Background: Therapeutic hypothermia (TH) shows considerable promise in laboratory ischemic stroke models. Delayed therapy confounds trials of any neuroprotectant, as well as inadvertent inclusion of non-recanalized patients in most clinical trials. The advent of intra-arterial thrombectomy (IAT) offers the opportunity to combine neuroprotection with controlled, documented recanalization. In contrast to prior rodent models using surface cooling techniques, clinical TH often uses endovascular cooling technology. We modeled delayed recanalization and simulated endovascular cooling in a rodent model.
Method: A perivascular catheter was implanted retroperitoneally in 8 male, 300g, Sprague Dawley rats 6 days prior to a 4h heat blunted nylon filament MCAo. At reperfusion animals were randomized by an investigator outside the laboratory to brain temperature 33°C or 37°C (n=4 per group) monitored by a temporalis muscle needle thermistor. Saline pumped through the closed loop cooling circuit convectively changed vena cava and body core temperature. After 2h the circuit was disconnected and the animals returned to cages. Bederson 3-point neuroscores were obtained 4h and 24h after occlusion. After 24 hours, rats were sacrificed for TTC exclusion.
Results: Perivascular cooling achieved very rapid target temperature (< 15min) and maintained temperature within 0.5°C for 4 hours. Mean±SD neuroscores were 2.5±0.5 after 4h MCAo; 1.8±0.4 at 24 hours (NS between groups). TTC exclusion lesions (% ipsi hemisphere, mean±SE ) were smaller after TH: 15±3 vs 30±4 (p<0.002, t-test).
Conclusions: A novel perivascular cooling catheter faithfully simulates endovascular cooling in a rat MCAo model. Filament removal simulates recanalization as would occur during IAT. The combination of recanalization after 4h MCAo and only 2h TH yielded highly significant neuroprotection, with a 50% treatment effect. Future clinical trials may consider combining brief, deep TH with IAT.