( 45 % vs. 17 % , P<0.001 ) . The 90‐day mortality rate was 14 % in the endovascular‐therapy group and 26 % in the medical‐therapy group ( P=0.05 ) , and there was no significant between‐group difference in the frequency of symptomatic intracranial hemorrhage ( 7 % and 4 % , respectively ; P=0.75 ) or of serious adverse events ( 43 % and 53 % , respectively ; P=0.18 ) . Conclusions Endovascular thrombectomy for ischemic stroke 6 to 16 hours after a patient was last known to be well plus st and ard medical therapy result ed in better functional outcomes than st and ard medical therapy alone among patients with proximal middle‐cerebral‐artery or internal‐carotid‐artery occlusion and a region of tissue that was ischemic but not yet infa rct ed . ( Funded by the National Institute of Neurological Disorders and Stroke ; DEFUSE 3 Clinical Trials.gov number , NCT02586415 .
Background and Purpose — Acute stroke treatment is challenging , and stroke remains a major cause of death and disability .
The purpose of this meta- analysis is to investigate the effects of postacute stroke intravenous administration of the neuroprotectant magnesium sulfate ( MgSO4 ) on global outcome , functional outcome , and mortality 90 days poststroke ( ischemic and nonischemic ) .