Tipicidad subjetiva en los delitos de comisión por omisión

Microembolic signals following TIA/non-disabling stroke

Tanaka et al suggest a ratio of middle cerebral artery (MCA) to anterior cerebral artery (ACA) blood flow of approximately 75:25 from the internal carotid artery180_{. A recent in vitro study by} Chung et al181 _{showed that embolus trajectory favours the middle cerebral artery, especially large} emboli. This preference of emboli to enter the MCA is consistent with the high ratio of MCA–ACA infarcts reported by the Harvard182 _{and Lausanne}183 _{stroke registries. In carotid disease, cerebral} infarcts occur more frequently in the territory of the middle, compared with that of the anterior, cerebral artery and occurrence of cerebral microembolism follows a similar distribution184_. Microembolic signals (MES) have been detected in approximately 40% of symptomatic carotid artery stenosis patients35, 185_{. The presence of microembolic signal has been associated with} recently symptomatic carotid stenosis, degree of stenosis185_{, intraluminal thrombosis and} unstable carotid plaque characteristics162, 186-188_.

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Forteza et al189 _{reported a higher occurrence of microembolic signals in patients presenting within} 4 days of their index symptoms, as compared to those who presented with 12 days of their most recent symptoms. Valton et al190 _{prospectively studied the association of microembolic signals in} the ipsilateral middle cerebral artery and early ischaemic recurrence in 73 consecutive patients with anterior circulation, stroke or TIA in whom the TCD examination was performed within 7 days from the onset of symptoms. A further report has shown that patients with MES are at a nine-fold increased risk of stroke190_{. In the more recent Clopidogrel and Aspirin for Reduction of} Emboli in Symptomatic Carotid Stenosis (CARESS trial)37_{, the presence of MES was associated with} a markedly increased risk of recurrent stroke and TIA at day 7 following the initial symptoms. This is also consistent with an epidemiological study demonstrating a high risk of early recurrent stroke or TIA at 7 days from the index symptom10_{. Ritter et al reported an increased prevalence of} patients with MES with a higher degree of carotid stenosis185_{. Valton et al}187 _{demonstrated that} microembolic signals were associated with the appearance of plaque ulceration on angiography. The analysis of endarterectomy specimens by Sitzer et al186 _{demonstrated that microembolism} before carotid surgery is closely related to surface thrombus and ulceration of the carotid plaque. These observations suggest that unstable ulcerated carotid plaque and surface thrombus are the source of the MES in acute symptomatic carotid disease patients. A more recent study by Van Lemmeren et al188 _{showed that spontaneous MES were detected in a quarter of symptomatic} carotid disease patients scheduled for CEA and were associated with unstable carotid plaque characteristics such as luminal thrombus.

Early work by Valton et al190 _{on symptomatic carotid stroke and TIA presenting within 7 days of} index symptoms showed patients with MES had significantly higher ischaemic recurrence than without MES (33% vs. 5%, P = 0.008). They demonstrated the daily incidence of ischaemic recurrence was 4.3% per 100 patients with MES and only 0.5% without MES.190 _{A more recent} prospective observational study by Mackinnon et al36 _{provided more conclusive evidence that} showed that MES predicts short-term ipsilateral stroke risk in symptomatic critical carotid artery stenosis patients (stenosis > 50%). In the same study Mackinnon et al36 _{prospectively monitored}

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200 consecutive, recently symptomatic patients with 50 – 99% stenosis who underwent TCD evaluation. They found a significant association between microembolic signal (MES) and both recurrent stroke alone (P = 0.001) and the combined endpoint of stroke and TIA (P = 0.00001)36_. The association between MES and stroke or stroke/TIA remained significant after taking into account the relevant clinical risk factors such as age, sex, smoking, hypertension, time from the last symptoms and degree of stenosis with an odds ratio of 4.67 (95% CI, 1.99 – 11.01, P < 0.0001)36_.

Ritter et al185 _{report a systematic review investigating the prognostic impact of MES in} symptomatic patients with carotid artery disease. They found that the daily risk of recurrent stroke or TIA was 1.3% in MES-positive patient, compared with 0.3% in MES-negative patients185_. The overall 30-day risk of recurring stroke or TIA was 21% in symptomatic carotid artery disease patients185_{. Ritter et al}185 _{calculated from the pooled data that symptomatic carotid artery disease} patients with MES have about a sevenfold increased risk of future events compared with patients without MES (OR 7.5, 95%CI 3.6 – 15.4, P < 0.0001). A more recent meta-analysis by King et al35 confirmed that the presence of MES in symptomatic carotid artery stenosis patients predicted both stroke alone (OR 9.57, 95% CI 1.54 – 59.3, P = 0.02) and the combined end point of stroke or TIA (OR 6.36, 95% CI 2.9 – 13.96, P < 0.00001).

Mackinnon et al demonstrated that the presence or absence of microembolic signal rather than the rate of MES predicted the risk of recurrent stroke and TIA191_{. Using a higher rate or threshold} of MES did not increase the predictive power of TCD. Ritter et al185 _{also recommended that the} stroke risk stratification in symptomatic carotid artery disease is dependent on the detection of one single MES. The predicted risk of recurrent ipsilateral TIA/stroke based on the presence or absence of MES was also used in a more recent prospective, multicentre, international study looking at the association between MES and risk of recurrent ipsilateral TIA/stroke in

46 Microembolic signals following carotid endarterectomy

Carotid endarterectomy reduces the risk of future stroke in patients with symptomatic critical artery stenosis38, 47_{. However, the procedure itself carries a significant peri-procedural risk of} stroke192_{. Current national guidelines}103 _{recommend that carotid endarterectomy should be} performed within 2 weeks of index TIA/minor stroke. Few studies have shown that early carotid endarterectomy confer higher risk of perioperative stroke146, 193_{. Reducing the risk of}

perioperative stroke improves the risk–to–benefit ratio for carotid endarterectomy.

The mechanisms of stroke following carotid endarterectomy are numerous. Early work on the pathogenesis of stroke from internal carotid artery occlusion showed that both

haemodynamically induced and embolic infarction could be distinguished based on the

anatomical distribution194_{. Thromboembolism generally give rise to infarcts within the territory of} a main arterial branch, whereas low-flow states are associated with watershed infarcts195_{. Early} work by Steed et al suggested thromboembolism as the principal mechanism of peri-operative stroke196_{. Morphological study of a cerebral infarct on CT scan following carotid endarterectomy} strongly suggested thromboembolism as the principal mechanism of ischaemic perioperative stroke195_{. Subsequent work showed that thromboembolism from the thrombogenic}

endarterectomised media zone was the principal of mechanism of perioperative ischaemic

stroke195, 197, 198_{. Recent clinical and radiological studies have confirmed that perioperative cerebral} microembolisation originating from the endarterectomised zone is strongly associated with thrombotic stroke following carotid endarterectomy199-201_{. Excision of the carotid plaque removes} the endothelium creating a thrombogenic surface on which platelet aggregation occurs. Human and experimental studies have shown that platelet deposition is increased at the site of carotid endarterectomy202, 203_{, reaching a maximum within 20 - 60 minutes and potentially giving rise to} microemboli causing thrombotic stroke. The platelet nature and origin of embolism in this group was further confirmed when the endarterectomised site was re-explored31, 204, 205 _{and by its} response to antiplatelet agents.

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Microemboli detected during the dissection phase (before carotid arteriotomy) are believed to be associated with thrombotic stroke risk35_{. In the dissection phase, the fragile carotid plaque has not} yet been removed. The exposure to the blood flow will potentially give rise to the emboli.

Meta-analysis by Markus et al35 _{has shown that the absence or presence of microemboli during} dissection phase of carotid endarterectomy did not predict intraoperative stroke. However, a high rate of microembolic signals during dissection phase predicted stroke (Odds Ratio 14.79, 95%CI 5.15 – 42.47, P < 0.00001)206_.

Increasing high rate of detected microembolic signals acutely following carotid endarterectomy have been demonstrated to be associated with post-operative thrombotic stroke31_.

Approximately up to 5% of patients developed persistent high rate of postoperative microembolic signals207 _{. Unfortunately, about 50% of these patients with high rate microembolic signals suffer a} thromboembolic stroke207_{. A previous study has shown that the early microemboli were detected} approximately 10 minutes following carotid artery flow restoration46_{. Work by Abbott et al}

showed that most of the patients who developed high microembolic signal rates, who were at risk of developing postoperative stroke, were identified during a 30 minute TCD study in the first post- operative hour207_{. More recent work by Sharpe et al}208 _{showed that a high risk cohort of patients} who would go on to develop high rate embolization that require treatment with Dextran could be identified by measuring the magnitude and rate of embolization in the first 30 minutes after arriving in theatre recovery. The vast majority of patients (85%) require no further monitoring208_. A meta-analysis by Markus et al35 _{showed that the absence or presence of microemboli did not} predict postoperative stroke. However, it did predict the combination of postoperative stroke and TIA (OR 3.56, 95%CI 1.37 – 9.22, P = 0.009). Further analysis has confirmed that high microembolic signals rate acutely after surgery predicted stroke alone and also stroke/TIA (OR 32.04, 95%CI 11.36 – 90.39, P < 0.00001)35_.

Currently, there is no consensus on the definitive threshold of MES rate which is associated with adverse neurological events following carotid endarterectomy due to variable outcomes between centres31, 199, 200, 209_{. The variation of the clinically significant threshold of MES rates could be}

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explained by the brain microcirculation which has considerable reserve capacity for microemboli. This capacity may be influenced by variables such as microembolus size, blood rheology, collateral flow and preoperative antiplatelet treatment31_{. Laman et al}200 _{evaluated the relationship between} the rate of microemboli (MES/min) and stroke complications following carotid endarterectomy. They found that a rate of 0.9 MES/min was associated with fourfold increase in the rate of early post-operative stroke following carotid endarterectomy200_{. Based on a prospective study by Levi} et al, 31 _{a threshold of MES rate > 50/hr (0.83 MES/min) has been shown to correlate with stroke} occurrence within a time frame of approximately 60 minutes following their detection. Levi’s group found that the positive predictive value for cerebral ischaemia of detecting MES rate > 50/hr was 0.71, and the negative predictive value of < 50/hr was 0.9831_{. Naylor et al}33 _started Dextran therapy in patients with 25 or more emboli in any 10 minute period of monitoring (2.5 MES/min). Cantelmo et al199 _{identified that MES rate of 0.33 MES/min was associated with}

clinically silent MRI ischaemic changes. Despite this variation of the MES rate threshold associated with thrombotic stroke between centres, a trend of increasing rates of embolisation carotid endarterectomy is strongly predictive of a high risk of progressing on to thrombotic stroke.