gms | German Medical Science

Cerebral hypoperfusion has been repeatedly demonstrated clinically and experimentally in the acute stage of subarachnoid hemorrhage (SAH), has been associated with detrimental brain injury and has been attributed to acute vasoconstriction. The purpose of this study was to investigate the effects of a novel selective endothelin A receptor antagonist, clazosentan, on the acute changes in cerebral perfusion after massive experimental SAH.

SAH was induced in 23 anesthetized rats by injection of 0.5ml of autologous arterial, non-heparinized blood into the cisterna magna within 60 seconds. In addition to intracranial pressure (ICP) and mean arterial blood pressure (ABP), Laser-Doppler-Flowmetry (LDF) was used for online recording of cerebral blood flow (CBF) from 30min prior to SAH up to 3h post SAH. While the control group received vehicle saline solution via a femoral venous catheter (n=14), the clazosentan group was treated prophylactically with the endothelin A receptor antagonist (n=9). Treatment was started 30min prior to insult with a bolus (1mg/kg BW) followed by continuous infusion of 1mg/kg BW per hour.

There was a trend to reduced ABP in treated animals at baseline. Induction of SAH caused a dramatic increase of ICP to more than 100mmHg in both groups resulting in a corresponding immediate decrease of cerebral perfusion pressure (CPP) and of LDF to 25±13% (control) and 20±9% (clazosentan; n.s.) of baseline. ICP and CPP recovered comparably in both groups thereafter. Independent of CPP changes, control animals demonstrated a prolonged hypoperfusion, finally approaching 80% of baseline at the end of the experiments. Clazosentan treatment did not influence the peracute, CPP-dependent hypoperfusion, but prevented continuous CBF reduction. One hour after SAH, for example, LDF remained depressed at 59±17% of baseline in control animals compared to 96±28% in clazosentan-treated animals (p=0.001).

The first hours after massive experimental SAH are characterized by a CPP-independent compromise in cerebral perfusion. Prophylactic treatment with a novel selective endothelin A receptor antagonist, clazosentan, prevents this hypoperfusion. Clinically, reduced CBF has been found in high-grade SAH in the first days after the insult. While research currently focuses on delayed cerebral vasospasm, administration of vasoactive drugs in the acute phase may reverse perfusion deficits and enhance recovery of these patients.