Subarachnoid hemorrhage and the distribution of drugs delivered into the cerebrospinal fluid. Laboratory investigation

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.

Fig. 1

Images from the animals in the SAH (top row) and sham SAH (bottom row) groups. SAH Group: On Day 7 after SAH, CT cisternography (A) revealed contrast material entering the sylvian fissure and distributed over the surface of the cerebral hemisphere on the side opposite the SAH, but no contrast present in the vicinity of the right MCA. There is significantly less contrast on the surface of the right hemisphere. Evans blue dye injected 3 hours before death (B) stains blue the proximal (M₁) portion of the right MCA, the segment close to the ICA, leaving the M₂ branches unstained. The convexity of the right hemisphere (C) and the base of the frontal and temporal lobes near the right Sylvian fissure (D) are also less stained than the corresponding areas of the left cerebral hemisphere. The graph (E) depicts the CSF attenuation in the sylvian fissure on the CT cisternographies performed every 30 minutes for 2 hours on postoperative Day 7 after SAH in the same animal. There was a significant difference (p < 0.05) in the CSF attenuation between the right (ipsilateral) and left (contralateral) sides. Sham SAH Group: On Day 7 after sham SAH, CT cisternography (A) revealed contrast material entering the sylvian fissure along the left MCA and distribution of the material over the convexity of the cerebral hemisphere on the side opposite surgery. Contrast is also present in the vicinity of the right MCA in the right sylvian fissure. There is less contrast on the surface of the right cerebral hemisphere. Evans blue dye injected 3 hours before death (B) evenly stained blue the right and left MCAs as well as the rest of the cerebral arteries, although there is an appreciable difference in dye distribution over the convexity of the right and left hemispheres (C) and at the base on the brain (D). The graph (E) depicts the CSF attenuation in the sylvian fissure on the CT cisternographies performed every 30 minutes for 2 hours on postoperative day 7 after sham SAH surgery in the same animal. There was no difference (p > 0.05) in the CSF attenuation between the right (ipsilateral) and left (contralateral) sides but there was diminished contrast in the parietal region on the ipsilateral compared with contralateral side (p < 0.02).

Fig. 2

Bar graph of the peak CSF attenuation adjacent to the M₁ segment of the MCA contralateral (contra) and ipsilateral (ipsi) to surgery in which either a clot was placed to mimic SAH or in which identical surgery was performed, but no clot was placed (sham-SAH). Contrast distribution in the region of the clot is limited compared with the contralateral side and compared with both sides after sham SAH (*p < 0.05, Student-Newman-Keuls test for all pairwise comparisons, 1-way ANOVA).

Fig. 3

Line graph depicting the relative density (%) of the contrast in the sylvian fissure on the side ipsilateral to surgery compared with the maximum density on the side contralateral to surgery after injection of contrast into the cisterna magna on CT cisternography on Days 7, 14, 21, and 28 after SAH and on Days 7, 14, and 28 after sham SAH surgery. The graph demonstrates a persistent decrease of contrast penetration for 2 weeks after sham SAH surgery and for 4 weeks (the end of study) after SAH. Note the undisturbed distribution of contrast on the unoperated side and initial limitation, but recovery, of CSF distribution on the side of sham surgery (Sham-SAH) between 2 and 4 weeks after surgery.