We thank Dr Liebeskind for his interest in our study and appreciate his comments underscoring the complexity of enhancing perfusion to improve outcome in metastable ischemic brain tissue. We see merit in most of his comments and recognize the contributions he has made to collateral therapeutics in acutely ischemic brain. We would like to take this opportunity to clarify what may have been lost in translation.
Dr Liebeskind observes that ischemic core was situated only microns away from the penumbra in our model, and considers this a marked discrepancy with human stroke. The calculation he makes underestimates considerably the values we obtained. To estimate salvageable penumbra in our model, we calculated that the infarct area was concentrically reduced from 17.8 to 11.4 mm2 over the cortical surface by induced hypertension. This corresponds to a reduction of infarct diameter by approximately 1 mm (ie, 20%) in a hemisphere that measures approximately 5 mm wide and 10 mm long. Obvious scale differences between human versus mouse brain notwithstanding, this is a much larger estimate than ‘microns’ suggested by Dr Liebeskind. We believe that the salvageable volume of penumbra in human brain is likely to be significantly larger than in the 400 mg mouse brain.
We agree that initiating induced hypertension 10 or 60 minutes after stroke onset, or successful reperfusion within 60 minutes, may not be practical in human stroke at the present time. However, those times were chosen because, in mice, 2 hours or longer transient focal cerebral ischemia usually leads to infarct volumes that do not differ from permanent ischemia. Evidence suggests that the therapeutic window of opportunity to deliver oxygenated blood to ischemic tissue is wider in human, because reperfusion 3 hours or more after stroke onset can still improve outcome, and PET studies demonstrate potentially viable tissue as long as 18 to 24 hours after stroke onset.1,2 The timing of intervention in our rodent study, largely dictated by technical limitations in small rodents, may appear ‘incredibly early’ by human standards, but it predicts a potential benefit in human stroke with persistent salvageable brain tissue many hours after stroke onset.
The failure of clinical stroke trials over the past 2 decades has taught us that no single experimental model can address the diversity of human stroke. It is well accepted that differences in scale, gray/white matter and neuron/glia ratios, circle of Willis and venous anatomy, absolute blood flow values and metabolic rates, collateral circulation, and comorbidities (eg, hypercholesterolemia, diabetes) all limit translation of experimental stroke into the human condition. The rich spatiotemporal information embedded in hemodynamic and metabolic evolution of acutely ischemic tissue is inevitably difficult to measure. However, as described, multimodal real-time imaging of cerebral blood flow and oxygenation clearly demonstrates that mild induced hypertension may be useful as a collateral salvaging strategy under the stated experimental conditions. Of course, there will be caveats, just as in any therapeutic strategy. Studies such as ours serve as proof-of-principle, and may prompt the development of models simulating common clinical scenarios to determine those most likely to benefit from collateral therapeutics. Until technologies that distinguish salvageable from irreversibly injured tissue, and image collateral flow in real-time, become clinically available to aid in patient selection, we must continue preclinical hypothesis testing in animal models and work toward improving their clinical translation.
Albers GW, Thijs VN, Wechsler L, Kemp S, Schlaug G, Skalabrin E, Bammer R, Kakuda W, Lansberg MG, Shuaib A, Coplin W, Hamilton S, Moseley M, Marks MP; DEFUSE Investigators. Magnetic resonance imaging profiles predict clinical response to early reperfusion: the diffusion and perfusion imaging evaluation for understanding stroke evolution (DEFUSE) study. Ann Neurol. 2006; 60: 508–517.
Marchal G, Beaudouin V, Rioux P, de la Sayette V, Le Doze F, Viader F, Derlon JM, Baron JC. Prolonged persistence of substantial volumes of potentially viable brain tissue after stroke: a correlative PET-CT study with voxel-based data analysis. Stroke. 1996; 27: 599–606.