Effect of nitric oxide donors on blood pressure and pulse pressure in acute and subacute stroke

High blood pressure (BP), pulse pressure (PP), and rate pressure product (RPP) areeach associated independently with a poor outcome in acute ischemic stroke. Whereas nitric oxide (NO) donors, such as glyceryl trinitrate (GTN), lower blood pressure in acute ischemic stroke, their effect on other hemodynamic measures is not known. We performed a systematic review of the effects of NO donors on systemic hemodynamic measures in patients with acute/subacute stroke. Randomized controlled trials were identified from searches of the Cochrane Library, Pubmed, and Embase. Information on hemodynamic measures, including systolic BP (SBP), diastolic BP (DBP), and heart rate, were assessed, and hemodynamic derivatives of these were calculated: PP (PP SBP DBP), mean arterial pressure (MAP DBP PP/3), mid blood pressure (MBP (SBP DBP)/2), pulse pressure index (PPI PP/MAP), and RPP (RPP SBP HR). The effect of treatment on hemodynamic measures was calculated as the weighted mean difference (WMD) between treated and control groups with adjustment for baseline. Results: Three trials involving 145 patients were identified; 93 patients received the NO donor, GTN, and 52 control. As compared with placebo, GTN significantly reduced SBP (WMD -9.80 mmHg, p< 0.001), DBP (WMD -4.43 mmHg, p<0.001), MAP (WMD -6.41 mmHg, p< 0.001), MBP (WMD -7.33 mmHg,p<0.001), PP (WMD -6.11 mmHg, p<0.001 ) and PPI (WMD -0.03, p=0.04 ). 3 GTN increased HR (WMD +3.87 bpm, p<0.001) and non-significantly lowered RPP (WMD -323 mmHg.bpm, p=0.14). Conclusion: The NO donor GTN reduces BP, PP and other derivatives in acute and subacute stroke whilst increasing heart rate.

Is there a link between aspirin therapy and stroke severity

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Granulocyte-colony-stimulating factor mobilizes bone marrow stem cells in patients with subacute ischemic stroke: the Stem Cell Trial of Recovery EnhanceMent After Stroke (STEMS) Pilot Randomized, Controlled Trial (ISRCTN 16784092)

Background and Purpose - Loss of motor function is common after stroke and leads to significant chronic disability. Stem cells are capable of self-renewal and of differentiating into multiple cell types, including neurones, glia, and vascular cells. We assessed the safety of granulocyte-colony-stimulating factor (G-CSF) after stroke and its effect on circulating CD34 stem cells. Methods - We performed a 2-center, dose-escalation, double-blind, randomized, placebo-controlled pilot trial (ISRCTN 16784092) of G-CSF (6 blocks of 1 to 10 g/kg SC, 1 or 5 daily doses) in 36 patients with recent ischemic stroke. Circulating CD34 stem cells were measured by flow cytometry; blood counts and measures of safety and functional outcome were also monitored. All measures were made blinded to treatment. Results - Thirty-six patients, whose mean SD age was 768 years and of whom 50% were male, were recruited. G-CSF (5 days of 10 g/kg) increased CD34 count in a dose-dependent manner, from 2.5 to 37.7 at day 5 (area under curve, P0.005). A dose-dependent rise in white cell count (P0.001) was also seen. There was no difference between treatment groups in the number of patients with serious adverse events: G-CSF, 7/24 (29%) versus placebo 3/12 (25%), or in their dependence (modified Rankin Scale, median 4, interquartile range, 3 to 5) at 90 days. Conclusions - ”G-CSF is effective at mobilizing bone marrow CD34 stem cells in patients with recent ischemic stroke. Administration is feasible and appears to be safe and well tolerated. The fate of mobilized cells and their effect on functional outcome remain to be determined. (Stroke. 2006;37:2979-2983.)

The Virtual International Stroke Trials Archive

Background and Purpose - Stroke has global importance and it causes an increasing amount of human suffering and economic burden, but its management is far from optimal. The unsuccessful outcome of several research programs highlights the need for reliable data on which to plan future clinical trials. The Virtual International Stroke Trials Archive aims to aid the planning of clinical trials by collating and providing access to a rich resource of patient data to perform exploratory analyses. Methods - Data were contributed by the principal investigators of numerous trials from the past 16 years. These data have been centrally collated and are available for anonymized analysis and hypothesis testing. Results - ”Currently, the Virtual International Stroke Trials Archive contains 21 trials. There are data on 15 000 patients with both ischemic and hemorrhagic stroke. Ages range between 18 and 103 years, with a mean age of 6912 years. Outcome measures include the Barthel Index, Scandinavian Stroke Scale, National Institutes of Health Stroke Scale, Orgogozo Scale, and modified Rankin Scale. Medical history and onset-to-treatment time are readily available, and computed tomography lesion data are available for selected trials. Conclusions - This resource has the potential to influence clinical trial design and implementation through data analyses that inform planning. (Stroke. 2007;38:1905-1910.)

Amphetamine increases blood pressure and heart rate but has no effect on motor recovery or cerebral haemodynamics in ischaemic stroke: a randomized controlled trial (ISRCTN 36285333)

Amphetamine enhances recovery after experimental ischaemia and has shown promise in small clinical trials when combined with motor or sensory stimulation. Amphetamine, a sympathomimetic, might have haemodynamic effects in stroke patients, although limited data have been published. Subjects were recruited 3-30 days post ischaemic stroke into a phase II randomised (1:1), double blind, placebo-controlled trial. Subjects received dexamphetamine (5mg initially, then 10mg for 10 subsequent doses with 3 or 4 day separations) or placebo in addition to inpatient physiotherapy. Recovery was assessed by motor scales (Fugl-Meyer, FM), and functional scales (Barthel index, BI and modified Rankin score, mRS). Peripheral blood pressure (BP), central haemodynamics and middle cerebral artery blood flow velocity were assessed before, and 90 minutes after, the first 2 doses. 33 subjects were recruited, age 33-88 (mean 71) years, males 52%, 4-30 (median 15) days post stroke to inclusion. 16 patients were randomised to placebo and 17 amphetamine. Amphetamine did not improve motor function at 90 days; mean (standard deviation) FM 37.6 (27.6) vs. control 35.2 (27.8) (p=0.81). Functional outcome (BI, mRS) did not differ between treatment groups. Peripheral and central systolic BP, and heart rate, were 11.2 mmHg (p=0.03), 9.5 mmHg (p=0.04) and 7 beats/minute (p=0.02) higher respectively with amphetamine, compared with control. A non-significant reduction in myocardial perfusion (Buckberg Index) was seen with amphetamine. Other cardiac and cerebral haemodynamics were unaffected. Amphetamine did not improve motor impairment or function after ischaemic stroke but did significantly increase BP and heart rate without altering cerebral haemodynamics.

Should data monitoring committees assess efficacy when considering safety in trails in acute stroke?

The primary role of a trials Data Monitoring Committee (DMC) is to ensure the safety of enrolled patients. In stroke trials, safety is monitored typically by comparing death and stroke specific events between treatment groups. DMCs may also have the remit for monitoring efficacy depending on the aims of the trial. We hypothesised that functional outcome at end of follow-up, a measure of efficacy, is also a powerful measure of safety and tested this in a systematic review