Summary Background Clazosentan, an endothelin receptor antagonist, significantly and dose-dependently reduced angiographic vasospasm after aneurysmal subarachnoid haemorrhage (aSAH). We investigated ...whether clazosentan reduced vasospasm-related morbidity and all-cause mortality. Methods In this randomised, double-blind, placebo-controlled, phase 3 study, we randomly assigned patients with aSAH secured by surgical clipping to clazosentan (5 mg/h, n=768) or placebo (n=389) for up to 14 days (27 countries, 102 sites, inpatient and outpatient settings) using an interactive web response system. The primary composite endpoint (week 6) included all-cause mortality, vasospasm-related new cerebral infarcts, delayed ischaemic neurological deficit due to vasospasm, and rescue therapy for vasospasm. The main secondary endpoint was dichotomised extended Glasgow outcome scale (GOSE; week 12). This trial is registered with ClinicalTrials.gov , number NCT00558311. Findings In the all-treated dataset, the primary endpoint was met in 161 (21%) of 764 clazosentan-treated patients and 97 (25%) of 383 placebo-treated patients (relative risk reduction 17%, 95% CI −4 to 33; p=0·10). Poor functional outcome (GOSE score ≤4) occurred in 224 (29%) clazosentan-treated patients and 95 (25%) placebo-treated patients (−18%, −45 to 4; p=0·10). Lung complications, anaemia, and hypotension were more common with clazosentan. Mortality (week 12) was 6% in both groups. Interpretation Clazosentan at 5 mg/h had no significant effect on mortality and vasospasm-related morbidity or functional outcome. Further investigation of patients undergoing endovascular coiling of ruptured aneurysms is needed to fully understand the potential usefulness of clazosentan in patients with aSAH. Funding Actelion Pharmaceuticals.
Background Because of the paucity of effective treatments for intracranial hemorrhage (ICH), the mortality rate remains at 40%-60%. A novel application of magnetic resonance-guided focused ultrasound ...(MRgFUS) for ICH may offer an alternative noninvasive treatment through the precise delivery of FUS under real-time MR imaging (MRI) guidance. The purpose of the present study was to optimize the parameters for rapid, effective, and safe trans-skull large clot liquefaction using in vivo porcine and ex vivo human skull models to provide a clinically relevant proof of concept. Methods The transcranial effectiveness of MRgFUS was tested ex vivo by introducing a porcine blood clot into a human skull, without introducing tissue plasminogen activator (tPA). We used an experimental human head device to deliver pulsed FUS sonications at an acoustic power of 600-900 W for 5-10 seconds. A 3-mL clot was also introduced in a porcine brain and sonicated in vivo with one 5-second pulse of 700 W through a bone window or with 3000 W when treated through an ex vivo human skull. Treatment targeting was guided by MRI, and the tissue temperature was monitored online. Liquefied volumes were measured as hyperintense regions on T2-weighted MR images. Results In both in vivo porcine blood clot through a craniectomy model and the porcine clot in an ex vivo human skull model targeted clot liquefaction was achieved, with only marginal increase in temperature in the surrounding tissue. Conclusions Our results demonstrate the feasibility of fast, efficient, and safe thrombolysis in an in vivo porcine model of ICH and in 2 ex vivo models using a human skull, without introducing tPA. Future studies will further optimize parameters and assess the nature of sonication-mediated versus natural clot lysis, the risk of rebleeding, the potential effect on the adjacent parenchyma, and the chemical and toxicity profiles of resulting lysate particles.
The response of spinal cord blood flow (SCBF) to high-dose barbiturate therapy is documented. In nine mongrel dogs with an arterial pCO2 (PaCO2) of 40 mm Hg, sodium thiopental was administered to ...produce 30, 60, 120, and 240 seconds of electroencephalographic (EEG) burst suppression. At 30-second intervals of EEG suppression, cervical and thoracic cord segments demonstrated a decrease in SCBF of 47% and 39%, respectively, from control values. Isoelectric EEG intervals longer than 30 seconds were not associated with any further significant decrease in SCBF. In 13 other dogs and in the absence of barbiturates, hypocapnia to 20 mm Hg from PaCO2 of 60 mm Hg produced reductions in SCBF of 89% for the cervical and 82% for the thoracic segments. In the presence of thiopental-induced 30- to 60-second intervals of EEG silence, the decrement in SCBF in response to the same degree of hypocapnia was 83% and 75%, respectively, although the absolute value of this reduction was half that without barbiturates. These findings of a significant reduction in SCBF in response to high-dose barbiturate therapy are suggestive of a protective effect of barbiturates upon spinal cord injury as occurs in the brain. Further studies of the influence of barbiturates upon spinal cord compressive syndromes are indicated.
In 13 dogs the response of the cerebral circulation to changes in PaCO2 ranging from 20 to 60 torr was studied before and after administration of high doses of sodium thiopental. Infusion of ...sufficient barbiturate to produce 30- to 60-second burst suppression in the electroencephalogram was associated with a profound degree of cerebral vasoconstriction, equivalent to that produced by hypocapnia with PaCO2 = 20 torr. Furthermore, once sodium thiopental was administered, no significant difference in cerebral blood flow (CBF) or vascular resistance (CVR) was noted between PaCO2 of 30 and 20 torr. However, changes of approximately 15% in CBF and 30% in CVR were noted between PaCO2 at 40 and 20 torr. These data suggest that hyperventilation of PaCO2 of less than 30 torr may not effectively increase the degree of cerebral vasoconstriction in these circumstances.
In normal dogs, the continuous infusion of 2 g of mannitol per kg resulted in a transient increase in cerebral blood flow of approximately 30%, which was accompanied by a concomitant reduction in ...cerebrovascular resistance. These changes were maximal 30 minutes after the infusion was initiated and resolved by 180 minutes. The changes were not related to alterations in arterial blood gases, systemic arterial or central venous pressures, or heart rate.
