Ketamine Mitigates Neurobehavioral Deficits in a Canine Model of Hypothermic Circulatory Arrest
Katherine Giuliano1, Eric W. Etchill1, Ana K. Velez1, Mary Ann Wilson2, Mary E. Blue2, Juan C. Troncoso1, Sujatha Kannan1, Michael V. Johnston1, Anjali Sharma1, Rishi Sharma1, Rangaramanujam M. Kannan1, William Baumgartner1, Jennifer Lawton1.
1Johns Hopkins University School of Medicine, Baltimore, MD, USA, 2Kennedy Krieger Institute, Baltimore, MD, USA.
Objective: Hypothermic circulatory arrest (HCA) is a protective technique used when complete cessation of circulation is required during cardiac surgery. Prior efforts to decrease neurologic injury with the NMDA receptor antagonist MK801have been limited by unacceptable side effects. We hypothesized that ketamine would provide neuroprotection without dose-limiting side effects.
Methods: Canines were peripherally cannulated for cardiopulmonary bypass, cooled to 18°C, then underwent 90 minutes of HCA. Ketamine-treated canines (n=4; total dose 2.85 mg/kg) were compared to untreated saline controls (n=11). A validated neurobehavioral deficit score was obtained on postoperative days (POD) one, two, and three (0=no deficits/normal exam; increasing score represents more deficits). Animals were euthanized on POD3, and their brains procured for blinded histopathologic injury scoring (higher score indicates more necrosis and apoptosis).
Results: Ketamine-treated canines had significantly improved neurobehavioral deficit scores compared to controls on PODs one, two, and three (POD1 mean 72 vs. 124, p=0.04; POD2: 40 vs. 94, p=0.02; POD3: 28 vs. 79, p=0.005) (Figure 1). The mean brain histopathologic injury score of the untreated control canines after 90 minutes of HCA was 13.6 (+/- 3.1), with a predominance of necrosis (more than apoptosis). The hippocampus was the most severely injured region. The histopathologic injury scores of ketamine-treated canines (11.3 +/- 3.6) did not differ significantly from controls.
Conclusions: Ketamine significantly reduced neurologic deficits in canines after HCA. Ketamine offers represents a safe, approved, and commonly used medication that can be potentially be utilized as a pharmacologic neuroprotectant during cardiac surgery with HCA.
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