Recanalization and reperfusion

Fig. 3.11. Patient who received t-PA following MRI. PI, = quantitative MTT map. There is a distal Ml occlusion on MRA, but no obvious tissue at risk (no perfusion-diffusion mismatch). The baseline DWI lesion is quite large. Thrombolysis successfully achieves recanalization and reperfusion, but there is also haemorrhagic transformation apparent on day 3 imaging...

Spontaneous recanalization, at least of middle cerebral artery occlusion, occurs in up to two-thirds of patients within a week of stroke onset, many in the first 48 hours (Fieschi et al. 1989 Kaps et al. 1992 Zanette et al. 1995 Arnold et al. 2005). In general, the CT identified and functional outcomes are both better with recanalization and reperfusion, and even with early hyperperfusion, than if the middle cerebral artery remains occluded (Wardlaw et al. 1993 Marchal et al. 1996b Barber et al. 1998b). 

Molina CA, Alvarez-Sabin J Recanalization and reperfusion therapies for acute ischemic stroke. Cerebrovasc Dis 2009 27 Suppl 1 pp. 162-167. 

Mokri B, Silbert PL, Schievink WI et al (1996) Cranial nerve palsy in spontaneous dissection of the extracranial internal carotid artery. Neurology 46 356-359 Molina CA, Montaner J, Abilleira S et al (2001) Timing of Spontaneous Recanalization and Risk of Hemorrhagic Transformation in Acute Cardioembolic Stroke. Stroke 32 1079-1084 Molina CA, Alvarez-Sabin J, Montaner J et al (2002) Thrombolysis-related hemorrhagic infarction a marker of early reperfusion, reduced infarct size, and improved outcome in patients with proximal middle cerebral artery occlusion. Stroke 33 1551-1556... 

Reperfusion as predictor of follow-up infarct volume. Revascularization therapies in acute ischemic stroke patients aim to rescue the ischemic penumbra by restoring the patency of the occluded artery (recanalization) and the downstream capillary blood flow (reperfusion). Although reperfusion and recanalization have been used interchangeably, the terms describe two distinct concepts [236]. Earlier studies supported the benefit of early recanalization in predicting smaller infarct volumes and clinical outcomes [2, 237, 238]. However, more recent studies have shown that recanalization does not always lead to reperfusion [239, 240]. One explanation is that the main clot may be fragmented and occlude smaller, downstream arterial branches, not allowing capillary reperfusion [241]. A second, distinct, but complementary reason is the noreflow phenomenon even if recanalization is achieved, tissue edema may not allow blood flow [242, 243]. 

The Penumbra stroke system (Penumbra Inc., San Leandro, CA) includes two different revascularization options (1) thrombus debulking and aspiration may be achieved by a reperfusion catheter that aspirates the clot while a separator device fragments it, and (2) direct thrombus extraction may be performed by a ring retriever while a balloon guide catheter is used to temporarily arrest flow. This system has been tested in a pilot trial in Europe. Twenty patients (mean NIHSS 21) with a total of 21 vessel occlusions (7 ICA, 5 MCA, and 9 Basilar) were treated up to 8 hours after symptom onset. Recanalization prior to lA lysis was achieved in all cases (48% TIMI 2 52% TIMI 3). Seven patients were also treated with lA UK or rt-PA. Good outcome at 30 days (defined as mRS < 2 or NIHSS 4-point improvement) was demonstrated in 42%. The mortality rate was 45%, but there were no device-related deaths. There was one asymptomatic SAH and three symptomatic ICHs. A prospective, single-arm, multicenter trial is being conducted in the United States and Europe currently. 

Thrombolysis aims to reduce the volume of infarcted brain by recanalizing the occluded vessel and restoring blood flow. Restoration of blood flow may not necessarily always be beneficial. First, studies in animals suggest that reperfusion of acutely ischemic brain may actually be harmful, through the release of free radicals and toxic products into the circulation. Second, thrombolysis will probably not be of benefit if infarction is completed or if the ischemic penumbra is small. Finally, thrombolysis may cause hemorrhagic transformation of the infarct or extracranial bleeding. 

Soares, B.P., J.D. Chien, M. Wintermark, MR and CT monitoring of recanalization, repeifusion, and penumbra salvage everything that recanalizes does not necessarily reperfuse Stroke, 2009. 40(3 Suppl) p. S24-7. 

Yasaka, M., et al.. Streptokinase in acute stroke ect on reperfusion and recanalization. Australian Streptokinase Trial Study Group. Neurology, 1998. 50(3) p. 626-32. 

Strong evidence supports the natural idea that recanalization of the occlusion and resulting tissue reperfusion translate into improved clinical outcomes (Fig. 12.4) [6, 9, 10]. While there is no randomized controlled trial data comparing lAT and intravenous therapy for PAO, multiple studies demonstrate improved rates of revascularization with lAT [6,11-13]. The promise of endovascular stroke therapy has led to the recent emergence of multiple stroke devices. Prospective, industry-sponsored trials of these devices have utilized reperfusion as their primary endpoint [6, 14, 15]. However, there is growing criticism of this emphasis on revascularization in lieu of clinical outcome [16,17]. Indeed, the clinical success of the endovascular approach is highly variable for incompletely understood reasons. 

Parenchymal imaging to characterize the infarct core and the ischemic penumbra follows the identification of a treatable anterior circulation arterial occlusion in considering whether to proceed to endovascular recanalization. Even with endovascular therapy, greater than half (54-72%) of acute stroke patients with proximal artery occlusions have a poor outcome, and a significant fraction (16-44%) are dead at 90 days [47]. Certainly some of this morbidity and mortality are related to suboptimal or delayed reperfusion, but a significant proportion is likely secondary to infarcts that have already completed or are near completion before the initiation of therapy [47]. The major issue is the lack of appropriate patient selection. 

The successful recanalization of an anterior circulation proximal artery occlusion will be of benefit to the patient only if it results in the prevention of infarction of brain tissue put at risk by that occlusion. Reperfusion into irreversibly injured tissue will not improve symptoms and may place the patient at risk for a hemorrhagic... 

Our thesis is based on the implicit assumption that faster, more complete reperfusion will translate into better long-term patient outcomes. Three types of reperfusion strategies have been described (1) recanalization or antegrade reperfusion, (2) global reperfusion (flow augmentation or transarterial retrograde reperfusion), and (3) transvenous retrograde reperfusion (flow reversal) (Table 13.1 and Fig. 13.1). 

The importance of time to reperfusion in patients with STEMI treated with primary PCI compared with thrombolytic drugs has recently been reexamined with respect to the extent of myocardial salvage (70). This study illustrates an ongoing difficulty in correlating outcomes with respect to time from symptom onset to balloon inflation as opposed to the interval from hospital admission to balloon inflation. Determination of the former is confounded by variability in the relationship between symptom onset and onset of irreversible ischemic injury as well as inaccuracies in reporting times of symptom onset. The relationship between time from hospital presentation to time to recanalization with primary PCI is clearer (34,53). 

Pharmacoinvasive recanalization with fibrinolytic therapy to induce initial reperfusion, conjunctive pharmacological therapy with anticoagulants to enhance the rapidity and extent of lysis and subsequent timely (within 12-24 hours) PCI to prevent reocclusion and reinfarction to eliminate underlying anatomical obstruction and thrombus are particularly promising for most patients with STEMI (30,73-77). This pharmacoinvasive approach for treatment of asymptomatic patients following thrombolysis should expand the interval during which PCI can be effective well beyond the 90-minute interval within which optimal benefits are seen with primary PCI. If so, it would be attractive for patients presenting to... 

Results from the Thrombolysis in Myocardial Infarction (TIMI) I study confirmed that prompt myocardial reperfusion decreased mortality (1). Results of several large-scale trials before and after TIMI I were consistent in establishing that treatment with intravenously administered thrombolytic agents to recanalize infarct-related arteries decreased mortality in patients with ST elevation myocardial infarction (STEMI) (2,3). However, despite the obvious benefits of thrombolysis, 30-day mortality in the GISSI-2 and ISIS-3 trials was as high as 8-10% (4,5). Because early restoration of myocardial blood flow was shown to... 

Refinements and improvements in pharmacologic ( thrombolysis ) and mechanical approaches ( primary angioplasty ) to recanalization have been impressive. Randomized clinical trials and registries have been used to compare and contrast the two, but assessment of both in combination lay dormant until quite recently. Improvements in coronary thrombolysis and coronary interventions now make reassessment of pharmacoinvasive therapy particularly desirable. Reassessment is indicated given the inherent limitations, when used alone, in both pharmacologic (failure to restore flow adequately) and mechanical approaches (unavoidable delay that can prolong the time to initiation of reperfusion). 

Recanalization remains the most important step in the treatment of ischemic stroke. In fact, without recanalization further treatment is very limited. However, recanalization alone does not restore all the function especially when ischemia has been allowed to last for several hours. Restoration of normal CBF to an ischemic brain region is beneficial only within the first 3-6 h. In very rare situations and mostly in the brain stem ischemias, recanaUzation procedures are undertaken beyond the 6-h limit. Recanalization into a severely ischanic tissue generates a cascade of untoward processes. Reperfusion injury leads to further deterioration of tissue that is already compromised. In general, shorter and less severe ischemia leads to fewer reperfusion injury consequences. In clinical practice the most significant and most visible complication of reperfusion into a severely injured brain parenchyma is hanonhage. It is mostly the increased risk of hemorrhagic transformation that limits the administration of thrombolytic therapy beyond 3 h. The key to success in thrombolysis remains a shorter duration of ischemia. 

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