Is there diurnal variation in neuroprotective and thrombolytic therapy effect upon acute cerebral ischemia outcome?

Background: Preclinical studies have found marked diurnal/circadian variation in the effect of neuroprotective agents in acute ischemic stroke. However, the presence of diurnal variation in treatment outcomes after neuroprotective therapy has not been analyzed in human clinical trials and variation after thrombolytic therapy has been under-studied.

Methods: We analyzed patients with acute cerebral ischemia enrolled in the Field Administration of Stroke Therapy - Magnesium (FAST-MAG) randomized trial of magnesium sulfate started in the ambulance within two hours of stroke onset (last known well time). Patients with stroke onset times during daytime (07:00-22:59) and nighttime (23:00-06:59) were compared for variation in magnesium neuroprotective effect, thrombolysis effect, supportive care effect upon early neurologic course and three-month functional outcomes.

Results: Among 1235 acute cerebral ischemia patients, final diagnoses were acute ischemic stroke in 83.6% and transient ischemic attack in 16.4%. Time of onset was daytime in 1147 (92.8%) and nighttime in 88 (7.2%). Thrombolytic therapy was administered to 473 (38.3%). Patients with night onset had longer onset to paramedic (median 32.5 vs 23 minutes); longer onset to Emergency Department arrival (median 70 vs 58 minutes); and higher prehospital systolic blood pressure (mean 162 vs 155 mm Hg). Among patients receiving thrombolysis, magnesium was associated with increased early neurological deterioration during night-time (50.0% vs 23.1%) but not day-time (21.1% vs 22.4%), p=0.03. However, no similar diurnal variation in magnesium or thrombolysis effects were noted for other early or three-month functional outcomes.

Conclusions: Among acute cerebral ischemia patients, efficacy, safety, neuroprotective agent, and thrombolytic response outcomes were largely unmodified by witnessed onset during active versus inactive phase clock times. These findings suggest biologic wake-sleep state rather than chronologic clock time is the driver of known circadian rhythmicity in stroke course.