DEFINE ISCHEMIC PENUMBRA ?
B ) WRITE A SHORT NOTE ON REPERFUSION STRATEGIES FOR ACUTE ISCHEMIC STROKE ACCORDING TO EVIDENCE SUPPORTED LITERATURE ?
A 2 A ) DEFINITION
1 Ischemic penumbra refers to a rim of tissue lying just outside the core ischemic region (area most severely damaged by stroke or ischemic event).
2 Within the core ischemic region, blood and oxygen flow is severely diminished, resulting in neuronal death. However, in the ischemic penumbra, cells are viable for a short amount of time ( VV IMP )
3 The penumbra receives its limited blood flow from the collateral arteries of the occluded vascular tree.
4 The penumbral tissue remains viable have reported anywhere from 6 h to 3 days.
5 However, it has been shown that once the subacute phase of the stroke sets in (6–11 days), the untreated penumbral area will succumb to necrosis (cell death). This is due to the fact that the demand for oxygen is too great for the occluded vascular tree to supply.
6 The penumbra region typically occurs when blood flow drops below 20 mL/100 g/min vv imp
7 At this point electrical communication between neurons fails to exist.
A ) Cells in this region are alive but metabolic pumps are inhibited, oxidative metabolism is reduced but neurons may begin to depolarize again.
8 Areas of the brain generally do not become infarcted until blood flow to the region drops below 10 to 12 mL/100 g/min.
A ) At this point, glutamate release becomes unregulated, ion pumps are inhibited andadenosine triphosphate (ATP) synthesis also stops which ultimately leads to the disruption ofintracellular processes and neuronal death
9 PET is the gold standard for imaging, but because PET is neither widely available nor rapidly accessible current research focuses on improved MRI techniques.
A ) The penumbral area can also be detected based upon an integration of three factors - These factors include -
1 the site of vessel occlusion
2 the extent of oligaemia (hypoperfused area surrounding the penumbra, but not at risk of infarction at that moment
3 and the mismatch between this perfusion defect and the area of the brain already infarcted
IMPORTANCE
The viability of the ischemic penumbra and its potential to recover make it a target for acute pharmacologic intervention following stroke.
B ) REPERFUSION STRATEGIES FOR ACUTE ISCHEMIC STROKE
INTRODUCTION
1 Time window period of intervention is 3 hrs
2 The first attempts to treat acute stroke by thrombolysis were reported in 1976
3 The first small randomized trial showing potential benefits of thrombolysis when used early in acute stroke was published in 1992 and in 1995 the first positive randomized trial of thrombolysis was published
4 The first official guidelines recommending thrombolysis for acute stroke were published in 2003.
5 Direct mechanical reperfusion using catheter-based thrombectomy without thrombolysis was first used in 2001,and there is yet no randomized trial completed to date comparing mechanical reperfusion (without thrombolysis) vs. intravenous (i.v.) thrombolysis. ( vv imp )
6 Thus, the latest official guidelines do not yet recognize direct mechanical intervention as the accepted routine therapy for acute stroke.
ETIOLOGY OF ACUTE ISCHEMIC STROKE ( VV IMP )
Is multifactorial - cardioembolic , arterioembolic , thrombosis in situ , lacunar and cryptogenic as compared to myocardial infarction which is solely due to clot breakdown in 95 %
MANAGEMENT ( EVIDENCE BASED )
1 Intravenous thrombolysis is the first-line treatment for reperfusion but recanalization can be slow and incomplete, particularly for proximal occlusions.
2 VV IMP Intra-arterial approaches have evolved from the local delivery of pharmacological agents to the employment of mechanical devices.
A ) While the first-generation approaches (intra-arterial thrombolytic agents, Merci, Penumbra) showed higher rates of recanalization than intravenous treatment, recently published randomized clinical trials failed to show a benefit of intra-arterial over intravenous treatment alone.
B ) A new generation of flow restoration devices (Solitaire, Trevo) has been shown in randomized trials to be far superior to the Merci device with respect to both recanalization rates and speed of recanalization translating into significant differences in clinical outcomes.
C ) These promising approaches require level I evidence of clinical efficacy compared with medical treatment in order to become standard of care across large patient population
D ) BUT SHOULD NOT BE APPLICABLE FOR ALL - patient selection is of utmost importance
3 TIMELY REPERFUSION OF THE BRAIN TISSUE WITHIN 3 HRS IS IMPORTANT - IV tPa ( ALTEPLASE - recombinant - 0.9 mg / kg with max dose of 90 mg per kg - 10 % bolus dose ) is the only FDA approved and it is to be administered within 4.5 hrs - PT SHOULD NOT HAVE SEIZURES AT THAT TIME
4 Combination therapy with epiphibitide is superior over heparin and direct inhibitors ( v imp )
5 Outcome of the patient is dependent on multiple factors such as age , comorbidities , thrombus size and composition ***
6 Intraarterial treatment are likely to be useful if performed for proximal arterial occlusions or post large vessels and within 6 hrs
IN DETAIL
I - Intravenous thrombolysis vs. conservative treatment
1 Many randomized clinical trials confirmed superiority of i.v. thrombolysis over placebo i when used early after symptom onset
2 In acute stroke, one of the two most positive thrombolytic trial did not show significant mortality benefit (17.3% 3-month mortality after thrombolysis vs. 20.5% mortality after placebo, P = 0.30), but found a significant decrease in overall unfavourable outcome (death or severe disability defined as modified Rankin Scale (mRS) > 2 was found in 57% after thrombolysis vs. 73% after placebo)—the difference caused by 13% absolute reduction in permanent disability.
A ) Symptomatic intracranial (6.4% thrombolysis vs. 0.6% placebo) as well as overall fatal (2.9% thrombolysis vs. 0.3% placebo) bleeding was significantly higher after recombinant tissue plasminogen activator (rt-PA).
3 The ECASS-III trial enrolled 821 patients treated between 3 and 4.5 h after the onset of a stroke.
A ) Fewer patients had an unfavourable outcome (death or severe disability) with alteplase over placebo (48 vs. 55%; P = 0.04).
B ) The incidence of symptomatic intracranial haemorrhage (sICH) was higher with alteplase than with placebo (2.4 vs. 0.2%; P = 0.008).
C ) Mortality did not differ significantly between the alteplase and placebo groups (7.7 and 8.4%, respectively; P = 0.68).
4 The Third International Stroke Trial (IST-321) randomized 3035 elderly (53% were >80 years) patients with acute ischaemic stroke <6 h from symptom onset in two groups: (i) i.v. rt-PA or (ii) control treatment.
A ) Unfavourable outcome (death or disability by Oxford Handicap Score >2) at 6 months was found in 63% (rt-PA) vs. 65% (control, P = 0.181).
B ) Fatal or non-fatal sICH within 7 days occurred in 7% after rt-PA vs. 1% in the control group.
C ) Early mortality was 11% (rt-PA) vs. 7% (control group, P = 0.001)—total 6-month mortality was equal in both groups (27%).
5 A comprehensive meta-analysis comparing i.v. thrombolysis vs. conservative therapy for acute stroke included 26 trials involving 7152 patients.
A ) Thrombolytic therapy within 6 h from symptom onset increased the risk of sICH (OR 3.49, 95% CI 2.81–4.33) and death (OR 1.31, 95% CI 1.14–1.50) at 3–6 months post-stroke.
B ) However, the proportion of patients who were dead or dependent (modified Rankin 3–6) at 3–6 months after stroke was reduced (odds ratio 0.81, 95% confidence interval 0.73–0.90).
C ) VV IMP Treatment within 3 h was more effective at reducing the combined endpoint of death or dependency (OR 0.71, 95% CI 0.52–0.96) but had no effect on mortality (OR 1.13, 95% CI 0.86–1.48).
6 Thus, i.v. thrombolysis is superior to placebo for acute stroke provided it is used timely: within <12 h in STEMI (with maximum benefit within <6 h) and within <4.5 h in acute stroke (with mortality benefit only within <90 min).
II - Intravenous plus/vs. intra-arterial thrombolysis
1 Meta-analysis of 15 studies on combined i.v. + intra-arterial (i.a.thrombolytic therapy in acute stroke found 35.1% complete recanalization rate, 17.9% mortality, 51.1% unfavourable outcome (death or disability mRs > 2 at 90 days), and 8.6% sICH (proven haemorrhage with an increase of National Institute of Health Stroke Scale (NIHSS) by ≥4 points).
2 Neither mortality difference nor difference in sICH was found when combined lytic therapy was compared with i.v. thrombolysis alone.
3 The PROACT-II trial randomized 180 patients with angiographically proven middle cerebral artery occlusion treated within 6 h of stroke onset to either i.a. thrombolysis or placebo.
A ) Mechanical manipulation of the thrombus was not permitted.
B ) The study showed clinical superiority of thrombolysis (40% good neurological outcomes—mRS ≤ 2) over placebo (25% mRS ≤ 2).
C ) The rate of sICH was 10.9% with thrombolysis and 2% with placebo. There was no difference in 90-day mortality
III - Facilitated intervention (thrombolysis + mechanical intervention)
A ) Many randomized trials in STEMI and others tested the attractive hypothesis: to use i.v. thrombolysis at the time of first medical contact (to save time), followed by coronary angiography and angioplasty (to maximize the recanalization rates)
B ) However, all these trials failed to show benefit of this approach over direct angioplasty alone.
C ) The results of most trials almost copied the two similarly designed three-arm trials facilitated angioplasty was slightly superior to i.v. thrombolysis alone, but was far less effective than primary angioplasty alone.
D ) vv imp The explanation is complex, but most important are two differences favouring primary over facilitated PCI: higher rates of re-infarction (including stent thrombosis) and higher rates of bleeding complications (including cardiac tamponade) after facilitated PCI.
IV - Primary catheter-based intervention (primary percutaneous coronary intervention, direct catheter-based thrombectomy)
A ) The benefits of primary PCI over thrombolysis in STEMI were clearly demonstrated 20 years ago
B ) These benefits are present even when patients require transportation from the first medical contact site to the nearest PCI-capable hospital.
C ) Similar evidence from randomized trials is lacking in acute ischaemic stroke.
D ) A few years ago, CBT was performed with bulky devices, and a significant risk of complications was present.
E ) vv imp In the last 3–5 years, several new clot retrieval devices (stent retrievers) have been introduced and received CE mark for the use in European patients.
F ) These devices (e.g. Solitaire® or Trevo®) are something between a tiny self-expanding stent and a soft ‘spider-web-like’ basket for clot removal, and the risks of complications with this latest generation stent retrievers are much smaller, whereas their success rates are higher. Detailed information about CBT was published in the JACC white paper.44
G ) good neurological outcome (58 vs. 33%, OR 2.78, P = 0.0001) and 90-day mortality (17 vs. 38%, OR 0.34, P = 0.0001) were more favourable in the Solitaire® group with a markedly lower rate of sICH (2 vs. 11%, OR 0.14, P = 0.057).
H ) The TREVO trial was similar to SWIFT and tested the Trevo® stent retriever vs. The Merci Retriever®. Recanalization (TICI 2 or greater) was higher with Trevo® than with Merci® (86 vs. 60%, OR 4.22, P < 0.0001) as was good clinical outcome (40 vs. 22%, OR 2.39, P = 0.013).
1 There were no differences in the risk of sICH (7 vs. 9%, OR 0.75, P = 0.78) or 90-day mortality (33 vs. 24%, OR 1.61, P = 0.18).
2 vv imp An important finding from the SWIFT trial was that the speed of recanalization with the stent retrievers was significantly lower (36 min with Solitaire® vs. 52 min with Merci®, P = 0.038). Several other devices with varying designs are currently being tested.