Abstract / Summary
BACKGROUND Hypothermic circulatory arrest (HCA) during cardiac surgery is associated with neurocognitive impairment. We previously demonstrated reduced brain injury with dendrimer-conjugated NMDA glutamate receptor antagonists and K ATP channel opener diazoxide. This study evaluated neuroprotection with mechanistic and hypothesis-driven alternate timing of administration of ketamine, dendrimer-conjugated ketamine (D-ket), and diazoxide, in a modernized canine model of HCA in an attempt to further improve outcomes. METHODS Canines underwent peripheral cardiopulmonary bypass, cooling to 18°C, and 90 minutes of HCA. Treatment groups included: ketamine (n=6), D-ket (n=6), diazoxide (n=6), diazoxide+5-hydroxydecanoate (n=6), and control (saline n=2; dimethyl sulfoxide (DMSO) n=3). Behavioral and cognitive testing and collection of biomarkers of neurological injury were conducted on postoperative days (POD) 1–3, and brain histopathology on POD3. RESULTS All animals demonstrated improved behavior scores over three postoperative days, and this was statistically significant in diazoxide, D-ket, and ketamine groups. No group had better behavior, cognition, histopathologic injury scores or biomarkers compared to controls. CONCLUSIONS Postoperative NMDA receptor antagonism with ketamine and preoperative K ATP channel activation by diazoxide did not offer neuroprotection during HCA at the tested doses and time points in this model. However, prior studies suggested that these drugs could be neuroprotective when administered at other time points.