Response to Letter by Culp and Culp
We greatly appreciate the thoughtful comments by Drs Culp and Culp. First, we would like to acknowledge the excellent work the authors have done describing the angiographic cerebral vascular anatomy of the rabbit.1 The first draft of our paper was submitted in November 2006 with several revisions before final acceptance.2 On resubmission, we failed to cite the article by Culp et al, which had appeared in the interim.
Concern is raised about the extent of MCA occlusion in our model and that infusion of thrombin may lead to a greater degree of vascular occlusion compared to that seen in the typical human stroke where there is only segmental occlusion of the MCA. This may lead to a smaller volume of penumbral tissue. We agree on this point and in fact we address this issue in our discussion. This follows directly to the next issue brought out regarding further work needed to delineate the extent of infarct and reproducibility of infarct size after MCA occlusion. Further work is indeed necessary and may include MRI studies to delineate the penumbral tissue or special stains to outline infarct size in the postmortem brain of the rabbit. We acknowledge that the extent of ischemia produced in this model may be more extensive than in a typical segmental occlusion of the MCA as seen in humans.
With respect to the timing of sacrifice, Culp et al mention that sacrifice at 2 hours is not adequate to histologically show the extent of infracted tissue. Although this is true, we emphasize the intent in developing this model was to test intra-arterial-delivered thrombolytic agents. For this purpose, we desired a model with reproducible occlusion that can be angiographically confirmed and that is amenable to thrombolysis. Furthermore, we desired a stable occlusion at 2 hours without spontaneous recanalization at which time thrombolytic is delivered. Clinical efficacy would require survival experiments that entail undue hardship on the rabbits. Furthermore, recanalization is our primary goal because this end point is the foundation of effective stroke therapy in humans.
With respect to spasm during catheterization, the ICA was entered only with the 1.2F flow directed Magic Balt catheter and Sorcerer guide wire which is 0.007 inches. The guide wire was rarely allowed to exit the end of the microcatheter and was only used to provide support for the very floppy distal end of the catheter to allow it to propel forward. This is a technique routinely used in catheterizing very small distal MCA branches that feed brain AVMs in humans. In fact, in most instances, with the support of the guide wire, the catheter would propel forward with little difficulty. In our initial feasibility studies before the 13 consecutive animals reported, we used different catheters including the Marathon 1.3F, the Echelon 10, the Prowler 10, none of which allowed us to reach the MCA successfully. The cost of the Balt microcatheter and the Sorcerer guide wire are indeed considerable, a drawback that cannot be avoided. Incidentally, we have not noted duplication of the MCA in >35 animals that we have studied now.
Dose-finding studies are underway now in our rabbit model to find the lowest efficacious safe dose of plasmin that achieves recanalization consistently. Studies of the natural history of the stroke in our model are also planned.
V.J.M. serves as a consultant for Talecris Biotherapeutics. R.J. reports no conflicts.