Georgios Tsivgoulis

A Pilot Randomized Clinical Safety Study of Sonothrombolysis Augmentation With Ultrasound-Activated Perflutren-Lipid Microspheres for Acute Ischemic Stroke

Background and Purpose— Ultrasound transiently expands perflutren-lipid microspheres (&mgr;S), transmitting energy momentum to surrounding fluids. We report a pilot safety/feasibility study of ultrasound-activated &mgr;S with systemic tissue plasminogen activator (tPA). Methods— Stroke subjects treated within 3 hours had abnormal Thrombolysis in Brain Ischemia (TIBI) residual flow grades 0 to 3 before tPA on transcranial Doppler (TCD). Randomization included Controls (tPA+TCD) or Target (tPA+TCD+2.8 mL &mgr;S). The primary safety end point was symptomatic intracranial hemorrhage (sICH) with worsening by ≥4 NIHSS points within 72 hours. Results— Fifteen subjects were randomized 3:1 to Target, n=12 or Control, n=3. After treatment, asymptomatic ICH occurred in 3 Target and 1 Control, and sICH was not seen in any study subject. &mgr;S reached MCA occlusions in all Target subjects at velocities higher than surrounding residual red blood cell flow: 39.8±11.3 vs 28.8±13.8 cm/s, P<0.001. In 75% of subjects, &mgr;S permeated to areas with no pretreatment residual flow, and in 83% residual flow velocity improved at a median of 30 minutes from start of &mgr;S infusion (range 30 s to 120 minutes) by a median of 17 cm/s (118% above pretreatment values). To provide perspective, current study recanalization rates were compared with the tPA control arm of the CLOTBUST trial: complete recanalization 50% versus 18%, partial 33% versus 33%, none 17% versus 49%, P=0.028. At 2 hours, sustained complete recanalization was 42% versus 13%, P=0.003, and NIHSS scores 0 to 3 were reached by 17% versus 8%, P=0.456. Conclusions— Perflutren &mgr;S reached and permeated beyond intracranial occlusions with no increase in sICH after systemic thrombolysis suggesting feasibility of further &mgr;S dose-escalation studies and development of drug delivery to tissues with compromised perfusion.

Effect of body positioning during transcranial Doppler detection of right-to-left shunts

We adopted an expanded transcranial Doppler (TCD) protocol to evaluate if additional injections of agitated saline in different positions would improve shunt detection or grading. We report the safety and feasibility of this expanded contrast TCD protocol. Patients with ischemic stroke were evaluated. The standard protocol for RLS detection was followed and expanded after the initial injection in the supine position to the right lateral decubitus, upright sitting, and sitting with right lateral leaning. Changes in blood pressure, heart rate, and any subjective complaints were noted. Changes in body position and additional agitated saline injections were tolerated. Right‐to‐left shunt (RLS) was detected in 35% of patients (nu2003=u200355). If the initial supine testing was negative, all subsequent positions/injections were also negative for RLS. However, if the supine injection was positive for RLS, the change in body positions increased the microbubble (μB) count in eight of 19 (42%) RLS‐positive patients. The mean μB count in RLS‐positive patients was 20 (95% CI: 9–32). The use of three additional body positions increased the μB count to 73 (95% CI: 13–132). The highest μB yield was achieved in the upright sitting position. Our findings support the safety and feasibility of the expanded TCD protocol. If the initial supine Valsalva‐aided contrast TCD test is negative, there may be no need to study the patient in additional positions. However, if μB are detected in the supine position, additional testing for RLS in alternative positions may be found to be worthwhile.

The Role of Sonolysis and Sonothrombolysis in Acute Ischemic Stroke: A Systematic Review and Meta-analysis of Randomized Controlled Trials and Case-Control Studies

To assess the evidence on the safety and efficacy of sonothrombolysis in acute stroke.

Design of a PROspective multi-national CLOTBUST collaboration on reperfusion therapies for stroke (CLOTBUST-PRO)

Background The benefit of intravenous (i.v.) tissue plasminogen activator (tPA) in acute ischemic stroke (IS) is attributable to lysis of thrombus and restoration of perfusion to ischemic but not yet infarcted brain. Aims Our multicentre collaborative group prospectively implemented a protocol for transcranial Doppler assessment of intracranial recanalization with tPA treatment based on the CLOTBUST clinical trial (CLOTBUST-PRO). We aim to determine whether early recanalization (within 1 h from tPA bolus) is independently associated with better 3-month outcome in patients with intracranial arterial occlusions and correlates to a shorter time interval elapsed from symptom onset to tPA bolus. Subjects and methods Consecutive patients with acute IS due to intracranial arterial occlusions will be treated with standard i.v.-tPA and continuously monitored with 2 MHz Transcranial Doppler for arterial recanalization. Early recanalization will be determined with the previously validated Thrombolysis in Brain Ischemia flow-grading system within 60 min after tPA bolus. Power calculations are based on the assumption of α = 0·05 (two-sided test) and probabilities of functional independence at 3 months of 0·50 and 0·35 in patients with early complete recanalization and persisting occlusion, respectively. Detection of a 15% difference with a power of 0·824 requires an estimated sample of 480 patients of whom 25% are expected to achieve early recanalization while 75% will have persisting occlusion at 1 h after tPA bolus. We also plan to test prespecified secondary hypotheses within the projected study sample. Conclusions CLOTBUST-PRO is designed to determine if the timing (within 1 h from tPA bolus) of tPA-induced arterial recanalization is an independent determinant of 3-month functional recovery. We also seek to demonstrate that the sooner the tPA is given to stroke patients, the earlier the recanalization occurs and the greater is the likelihood of functional independence at 3 months. Introduction Intravenous (i.v.) tissue plasminogen activator (tPA) remains the only approved therapy for acute ischemic stroke (IS) with faster time to treatment being associated with better outcomes at 3 months (1). Although the benefit of tPA is attributable to lysis of thrombus and restoration of perfusion to ischemic but not yet infarcted brain (2), recanalization was not documented in pivotal tPA trials. This hypothesis is supported by both animal and smaller human studies showing that the duration of impaired perfusion is associated with final infarct volume and that early recanalization correlates with smaller infarct size (3–5).

Reperfusion and outcomes in Penumbra vs. systemic tissue plasminogen activator clinical trials

Background An uncontrolled clinical study of the Penumbra™ system showed high rates of recanalisation and relatively poor functional outcomes that were inadequately compared with historic controls. We aimed to compare the findings in Penumbra with intravenous tissue plasminogen activator trials that determined recanalisation (Combined Lysis Of Thrombus in Brain ischaemia using transcranial Ultrasound and Systemic tissue plasminogen activator and Transcranial Ultrasound in Clinical Sonothrombolysis). Methods Control patients treated with intravenous tissue plasminogen activator and intermittent ultrasound surveillance had National Institutes of Health Stroke Scale scores >7. The Penumbra trial definition of symptomatic intracranial haemorrhage was used. Revascularisation was defined using thrombolysis in brain ischaemia scores predictive of thrombolysis in myocardial infarction flow grades and compared with thrombolysis in myocardial infarction data from Penumbra. Favourable functional outcomes was defined as a modified Rankin Scale of 0–2. Results Pretreatment stroke severity (National Institutes of Health Stroke Scale score) was 17·6 ± 5·2 points in Penumbra patients (n=125) and 16·3 ± 5·3 in controls (n=68; P=0·101). The control group was older compared with Penumbra (68·8 ± 13·4 vs. 63·5 ± 13·5-years; P=0·010). Time-to-treatment initiation was on average 2u2009h later (2·3 ± 0·6 vs. 4·3 ± 1·5u2009h; P<0·001) in Penumbra. The rate of any revascularisation after treatment with Penumbra was higher than that following intravenous thrombolysis: 82% (54% thrombolysis in myocardial infarction II and 27% thrombolysis in myocardial infarction III) vs. 40% (25% partial, 15% complete revascularisation), P<0·001. Symptomatic intracranial haemorrhage tended to be higher with Penumbra (11·2% vs. 4·4%; P=0·182, Fishers exact test). At three-months, mortality with Penumbra was higher (32·8%) than controls (14·1%; P=0·006). Favourable functional outcomes were higher in historic controls (39% vs. 25%; P=0·046). Conclusions Despite lower revascularisation rates, patients treated with systemic thrombolysis achieved better functional outcomes likely due to earlier treatment initiation. These data indicate that it is unrealistic to expect primary intraarterial revascularisation to be any better than systemic plasminogen activator within the 3-h time window. Improvements in the speed of delivery and performance of intraarterial reperfusion are needed.

Exploratory Analysis of Estimated Acoustic Peak Rarefaction Pressure, Recanalization, and Outcome in the Transcranial Ultrasound in Clinical Sonothrombolysis Trial

Acoustic peak rarefaction pressure (APRP) is the main factor that influences ultrasound‐enhanced thrombolysis. We sought to determine whether recanalization rate and functional outcomes in the Transcranial Ultrasound in Clinical SONothrombolysis (TUCSON) trial could be predicted by estimated in vivo APRP.

Body Weight, Not Thrombus-Burden Tissue Plasminogen Activator Dosing But Still

See related article, pages 2867–2871. nnAfter studies in cardiology that used body weight dosing, intravenous tissue plasminogen activator (tPA) dose for stroke (0.9 mg/kg alteplase, maximum 90 mg) emerged from small dose-escalation studies that started with doses far less than those for myocardial infarction.1 These studies were conducted before tests like CT angiography became readily available to determine thrombus location and extent in acute ischemic stroke. Current guidelines endorse this body weight-based dose as standard of care after pivotal randomized trials showed a significant benefit from systemic thrombolysis.2,3 During clinical trials and in daily practice, clinicians have to obtain body weight (actual or estimate) urgently when special beds equipped with calibrated scales are generally not available in emergency departments. Weighing the patient without a stretcher with built-in bed scales would require a Hoyer lift scale, and because tPA should be given as soon as possible, this could delay care. As a result, dosing errors could be frequent. These errors were documented by many across different patient populations.4,5nnBruer et al provide a useful account that details body weight estimation …

Response to Letter by Makris et al Regarding Article, “Carotid Artery Stenting Versus Carotid Endarterectomy: A Comprehensive Meta-Analysis of Short-Term and Long-Term Outcomes”

Response:nnWe would like to thank Makris et al for their constructive comments regarding our recent meta analysis.1 Indeed, information regarding carotid plaque stability, statin administration protocols, detection of microembolic signals using transcranial doppler monitoring,2 as well as carotid and aortic arch anatomy have not been systematically examined by the individual studies. Rather expectedly, the meta analysis reflects the limitations of the existing literature.nnRegarding the notion of symptomatic/asymptomatic patients, we agree that the majority of subjects included in this meta analysis were symptomatic. Specifically, …

Detection of Right-to-Left Shunt With Transcranial Doppler Is Affected by Body-Positioning

To the Editor:nnWe read with great interest the recent study by Caputi et al regarding the postural dependency of right-to-left shunt (RLS) detection using contrast-enhanced transcranial Doppler (TCD).1 After using TCD to detect the bubble-load in 2 different body positions (recumbent and standing) in consecutive RLS-positive patients (confirmed by transthoracic echocardiogram), the authors concluded that the amount of bubbles detected was dependent on body position, with 42% of the study population exhibiting almost a 3-fold increase in the yield of microbubbles in the standing compared to the supine position.1nnOur group has previously investigated whether body-positioning may affect the sensitivity of TCD in detecting and grading RLS in patients with ischemic stroke …