Lessons from the CONSCIOUS-1 Study

Abstract

After years of research on treatment of aneurysmal subarachnoid hemorrhage (aSAH), including randomized clinical trials, few treatments have been shown to be efficacious. Nevertheless, reductions in morbidity and mortality have occurred over the last decades. Reasons for the improved outcomes remain unclear. One randomized clinical trial that has been examined in detail with these questions in mind is Clazosentan to Overcome Neurological Ischemia and Infarction Occurring After Subarachnoid Hemorrhage (CONSCIOUS-1). This was a phase-2 trial testing the effect of clazosentan on angiographic vasospasm (aVSP) in patients with aSAH. Clazosentan decreased moderate to severe aVSP. There was no statistically significant effect on the extended Glasgow outcome score (GOS), although the study was not powered for this endpoint. Data from the approximately 400 patients in the study were detailed, rigorously collected and documented and were generously made available to one investigator. Post-hoc analyses were conducted which have expanded our knowledge of the management of aSAH. We review those analyses here.

Malignant astrocyte swelling and impaired glutamate clearance drive the expansion of injurious spreading depolarization foci

“…The clinical management of cerebral edema in acute brain injury currently aims at the reduction of intracranial pressure and the maintenance of cerebral perfusion pressure by sedation, hyperventilation, osmotherapy, hypothermia, and in the most severe cases decompressive craniectomy (Bardutzky and Schwab, 2007;Carney et al, 2017;Jha et al, 2019). However, for example, in severe subarachnoid hemorrhage intravenous high sodium fluids are administered increasingly more frequntly because hypoosmolarity is suggested to increase the risk and severity of delayed strokes (Schupper et al, 2020). Our results that preventive hyperosmotic intervention reduced the excitability of the nervous tissue and most importantly, averted SiD, provide pathophysiological insight into this empirical clinical strategy for the first time and emphasize the need to invent new ways of preventive osmotherapy in the treatment of acute brain injury.…”

Malignant astrocyte swelling and impaired glutamate clearance drive the expansion of injurious spreading depolarization foci

“…[64][65][66] However, for example, in severe subarachnoid hemorrhage intravenous high sodium fluids are administered increasingly more frequently because hypoosmolarity is suggested to increase the risk and severity of delayed ischemic injury. 67 Our results that preventive hyperosmotic intervention reduced the excitability of the nervous tissue and most importantly, averted SiD, provide pathophysiological insight into this empirical clinical strategy for the first time, and emphasize the need to invent new ways of preventive osmotherapy in the treatment of acute brain injury.…”

A Quantitative Subarachnoid Hemorrhage Grading System, Including Supratentorial and Infratentorial Cisterns, With Multiplanar Computed Tomography Reformations

“…CONSCIOUS 1 to 3 trials evaluating the efficacy of the endothelin receptor antagonist, clazosentan, in the treatment of cerebral vasospasm, rely on simple quantitative measurements of variables such as the thickness and length of SAH in a cistern rather than using qualitative grading scales [15][16][17]. Measurement of the short-axis thicknesses of SAH using our scale permits a similar approach and allows evaluation of the extent and severity of SAH in all major intracranial cisterns, including the often-neglected infratentorial cisterns.…”