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In ischaemic stroke, expansion of the infarct core occurs at the expense of surrounding hypoxic, metabolically compromised tissue over a period of 24 h or more in a considerable proportion of patients. It is uncertain whether hypoxic tissue observed at later times after stroke onset retains the potential for survival or whether such survival has an impact on functional outcome. These factors may determine the effectiveness of therapeutic strategies aimed at salvaging this tissue. We tested the hypotheses that metabolically compromised hypoxic tissue observed within 48 h after onset of ischaemic stroke retains the potential for spontaneous survival and that the impact of such survival on functional outcome is time dependent. Consecutive patients presenting within 48 h of ischaemic stroke were studied with [(18)F]fluoromisonidazole, a ligand binding to hypoxic but viable tissue, and PET. Subjects were grouped into two time epochs, 12 h, based on the interval from stroke onset to the time of tracer injection, and had infarct volumes measured on CT/MRI at 7 days (n = 60). The total ischaemic volume (TIV) and the proportion of the TIV that spontaneously survived (surviving hypoxic volume ratio, SHVR) were defined from the co-registered CT/MRI images. These volumetric measures were correlated with neurological outcome assessed at day 7-10 by percentage change in the National Institutes of Health Stroke Scale (DeltaNIHSS), and at 3 months by Barthel Index (BI) and modified Rankin Score (mRS). Of 66 patients investigated, hypoxic tissue occurred in 33 and outcome data was available in 27. Hypoxic tissue constituted >20% of the TIV in 60% of studies 12 h. The spontaneously surviving proportion of the TIV (median 6.9%) or hypoxic tissue (median 45.9%) was not significantly different in patient subgroups studied 12 h after stroke onset. Spontaneous survival of hypoxic tissue (surviving hypoxic volume ratio) was associated with improved neurological outcome in both time epochs: 12 h, DeltaNIHSS (r = 0.59, P < 0.01) and day 90 mRS (r = -0.46, P < 0.05). The finding that similar proportions of hypoxic tissue survived spontaneously within each time epoch suggests that its fate is not predetermined. The favourable neurological outcome associated with spontaneous survival of hypoxic tissue, even 12-48 h after stroke onset, suggests that the volume of hypoxic tissue that progressed to infarction may represent a valuable target for therapeutic intervention.

PET with 18F-FMISO can detect peri-infarct hypoxic tissue after acute ischemic stroke. The distribution of hypoxic tissue suggests that it may represent the ischemic penumbra. Hypoxic tissues do not persist to the subacute phase of stroke (6 to 11 days).

Background and Purpose-We sought to characterize the spatial and temporal evolution of human cerebral infarction.Using a novel method of quantitatively mapping the distribution of hypoxic viable tissue identified by 18 Ffluoromisonidazole ( 18 F-FMISO) PET relative to the final infarct, we determined its evolution and spatial topography in human stroke. Methods-Patients with acute middle cerebral artery territory stroke were imaged with 18 F-FMISO PET (nϭ19; Ͻ6 hours, 4; 6 to 16 hours, 4; 16 to 24 hours, 5; 24 to 48 hours, 6). The hypoxic volume (HV) comprised voxels with significant (PϽ0.05; Ͼ1 mL) uptake on statistical parametric mapping compared with 15 age-matched controls. Central, peripheral, and external zones of the corresponding infarct on the anatomically coregistered delayed CT were defined according to voxel distance from the infarct center and subdivided into 24 regions by coronal, sagittal, and axial planes. Maps ("penumbragrams") displaying the percentage of HV in each region were generated for each time epoch. Results-Higher HV was observed in the central region of the infarct in patients studied within 6 hours of onset (analysis of covariance [ANCOVA]; PϽ0.05) compared with those studied later, in whom the HV was mainly in the periphery or external to the infarct. HV was maximal in the superior, mesial, and posterior regions of the infarct (ANCOVA; PϽ0.05). Conclusions-These observations suggest that infarct expansion occurs at the expense of hypoxic tissue from the center to the periphery of the ischemic region in humans, similar to that seen in experimental animal models. These findings have important pathophysiological and therapeutic implications.

Redox reaction volumes, obtained by high-pressure cyclic voltammetry, are reported for a selection tris(diimine), tris(diamine), hexaammine, and hexaaqua couples of Fe(III/II), Cr(III/II), Ru(III/II), and Co(III/II). Separation of the intrinsic and electrostrictive volume contributions for these couples has been achieved, some in both aqueous and acetonitrile solutions. For the Co(phen)(3)(3+/2+) system, the intrinsic volume change is estimated to be +15.3 +/- 2.1 cm(3) mol(-)(1) (based on measurements in water) and +16.5 +/- 2.0 cm(3) mol(-)(1) (in acetonitrile). For the Co(bipy)(3)(3+/2+) system, values are +12.7 +/- 1.4 cm(3) mol(-)(1) (in water) and +15.5 +/- 2.5 cm(3) mol(-)(1) (in acetonitrile). Using these experimentally determined intrinsic contributions, a simple structural model suggests that the intrinsic volume change for these reactions can be described using the change in effective volume of a sphere with radius close to that of the coordinating-atom-metal bond length. Electrostrictive volume changes for the 3+/2+ complex-ion couples are a function of solute size and coordinated ligands. For Ru(H(2)O)(6)(3+) and Fe(H(2)O)(6)(3+) reduction, volume behavior is significantly different from that of the other systems studied and can be rationalized in terms of possible H-bonding interactions with surrounding solvent which affect the electrostrictive volume changes but which are not available for the ammine and other complexes studied.

A contributing factor to the failure of trials of neuroprotectants in acute ischemic stroke may be the differing vulnerability to ischemia of white compared with gray matter. To address this issue, we determined to establish the existence of potentially viable tissue in white matter and its evolution to infarction or salvage in both gray and white matter compartments in patients with ischemic stroke. Twenty-seven patients (mean age, 73.4 years) at a median of 16.5 hours after symptom onset were studied using the hypoxic marker 18F-misonidazole with positron emission tomography (PET). Tissue was segmented using an magnetic resonance probabilistic map. Although there was a greater volume of initially "at-risk tissue" in gray matter (58.3 cm3, 29.9-93.0 cm3 than white matter (42.0 cm3, 15.8-74.0 cm3; p <0.001) at the time of PET imaging, a higher proportion of this was still potentially viable in white matter (41.4%, 4.6-74.5%) than in gray matter (23.6%, 3.2-61.1%; p <0.05). However, a similar proportion in each compartment spontaneously survived. These data provide evidence for the existence of potentially salvageable tissue in human white matter and is consistent with it having a similar or even greater resistance to ischemia than gray matter. For the latter possibility, alternative therapeutic strategies may be required for its salvage.

We studied 24 patients up to 51 hours after ischemic stroke using 18F-fluoromisonidazole positron emission tomography to determine the fate of hypoxic tissue likely to represent the ischemic penumbra. Areas of hypoxic tissue were detected on positron emission tomography in 15 patients, and computed tomography was available in 12 patients, allowing comparison with the infarct volume to determine the proportions of the hypoxic tissue volume that infarcted and survived. The proportion of patients with hypoxic tissue and the amount of hypoxic tissue detected declined with time. On average, 45% of the total hypoxic tissue volume survived and 55% infarcted. Up to 68% (mean, 17.5%) of the infarct volume was initially hypoxic. Most of the tissue "initially affected" proceeded to infarction. We correlated hypoxic tissue volumes with neurological and functional outcome assessed using the National Institutes of Health Stroke Scale, Barthel Index, and Rankin Score. Initial stroke severity correlated significantly with the "initially affected" volume, neurological deterioration during the first week after stroke with the proportion of the "initially affected" volume that infarcted, and functional outcome with the infarct volume. Significant reductions in the size of the infarct and improved clinical outcomes might be achieved if hypoxic tissue can be rescued.

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