Subarachnoid hemorrhage and the distribution of drugs delivered into the cerebrospinal fluid

Abstract

Object Investigators in experimental and clinical studies have used the intrathecal route to deliver drugs to prevent or treat vasospasm. However, a clot near an artery or arteries after subarachnoid hemorrhage (SAH) may hamper distribution and limit the effects of intrathecally delivered compounds. In a primate model of right middle cerebral artery (MCA) SAH, the authors examined the distribution of Isovue-M 300 and 3% Evans blue after infusion into the cisterna magna CSF. Methods Ten cynomolgus monkeys were assigned to SAH and sham SAH surgery groups (5 in each group). Monkeys received CSF injections as long as 28 days after SAH and were killed 3 hours after the contrast/Evans blue injection. The authors assessed the distribution of contrast material on serial CT within 2 hours after contrast injection and during autopsy within 3 hours after Evans blue staining. Results Computed tomography cisternographies showed no contrast in the vicinity of the right MCA (p < 0.05 compared with left); the distribution of contrast surrounding the entire right cerebral hemisphere was substantially reduced. Postmortem analysis demonstrated much less Evans blue staining of the right hemisphere surface compared with the left. Furthermore, the Evans blue dye did not penetrate into the right sylvian fissure, which occurred surrounding the left MCA. The authors observed the same pattern of changes and differences in contrast distribution between SAH and sham SAH animals and between the right and the left hemispheres on Days 1, 3, 7, 14, 21, and 28 after SAH. Conclusions Intrathecal drug distribution is substantially limited by SAH. Thus, when using intrathecal drug delivery after SAH, vasoactive drugs are unlikely to reach the arteries that are at the highest risk of delayed cerebral vasospasm.

Haptoglobin administration into the subarachnoid space prevents hemoglobin-induced cerebral vasospasm

“…Finally, we do not know how haptoglobin may be distributed within the subarachnoid space when a subarachnoid blood clot compromises physiologic flow and free diffusion in the CSF. Mechanical obstruction would likely reduce the accessibility of cell-free Hb within the clot and in the vicinity of the culprit blood vessel (83). However, as demonstrated in our patients and in the sheep model, cell-free Hb distributes in the CSF after erythrolysis, well beyond the site of the initial bleeding with potentially far-reaching toxic effects, and we consider this fraction of Hb as the accessible target of a haptoglobin-based therapeutic formula.…”

Regulation of enhanced cerebrovascular expression of proinflammatory mediators in experimental subarachnoid hemorrhage via the mitogen-activated protein kinase kinase/extracellular signal-regulated kinase pathway

“…This is in contrast to the recent Clazosentan studies that were positive in reducing vessels diameter but failed to improve neurological outcome [64,65]. Thus, inhibition of early MEK-ERK1/2 signaling after SAH provides a novel therapeutic target that can be treated within a clinically relevant time window and has the potential of improving outcome after SAH.…”

Free Fatty Acids and Delayed Cerebral Ischemia After Subarachnoid Hemorrhage

“…Vasospasm is thought to be the end result of the activation of inflammatory cytokines that affect the reactivity and relaxation of smooth muscles in cerebral vessels. Despite advances in our knowledge of risk factors, prevention and treatment protocols have not significantly altered incidence or sequelae of vasospasm 3 .…”