Aneurysmal subarachnoid hemorrhage (aSAH) is a medical emergency that accounts for 5% of all stroke cases. Individuals affected are typically in the prime of their lives (mean age 50 years). Approximately 12% of patients die before receiving medical attention, 33% within 48 hours and 50% within 30 days of aSAH. Of the survivors 50% suffer from permanent disability with an estimated lifetime cost more than double that of an ischemic stroke. Traditionally, spasm that develops in large cerebral arteries 3-7 days after aneurysm rupture is considered the most important determinant of brain injury and outcome after aSAH. However, recent studies show that prevention of delayed vasospasm does not improve outcome in aSAH patients. This finding has finally brought in focus the influence of early brain injury on outcome of aSAH. A substantial amount of evidence indicates that brain injury begins at the aneurysm rupture, evolves with time and plays an important role in patients’ outcome. In this manuscript we review early brain injury after aSAH. Due to the early nature, most of the information on this injury comes from animals and few only from autopsy of patients who died within days after aSAH. Consequently, we began with a review of animal models of early brain injury, next we review the mechanisms of brain injury according to the sequence of their temporal appearance and finally we discuss the failure of clinical translation of therapies successful in animal models of aSAH.

Delayed vasospasm that develops 3–7 days after aneurysmal subarachnoid hemorrhage (SAH) has traditionally been considered the most important determinant of delayed ischemic injury and poor outcome. Consequently, most therapies against delayed ischemic injury are directed towards reducing the incidence of vasospasm. The clinical trials based on this strategy, however, have so far claimed limited success; the incidence of vasospasm is reduced without reduction in delayed ischemic injury or improvement in the long-term outcome. This fact has shifted research interest to the early brain injury (first 72 h) evoked by SAH. In recent years, several pathological mechanisms that activate within minutes after the initial bleed and lead to early brain injury are identified. In addition, it is found that many of these mechanisms evolve with time and participate in the pathogenesis of delayed ischemic injury and poor outcome. Therefore, a therapy or therapies focused on these early mechanisms may not only prevent the early brain injury but may also help reduce the intensity of later developing neurological complications. This manuscript reviews the pathological mechanisms of early brain injury after SAH and summarizes the status of current therapies.

Brain injury after subarachnoid hemorrhage (SAH) is a biphasic event with an acute ischemic insult at the time of the initial bleed and secondary events such as cerebral vasospasm 3 to 7 days later. Although much has been learned about the delayed effects of SAH, less is known about the mechanisms of acute SAH-induced injury. Distribution of blood in the subarachnoid space, elevation of intracranial pressure, reduced cerebral perfusion and cerebral blood flow (CBF) initiates the acute injury cascade. Together they lead to direct microvascular injury, plugging of vessels and release of vasoactive substances by platelet aggregates, alterations in the nitric oxide (NO)/nitric oxide synthase (NOS) pathways and lipid peroxidation. This review will summarize some of these mechanisms that contribute to acute cerebral injury after SAH.

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Summary: Disturbances in the nitric oxide (NO) vasodilatory pathway have been implicated in acute vasoconstriction and ischemia after subarachnoid hemorrhage (SAH). The authors hypothesize that blood released during SAH leads to vasocon striction by scavenging NO and limiting its availability. This was tested by measuring the major NO metabolites nitrite and nitrate in five different brain regions before and after experi mental SAH. The basal NO metabolites levels were as follows (mean ± SO, f.Lmol/mg wet weight): brain stem, 0.14 ± 0.07; cerebellum, 0.12 ± 0.08; ventral convexity cortex, 0.22 ± 0.15; dorsal convexity cortex, 0.16 ± 0.11; and hippocampus, 0.26 ± 0.17. In sham-operated animals, no effect of the nitric oxide synthase (NOS) inhibitor L G -nitro-L-arginine-methyl-ester (30 mg/kg) was found on NO metabolites 40 minutes after admin istration, but a significant decrease was seen after 120 minutes.Cerebral blood flow decreases acutely and ischemic injury occurs after subarachnoid hemorrhage (SAH) in both experimental and clinical studies. Cerebral arteries have been shown to respond to SAH with a biphasic constriction. An acute constriction begins minutes after the bleed, and delayed vasospasm begins 48 hours later . Although the significance of de layed vasospasm is recognized (Sobey and Faraci, 1998 604The NO metabolites decreased significantly 10 minutes after SAH in all brain regions except for hippocampus, and recov ered to control levels in cerebellum at 60 minutes and in brain stem and dorsal cerebral cortex 180 minutes after SAH, while remaining low in ventral convexity cortex. Nitrite recovered completely in all brain regions at 180 minutes after SAH, whereas nitrate remained decreased in brain stem and ventral convexity cortex. Our results indicate that SAH causes acute decreases in cerebral NO levels by a mechanism other than NOS inhibition and provide further support for the hypothesis that alterations in the NO vasodilatory pathway contribute di rectly to the ischemic insult after SAH.