Acute ischemic stroke treatment, part 1: patient selection “The 50% barrier and the capillary index score”

This current strategy misses the whole problem of the neuronal cascade of death. Their assumption is wrong.  Doesn't ANYONE  in stroke read at all?
http://journal.frontiersin.org/article/10.3389/fneur.2015.00083/full?

Firas Al-Ali¹*, John J. Elias², Danielle E. Filipkowski² and James E. Faber³

• ¹Summit Neurovascular Specialists, Akron, OH, USA
• ²Department of Research, Akron General Medical Center, Akron, OH, USA
• ³Department of Cell Biology and Physiology, University of North Carolina School of Medicine, Chapel Hill, NC, USA

The current strategy for intra-arterial treatment (IAT) of acute ischemic stroke focuses on minimizing time from ictus to revascularization and maximizing revascularization. Employing this strategy has yet to lead to improved rates of successful outcomes. However, the collateral blood supply likely plays a significant role(Why?) in maintaining viable brain tissue during ischemia. Based on our prior work, we believe that only approximately 50% of patients are genetically predisposed to have sufficient collaterals for a good outcome following treatment, a concept we call the 50% barrier. The Capillary Index Score (CIS) has been developed as a tool to identify patients with a sufficient collateral blood supply to maintain tissue viability prior to treatment. Patients with a favorable CIS (f CIS) may be able to achieve a good outcome with IAT beyond an arbitrary time window. The CIS is incorporated into a proposed patient treatment algorithm. For patients suffering from a large stroke without aphasia, a non-enhanced head CT should be followed by CT angiography (CTA). For patients without signs of stroke mimics or visible signs of structural changes due to large irreversible ischemia, CTA can help confirm the vascular occlusion and location. The CIS can be obtained from a diagnostic cerebral angiogram, with IAT offered to patients categorized as f CIS.

Introduction

The current strategy for acute ischemic stroke (AIS) treatment is based on two pillars: time from ictus to revascularization (TIR) and revascularization success as measured by the modified thrombolysis in cerebral ischemia scale (mTICI). The assumption is that clinical outcome following AIS is dependent on the interaction of these two factors. The shorter the TIR and the higher the mTICI, the better the outcome. It follows that the strategy behind current intra-arterial treatment for acute ischemic stroke (IAT-AIS) is the faster and more complete the revascularization, the better the clinical outcome. However, despite the recent impressive improvement in revascularization rates and decrease in time to revascularization, until recently the clinical improvement rate remained unchanged at approximately 40–45% (Table 1) with a ratio of good clinical outcome (GCO) in treatment vs. control arms of approximately 1.7 (1–11). Recent trials have published GCOs above 50% in the treatment arm, but with the same ratio of GCOs between the treated and untreated arms around 1.7 (12, 13). How we can explain this consistency? A fresh look at our strategy and selection criteria is obviously warranted.

TABLE 1

Table 1. Clinical outcomes across IAT-AIS trials.

Physiological Background and the 50% Barrier

Normal cerebral blood flow (CBF) is 50–55 ml/100 g/min (14, 15). AIS induces a rapid and sustained reduction in CBF. Clinical signs of ischemia generally become apparent when CBF drops below 23 ml/100 g/min (16). If residual CBF (rCBF) further decreases to 15–16 ml/100 g/min, the cortical-evoked potential ceases within seconds (16). The rate of depression of the evoked potential (EP) amplitude (expressed in units of percent of control/min) is highly correlated with the residual flow, following a linear relationship with the regression line intercepting the flow axis at 15.2 ml/100 g/min (17). The data strongly suggest a threshold-like relationship also exists between the amplitude of the EP and local blood flow. If flow is greater than approximately 16 ml/100 g/min the EP is not affected, but at flows less than approximately 12 ml/100 g/min the EP is abolished (17). Neither the clinical signs of ischemia nor cessation of the EP is synonymous with cell death, but cessation of the EP is one of the final stages before irreversible injury (infarction). Its physiological purpose is to conserve energy by decreasing cell metabolism to the minimal level possible; however, cell death ensues thereafter.

Similarly, the relationship between time to irreversible damage and rCBF is well-documented (18). In one study, rCBF in monkeys was measured in the ischemic area with time after occlusion until irreversible tissue damage occurred (16). An infarction threshold was observed relating the rCBF to time between the initial drop in CBF to irreversible ischemia (Figure 1). This work confirmed prior studies using the neuronal EP and showed that when rCBF reached a low level of around 10 ml/100 g/min, the available time to salvage the brain tissue was extremely short (<1 h) (16).

 

FIGURE 1

Figure 1. Depth of ischemia and time to irreversible cerebral damage: time to irreversible cerebral damage depends on the depth of ischemia, which depends on the pial collateral supply to the ischemic territory. Since different patients have different collaterals, the depth of ischemia will vary among patients, as will the time available for therapy to salvage the tissue (16).

 

 

The depth of ischemia, i.e., the level of rCBF, will vary from patient to patient depending on the available retrograde pial collaterals to the ischemic area. The major determinants of the amount of collateral perfusion are the number and diameter of these pial collaterals, plus perfusion pressure and resistance above and below the collateral network. Greater collateral numbers and diameters sustain a higher rCBF, thus more salvageable brain and a smaller final infarct volume.

Following AIS, rCBF stays virtually unchanged if spontaneous recanalization of the occluded blood vessels does not occur (16, 18, 19). While the clinical symptoms of ischemia will often resolve if CBF is restored promptly, prolonged low levels of rCBF leads to irreversible brain tissue damage. Since the time of ischemia that the brain tissue can tolerate before irreversible damage ensues depends on the rCBF value, which is patient-specific and highly dependent on the collaterals, it follows that every patient has his or her own time (Figure 1) (16, 18, 19). Hence, if we correctly select patients that are optimal candidates (patients with ischemic but viable tissue) and are able to achieve safe, full, and timely revascularization (prior to irreversible ischemic damage occurring), the clinical symptoms of a stroke should improve significantly and rather quickly.

Given this information, the most logical explanation for the remarkably consistent results of the different IAT-AIS trials, with <50% GCOs (modified Rankin Score, or mRS, ≤2), is that around half of treated patients have poor pial collaterals, thus causing them to have a relatively low rCBF such that they enter into irreversible ischemia before therapy can be administered, even when timely (within 6 h) revascularization is achieved. This observation implies a potential ceiling effect for IAT-AIS; we call this phenomenon the 50% barrier (Figure 2).

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