Rebecca M. Sugg

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.

Collaterals at Angiography and Outcomes in the Interventional Management of Stroke (IMS) III Trial

Background and Purpose— Endovascular strategies provide unique opportunity to correlate angiographic measures of collateral circulation at the time of endovascular therapy. We conducted systematic analyses of collaterals at conventional angiography on recanalization, reperfusion, and clinical outcomes in the endovascular treatment arm of the Interventional Management of Stroke (IMS) III trial. Methods— Prospective evaluation of angiographic collaterals was conducted via central review of subjects treated with endovascular therapy in IMS III (n=331). Collateral grade before endovascular therapy was assessed with the American Society of Interventional and Therapeutic Neuroradiology/Society of Interventional Radiology scale, blinded to all other data. Statistical analyses investigated the association between collaterals with baseline clinical variables, angiographic measures of recanalization, reperfusion and clinical outcomes. Results— Adequate views of collateral circulation to the ischemic territory were available in 276 of 331 (83%) subjects. Collateral grade was strongly related to both recanalization of the occluded arterial segment (P=0.0016) and downstream reperfusion (P<0.0001). Multivariable analyses confirmed that robust angiographic collateral grade was a significant predictor of good clinical outcome (modified Rankin Scale score ⩽2) at 90 days (P=0.0353), adjusted for age, history of diabetes mellitus, National Institutes of Health Stroke Scale strata, and Alberta Stroke Program Early CT Score. The relationship between collateral flow and clinical outcome may depend on the degree of reperfusion. Conclusions— More robust collateral grade was associated with better recanalization, reperfusion, and subsequent better clinical outcomes. These data, from the largest endovascular trial to date, suggest that collaterals are an important consideration in future trial design. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT00359424.

Is Intra-Arterial Thrombolysis Safe After Full-Dose Intravenous Recombinant Tissue Plasminogen Activator for Acute Ischemic Stroke?

Background and Purpose— The optimal approach for acute ischemic stroke patients who do not respond to intravenous recombinant tissue plasminogen activator (IV rt-PA) is uncertain. This study evaluated the safety and response to intra-arterial thrombolytics (IATs) in patients unresponsive to full-dose IV rt-PA. Methods— A case series from a prospectively collected database on consecutive acute ischemic stroke patients treated with IATs after 0.9 mg/kg IV rt-PA during a 7-year interval was collected. Primary outcome measures included symptomatic intracranial hemorrhage and mortality. As indicators of response, secondary outcome measures were recanalization and discharge disposition. Results— Sixty-nine patients (mean±SD age, 60±13 years; range, 26 to 85 years; 55% male) with a median pretreatment National Institutes of Health Stroke Scale score of 18 (range, 6 to 39) were included. IV rt-PA was started at 124±32 minutes (median, 120 minutes) and IAT, at 288±57 minutes (median, 285 minutes). IATs consisted of reteplase (n=56), alteplase (n=7), and urokinase (n=6), with an average total dosage of 2.8 U, 8.6 mg, and 700 000 U, respectively. Symptomatic intracranial hemorrhage occurred in 4 of 69 (5.8%) patients; 3 cases were fatal. Recanalization was achieved in 50 (72.5%) and a favorable outcome (home or inpatient rehabilitation) in 38 (55%). Conclusions— IAT therapy after full-dose IV rt-PA in patients with persisting occlusion and/or lack of clinical improvement appears safe compared with IV rt-PA alone or low-dose IV rt-PA followed by IAT. A high rate of recanalization and favorable outcome can be achieved.

The Argatroban and Tissue-Type Plasminogen Activator Stroke Study Final Results of a Pilot Safety Study

Background and Purpose— Argatroban is a direct thrombin inhibitor that safely augments recanalization achieved by tissue-type plasminogen activator (tPA) in animal stroke models. The Argatroban tPA Stroke Study was an open-label, pilot safety study of tPA plus Argatroban in patients with ischemic stroke due to proximal intracranial occlusion. Methods— During standard-dose intravenous tPA, a 100-&mgr;g/kg bolus of Argatroban and infusion for 48 hours was adjusted to a target partial thromboplastin time of 1.75× baseline. The primary outcome was incidence of significant intracerebral hemorrhage defined as either symptomatic intracerebral hemorrhage or Parenchymal Hematoma Type 2. Recanalization was measured at 2 and 24 hours by transcranial Doppler or CT angiography. Results— Sixty-five patients were enrolled (45% men, mean age 63±14 years, median National Institutes of Health Stroke Scale=13). The median (interquartile range) time tPA to Argatroban bolus was 51 (38–60) minutes. Target anticoagulation was reached at a median (interquartile range) of 3 (2–7) hours. Significant intracerebral hemorrhage occurred in 4 patients (6.2%; 95% CI, 1.7–15.0). Of these, 3 were symptomatic (4.6%; 95% CI, 0.9–12.9). Seven patients (10%) died in the first 7 days. Within the 2-hour monitoring period, transcranial Doppler recanalization (n=47) occurred in 29 (61%) patients: complete in 19 (40%) and partial in another 10 (21%). Conclusions— The combination of Argatroban and intravenous tPA is potentially safe in patients with moderate neurological deficits due to proximal intracranial arterial occlusions and may produce more complete recanalization than tPA alone. Continued evaluation of this treatment combination is warranted. Clinical Trial Registration— URL: www.clinicaltrials.gov. Unique identifier: NCT00268762.

Cerebral mycotic aneurysms treated with a neuroform stent: technical case report.

OBJECTIVE AND IMPORTANCE: We describe the first documented endovascular treatment of proximal intracranial mycotic aneurysms by a self-expanding, flexible, dedicated, intracranial Neuroform stent. Treatment with this stent rapidly obliterated the aneurysms, eliminated the need for additional coiling, and maintained the patency of the parent arteries. CLINICAL PRESENTATION: A 47-year-old male patient with infective endocarditis presented with ischemic stroke and minimal subarachnoid hemorrhage. Cerebral angiography demonstrated a fusiform aneurysm of the supraclinoid segment of the left internal carotid artery and horizontal segment of the left middle cerebral artery, with superimposing side-wall focal aneurysms. Despite antibiotic therapy, the focal aneurysms progressively enlarged, as demonstrated on a subsequent cerebral angiogram at Day 11. INTERVENTION: A 4-mm × 2-cm Neuroform stent was deployed along the fusiform aneurysm of the left supraclinoid internal carotid artery and the horizontal middle cerebral artery M-1 segment encompassing the focal side-wall aneurysms with preserved patency of the parent arterial segments. CONCLUSION: Endovascular stent placement can be an effective treatment for proximal intracranial mycotic aneurysms that fail to respond to medical therapy.Accepted, September 7, 2005. OBJECTIVE AND IMPORTANCE: We describe the first documented endovascular treatment of proximal intracranial mycotic aneurysms by a self-expanding, flexible, dedicated, intracranial Neuroform stent. Treatment with this stent rapidly obliterated the aneurysms, eliminated the need for additional coiling, and maintained the patency of the parent arteries. CLINICAL PRESENTATION: A 47-year-old male patient with infective endocarditis presented with ischemic stroke and minimal subarachnoid hemorrhage. Cerebral angiography demonstrated a fusiform aneurysm of the supraclinoid segment of the left internal carotid artery and horizontal segment of the left middle cerebral artery, with superimposing side-wall focal aneurysms. Despite antibiotic therapy, the focal aneurysms progressively enlarged, as demonstrated on a subsequent cerebral angiogram at Day 11. INTERVENTION: A 4-mm 2-cm Neuroform stent was deployed along the fusiform aneurysm of the left supraclinoid internal carotid artery and the horizontal middle cerebral artery M-1 segment encompassing the focal side-wall aneurysms with preserved patency of the parent arterial segments. CONCLUSION: Endovascular stent placement can be an effective treatment for proximal intracranial mycotic aneurysms that fail to respond to medical therapy.

Impact of General Anesthesia on Safety and Outcomes in the Endovascular Arm of Interventional Management of Stroke (IMS) III Trial

Background and Purpose— General anesthesia (GA) for endovascular therapy (EVT) of acute ischemic stroke may be associated with worse outcomes. Methods— The Interventional Management of Stroke III trial randomized patients within 3 hours of acute ischemic stroke onset to intravenous tissue-type plasminogen activator±EVT. GA use within 7 hours of stroke onset was recorded per protocol. Good outcome was defined as 90-day modified Rankin Scale ⩽2. A multivariable analysis adjusting for dichotomized National Institutes of Health Stroke Scale (NIHSS; 8–19 versus ≥20), age, and time from onset to groin puncture was performed. Results— Four hundred thirty-four patients were randomized to EVT, 269 (62%) were treated under local anesthesia and 147 (33.9%) under GA; 18 (4%) were undetermined. The 2 groups were comparable except for median baseline NIHSS (16 local anesthesia versus 18 GA; P<0.0001). The GA group was less likely to achieve a good outcome (adjusted relative risk, 0.68; confidence interval, 0.52–0.90; P=0.0056) and had increased in-hospital mortality (adjusted relative risk, 2.84; confidence interval, 1.65–4.91; P=0.0002). Those with medically indicated GA had worse outcomes (adjusted relative risk, 0.49; confidence interval, 0.30–0.81; P=0.005) and increased mortality (relative risk, 3.93; confidence interval, 2.18–7.10; P<0.0001) with a trend for higher mortality with routine GA. There was no significant difference in the adjusted risks of subarachnoid hemorrhage (P=0.32) or symptomatic intracerebral hemorrhage (P=0.37). Conclusions— GA was associated with worse neurological outcomes and increased mortality in the EVT arm; this was primarily true among patients with medical indications for GA. Relative risk estimates, though not statistically significant, suggest reduced risk for subarachnoid hemorrhage and symptomatic intracerebral hemorrhage under local anesthesia. Although the reasons for these associations are not clear, these data support the use of local anesthesia when possible during EVT. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT00359424.

Perfusion Augmentation in Acute Stroke Using Mechanical Counter-Pulsation–Phase IIa Effect of External Counterpulsation on Middle Cerebral Artery Mean Flow Velocity in Five Healthy Subjects

Background and Purpose— External counterpulsation (ECP) improves coronary perfusion, increases left ventricular stroke volume similar to intraaortic balloon counterpulsation, and recruits arterial collaterals within ischemic territories. We sought to determine ECPs effect on middle cerebral artery (MCA) blood flow augmentation in normal controls as a first step to support future clinical trials in acute stroke. Methods— Healthy volunteers were recruited and screened for exclusions. Bilateral 2-MHz pulsed wave transcranial Doppler (TCD) probes were mounted by head frame, and baseline M1 MCA TCD measurements were obtained. ECP was then initiated using standard procedures for 30 minutes, and TCD readings were repeated at 5 and 20 minutes. Physiological correlates associated with ECP-TCD waveform morphology were identified, and measurable criteria for TCD assessment of ECP arterial mean flow velocity (MFV) augmentation were constructed. Results— Five subjects were enrolled in the study. Preprocedural M1 MCA TCD measurements were within normal limits. Onset of ECP counterpulsation produced an immediate change in TCD waveform configuration with the appearance of a second upstroke at the dicrotic notch, labeled peak diastolic augmented velocity (PDAV). Although end-diastolic velocities did not increase, both R-MCA and L-MCA PDAVs were significantly higher than baseline end-diastolic values (P<0.05 Wilcoxon rank-sum test) at 5 and 20 minutes. Augmented MFVs (aMFVs) were also significantly higher than baseline MFV in the R-MCA and L-MCA at both 5 and 20 minutes (P<0.05). Conclusions— ECP induces marked changes in cerebral arterial waveforms and augmented peak diastolic and mean MCA flow velocities on TCD in 5 healthy subjects.

Myocardial injury in patients with intracerebral hemorrhage treated with recombinant factor VIIa

We report myocardial injury in 20 recombinant factor VIIa (rFVIIa) treated and 110 nontreated patients with intracerebral hemorrhage. Patients were treated or received standard medical management. All received EKG and cardiac enzyme testing. Elevated troponin occurred in 20% treated vs 3% nontreated (p = 0.02). Myocardial infarction occurred in 10% vs 1% (p = 0.01). We found a significant increase in myocardial injury in rFVIIa treated patients.

Is Mechanical Embolectomy Performed in Nonanesthetized Patients Effective

BACKGROUND AND PURPOSE: In centers performing endovascular treatment for patients with AIS, there is variability in placing patients under general anesthesia. Nonanesthetized patients might move during the procedure leading to complications and prolonging the time to revascularization due to lack of cooperation. However, general anesthesia can lead to a delay of the procedure, an inability to assess the patient during the procedure, and fluctuations of blood pressure. Our center does not routinely either use general anesthesia or sedate patients. We report our experience with nonanesthetized patients undergoing emergent mechanical embolectomy. MATERIALS AND METHODS: We performed a retrospective analysis of 66 consecutive patients enrolled in the MERCI Registry at our center from June 2007 to June 2009. A univariate statistical analysis was performed by using the Fisher exact test for categoric variables and the Student t test for continuous variables in comparing use of general anesthesia with nonanesthetized patient demographics, procedural times, procedural complications, good outcome, and mortality. RESULTS: Nine patients (13.6%) were placed under general anesthesia, and 57 (86.4%) were awake. Higher baseline NIHSS scores and older age were statistically associated with general anesthesia. No significant difference occurred between groups in the time to groin puncture or procedural times. Revascularization rates were 77% for general anesthesia patients and 70% for nonanesthetized patients (P = .331). The nonanesthetized group had better outcomes, but we did not control these outcomes for other factors. Complications were much more frequent in the general anesthesia patients (22%) than in the nonanesthetized patients (3.5%) (P = .0288). CONCLUSIONS: Performing mechanical embolectomy in nonanesthetized patients at our institution does not prolong procedure time, decrease revascularization rates, increase complication rates, or decrease good outcome. Mechanical embolectomy in nonanesthetized patients is effective and should be considered an option in the treatment of the patient with AIS.

The Argatroban and tPA Stroke Study: final results of a pilot safety study

Background and Purpose— Argatroban is a direct thrombin inhibitor that safely augments recanalization achieved by tissue-type plasminogen activator (tPA) in animal stroke models. The Argatroban tPA Stroke Study was an open-label, pilot safety study of tPA plus Argatroban in patients with ischemic stroke due to proximal intracranial occlusion. Methods— During standard-dose intravenous tPA, a 100-&mgr;g/kg bolus of Argatroban and infusion for 48 hours was adjusted to a target partial thromboplastin time of 1.75× baseline. The primary outcome was incidence of significant intracerebral hemorrhage defined as either symptomatic intracerebral hemorrhage or Parenchymal Hematoma Type 2. Recanalization was measured at 2 and 24 hours by transcranial Doppler or CT angiography. Results— Sixty-five patients were enrolled (45% men, mean age 63±14 years, median National Institutes of Health Stroke Scale=13). The median (interquartile range) time tPA to Argatroban bolus was 51 (38–60) minutes. Target anticoagulation was reached at a median (interquartile range) of 3 (2–7) hours. Significant intracerebral hemorrhage occurred in 4 patients (6.2%; 95% CI, 1.7–15.0). Of these, 3 were symptomatic (4.6%; 95% CI, 0.9–12.9). Seven patients (10%) died in the first 7 days. Within the 2-hour monitoring period, transcranial Doppler recanalization (n=47) occurred in 29 (61%) patients: complete in 19 (40%) and partial in another 10 (21%). Conclusions— The combination of Argatroban and intravenous tPA is potentially safe in patients with moderate neurological deficits due to proximal intracranial arterial occlusions and may produce more complete recanalization than tPA alone. Continued evaluation of this treatment combination is warranted. Clinical Trial Registration— URL: www.clinicaltrials.gov. Unique identifier: NCT00268762.