Rapid CO₂ Correction Impairs Cerebrovascular Autoregulation and Exacerbates Neuronal Injury in a Porcine Model of Extracorporeal Resuscitation

Background Prior clinical research demonstrated that rapid reduction in arterial carbon dioxide (PaCO ₂ ) levels during extracorporeal membrane oxygenation (ECMO) is associated with acute brain injury (ABI), which may be due to sudden cerebral vasoconstriction and impaired cerebrovascular autoregulation (CVAR). However, the causal relationship between rapid PaCO₂ correction and its impact on ABI has not been firmly established due to the lack of high-quality evidence. We aimed to investigate whether rapid PaCO₂ correction following extracorporeal cardiopulmonary resuscitation (ECPR) causes CVAR impairment and neuronal injury in a porcine model. Methods In this prospective preclinical experimental study, six female pigs (mean weight: 50.75 ± 1.89 kg) were subjected to 15 minutes of ventricular fibrillation and were supported by ECMO. Then, they were randomly assigned to three CO ₂ correction strategies: rapid (200% sweep gas flow), slow (25%), and control (100%). Arterial blood gases, mean arterial pressure (MAP), and intracranial pressure (ICP) were continuously monitored throughout the experiments. CVAR function was quantified by calculating the pressure reactivity index (PRx), defined as the moving Pearson correlation coefficient between MAP and ICP, with PRx > 0.2 indicating impaired CVAR. We peformed baseline correction to calculate ΔMAP, ΔICP, and ΔPRx. Brain tissues were harvested and histologically analyzed for neuronal injury ischemia vulnerable regions: midbrain, cerebellum, striatum in the basal ganglia, temporal cortex, hypothalamus and hippocampus. Results In the rapid group, PaCO₂ correction caused a steep drop in PaCO₂—from 60 to approximately 30 mmHg within 5 minutes—and was associated with impaired CVAR, as indicated by ΔPRx became significantly larger in the rapid group (median = 0.577, IQR = 0.44, 0.67) during ECMO III compared to both the control (median=-0.034, IQR=-0.35, 0.26, d = 1.77) and the slow groups (median = 0.192, IQR=-0.01, 0.30, d = 1.83). PRx values were elevated above 0.2 at 10–15 minutes post-ECMO (median = 0.617, interquartile range (IQR) = 0.49, 0.72). In contrast, the slow correction group showed significantly lower PRx (median = 0.078, IQR =-0.06, 0.21, p  < 0.001, d  = 1.64), and the control group remained near baseline (median = 0.002, IQR=-0.30, 0.28), indicating intact CVAR function. Histologically, the rapid correction group exhibited significantly increased ischemic neuronal injury in ischemia-prone regions: caudate (43.1% injured neurons vs. 10.6% in control, p  = 0.041), putamen (66.6% vs. 23.9%, p  = 0.003), temporal cortex (34.9% vs. 8.9%, p  = 0.013), and hippocampal CA-3 region (4.7% vs. 18.0%, p  = 0.026). Compared to rapid correction, the slow correction group demonstrated improved gas stability (PaCO₂ decline of ~ 10 mmHg over 10 min), preserved PRx (mean PRx < 0.2), and significantly reduced neuronal injury in the putamen ( p  = 0.004). Conclusion Rapid CO₂ correction after ECMO initiation impairs CVAR and exacerbates neuronal ischemia, while gradual correction (slow correction and control) preserves neurovascular integrity. Controlled CO₂ correction should be considered a key neuroprotective strategy during ECMO initiation.