Penumbral Rescue by normobaric O = O administration in patients with ischemic stroke and target mismatch proFile (PROOF): Study protocol of a phase IIb trial.

Oxygen is essential for cellular energy metabolism. Neurons are particularly vulnerable to hypoxia. Increasing oxygen supply shortly after stroke onset could preserve the ischemic penumbra until revascularization occurs. PROOF investigates the use of normobaric oxygen (NBO) therapy within 6 h of symptom onset/notice for brain-protective bridging until endovascular revascularization of acute intracranial anterior-circulation occlusion. Randomized (1:1), standard treatment-controlled, open-label, blinded endpoint, multicenter adaptive phase IIb trial. Primary outcome is ischemic core growth (mL) from baseline to 24 h (intention-to-treat analysis). Secondary efficacy outcomes include change in NIHSS from baseline to 24 h, mRS at 90 days, cognitive and emotional function, and quality of life. Safety outcomes include mortality, intracranial hemorrhage, and respiratory failure. Exploratory analyses of imaging and blood biomarkers will be conducted. Using an adaptive design with interim analysis at 80 patients per arm, up to 456 participants (228 per arm) would be needed for 80% power (one-sided alpha 0.05) to detect a mean reduction of ischemic core growth by 6.68 mL, assuming 21.4 mL standard deviation. By enrolling endovascular thrombectomy candidates in an early time window, the trial replicates insights from preclinical studies in which NBO showed beneficial effects, namely early initiation of near 100% inspired oxygen during short temporary ischemia. Primary outcome assessment at 24 h on follow-up imaging reduces variability due to withdrawal of care and early clinical confounders such as delayed extubation and aspiration pneumonia. ClinicalTrials.gov: NCT03500939; EudraCT: 2017-001355-31

Intravenous thrombolysis in acute ischemic stroke: Standard and potential future applications

Acute ischemic stroke is a medical emergency requiring urgent treatment. Randomized clinical trial and Phase IV data have provided unequivocal evidence that intravenous thrombolysis with recombinant tissue plasminogen activator (rt-PA) improves early functional outcomes by restoring brain perfusion. Moreover, these studies have shed substantial light on the factors which are associated with more favorable outcome with tPA and are related to the highest benefit-to-risk ratio. Stroke physicians should consider vascular imaging techniques to aid decision making with thrombolytic therapy. The presence of intracranial occlusion is the target of treatment with early recanalization being the goal. Successful use of intravenous thrombolysis depends on a sound understanding of the decision-making process and organization of the treating team who strives for early treatment initiation and strict adherence to the protocol. Intravenous rt-PA within 4.5 h of onset should now be a standard treatment of acute disabling ischemic stroke throughout the world. This review also summarizes intravenous thrombolysis contraindications as well as the safety of novel reperfusion therapies including tenecteplase, sonothrombolysis and the combination of alteplase with direct thrombin inhibitors or glycoprotein IIb/IIIa receptor antagonists. © 2014 Informa UK, Ltd

Intravenous thrombolysis for acute ischemic stroke occurring during hospitalization for transient ischemic attack

10.1111/ijs.12125International Journal of Stroke94413-41

Intravenous thrombolysis for acute ischemic stroke occurring during hospitalization for transient ischemic attack

Background: There are limited data regarding the use of intravenous thrombolysis in patients who experienced acute ischemic symptoms during their hospitalization for prior transient ischemic attack. Aim: We sought to prospectively evaluate the safety and efficacy of intravenous thrombolysis for the treatment of acute ischemic stroke occurring during hospitalization for transient ischemic attack in an international, multicenter study. Methods: Consecutive patients with acute ischemic stroke that occurred during hospitalization for prior transient ischemic attack were treated with intravenous thrombolysis in five tertiary-care stroke centers. Early arterial recanalization was determined by transcranial Doppler at the end of recombinant tissue plasminogen activator infusion using previously validated criteria. Symptomatic intracranial hemorrhage complicating intravenous thrombolysis was evaluated using the National Institute of Neurological Disorders and Stroke Recombinant Tissue Plasminogen Activator Stroke Study definition. Functional independence at three-months was defined as Modified Rankin Scale score of 0-2. Results: Systemic recombinant tissue plasminogen activator infusion (median onset-to-treatment time 70mins, interquartile range 50-150) was given in 25 consecutive patients (mean age 66±10 years) who developed acute ischemic stroke symptoms (median National Institutes of Health Stroke Scale score 10 points; interquartile range 8-14) during hospitalization for prior transient ischemic attack (median ABCD2 score 5 points; median time-to-symptom recurrence 24h, interquartile range 24-48). No symptomatic intracranial hemorrhage (0%; 95% confidence interval 0-12%) was documented. Early complete recanalization occurred in 64% of patients (95% confidence interval 44-80%), and 84% (95% confidence interval 65-94%) achieved three-month functional independence. The rate of three-month functional independence was higher in patients treated with intravenous tissue plasminogen activator within 90mins from symptom onset compared with those with onset-to-treatment time>90mins (81% vs. 33%; P=0·031). Conclusions: Intravenous thrombolysis for symptoms of acute ischemic stroke occurring after hospitalization for transient ischemic attack appears to be safe. These pilot data support resetting the clock if new symptoms recur shortly after transient ischemic attack. © 2013 World Stroke Organization