Inhaled Carbon Dioxide Improves Neurological Outcomes by Downregulating Hippocampal Autophagy and Apoptosis in an Asphyxia‐Induced Cardiac Arrest and Resuscitation Rat Model
Chih‐Hung Wang, Chien‐Hua Huang, Min‐Shan Tsai, Chan‐Chi Wang, Wei‐Tien Chang, Shing‐Hwa Liu, Wen‐Jone Chen
Abstract
Background Protracted cerebral hypoperfusion following cardiac arrest (CA) may cause poor neurological recovery. We hypothesized that inhaled carbon dioxide (CO 2 ) could augment cerebral blood flow (CBF) and improve post‐CA neurological outcomes. Methods and Results After 6‐minute asphyxia‐induced CA and resuscitation, Wistar rats were randomly allocated to 4 groups (n=25/group) and administered with different inhaled CO 2 concentrations, including control (0% CO 2 ), 4% CO 2 , 8% CO 2 , and 12% CO 2 . Invasive monitoring was maintained for 120 minutes, and neurological outcomes were evaluated with neurological function score at 24 hours post‐CA. After the 120‐minute experiment, CBF was 242.3% (median; interquartile range, 221.1%–267.4%) of baseline in the 12% CO 2 group while CBF fell to 45.8% (interquartile range, 41.2%–58.1%) of baseline in the control group ( P <0.001). CBF increased along with increasing inhaled CO 2 concentrations with significant linear trends ( P <0.001). At 24 hours post‐CA, compared with the control group (neurological function score, 9 [interquartile range, 8–9]), neurological recovery was significantly better in the 12% CO 2 group (neurological function score, 10 [interquartile range, 9.8–10]) ( P <0.001) while no survival difference was observed. Brain tissue malondialdehyde ( P =0.02) and serum neuron‐specific enolase ( P =0.002) and S100β levels ( P =0.002) were significantly lower in the 12% CO 2 group. TUNEL (terminal deoxynucleotidyl transferase–mediated biotin–deoxyuridine triphosphate nick‐end labeling)‐positive cell densities in hippocampal CA1 ( P <0.001) and CA3 ( P <0.001) regions were also significantly reduced in the 12% CO 2 group. Western blotting showed that beclin‐1 ( P =0.02), p62 ( P =0.02), and LAMP2 (lysosome‐associated membrane protein 2) ( P =0.01) expression levels, and the LC3B‐II:LC3B‐I ratio ( P =0.02) were significantly lower in the 12% CO 2 group. Conclusions Administering inhaled CO 2 augmented post‐CA CBF, mitigated oxidative brain injuries, ameliorated neuronal injury, and downregulated apoptosis and autophagy, thereby improving neurological outcomes.