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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