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  • Porcine Model of Early Cortical Infarction after Subarachnoid Hemorrhage

    Final Number:

    Christopher Patrick Carroll MD MA; Bryan Matthew Krueger MD; Eric J Mahoney MS; Jason Hinzman PhD; Jed Hartings PhD

    Study Design:
    Laboratory Investigation

    Subject Category:

    Meeting: Congress of Neurological Surgeons 2017 Annual Meeting

    Introduction: Early cortical infarcts (ECI) are common in subarachnoid hemorrhage (SAH) patients, but animal models of this phenomenon are lacking and mechanisms are unknown. After subarachnoid infusion of fresh blood in the swine brain, we previously observed ECI in association with organized sulcal clots in some animals. Here we refined our model for improved consistency and to explore mechanisms by injecting clotted blood into a sulcus.

    Methods: Juvenile swine underwent frontal craniotomy and cruciate sulcus exposure. The sulcus was injected with normal saline (surgical control), fibrin sealant (mass effect control), or autologous blood clotted ex vivo, followed by six hours of survival and electrocorticographic monitoring. Animals were then sacrificed for TTC and H&E staining.

    Results: Sulcal injection of 1cc clotted blood caused persistent sulcal clots and adjacent cortical infarction in 6/6 animals. Cortical spreading depolarizations (CSD), a known mechanism of infarction, were recorded in 5/6 animals (count range: 4-20). H&E staining demonstrated well-demarcated cerebral edema and ischemic neuronal injury. To determine the roles of surgical injury and mass effect, subsequent groups were randomized to injection of normal saline (n=4), fibrin sealant (n=4), or autologous blood clot (n=5). While fibrin sealant and clot volumes did not differ (p=0.598), infarct volumes were significantly greater for the clot group (M=113.4 mm3, SD=45.3) than the fibrin sealant (M=45.2 mm3, SD=34.5) and saline (M=16.7 mm3, SD=12.8) groups (ANOVA [F(2,10)=9.1823, p=0.005] with Tukey-HSD [p’s<0.05]). Saline and fibrin sealant infarct volumes did not differ (p=0.510). Spearmann’s rank-order analysis demonstrated a significant correlation between CSD count and infarct volume across groups (rS(9)=0.767, p=0.006).

    Conclusions: Organized sulcal clots cause adjacent cortical infarction, which cannot be attributed to surgical manipulation or mass effect alone. Further studies are needed to elucidate factors that trigger CSDs and ischemia and to test potential therapies targeting CSDs in this gyrencephalic model of clinical ECI.

    Patient Care: We describe the first gyrencephalic large animal model to reliably reproduce the clinical phenotype of organized sulcal subarachnoid hemorrhage; recurrent cortical spreading depolarizations; and early cortical infarction. Our experiments provide further evidence of the relationship between early cortical infarction and organized sulcal subarachnoid clot. Furthermore, we demonstrate a significant correlation between the number of cortical spreading depolarizations and early cortical infarction volumes. This large-animal model of sulcal subarachnoid hemorrhage offers a platform for further investigation of the relationship between sulcal subarachnoid clot, CSD, and ECI as well as pharmacologic targeting of CSDs which can then be translated to the bedside to reduce the burden of ECI after aneurysmal SAH.

    Learning Objectives: By the conclusion of this session, participants should be able to: (1) Describe cortical spreading depolarizations as they relate to aneurysmal subarachnoid hemorrhage. (2) Discuss, in small groups, the gyrencephalic porcine model of early cortical infarction after SAH; in particular, the relationship between sulcal subarachnoid clot, CSDs, and ECI. (3) Identify potential further animal studies to investigate the relationship between SAH, CSD, and cortical infarction; identify CSD as a potential therapeutic target to reduce ECI after SAH.

    References: 1. Drier JP. The role of spreading depolarization and spreading ischemia in neurological disease. Nat Med (2011) 17(4): 439-47. 2. Dreier JP; Ebert N; Priller J; Megow D; Lindauer U et al. Products of hemolysis in the subarachnoid space inducing spreading ischaemia in the cortex and focal necrosis in rats: a model for delayed ischemic neurological deficits after subarachnoid hemorrhage? J Neurosurg (2000) 93: 658-666. 3. Dreier JP; Kleeberg J; Petzold G; Priller J; Windmuller O et al. Endothelin-1 potently induces Leao's cortical spreading depression in vivo in the rat: a model for an endothelial trigger of migrainous aura? Brain (2002); 125(Pt 1): 102-12. 4. Dreier JP: Korner K; Ebert N; Gorner A; Rubin I et al. Nitric Oxide Scavenging by Hemoglobin or Nitric Oxide Sythase Inhibition by N-Nitro-L-Arginine Induces Cortical Spreading Ischemia when K+ Is Increased in the Subarachnoid Space. J Cereb Blood Flow Metab (1998) 18(9): 978-990. 5. Dreier JP; Major S; Manning A; Woitzik J; Drenckhahn C et al. Cortical spreadin ischaemia is a novel process involved in ischaemic damage in patients with aneurysmal subarachnoid hemorrhage. Brain (2009) 132: 1866-1881. 6. Dreier JP; Major S; Pannek HW; WoitzikJ;Scheel M et al. Speading convulsions, spreading depolarization and epileptogenesis in human cerebral cortex. Brain (2012) 135(Part 1): 259-75. 7. Dreier JP; Sakowitz OW; Harder A; Zimmer C; Dirnagl U; Valdueza JM et al. Focal laminar cortical MR signal abnormalities after subarachnoid hemorrhage. Ann Neurol 2002; 52(6): 825-9. 8. Dreier JP; Woitzik J; Fabricius M; Bhatia R; Major S et al. Delayed ischaemic neurological deficits after subarachnoid haemorrhage are associated with clusters of spreading depolarizations. Brain (2006) 129: 3224-3237. 9. Hadeishi H; Suzuki A; Yasui N; Hatazawa J; Shimosegawa E. Diffusion-weighted Magnetic Resonance Imaging in Patients with Subarachnoid Hemorrhage. Neurosurgery (April 2002) 50(4): 741-748. 10. Hartings JA, Shuttleworth CW, Kirov SA, Ayaata C, Hinzman JM et al. The continuum of spreading depolarizations in acute cortical lesion development: Examining Leao’s legacy. J Cereb Blood Flow Metab (2016) Epub ahead of print: 1-24. 11. Kistler JP, Crowell RM, Davis KR, Heros R, Ojemann RG, et al. The relation of cerebral vasospasm to the extent and location of subarachnoid blood visualized by CT scan: a prospective study. Neurolog (1983) 33(4): 424-36. 12. Neil-Dwyer G; Lang DA; Doshi B; Gerber CJ, Smith PWF. Delayed Cerebral Ischaemia: The Pathological Substrate. Acta Neurochir (Wien) (1994) 131: 137-145. 13. Pluta RM, Afshar JK, Boock RJ, Oldfield EH. Temporal changes in perivascular concentrations of oxyhemoglobin, deoxyhemoglobin, and methemoglobin after subarachnoid hemorrhage. J Neurosurg (1998) 88(3): 557-61. 14. Schatlo B; Dreier JP; Glasker S; Fathi A; Moncrief T et al. Report of Selective Cortical Infarcts in the Primate Clot Model of Vasospasm After Subarachnoid Hemorrhage. Neurosurgery (2010) 67(3): 721-729. 15. Wartenberg KE; Sheth SJ; Schmidt JM; Frontera JA; Rincon F; et al. Acute Ischemic Injury on Diffusion-Weighted Magnetic Resonance Imaging after Poor Grade Subarachnoid Hemorrhage. Neurocrit Care (2011) 14: 407-15. 16. Weidauer S; Vatter H; Beck J; Raabe A; Lanfermann H et al. Focal laminar cortical infarcts following aneurysmal subarachnoid hemorrhage. Neuroradiology (2008) 50: 1-8. 17. Woitzik J; Dreier JP; Hecht N; Fiss I; Sandow N et al. Delayed cerrebral ischemia and spreading depolarization in absence of angiographic vasospasm after suvarachnoid hemorrhage. J Cereb Blood Flow Metab (2012) 32(2): 203-12. 18. York JA; Hinzman JM; Dreier JP; Krueger BM; Zuccarello MA et al. (September 2015). “Subarachnoid Hemorrhage Acutely Induces Spreading Depolarizations and Cortical Infarction”. Vasospasm 2015, 13th International Conference on Neurovascular Events after Subarachnoid Hemorrhage: Nagano, Japan.

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