Pulsed-wave ultrasound increases the exposure of an intracranial thrombus to alteplase (recombinant tissue plasminogen activator), potentially facilitating early reperfusion. We aimed to ascertain if ...a novel operator-independent transcranial ultrasound device delivering low-power high-frequency ultrasound could improve functional outcome in patients treated with alteplase after acute ischaemic stroke.
We did a multicentre, double-blind, phase 3, randomised controlled trial (CLOTBUST-ER) at 76 medical centres in 14 countries. We included patients with acute ischaemic stroke (National Institutes of Health Stroke Scale score ≥10) who received intravenous thrombolysis (alteplase bolus) within 3 h of symptom onset in North America and within 4·5 h of symptom onset in all other countries. Participants were randomly allocated (1:1) via an interactive web response system to either active ultrasound (2 MHz pulsed-wave ultrasound for 120 min sonothrombolysis; intervention group) or sham ultrasound (control group). Ultrasound was delivered using an operator-independent device, which had to be activated within 30 min of the alteplase bolus. Participants, investigators, and those assessing outcomes were unaware of group assignments. The primary outcome was improvement in the modified Rankin Scale score at 90 days in patients enrolled within 3 h of symptom onset, assessed in the intention-to-treat population as a common odds ratio (cOR) using ordinal logistic regression shift analysis. This trial is registered with ClinicalTrials.gov, number NCT01098981. The trial was stopped early by the funder after the second interim analysis because of futility.
Between August, 2013, and April, 2015, 335 patients were randomly allocated to the intervention group and 341 patients to the control group. Compared with the control group, the adjusted cOR for an improvement in modified Rankin Scale score at 90 days in the intervention group was 1·05 (95% CI 0·77–1·45; p=0·74). 51 (16%) of 317 patients in the intervention group and 44 (13%) of 329 patients in the control group died (unadjusted OR 1·24, 95% CI 0·80–1·92; p=0·37) and 83 (26%) and 79 (24%), respectively, had serious adverse events (1·12, 0·79–1·60; p=0·53).
Sonothrombolysis delivered by an operator-independent device to patients treated with alteplase after acute ischaemic stroke was feasible and most likely safe, but no clinical benefit was seen at 90 days. Sonothrombolysis could be further investigated either in randomised trials undertaken in stroke centres that are dependent on patient transfer for endovascular reperfusion therapies or in countries where these treatments cannot yet be offered as the standard of care.
Cerevast Therapeutics.
Although arbitrary blood pressure (BP) thresholds exist for acute ischemic stroke (AIS) patients eligible for intravenous thrombolysis (IVT), current international recommendations lack clarity on the ...impact of mean pre- and post-IVT BP levels on clinical outcomes.
Eligible studies involving IVT-treated AIS patients were identified that reported the association of mean systolic BP (SBP) or diastolic BP levels before and after IVT with the following outcomes: 3-month favorable functional outcome (modified Rankin Scale mRS scores of 0-1) and 3-month functional independence (mRS scores of 0-2), 3-month mortality and symptomatic intracranial hemorrhage (sICH). Unadjusted analyses of standardized mean differences and adjusted analyses of studies reporting odds ratios (ORadj) per 10 mm Hg BP increment were performed using random-effects models.
We identified 26 studies comprising 56,513 patients. Higher pre- (P=0.02) and posttreatment (P=0.006) SBP levels were observed in patients with sICH. Patients with 3-month functional independence had lower post-treatment (P<0.001) SBP whereas trended towards lower pre-treatment (P=0.06) SBP. In adjusted analyses, elevated pre- (ORadj, 1.08; 95% confidence interval CI, 1.01 to 1.16) and post-treatment (ORadj, 1.13; 95% CI, 1.01 to 1.25) SBP levels were associated with increased likelihood of sICH. Increasing pre- (ORadj, 0.91; 95% CI, 0.84 to 0.98) and post-treatment (ORadj, 0.70; 95% CI, 0.57 to 0.87) SBP values were also related to lower odds of 3-month functional independence.
s We found that elevated BP levels adversely impact AIS outcomes in patients receiving IVT. Future randomized-controlled clinical trials will provide definitive data on the aforementioned association.
Establishment of stroke centers, combined with accurate paramedic diagnosis and rapid transport, is essential to deliver acute stroke therapy. We wanted to measure and improve paramedic and hospital ...performance through implementation of the Brain Attack Coalition and American Stroke Association guidelines.
Pre-intervention and active-intervention phases with parallel data measurement points were used. The study involved six hospitals comprising the majority of acute-stroke admissions in Houston, Tex. Hospital, paramedic, and patient data were collected prospectively pre-intervention and during the active-intervention phase on all suspected acute-stroke patients admitted by Houston Fire Department-Emergency Medical Services. A multilevel educational intervention included paramedic, hospital, and community education. Paramedic diagnostic accuracy, hospital-performance efficiency, and thrombolytic treatment rates were the main outcome measures of the study.
Four hundred forty-six patients (74 per month) were transported in the pre-intervention phase to participating hospitals (59.8% of all suspected stroke patients transported city wide by Houston Fire Department-Emergency Medical Services), compared with 1072 patients (89 per month, or 68.7%) transported in the active-intervention phase (P<0.001). Accuracy of paramedic diagnosis of stroke increased from 61% to 79%. Admission within 2 hours of symptom onset increased from 58% to 62% (P=0.002). Thrombolysis rates increased in 4 of 6 centers, with 1 post- tissue plasminogen activator hemorrhage (3.7%) reported.
A multilevel educational program improves rapid hospitalization and paramedic diagnostic accuracy and increases the number of patients presenting for evaluation within the 3-hour tissue plasminogen activator window. Stroke center development supports safe thrombolytic practice in community settings.
Objective
Patent foramen ovale (PFO) can be detected in up to 43% of patients with cryptogenic cerebral ischemia undergoing investigation with transesophageal echocardiography (TEE). The diagnostic ...value of transthoracic echocardiography (TTE) in the detection of PFO in patients with cryptogenic ischemic stroke or transient ischemic attack has not been compared with that of transcranial Doppler (TCD) using a comprehensive meta‐analytical approach.
Methods
We performed a systematic literature review to identify all prospective observational studies of patients with cryptogenic cerebral ischemia that provided both sensitivity and specificity measures of TTE, TCD, or both compared to the gold standard of TEE.
Results
Our literature search identified 35 eligible studies including 3,067 patients. The pooled sensitivity and specificity for TCD was 96.1% (95% confidence interval CI = 93.0–97.8%) and 92.4% (95% CI = 85.5–96.1%), whereas the respective measures for TTE were 45.1% (95% CI = 30.8–60.3%) and 99.6% (95% CI = 96.5–99.9%). TTE was superior in terms of higher positive likelihood ratio values (LR+ = 106.61, 95% CI = 15.09–753.30 for TTE vs LR+ = 12.62, 95% CI = 6.52–24.43 for TCD; p = 0.043), whereas TCD demonstrated lower negative likelihood values (LR− = 0.04, 95% CI = 0.02–0.08) compared to TTE (LR− = 0.55, 95% CI = 0.42–0.72; p < 0.001). Finally, the area under the summary receiver operating curve (AUC) was significantly greater (p < 0.001) in TCD (AUC = 0.98, 95% CI = 0.97–0.99) compared to TTE studies (AUC = 0.86, 95% CI = 0.82–0.89).
Interpretation
TCD is more sensitive but less specific compared to TTE for the detection of PFO in patients with cryptogenic cerebral ischemia. The overall diagnostic yield of TCD appears to outweigh that of TTE. Ann Neurol 2016;79:625–635
Since there are contradictory data regarding the association of antiplatelet pretreatment (AP) with safety and efficacy outcomes of intravenous thrombolysis (IVT) for acute ischemic stroke (AIS), we ...conducted a systematic review and meta-analysis of available randomized-controlled clinical trials (RCTs) to investigate the association of AP with outcomes of AIS patients treated with intravenous alteplase. The outcome events of interest included symptomatic intracranial hemorrhage (sICH), fatal ICH, complete recanalization (CR), 3-month favorable functional outcome (FFO, mRS score 0–1), 3-month functional independence (FI, mRS score 0–2), and mortality. The corresponding odds ratios (ORs) were calculated for all the outcome events using random-effects model. The adjusted age and admission NIHSS OR (OR
adjusted
) were also estimated for all available outcomes. We included 7 RCTs (4376 patients, 33.7% with AP). In unadjusted analyses, AP was associated with higher likelihood of sICH (OR = 1.89, 95% CI 1.40–2.56), death (OR = 1.59, 95% CI 1.24–2.03), and lower likelihood of 3-month FI (OR = 0.69, 95% CI 0.56–0.85). No association was detected between AP and fatal ICH (OR = 1.53, 95% CI 0.75–3.15), 3-month FFO (OR = 0.79, 95% CI 0.58–1.07), and CR (OR = 0.64, 95% CI 0.04–11.66). After adjustment for age and admission stroke severity, AP was not related to sICH (OR
adjusted
= 1.67, 95% CI 0.75–3.72), 3-month FI (OR
adjusted
= 0.88, 95% CI 0.54–1.42), or death (OR
adjusted
= 1.01, 95% CI 0.55–1.86) in adjusted analyses. In conclusion, after adjusting for confounders, AP was not associated with a higher risk of sICH and worse 3-month functional outcome in AIS treated with intravenous alteplase. Antiplatelet intake prior to tPA-bolus should not be used as a reason to withhold or lower alteplase dose in AIS patients treated with IVT.
In this multicenter study, we sought to evaluate comparative safety and efficacy of combined IV thrombolysis (IVT) and mechanical thrombectomy (MT) vs direct MT in emergent large vessel occlusion ...(ELVO) patients.
Consecutive ELVO patients treated with MT at 6 high-volume endovascular centers were evaluated. Standard safety and efficacy outcomes (successful reperfusion modified Thrombolysis in Cerebral Infarction IIb/III, functional independence FI modified Rankin Scale (mRS) score of 0-2 at 3 months, favorable functional outcome mRS of 0-1 at 3 months, functional improvement mRS shift by 1-point decrease in mRS score) were compared between patients who underwent combined IVT and MT vs MT alone. Additional propensity score-matched analyses were performed.
A total of 292 and 277 patients were treated with combination therapy and direct MT, respectively. The combination therapy group had greater functional improvement (
= 0.037) at 3 months. After propensity score matching, 104 patients in the direct MT group were matched to 208 patients in the combination therapy group. IVT pretreatment was independently (
< 0.05) associated with higher odds of FI (odds ratio OR 1.75; 95% confidence interval CI 1.02-2.99) and functional improvement (common OR 1.64; 95% CI 1.05-2.56). Combination therapy was independently (
< 0.05) related to lower likelihood of 3-month mortality (0.50; 95% CI 0.26-0.96).
This observational study provides preliminary evidence that IVT pretreatment may improve outcomes in ELVO patients treated with MT. The question of the potential effect of IVT on ELVO patients treated with MT should be addressed with a randomized controlled trial.
This study provides Class III evidence that for stroke patients with emergent large vessel occlusion, combined IVT and MT is superior to direct MT in improving functional outcomes.
There are inconsistencies in concept, criteria, practice, and documentation of brain death/death by neurologic criteria (BD/DNC) both internationally and within countries.
To formulate a consensus ...statement of recommendations on determination of BD/DNC based on review of the literature and expert opinion of a large multidisciplinary, international panel.
Relevant international professional societies were recruited to develop recommendations regarding determination of BD/DNC. Literature searches of the Cochrane, Embase, and MEDLINE databases included January 1, 1992, through April 2020 identified pertinent articles for review. Because of the lack of high-quality data from randomized clinical trials or large observational studies, recommendations were formulated based on consensus of contributors and medical societies that represented relevant disciplines, including critical care, neurology, and neurosurgery.
Based on review of the literature and consensus from a large multidisciplinary, international panel, minimum clinical criteria needed to determine BD/DNC in various circumstances were developed.
Prior to evaluating a patient for BD/DNC, the patient should have an established neurologic diagnosis that can lead to the complete and irreversible loss of all brain function, and conditions that may confound the clinical examination and diseases that may mimic BD/DNC should be excluded. Determination of BD/DNC can be done with a clinical examination that demonstrates coma, brainstem areflexia, and apnea. This is seen when (1) there is no evidence of arousal or awareness to maximal external stimulation, including noxious visual, auditory, and tactile stimulation; (2) pupils are fixed in a midsize or dilated position and are nonreactive to light; (3) corneal, oculocephalic, and oculovestibular reflexes are absent; (4) there is no facial movement to noxious stimulation; (5) the gag reflex is absent to bilateral posterior pharyngeal stimulation; (6) the cough reflex is absent to deep tracheal suctioning; (7) there is no brain-mediated motor response to noxious stimulation of the limbs; and (8) spontaneous respirations are not observed when apnea test targets reach pH <7.30 and Paco2 ≥60 mm Hg. If the clinical examination cannot be completed, ancillary testing may be considered with blood flow studies or electrophysiologic testing. Special consideration is needed for children, for persons receiving extracorporeal membrane oxygenation, and for those receiving therapeutic hypothermia, as well as for factors such as religious, societal, and cultural perspectives; legal requirements; and resource availability.
This report provides recommendations for the minimum clinical standards for determination of brain death/death by neurologic criteria in adults and children with clear guidance for various clinical circumstances. The recommendations have widespread international society endorsement and can serve to guide professional societies and countries in the revision or development of protocols and procedures for determination of brain death/death by neurologic criteria, leading to greater consistency within and between countries.
Even though current guidelines suggest that noninvasive ventilatory correction (NIVC) could be considered for acute ischemic stroke patients with obstructive sleep apnea, available evidence is ...conflicting, with no adequately powered randomized clinical trial being available to date.
We conducted a systematic review and meta-analysis of all available literature data evaluating the effect of NIVC on neurological improvement (based on decrease in National Institutes of Health Stroke Scale score), vascular events (recurrent stroke, transient ischemic attack, myocardial infarction and unstable angina), and mortality during the follow-up period.
We identified 4 randomized clinical trials and 1 prospectively matched observational cohort, comprising a total of 389 patients (59.8% males, mean age: 64.4 years). The risk of both performance and detection bias was considered high in most of the included randomized clinical trials because of the lack of blinding in participants, personnel and/or outcome assessors. The mean decrease in National Institutes of Health Stroke Scale scores during the first (≤30) days of acute ischemic stroke was found to be greater in NIVC-treated patients in comparison to controls (standardized mean difference, 0.38; 95% confidence interval, 0.11-0.66;
=0.007). However, no significant differences were detected between NIVC-treated acute ischemic stroke patients and controls on both the risk of vascular events (risk ratio, 0.53; 95% confidence interval, 0.25-1.14;
=0.11) and mortality (risk ratio, 0.71; 95% confidence interval, 0.37-1.36;
=0.30). No evidence of heterogeneity (
=0%;
for Cochran Q>0.50) or publication bias were detected in all analyses.
NIVC seems to be associated with greater short-term neurological improvement in acute ischemic stroke patients with obstructive sleep apnea. This finding deserves further investigation within the settings of an adequately powered, sham-control, randomized clinical trial.
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