Impact of Hypo- and Hyper-capnia on Spreading Depolarizations in Rat Cerebral Cortex

Patients with traumatic brain injury are typically maintained at low-normal levels of arterial partial pressure of carbon dioxide (P_aCO₂) to counteract the risk of elevated intracranial pressure during intensive care. However, several studies suggest that management at hypercarbic levels may have therapeutic benefit. Here we examined the impact of CO₂ levels on spreading depolarizations (SD), a mechanism and marker of acute lesion development in stroke and brain trauma. In an acute preparation of mechanically ventilated (30/70 O₂/N₂) female rats, SDs were evoked by cortical KCl application and monitored by electrophysiology and laser doppler flowmetry; CO₂ levels were adjusted by ventilator settings and supplemental CO₂. During 90 min of KCl application, rats were maintained at hypocapnia (end-tidal CO₂ 22 ± 2 mmHg) or hypercapnia (57 ± 4 mmHg) but did not differ significantly in arterial pH (7.31 ± 0.10 vs. 7.22 ± 0.08, p = 0.31) or other variables. Surprisingly, there was no difference between groups in the number of SDs recorded (10.7 ± 4.2 vs. 11.7 ± 3.1; n = 3 rats/group; p = 0.75) nor in SD durations (64 ± 27 vs. 69 ± 37 sec, p = 0.54). In separate experiments (n = 3), hypoxia was induced by decreasing inhaled O₂ to 10% and single SDs were induced under interleaved conditions of hypo-, normo-, and hypercapnia. No differences in SD duration were observed. In both normoxia and hypoxia experiments, however, mean arterial pressures were negatively correlated with SD durations (normoxia R² = -0.29; hypoxia R² = -0.61, p's < 0.001). Our results suggest that any therapeutic benefit of elevated CO₂ therapy may be dependent on an acidic shift in pH or may only be observed in conditions of focal brain injury.