Prevention of chronic cerebral vasospasm in dogs with ibuprofen and high-dose methylprednisolone.

Abstract

Severe chronic cerebral vasospasm was produced in dog basilar arteries by two injections, 2 days apart, of autologous blood into the cisterna magna of 25 dogs. Treatment with ibuprofen (ra=8) or high-dose methylprednisolone (n=8) after the first injection of blood prevented or reduced angiographic vasospasm. Cerebrospinal fluid concentrations of prostaglandin E 2 , prostaglandin F 2a , 6-ketoprostaglandin F l a (a metabolite of prostacyclin), and thromboxane B 2 (a metabolite of thromboxane A 2 ) were measured in both treated and untreated (n=7) dogs. In untreated dogs, the level of prostaglandin E 2 increased 94-fold by Day 8 after the first injection of blood and was strongly and positively correlated with the degree of angiographic vasospasm. Treatment with ibuprofen and high-dose methylprednisolone prevented or significantly reduced this increase in prostaglandin E 2 concentration. Smaller increases in cerebrospinal fluid concentrations of thromboxane B 2 and 6-ketoprostaglandin ¥ la occurred after experimental subarachnoid hemorrhage; the magnitude of these increases was also reduced by ibuprofen or high-dose methylprednisolone treatment. In contrast, prostaglandin F 2a levels were not significantly altered during the study. These data show that enhanced prostaglandin E 2 synthesis occurs during experimental subarachnoid hemorrhage, and the by-products generated in its synthesis may play a role in the pathogenesis of cerebral vasospasm.

Pharmacologic irreversible narrowing in chronic cerebrovasospasm in rabbits is associated with functional damage.

“…A recent report of angioplasty for dilating narrowed arteries indicates that structural changes are a main feature of cerebrovasospasm. 50 Recent clinical and experimental observations by Chyatte 51 and colleagues 52 -53 support the damage hypothesis. Monkeys pretreated with diltiazem were also protected, presumably due to minimization of calcium entry and prevention of calcium overload.…”

EP1- and EP3-Receptors Mediate Prostaglandin E2–Induced Constriction of Porcine Large Cerebral Arteries

“…The interaction between PGE 2 and HbO 2 , both implicated as causative agents in cerebral vasospasm after SAH (Chyatte 1989;Macdonald and Weir, 1991;Pickard et al, 1994;Walker et al, 1983), was examined by studying and comparing PGE 2 -induced constriction before and after incubation with HbO 2 . The PGE 2 -induced constriction in endothelium-denuded porcine basilar arteries in the absence of active muscle tone was potentiated in a concentration-dependent manner after 1-hour incubation with HbO 2 (10 mol/L) (Fig.…”

“…It has been shown that PGE 2 is the eicosanoid present in the highest concentration in the CSF after SAH (Walker et al, 1983). The levels of PGE 2 in the CSF have been shown to increase 90-fold in dogs (Chyatte, 1989) and up to 250-fold in humans (Pickard et al, 1994) after SAH. In addition, our present experiments showed that constriction induced by PGE 2 was greatly potentiated by HbO 2 , supporting a potential role for PGE 2 in SAH and suggesting a possible mechanism of interaction between these putative causative agents.…”

The Burden of the Systemic Inflammatory Response Predicts Vasospasm and Outcome after Subarachnoid Hemorrhage

“…Cytokines and endothelial activation promote changes in smooth muscle cells, while activated leukocytes release potent vasoconstrictors such as endothelin-1 [19]. Agents that block this inflammatory cascade, including corticosteroids and non-steroidal anti-inflammatory agents, have been shown to reduce experimental vasospasm [20]. Thus, a greater degree of early neurogenic inflammatory activation may place patients at higher risk for the subsequent development of disabling cerebral ischemia.…”