An In Vivo,MRI-Integrated Real-Time Model of Active Contrast Extravasation in Acute Intracerebral Hemorrhage

BACKGROUND AND PURPOSE:The “spot sign” or contrast extravasation is strongly associated with hematoma formation and growth. An animal model of contrast extravasation is important to test existing and novel therapeutic interventions to inform present and future clinical studies. The purpose of this study was to create an animal model of contrast extravasation in acute intracerebral hemorrhage.MATERIALS AND METHODS:Twenty-eight hemispheres of Yorkshire male swine were insonated with an MR imaging–guided focused sonography system following lipid microsphere infusion and mean arterial pressure elevation. The rate of contrast leakage was quantified by using dynamic contrast-enhanced MR imaging and was classified as contrast extravasation or postcontrast leakage by using postcontrast T1. Hematoma volume was measured on gradient recalled-echo MR imaging performed 2 hours postprocedure. Following this procedure, sacrificed brain was subjected to histopathologic examination. Power level, burst length, and blood pressure elevation were correlated with leakage rate, hematoma size, and vessel abnormality extent.RESULTS:Median (intracerebral hemorrhage) contrast extravasation leakage was higher than postcontrast leakage (11.3; 6.3–23.2 versus 2.4; 1.1–3.1 mL/min/100 g; P < .001). Increasing burst length, gradient recalled-echo hematoma (ρ = 0.54; 95% CI, 0.2–0.8; P = .007), and permeability were correlated (ρ = 0.55; 95% CI, 0.1–0.8; P = .02). Median permeability (P = .02), gradient recalled-echo hematoma (P = .02), and dynamic contrast-enhanced volumes (P = .02) were greater at 1000 ms than at 10 ms. Within each burst-length subgroup, incremental contrast leakage was seen with mean arterial pressure elevation (ρ = 0.2–0.8).CONCLUSIONS:We describe a novel MR imaging–integrated real-time swine intracerebral hemorrhage model of acute hematoma growth and contrast extravasation.

Intracerebral hemorrhage (ICH) accounts for 10%–30% of strokes and is the most deadly and disabling stroke type with little improvement in mortality seen during the past 20 years.¹ These characteristics underscore the importance of developing a better understanding of the pathophysiology of ICH formation and growth to facilitate the development of improved therapeutic agents or interventions.² The causative lesion in primary ICH is yet to be elucidated, though pathologic studies demonstrate focal vessel integrity loss in association with blood extravasation into the brain parenchyma.³ Following initial ICH formation, continuous^4,5 or delayed⁶ extravasation results in hematoma expansion,⁷ which is associated with early neurologic deterioration and significant mortality.⁸Several recent studies have shown an association between contrast extravasation (CE) detected on CTA, coined the CTA “spot sign,” and hematoma growth.^9–14 Prospective studies have demonstrated that contrast extravasation independently predicts a larger hematoma size and a poorer clinical outcome.^13,14 These are the first clinical studies to suggest a robust “real-time” imaging marker of hematoma expansion. Three clinical studies are presently enrolling patients dichotomized by the CTA spot sign to validate the prior study findings and to determine the therapeutic efficacy of recombinant factor VIIa or tranexamic acid.^15–17 A more recent study using dynamic spot sign imaging with a biphasic CT perfusion protocol¹⁸ has confirmed 2 patterns of contrast extravasation associated with significantly different rates of leakage. These patterns, comprising a brisker active extravasation (spot sign) and slower postcontrast leakage (PCL),¹⁹ are also demonstrated with early and late structural imaging,^10,19 dynamic CTA/CTP,¹⁸ and biphasic or repeat delayed CTA acquisitions.¹²Morphologic patterns and more recent studies illustrate that the spot sign is not an all-or-none phenomenon but constitutes a spectrum of extravasation.^18,19 The extravasation rate likely significantly impacts timely and clinically meaningful hemostasis.²⁰ A bleeding threshold likely exists beyond which prothrombotic treatment is futile, exposing patients to harmful adverse effects without hope of therapeutic benefit.²¹ Increasingly, new innovative surgical techniques are being developed to address contrast extravasation.²² Knowledge of the impact of the extravasation rate on therapeutic response is critical to stratify patients to the most appropriate therapies. An animal model of acute contrast extravasation in ICH could potentially inform the patient-selection process. We describe a novel MR imaging–integrated real-time swine model of acute hematoma growth and contrast extravasation.