Reperfusion beyond 6 hours impacts Tissue Fate of Moderate Ischemia
Hongyu An1, Andria L Ford2, Cihat Eldeniz1, Yasheng Chen2, Katie D Vo3, Hongtu Zhu4, William J Powers5, Weili Lin6, and Jin-Moo Lee2

1Washington University in St. Louis, St. Louis, MO, United States, 2Neurology, Washington University in St. Louis, St. Louis, MO, United States, 3Radiology, Washington University in St. Louis, St. Louis, MO, United States, 4Biostatistics, University of North Carolina At Chapel Hill, Chapel Hill, NC, United States, 5Neurology, University of North Carolina At Chapel Hill, Chapel Hill, NC, United States, 6Radiology, University of North Carolina At Chapel Hill, Chapel Hill, NC, United States

Synopsis

The fate of mild to moderate ischemic tissue is greatly impacted by both hyperacute (3-6 hr) and acute (6-24hr) perfusion changes. Thus, such regions could be targeted for intervention beyond current treatment windows.

PURPOSE

Pooled data from clinical trials demonstrate the time-dependence of reperfusion-promoting therapies for enhancing favorable outcomes in acute ischemic stroke.1, 2 For intravenous tPA, therapeutic benefit is lost 4.5 hours after stroke onset. 3-7. Recent randomized clinical trials have demonstrated that endovascular thrombectomy following intravenous tPA improved recanalization of proximal artery occlusions and clinical outcomes in patients with large vessel occlusion 3-6. In these trials, the mean time from symptom onset to recanalization ranged from 4.0 to 5.5 hours. In this study, we aimed to evaluate whether reperfusion beyond 6 hours may still benefit ischemic tissue and whether this benefit depends on the severity of ischemia.

METHODS

With IRB approval and consent forms, ischemic stroke patients underwent four serial MRI scans: at 3 hours, at 6 hours, at 24 hours, and at 1 month after stroke onset. DSC perfusion and FLAIR images were acquired. Rigid image registration was performed to align all images across four scans for each patient. Final infarct was delineated on the 1 month FLAIR image. The baseline perfusion deficit was determined using MTT prolongation (MTTp =[MTT]–[median MTT of contralateral hemisphere]. Perfusion changes between 3 to 6 hours and 6 to 24 hours were defined as: [ΔMTT3_6=6hr MTTp –3hr MTTp] and [ΔMTT6_24=24hr MTTp –6hr MTTp], respectively. For each patient, voxel based logistic regression models were created as:

$$Logit(P(tissue infarction))=a0+a1\cdot MTTp_{3hr}+a2\cdot \triangle MTT_{3\_6}+a3\cdot \triangle MTT_{6\_24}$$

in four 5-second MTTp strata as [0-5], [5-10], [10-15], and [15-20], where P(tissue infarction) is the probability of tissue infarction. Wilcoxon signed-rank tests on logistic regression coefficients a1, a2, and a3 were performed across patients to evaluate whether MTTp, ΔMTT3_6 and ΔMTT6_24 significantly impact tissue fates. Multiple comparisons were adjusted using a false discovery rate (FDR) of 5%. Three-dimensional color plots were generated to demonstrate infarct probability as a function of 3hr MTTp and 6hr MTTp and as a function of 6hr MTTp and 24hr MTTp. Correlation between clinical outcome ΔNIHSS3hr_1mo and volume of mild to severe (3< MTTp3hr ≤ 15 seconds) ischemic tissue with an improved perfusion (ΔMTT3_6 <=-2 sec), and ΔNIHSS6hr_1mo and volume of mild to moderate (3< MTTp3hr ≤ 10 seconds) ischemic tissue with an improved perfusion (ΔMTT6_24 <= -2sec) were performed.

RESULTS

Perfusion changes were commonly observed during both 3 to 6 and 6-24 hours in patients. The median and IQR of logistic regression coefficients a1, a2, and a3 were summarized in Table. ΔMTT3_6 significantly impacted tissue fate across a wide range of baseline perfusion deficit (MTTp 0-15s). ΔMTT6_24 also impacted ischemic tissue fate, but its influence was restricted to mild to moderate baseline ischemia (MTTp 0-10s). Perfusion changes ΔMTT in tissue with extremely severe baseline ischemia (MTTp 15-20 sec), did not significantly impact tissue fate in either the hyperacute or acute phases studied (Table).

The 3D color plots demonstrated that the fate of tissue with moderate ischemia is greatly impacted by both hyperacute (Fig 1A) and acute (Fig 1B) perfusion changes, while the fate of severely ischemic tissue was only affected by hyperacute perfusion change. Tissue with extremely severe ischemia was not impacted by either hyperacute or acute perfusion changes.

The volume of ischemic tissue with improved perfusion during 3-6 hrs and during 6- 24 hours significantly correlated with DNIHSS3hr_1mo (Fig. 2A, R=-0.48, P=0.014) and DNIHSS6hr_1mo (Fig. 2B, R=-0.41, P=0.038), respectively.

DISCUSSION

Our key findings include: (1) perfusion improvement was associated with reduced infarct probability for tissue with mild to moderate ischemia both within and beyond six hours; (2) dynamic perfusion for tissue with severe ischemia influenced tissue fate within, but not beyond six hours; while (3) perfusion changes either within or beyond six hours had little impact at extremely severe ischemia. This data provides tissue-level evidence in ischemic stroke patients for a closing therapeutic window that is impacted by both time and depth of ischemia. Moreover, volume of tissue with perfusion improvement during both 3 to 6 hours and 6 to 24 hours was associated with improved NIHSS at 1 month after stroke.

CONCLUSION

Our study suggests that tissue with mild to moderate ischemia may have a prolonged therapeutic window beyond six hours such that a subgroup of patients may still benefit from late reperfusion-promoting therapies if selected properly.

Acknowledgements

No acknowledgement found.

References

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Figures

Figure 1: Dynamic perfusion influences tissue fate with moderate ischemia during both 3-6 hours and 6-24 hours, but only impact tissues outcome with severe ischemia during 3-6 hours.

Figure 2: Correlation between ΔNIHSS and volume of improved perfusion between 3 to 6 hours (A) and between 6 to 24 hours (B).

Table



Proc. Intl. Soc. Mag. Reson. Med. 24 (2016)
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