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

Rapid CO₂ Correction Impairs Cerebrovascular Autoregulation and Exacerbates Neuronal Injury in a Porcine Model of Extracorporeal Resuscitation | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Rapid CO₂ Correction Impairs Cerebrovascular Autoregulation and Exacerbates Neuronal Injury in a Porcine Model of Extracorporeal Resuscitation Mingfeng Cao, Camila S. Contreras-Rojas, Qihong Wang, Yaman Ahmed, and 8 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6559635/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 12 Aug, 2025 Read the published version in Translational Stroke Research → Version 1 posted 13 You are reading this latest preprint version Abstract 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. ECPR ECMO CVAR histology PaCO2 Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Introduction Extracorporeal cardiopulmonary resuscitation (ECPR), which combines venoarterial extracorporeal membrane oxygenation (VA-ECMO) with conventional cardiopulmonary resuscitation (CPR), has become a critical rescue strategy for patients experiencing refractory cardiac arrest. ECPR significantly improves survival rates and neurological outcomes in select patient populations by rapidly restoring cerebral blood flow (CBF) and minimizing prolonged ischemic injury 1 . Despite these notable benefits, ECMO is associated with a substantial risk of acute brain injury (ABI), driven by mechanisms such as ischemia-reperfusion injury, hemodynamic instability, and metabolic derangements—including dysregulated arterial partial pressure of carbo dioxide (PaCO₂) and oxygen (PaO₂) 2 – 5 . PaCO₂ is critical for maintaining adequate cerebral perfusion and autoregulatory function, primarily through its potent influence on cerebrovascular tone. Hypercapnia induces cerebral vasodilation, increasing CBF, whereas hypocapnia prompts vasoconstriction, reducing cerebral perfusion 4 , 5 . Prior experiments suggested that decreases in PaCO 2 can cause dose-dependent vasoconstriction 6 . Normally, cerebrovascular autoregulation (CVAR) mechanisms buffer acute fluctuations in PaCO₂, stabilizing cerebral perfusion across a wide range of blood pressures 7 . However, abrupt large decreases in PaCO₂ such as those commonly observed immediately after ECMO cannulation may overwhelm CVAR function and subsequently CBF and perfusion. Retrospective observational clinical studies indicated an association between rapid, large magnitude decreases in PaCO₂ during ECMO initiation and higher frequency of seizure, ischemic stroke, intracranial hemorrhage (ICH), or brain death 8 – 10 . A rapid decrease of PaCO₂ in hypercapnia immediately after ECMO initiation has been proposed to increase ABI risk by impairing CVAR, leading to cerebral vasoconstriction and subsequent ischemic injury 1 , 7 . One large multicenter analysis of nearly 12,000 adult ECMO patients (VA, VV or hybrid) demonstrated that a > 50% drop in PaCO₂ within the first 24 hours of cannulation was associated with neurological complications (adjusted OR = 1.73; p < 0.001) 8 . A single-center retrospective observational study on VA-ECMO patients (n = 129) similarly found that a greater PaCO₂ decrease during ECMO peri-cannulation period was associated with an increased risk of intracranial hemorrhage (odds ratio = 2.69) 11 . These clinical “association” studies led to the hypothesis that rapid PaCO₂ correction may impair CVAR, contributing to ABI occurrence, especially early during ECMO support. However, several studies also reported that rapid CO2 correction was not associated with ABI in VA-ECMO (Shou, et al n = 3125; Yu, et al n = 323) and VV-ECMO (Yu, et al n = 295) 4,12 . Yu et al. (2024) explicitly contradicted the rapid correction hypothesis, concluding that rapid PaCO₂ correction did not directly cause brain injury in their cohort (both VV and VA-ECMO) 12 . Diehl et al. (2020) suggested neurological injury was associated with large reductions (greater than 20 mmHg) in PaCO2 over 24 hours, without considering the rate of PaCO₂ correction itself in patients treated with VA-ECMO 13 . Hong et al. (2022) emphasize hypercapnia and extreme hyperoxia as problematic factors during VA-ECMO but did not find significant evidence directly implicating the rapid correction of hypercapnia toward normocapnia as causative in ABI 14 . This conflicting evidence underscores a critical lack of knowledge regarding the role of PaCO₂ dynamics in ABI pathogenesis during ECMO. To address this critical knowledge gap and overcome limitations inherent to retrospective observational clinical research with many confounding factors, we conducted a controlled experimental study evaluating the impact of PaCO₂ correction rate on CVAR function and neuronal injury following ECPR. Employing a porcine cardiac arrest model, we rigorously compared rapid (200%), slow (25%), and standard (100%) CO₂ correction strategies, integrating continuous physiological data with detailed histopathological analysis of brain tissue susceptible to ischemia during circulatory shock such as the hippocampus, basal ganglia, thalamus, and cerebellum 15 – 17 . We hypothesized that rapid PaCO₂ correction would acutely disrupt CVAR function and exacerbate neuronal injury, particularly in ischemia sensitive brain regions. Conversely, we anticipate that gradual CO₂ correction would better preserve CVAR integrity and mitigate neuronal damage. By illuminating the interplay between CO₂ correction rate, CVAR function, and neuronal outcomes in the ECPR context, our study aims to inform safer ECMO initiation strategies and improve neurological recovery in cardiac arrest patients. Methods Experimental Procedures Procedures were approved by the Johns Hopkins University Animal Care and Use Committee (Protocol SW21M451) and adhered to the Animal Welfare Act regulations and Public Health Service Policy. Porcine subjects were anesthetized with intramuscular ketamine (4.5 mg/kg), xylazine (88 µg/kg), and telazol (1.1 mg/kg), followed by maintenance with intravenous propofol (12–20 mg/kg/hr). Animals were intubated and ventilated with a tidal volume of 8 mL/kg, PEEP of 5 cm H₂O, a respiratory rate of 10 breaths/min, and an FiO₂ of 40%. Ventilation and ECMO settings aimed to maintain PaO₂ at 65–200 mmHg. Bilateral femoral arteries and veins were accessed percutaneously for medication administration, monitoring, and ABG sampling. ABG samples were collected at 5 minutes before ECMO initiation, followed by at 5 and 10 minutes after ECMO, including blood pH, PaCO 2 , PaO 2 , HCO₃⁻, and base excess (BE). Mean arterial pressure (MAP), ECMO Flow, and intracranial pressure (ICP) were continuously monitored throughout the experiment. The return of spontaneous circulation (ROSC) was attempted at 20 minutes of ECMO support via one 200 J shock. If the first 200J shock was unsuccessful, additional shocks were delivered at 2-minute intervals. After 2 hours of ECMO, animals were euthanized with potassium chloride and cold saline perfusion. Cranial Access and ICP Monitor Placement Bilateral cranial burr holes were performed to place the ICP monitor (Integra LifeSciences Production Corporation, Mansfield, MA). The pig was positioned laterally, and a 6 cm rostral-to-caudal incision was made, centered at the intersection of lines drawn from the external acoustic meatus to the contralateral pupil. The incision was created with a 10-blade scalpel and hemostasis was achieved using a Bovie cauterizing instrument. The skin flap was retracted with a Weitlaner retractor, and the Galea was cleared to visualize landmarks. A burr hole was drilled in each hemisphere using a 2.7-mm bit, positioned ~ 2 cm lateral to the sagittal suture and 1 cm anterior to the coronal suture. Dural punctures were made with an 18-gauge needle using room-temperature saline irrigation for hemostasis. Monitoring leads were positioned to a depth of 2 cm. The skin was closed with Vicryl sutures. Heparin (150 units/kg) was then administered to achieve activated clotting time > 300 seconds. The left femoral artery received a 15–17F arterial cannula, and the right femoral vein received a 19–21F venous cannula for ECMO. Cardiac Arrest and ECPR Protocol Ventricular fibrillation was induced through a fibrillation pad placed on the chest. After 15 minutes of arrest without intervention, ECPR was initiated with a pump flow set between 60 mL/kg/min. Sweep gas percent oxygen was set to 60%, with ECMO sweep flow adjusted to assess 4 different CO2 concentrations, hypocapnia (25–30 mmHg), normocapnia (35–45 mmHg), mild hypercapnia (50–55 mmHg), and severe hypercapnia (> 60 mmHg), as part of the experimental protocol. During ECMO, circuit flow rates were advanced to 80–100 mL/kg/min, targeting a Mean Arterial Pressure (MAP) > 45 mmHg. Lactated Ringer’s (LR) boluses were administered to optimize preload, and norepinephrine was used to maintain adequate perfusion pressure. CO Correction Protocol CO₂ removal was adjusted by modifying the sweep gas flow rate within the ECMO oxygenator. For this study, two of the six animals were assigned to each of the three CO₂ correction strategies: 1) Control Group with 100% sweep gas flow rate; 2) Rapid CO₂ Correction Group in which a 200% sweep gas flow rate was applied to induce accelerated CO₂ removal; and 3) Slow CO₂ Correction Group where a 25% sweep gas flow rate was used to promote gradual CO₂ correction over time. Sweep gas flow adjustments were continuously monitored to ensure the target CO₂ removal rate was achieved while maintaining physiological stability. Tissue Preparation Brain tissue was initially stored in 10% Formalin. For each specimen, 1 cm slabs from the midbrain, cerebellum, diencephalon, basal ganglia including temporal cortex, and hippocampus, were collected, preserved in Peripheral Blood Smear (PBS), sectioned into 10-µm coronal sections and stained with hematoxylin and eosin (H&E). Counting and Injury Assessment All slides were examined under light microscopy, and anatomical regions were identified and validated according to the Stereotaxic atlas of the pig brain 18 . Target regions included the bilateral oculomotor nuclei (midbrain), Purkinje cells (cerebellum), hypothalamus, caudate and putamen nuclei at the striatal level, external pyramidal layer of the temporal cortex, and pyramidal neurons in hippocampal subregions CA-1 through CA-4. To ensure rigorous and reproducible histological analysis, neuronal counts were consistently compared within matched anatomical regions on the same slide, thus minimizing variability due to slide preparation and staining. For the midbrain, neuronal counts were performed bilaterally in both oculomotor nuclei. In the cerebellum and hypothalamus, neurons were counted bilaterally within matched coronal sections, labeled as side 1 (S1) and side 2 (S2). For all other structures (caudate, putamen, temporal cortex, and hippocampal subregions CA-1 through CA-4), neuronal counting was conducted across three to five non-overlapping fields aligned longitudinally with the neuroanatomical axis. Images were acquired at standardized magnifications (10x or 20x) appropriate to the anatomical region, ensuring consistent neuron identification and counting accuracy. Within each defined counting area, neurons were manually classified as injured or healthy based on standardized morphological criteria. Healthy neurons were defined as cells with a round or oval cell body (8–10 µm in diameter) with an open nucleus and often with a nucleolus; preserved nuclear and cell membranes; and no apoptotic or ischemic morphology 19 . Injured neurons were characterized by shrunken or angular cell bodies, cytoplasmic vacuolization or condensation, chromatin fragmentation or nuclear disintegration, pyknotic nuclei, loss of perinuclear pallor, and absent nucleoli 20 , 21 . The healthy neurons were outlined as green and the injured cells in red, to calculate the ratio of abnormal cells related to the total. Neurons where the nucleus or nucleolus could not be visualized were excluded from the counting, as well as granular neurons in the hippocampus, cortex, and cerebellum. Counts of injured versus healthy neurons were aggregated per brain region per animal, and the proportion of injured neurons relative to the total neuronal count (injured plus healthy) was calculated. The counting technique was validated, and the results were reviewed in 3 different moments: first, blind to the interventions performed on the specimens; second, after the disclosure of the groups and interventions; and third, all images were systematically retaken and meticulously counted from the beginning to validate the proportions that were initially analyzed. Pressure Reactivity Index (PRx) and CVAR assessment We quantified real-time CVAR by the PRx, a moving correlation between MAP and ICP 22 – 24 ; with PRx values above ~ 0.2 indicating impaired CVAR 25 , 26 . Signal processing employed a 1-minute sliding window with 50% overlap. A 7-second time lag was introduced from ICP to MAP to accommodate physiological delays in cerebrovascular pressure responses. The PRx was computed continuously throughout the experiment, and values were binned into experimental phases for group-level comparison. We defined PRx > 0.2 as an indication of impaired CVAR in this study, while values near zero or negative suggest preserved cerebrovascular reactivity. Baseline Correction To account for inter-subject variability at baseline, MAP, ICP, and PRx were baseline-corrected for each subject. Baseline correction was performed by calculating the mean value of each parameter during the Baseline phase and subtracting this value from subsequent measurements across all later time phases (Fibrillation; ECMO I: 0–5 min after onset; ECMO II: 5–10 min; ECMO III: 10–15 min). This approach enabled the analysis of relative changes (ΔMAP, ΔICP, ΔPRx) over time, emphasizing variations from each subject's own physiological starting point rather than absolute values. Variation from baseline was demonstrated as the primary outcome metric throughout the study to focus on dynamic physiological responses to the experimental interventions. The results in absolute values were included in the Supplementary Materials. Statistical Analysis For MAP, ICP, ECMO flow, and PRx, a two-step statistical approach was employed to compare physiological parameters across experimental groups (Control, Rapid, and Slow) and time phases (Baseline; Fibrillation; ECMO I; ECMO II; ECMO III). First, data were preprocessed by removing outliers within each signal and phase using an interquartile range (IQR) method. A one-way analysis of variance (ANOVA) was then conducted for each phase to determine whether significant differences existed between groups. Following a significant ANOVA result, Tukey’s Honestly Significant Difference (HSD) post hoc test was performed to assess pairwise group differences. To correct for multiple comparisons, a Bonferroni adjustment was applied, setting the significance threshold at α = 0.0167 (0.05/3 comparisons). Since we used continuous MAP and ICP data to represent each subject across experimental phases, there was a risk of inflating statistical significance. To address this, effect size was calculated using Cohen’s d, and only comparisons that met both the Bonferroni-corrected significance threshold and demonstrated a strong effect size (|d| ≥ 0.8) were considered biologically meaningful. Due to the limited number of data points available, no statistical analysis was carried out on ABG measurements. To further assess distributional changes in PRx across time phases within each group, a two-sample Kolmogorov–Smirnov (K-S) test was applied. The K-S test compares the empirical cumulative distribution functions (ECDFs) of two samples and identifies the maximum vertical distance between them (KS statistic) to detect differences in distribution shape, location, and spread. To avoid overinterpreting small, statistically significant differences, a KS statistic ≥ 0.4 threshold was applied. For histological data, neuronal injury was expressed as the proportion of injured neurons relative to total neurons counted in each region. Tukey’s multiple comparison test was chosen for histological data as it allows for pairwise comparisons between the Control, Rapid, and Slow CO₂ correction groups while controlling for family-wise error. To identify specific group differences in neuronal viability, p-values < 0.05 were considered significant. Results Physiological results Continuous Monitoring of MAP, Flow, and ICP Six female porcine subjects (50.75 ± 1.89 kg) were evenly assigned to control, rapid, and slow CO₂ correction groups. Figure 1 and Table 1 summarize the temporal changes in ΔMAP, ΔICP, and ECMO flow across experimental phases and groups. During fibrillation, ΔMAP was higher in the rapid group compared to the slow group (d = 1.31). ΔICP was significantly smaller in the rapid group compared to both the control (d = 3.09) and the slow (d = 2.21) group. Following ECMO initiation, ΔMAP showed no significant differences between groups, while ΔICP of the rapid group remains lower than both the control and the slow groups during ECMO I (d = 1.63; d = 2.24), ECMO II (d = 1.08; d = 2.02), and ECMO III (d = 1.20; d = 0.96). All pairwise comparisons of ΔMAP did not yield strong effect sizes at ECMO I, II, and III. Flow measurements revealed that ECMO circuit output was higher in the rapid group compared to control during ECMO I (d = 0.88). No meaningful differences were observed between groups at later timepoints (all d < 0.8). The results of MAP and ICP in terms of absolute values were included in Figure S1 and Table S1 . Table 1. Pairwise Comparisons of ΔMAP, ΔICP, and Flow Between Groups Parameter Phase Alternative Hypothesis p-value Cohen's d ΔMAP (mmHg) Fibrillation Control < Rapid < 0.001 0.34 (ns) Control < Slow Slow Rapid Slow < 0.001 0.29 (ns) Rapid < Slow Rapid Slow Slow Rapid Slow Slow Rapid Slow < 0.001 0.69 (ns) Rapid < Slow Rapid < 0.001 1.63 *** Control < Slow < 0.001 0.22 (ns) Rapid < Slow Rapid < 0.001 1.08 *** Control < Slow < 0.001 0.34 (ns) Rapid < Slow Rapid Slow < 0.001 0.10 (ns) Rapid < Slow < 0.001 0.96 *** Flow (L/min) ECMO I Control < Rapid < 0.001 0.88 *** Control < Slow Slow Rapid < 0.001 0.75 (ns) Control < Slow < 0.001 0.19 (ns) Rapid < Slow Rapid Slow Slow < 0.001 0.16 (ns) Pairwise comparisons were conducted using one-way ANOVA followed by Tukey’s Honestly Significant Difference post hoc test. Cohen’s d was calculated to assess effect size. Values marked with (***) indicate statistically significant and clinically meaningful differences (p < 0.0167 and |d| ≥ 0.8) after Bonferroni correction for multiple comparisons. Abbreviations: MAP: Mean Arterial Pressure; ICP: Intracranial Pressure; ECMO: Extracorporeal Membrane Oxygenation; ANOVA: Analysis of Variance. Rapid CO 2 Correction Impaired CVAR During ECMO Support Group-wise comparisons of ΔPRx values are presented in Fig. 2 and detailed in Table 2 . ΔPRx of the slow group (median = 0.018, IQR=-0.13, 0.25) was significantly larger than the control group (median=-0.131, IQR=-0.33, 0.02) during the fibrillation period (d = 0.81), while no significant differences were observed between rapid vs control and rapid vs slow groups. During ECMO I and ECMO II, there were only small-to-moderate effect sizes (d < 0.8) for all comparisons, but 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). Table 2 Phase-wise Group Comparisons of ΔPRx (Tukey HSD + Cohen’s d) Phase Alternative Hypothesis p-value Cohen's d Fibrillation Control < Rapid p < 0.001 0.23 (ns) Control < Slow p < 0.001 0.81 (***) Rapid < Slow p Rapid p = 0.556 0.06 (ns) Control < Slow p < 0.001 0.18 (ns) Rapid < Slow p < 0.001 0.34 (ns) ECMO II Control < Rapid p Slow p Slow p < 0.001 0.44 (ns) ECMO III Control < Rapid p < 0.001 1.77 (***) Control < Slow p Slow p < 0.001 1.83 (***) Variations from baseline in Pressure Reactivity Index ( Δ PRx) values were compared across experimental groups (Control, Rapid, Slow) and time intervals using Tukey’s HSD test. Cohen’s d was calculated to evaluate effect size. A significance threshold of p < 0.0167 and |d| ≥ 0.8 was applied to denote both statistical and clinical relevance. Significant comparisons are marked (***); non-significant comparisons are marked (ns). The absolute values of PRx across experimental phases showed a similar pattern ( Figure S2 and Table S2 ). By ECMO II (5–10 min), the rapid correction group exhibited significantly elevated PRx (median = 0.063, IQR=-0.09, 0.61) compared to the slow group (median=-0.021, IQR=-0.08, 0.03, d = 1.03, p < 0.001). This divergence intensified at ECMO III (10–15 min), where the rapid group showed markedly higher PRx values (median = 0.617, IQR=[0.49, 0.72]) than both the control (median = 0.002, IQR=-0.30, 0.28, d = 1.64) and slow groups (median = 0.078, IQR=-0.06, 0.21, d = 2.37). Histogram distributions of ΔPRx and PRx values further confirm this pattern: the rapid group demonstrated a pronounced rightward shift, indicating elevation of ΔPRx and PRx with more PRx values clustering above the critical threshold (0.2) during ECMO II and III, consistent with loss of autoregulatory function (Fig. 2 , S2). In contrast, the control and slow groups maintained ΔPRx and PRx distributions centered near zero, indicating preserved CVAR throughout the ECMO phases. The differences between both ΔPRx and PRx distributions in ECMO II and ECMO III showed significance (KS statistics = 0.528) in the K-S test (Table 3 , S3). Table 3 K-S Test for ΔPRx Distribution Shifts Across Phases Group Comparison p-value KS Statistic Control Fibrillation vs ECMO I p < 0.001 0.204 (ns) ECMO I vs ECMO II p < 0.001 0.162 (ns) ECMO II vs ECMO III p < 0.001 0.151 (ns) Rapid Fibrillation vs ECMO I p < 0.001 0.236 (ns) ECMO I vs ECMO II p < 0.001 0.367 (ns) ECMO II vs ECMO III p < 0.001 0.528 (***) Slow Fibrillation vs ECMO I p < 0.001 0.077 (ns) ECMO I vs ECMO II p < 0.001 0.118 (ns) ECMO II vs ECMO III p < 0.001 0.250 (ns) Phase-to-phase comparisons of ΔPRx distributions were conducted within each experimental group (Control, Rapid, and Slow) using two-sample Kolmogorov–Smirnov tests. To minimize false-positive significance from large sample sizes, only comparisons meeting both a p-value < 0.01 and a KS statistic ≥ 0.4 were considered biologically meaningful. ABG Dynamics Across Groups Figure 3 shows subject-level trends and group-averaged heatmaps for ABG parameters. pH remained stable across all groups during ECMO. PaCO₂ and HCO₃ − levels changed in accordance with CO₂ removal speed: the slow group showed higher PaCO₂ at ECMO start with a gradual decline, while rapid and control groups showed early reductions. HCO₃ − dropped more sharply in the slow group. PaO₂ was higher in the rapid and control groups throughout, while BE decreased similarly across groups at ECMO initiation and then stabilized. Histopathological Results Histological findings and regional analysis Schematic representation from the analyzed regions: midbrain, cerebellum, hypothalamus, basal ganglia (caudate and putamen), temporal cortex, and hippocampal regions (CA-1 through CA-4) are illustrated in Fig. 4 . High-resolution photomicrographs (20x magnification) were acquired from 3–5 non-overlapping fields per brain region per specimen, generating over 400 images. Neuronal viability was rigorously quantified, and neuronal injury was determined by evaluating the morphological integrity of neurons. Counting technique for all the specimens is evidenced in Figure S3. During morphology evaluation, we found that one specimen from the rapid CO₂ correction group and one from the slow CO₂ correction group exhibited cortical hemorrhages (Figure S4). Histological evaluation revealed that neuronal injury was most pronounced in the basal ganglia (Fig. 5 ), cortex (Fig. 6 ), and hippocampus in the rapid CO₂ correction group. These regions, known for their vulnerability to ischemia, displayed a high proportion of pyknotic neurons, nuclear fragmentation, and cytoplasmic vacuolization. In contrast, the cerebellum, hypothalamus, and hippocampal CA-1 region did not show apparent differences across experimental groups. Examples from these findings are evidenced in Figures S5, S6 and S7. Tukey’s multiple comparison test (Table 4 ) demonstrated that rapid CO₂ correction significantly increased neuronal injury compared to the control group in the caudate nucleus (Mean difference = -32.5, 95% CI: -63.64 to -1.361, p = 0.041), putamen (Mean difference = -42.7, 95% CI: -64.50 to -20.90, p = 0.003), temporal cortex (Mean difference = -26, 95% CI: -45.67 to -6.325, p = 0.013), and hippocampal CA-3 region (Mean difference = -13.33, 95% CI: -24.82 to -1.851, p = 0.026). Borderline trends were observed in the rapid CO2 removal group for the midbrain (p = 0.087), cerebellum (p = 0.075), and hippocampal regions CA-4 (p = 0.123) and CA-2 (p = 0.07). Table 4 Tukey Test Summary for Histological Findings and Regional Analysis Region Comparison (Slices = N) Mean 1 Mean 2 Mean Diff SE Diff 95.00% CI of diff. p-value Midbrain Control (4) vs. Rapid (4) 23.25 7 16.25 6.183 -2.726 to 35.23 0.087 Control (4) vs. Slow (4) 23.25 17 6.25 6.183 -12.73 to 25.23 0.597 Rapid (4) vs. Slow (4) 7 17 -10 6.272 -29.24 to 9.243 0.318 Cerebellum (S1) Control (6) vs. Rapid (6) 46 13.5 32.5 12.13 -3.689 to 68.69 0.075 Control (6) vs. Slow (6) 46 6.833 39.17 11.73 3.051 to 75.28 0.037 Rapid (6) vs. Slow (6) 13.5 6.833 6.667 5.757 -9.336 to 22.67 0.505 Cerebellum (S2) Control (6) vs. Rapid (5) 12.17 27.4 -15.23 8.702 -42.23 to 11.77 0.266 Control (6) vs. Slow (6) 12.17 24.5 -12.33 9.31 -39.90 to 15.23 0.428 Rapid (5) vs. Slow (6) 27.4 24.5 2.9 11.6 -29.48 to 35.28 0.966 Hypothalamus (S1) Control (6) vs. Rapid (6) 36.67 47.83 -11.17 17.9 -64.17 to 41.83 0.812 Control (6) vs. Slow (6) 36.67 33.33 3.333 13.05 -33.39 to 40.06 0.965 Rapid (6) vs. Slow (6) 47.83 33.33 14.5 19.69 -40.84 to 69.84 0.749 Hypothalamus (S2) Control (6) vs. Rapid (6) 29.17 32.67 -3.5 10.65 -32.70 to 25.70 0.943 Control (6) vs. Slow (6) 29.17 31.17 -2 15.55 -46.76 to 42.76 0.991 Rapid (6) vs. Slow (6) 32.67 31.17 1.5 15.63 -43.36 to 46.36 0.995 Caudate Control (10) vs. Rapid (10) 10.6 43.1 -32.5 11.27 -63.64 to -1.361 0.041 Control (10) vs. Slow (10) 10.6 17.9 -7.3 4.373 -18.82 to 4.219 0.253 Rapid (10) vs. Slow (10) 43.1 17.9 25.2 11.77 -6.506 to 56.91 0.126 Putamen Control (10) vs. Rapid (5) 23.9 66.6 -42.7 6.65 -64.50 to -20.90 0.003 Control (10) vs. Slow (10) 23.9 29.7 -5.8 4.347 -17.18 to 5.582 0.401 Rapid (5) vs. Slow (10) 66.6 29.7 36.9 7.375 15.20 to 58.60 0.004 Temporal Cortex Control (8) vs. Rapid (8) 8.875 34.88 -26 7.056 -45.67 to -6.325 0.013 Control (8) vs. Slow (10) 8.875 17.4 -8.525 5.143 -21.99 to 4.944 0.256 Rapid (8) vs. Slow (10) 34.88 17.4 17.48 7.95 -3.553 to 38.50 0.109 CA-4 Control (10) vs. Rapid (10) 5.8 10.5 -4.7 2.108 -10.09 to 0.6893 0.094 Control (10) vs. Slow (10) 5.8 10.1 -4.3 2.067 -9.580 to 0.9795 0.123 Rapid (10) vs. Slow (10) 10.5 10.1 0.4 2.205 -5.227 to 6.027 0.982 CA-3 Control (6) vs. Rapid (6) 18 4.667 13.33 3.938 1.851 to 24.82 0.026 Control (6) vs. Slow (6) 18 9.5 8.5 4.559 -4.079 to 21.08 0.201 Rapid (6) vs. Slow (6) 4.667 9.5 -4.833 3.371 -14.41 to 4.742 0.369 CA-2 Control (10) vs. Rapid (10) 12.5 6.4 6.1 4.273 -5.088 to 17.29 0.354 Control (10) vs. Slow (10) 12.5 2.8 9.7 3.777 -0.7880 to 20.19 0.070 Rapid (10) vs. Slow (10) 6.4 2.8 3.6 2.103 -2.171 to 9.371 0.249 CA-1 Control (10) vs. Rapid (10) 6.8 2.9 3.9 2.078 -1.697 to 9.497 0.190 Control (10) vs. Slow (10) 6.8 2.8 4 2.014 -1.520 to 9.520 0.166 Rapid (10) vs. Slow (10) 2.9 2.8 0.1 0.8333 -2.053 to 2.253 0.992 Tukey’s multiple comparison test was used to compare the percentage of injured neurons across experimental groups and brain regions. The table includes mean injury percentages, mean difference, standard error (SE) of the difference, 95% confidence intervals (CI), and p-values. Statistically significant findings (p < 0.05) are shown in bold. Abbreviations: SE: Standard Error; CI: Confidence Interval; CA: Cornu Ammonis region of the hippocampus; HSD: Honestly Significant Difference; ECMO: Extracorporeal Membrane Oxygenation. When comparing rapid vs. slow CO₂ correction, neuronal injury in the putamen was significantly higher (Mean difference = 36.9, 95% CI: 15.20 to 58.60, p = 0.004), highlighting the protective effect of gradual CO₂ removal in this region. The cerebellum (S1) showed a significant difference in neuronal viability when compared slow vs control groups (Mean difference = 39.17, 95% CI: 13.051 to 75.28, p = 0.037), suggesting a neuroprotective effect, however no other region suggested that effect. No significant differences were observed in the hypothalamus, cerebellum (S2) and hippocampal CA-1 region. Overall, high-resolution imaging confirmed distinct neuronal injury patterns in the most affected regions, with a notable distinction between rapid and slow CO₂ correction groups. Discussion In this porcine model of ECPR, we demonstrate for the first time that the rate of CO₂ correction immediately following ECMO initiation significantly impacts CVAR and neuronal injury. Rapid correction of PaCO₂ markedly impaired CVAR – as evidenced by a sustained increase in ΔPRx and PRx values above the critical threshold during ECMO II and III – and led to significantly greater neuronal insult in ischemia-vulnerable brain regions, including the putamen, caudate nucleus, temporal cortex, and hippocampal CA-3 region. In contrast, gradual controlled PaCO₂ reduction preserved CVAR function (PRx near zero) and was associated with minimal neuronal damage. Nevertheless, given the small sample size (n = 2 per group), results should be interpreted with caution and viewed as hypothesis-generating. These findings align with prior pre-clinical animal-model studies, indicating that PaCO₂ modulates cerebral perfusion via direct effects on vascular tone and influences cellular bioenergetics and inflammation 27 – 31 . Rapid removal of CO₂ likely induces abrupt cerebral vasoconstriction, reducing CBF when reperfused brain tissue requires optimal blood flow. This hemodynamic disruption is compounded by respiratory alkalosis, which shifts the oxyhemoglobin dissociation curve to the left, impairing oxygen delivery at the tissue level despite adequate arterial saturation 32 . The net effect is a perfusion–metabolism mismatch that exacerbates neuronal stress and injury during reperfusion of the brain 8 , 33 , 34 . At the cellular level, several animal studies have demonstrated that both hypocapnia and hypercapnia can impair mitochondrial function, deplete ATP and phosphocreatine reserves, and activate apoptotic pathways through upregulation of pro-apoptotic markers such as Bax and DNA fragmentation 27 – 29 . Hypercapnia, in particular, has been associated with activation of the NLRP3 inflammasome and pyroptosis in hypoxemic conditions, suggesting that dysregulated CO₂—whether too high, too low, or rapidly changing—can amplify neuroinflammatory cascades 30 , 31 . Our data support this mechanistic framework by showing that rapid correction, rather than PaCO₂ level per se, may be the critical driver of neurological injury in ECMO. Histological analysis revealed distinct regional susceptibilities or selective vulnerabilities. The basal ganglia, especially the putamen and caudate, were the most severely affected by rapid CO₂ correction. These structures are known to be metabolically active, with limited collateral blood supply, and particularly vulnerable to fluctuations in perfusion and oxygenation 35 , 36 . Injuries in these regions were consistent and pronounced, reinforcing their role as sentinel sites of ischemic vulnerability. Our findings corroborate this selective vulnerability of basal ganglia as a common area of ischemic insult, supporting our hypothesis that the rapid CO 2 correction leads to subsequent cerebral ischemia mediated by vascular and cellular level changes 37 – 40 . In contrast, slow correction was associated with preserved neuronal integrity in most regions, including the cerebellum, which showed significantly less damage compared to both rapid-correction and control groups. Previous studies have also demonstrated that slow CO₂ correction facilitates a controlled adjustment in CBF, mitigating ischemia-reperfusion injuries and maintaining metabolic homeostasis 33 , 41 , 42 . Furthermore, studies by other authors have also confirmed the beneficial effects of slow PaCO₂ correction in stabilizing intracellular calcium metabolism and mitochondrial function, which are critical factors for neuronal survival 32 , 43 , 44 . Clinical studies of ECMO patients frequently report intracranial hemorrhage (ICH) as a major neurological complication in patients undergoing both VV and VA-ECMO 45 , 46 . According to a systematic review by Sutter et al., the median frequency of ICH in adults on ECMO is approximately 5%, a life-threatening complication with high mortality rates 47 . Nevertheless, our histopathological findings predominantly reflected ischemic injury. Only two specimens in our study—one from the slow correction group and one from the rapid correction group—demonstrated cortical hemorrhages, and no consistent pattern of hemorrhagic transformation was observed across groups. This discrepancy likely reflects the intentionally short duration of ECMO support in our model, which was designed to capture early perfusion-related injury while minimizing confounding factors such as coagulopathy and anticoagulant-induced bleeding that typically emerge during prolonged runs. In clinical settings, the risk of hemorrhagic complications increases over time due to systemic anticoagulation, platelet dysfunction, and endothelial injury 48 – 50 . Our findings are consistent with previous literature underscoring the importance of early detection of cerebral injury and the urgent need for standardized neuromonitoring protocols that can identify evolving neurological insults—ischemic or hemorrhagic—during the most vulnerable period following ECPR initiation 51 , 52 . The observed loss of CVAR with rapid PaCO₂ reduction likely plays a central role in mediating neuronal injury. As PRx values rise above the critical threshold, the brain's ability to maintain stable cerebral blood flow becomes impaired, making perfusion highly dependent on systemic blood pressure. In the vulnerable period following cardiac arrest, this loss of autoregulation can amplify even minor blood pressure fluctuations into periods of hypoperfusion, exacerbating ischemic damage 8 , 32 . In addition, the rapid development of respiratory alkalosis associated with CO₂ removal may reduce oxygen unloading at the tissue level and adversely affect intracellular homeostasis 32 . Specifically, abrupt alkalosis and vasoconstriction have been shown to impair calcium handling and mitochondrial function in neurons, increasing the risk of oxidative stress and promoting apoptosis. Prior experimental studies in animal models confirm that rapid shifts in PaCO₂—both toward hypocapnia and hypercapnia—can reduce ATP production, compromise mitochondrial membrane potential, and activate pro-apoptotic signaling cascades in the cerebral cortex 8 , 33 , 34 . Several limitations of this study warrant consideration. First, the small sample size limited statistical power, potentially obscuring subtle or region-specific effects and rare adverse outcomes. To account for multiple comparisons across continuous physiological recordings, we emphasized effect size thresholds alongside statistical significance testing to reduce false-positive findings driven by large numbers of datapoints per subject. Nevertheless, the limited cohort size constrained our ability to fully characterize inter-subject variability. While we observed robust and consistent changes in CVAR and neuronal injury using continuous physiological monitoring and histological analysis across multiple brain regions, a larger cohort would allow for better characterization of inter-subject variability and increased confidence in negative or borderline findings, particularly in regions with less pronounced injury. Second, an abnormal increase in ICP was observed in the Control and Slow correction groups during the fibrillation phase. Only the Rapid correction group demonstrated the anticipated ICP drop. This unexpected ICP elevation in the Control and Slow groups, and corresponding ICP drop in the Rapid group, suggests differences in cerebral perfusion during fibrillation that may confound the interpretation of subsequent outcomes. Specifically, the greater ICP drop in the Rapid group could indicate more severe ischemic injury during arrest itself, independently impairing CVAR and increasing neuronal vulnerability before any CO₂ correction was initiated. Third, the acute nature of this study (2-hour ECMO support) enabled us to capture early perfusion and injury dynamics, but it precludes insight and assessment of chronic neurological outcomes. We could not assess, for example, whether the damage observed would translate into permanent neurological deficits, or if some injuries might evolve (either worsen or partially recover) over time. Longer-duration studies or survival models will be important to determine whether gradual CO₂ correction confers lasting neuroprotective benefits and to identify any delayed effects of reperfusion injury. Future studies in larger cohorts with longer observation period are needed to validate these findings and better delineate the optimal timing for PaCO₂ correction. Taken together, our findings highlight that the rapidity of PaCO₂ normalization is a critical and modifiable factor during the early ECMO period. While restoration of normocapnia is a therapeutic goal, our data suggest that how quickly this is achieved may determine whether the intervention is protective or harmful. These results support a paradigm in which slow, controlled PaCO₂ correction helps preserve autoregulation, stabilize oxygen delivery, and reduce metabolic stress, ultimately improving neuronal survival. Clinically, our findings suggest that CO₂ correction speed is a critical, modifiable factor that could be optimized to protect the brain during ECPR and this evidence strongly supports adopting a more gradual, controlled CO₂ correction approach during the initial ECMO stabilization period. Conclusions Rapid correction of severe hypercapnia upon ECMO initiation can destabilize cerebral autoregulation and exacerbate neuronal injury, whereas a slow, stepwise correction of PaCO₂ avoids this insult and better preserves neurovascular integrity. These results suggest that meticulous control of PaCO₂ rise and fall rates should be considered in ECMO management as a potential neuroprotective strategy. Declarations Animal Ethics Declaration All animal procedures were conducted in accordance with the Animal Welfare Act regulations and the Public Health Service Policy on Humane Care and Use of Laboratory Animals. The study protocol was reviewed and approved by the Johns Hopkins University Animal Care and Use Committee (Protocol Number SW21M451). Funding Declaration Dr. Cho is funded by NIH (1K23HL157610; 1R21NS135045). This study is funded by Johns Hopkins Magic That Matters foundation grant. Conflicts of Interest The authors declare that they have no conflict of interest. Author Contribution Camila S. Contreras-Rojas contributed to study conceptualization, methodology development, data acquisition, and drafting of the manuscript. Mingfeng Cao contributed to study conceptualization, methodology development, data acquisition, formal data analysis, visualization, and drafting of the manuscript. Qihong Wang critically reviewed the manuscript. Jessica B. Briscoe provided support in surgical procedures, animal care, and experimental logistics. Carlos A. Pardo validated the histological assessment protocols. Hannah Rando contributed to animal preparation and assisted with experimental data collection. Jin Kook Kang provided assistance with experimental design. Glenn Whitman contributed to resource provision and study support. Steve Keller provided consultation on experimental design. Tito Porras supervised animal studies and participated in data acquisition. 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Supplementary Files SupplementaryMaterials.docx Cite Share Download PDF Status: Published Journal Publication published 12 Aug, 2025 Read the published version in Translational Stroke Research → Version 1 posted Editorial decision: Revision requested 30 May, 2025 Reviews received at journal 30 May, 2025 Reviews received at journal 25 May, 2025 Reviewers agreed at journal 14 May, 2025 Reviews received at journal 11 May, 2025 Reviewers agreed at journal 10 May, 2025 Reviewers agreed at journal 10 May, 2025 Reviewers agreed at journal 08 May, 2025 Reviewers agreed at journal 06 May, 2025 Reviewers invited by journal 05 May, 2025 Editor assigned by journal 05 May, 2025 Submission checks completed at journal 04 May, 2025 First submitted to journal 29 Apr, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Contreras-Rojas","email":"","orcid":"","institution":"University of Chicago","correspondingAuthor":false,"prefix":"","firstName":"Camila","middleName":"S.","lastName":"Contreras-Rojas","suffix":""},{"id":453324349,"identity":"0ec61f1c-ae10-4ffd-89ef-942c07fa054a","order_by":2,"name":"Qihong Wang","email":"","orcid":"","institution":"Johns Hopkins University","correspondingAuthor":false,"prefix":"","firstName":"Qihong","middleName":"","lastName":"Wang","suffix":""},{"id":453324350,"identity":"31433dca-f0e5-4ad6-9929-a11893872c8f","order_by":3,"name":"Yaman Ahmed","email":"","orcid":"","institution":"Johns Hopkins Hospital","correspondingAuthor":false,"prefix":"","firstName":"Yaman","middleName":"","lastName":"Ahmed","suffix":""},{"id":453324351,"identity":"6a493064-6398-47f3-beee-872632ec0520","order_by":4,"name":"Jessica Briscoe","email":"","orcid":"","institution":"Johns Hopkins Hospital","correspondingAuthor":false,"prefix":"","firstName":"Jessica","middleName":"","lastName":"Briscoe","suffix":""},{"id":453324352,"identity":"2b5af221-49e8-4d22-834d-f57d5e3d9cdd","order_by":5,"name":"Carlos A. Pardo","email":"","orcid":"","institution":"Johns Hopkins University","correspondingAuthor":false,"prefix":"","firstName":"Carlos","middleName":"A.","lastName":"Pardo","suffix":""},{"id":453324353,"identity":"6a9236bf-4d6d-4b45-902d-0d764414e559","order_by":6,"name":"Hannah Rando","email":"","orcid":"","institution":"Johns Hopkins University","correspondingAuthor":false,"prefix":"","firstName":"Hannah","middleName":"","lastName":"Rando","suffix":""},{"id":453324354,"identity":"25470f87-7c49-4492-999b-60cf2e5b6797","order_by":7,"name":"Jin Kook Kang","email":"","orcid":"","institution":"Johns Hopkins University","correspondingAuthor":false,"prefix":"","firstName":"Jin","middleName":"Kook","lastName":"Kang","suffix":""},{"id":453324355,"identity":"1e2bad3e-cb81-4d38-af5b-cf76d39d263c","order_by":8,"name":"Glenn Whitman","email":"","orcid":"","institution":"Johns Hopkins Hospital","correspondingAuthor":false,"prefix":"","firstName":"Glenn","middleName":"","lastName":"Whitman","suffix":""},{"id":453324356,"identity":"28483834-b6e6-4174-9986-4e093894b8bd","order_by":9,"name":"Steve Keller","email":"","orcid":"","institution":"Johns Hopkins University","correspondingAuthor":false,"prefix":"","firstName":"Steve","middleName":"","lastName":"Keller","suffix":""},{"id":453324357,"identity":"b2589628-a716-4440-9d2b-6b7e14617a31","order_by":10,"name":"Tito Porras","email":"","orcid":"","institution":"Johns Hopkins Hospital","correspondingAuthor":false,"prefix":"","firstName":"Tito","middleName":"","lastName":"Porras","suffix":""},{"id":453324358,"identity":"8168b627-231a-49d3-8d24-0d5388ae4ffd","order_by":11,"name":"Sung-Min Cho","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAw0lEQVRIie3RMQrCMBSA4VdcA1kTau8QCESHolepCJ06i5PkBLrqLTp1jhS36Fw3PYKDUCeNzwMkboL5pwzv4z0IQCz2uzFCwQIUAIkOJUOuvySQC0Pw4Sd0Y9X1Xo2J3B8P9QXyrDa+i7pqJLOGEWVOZVdAKb1EuOGUI7HKkXbmJ9R+iNRIngEEKsVvjghAYvyEdeUiTRxheJiYy52P0E3b8EezmtKtVed+OcnWPvJugD/CDN4ZVtLjPh04HovFYn/XCx7ORCONBXaPAAAAAElFTkSuQmCC","orcid":"","institution":"Johns Hopkins Hospital","correspondingAuthor":true,"prefix":"","firstName":"Sung-Min","middleName":"","lastName":"Cho","suffix":""}],"badges":[],"createdAt":"2025-04-29 22:23:05","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6559635/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6559635/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1007/s12975-025-01376-8","type":"published","date":"2025-08-12T15:56:58+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":82307398,"identity":"8845368f-437a-4c26-ab18-0cc939320da6","added_by":"auto","created_at":"2025-05-09 01:23:40","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":82167,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eGroup-wise comparisons of variations from baseline in mean arterial pressure (ΔMAP), extracorporeal circuit flow, and intracranial pressure (ΔICP) across experimental phases.\u003c/strong\u003eBox plots display ECMO flow, \u003cstrong\u003eΔ\u003c/strong\u003eMAP, and \u003cstrong\u003eΔ\u003c/strong\u003eICP during ventricular fibrillation, and at three ECMO time intervals (ECMO I: 0–5 min, ECMO II: 5–10 min, ECMO III: 10–15 min). Groups include control (blue), rapid CO₂ correction (red), and slow CO₂ correction (yellow).\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-6559635/v1/555cc63f2c5411e6a105abba.png"},{"id":82307106,"identity":"8974b6b4-4e33-48cd-a53d-7984ac38d643","added_by":"auto","created_at":"2025-05-09 01:15:40","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":95719,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eTemporal progression of cerebrovascular autoregulation (CVAR) across groups during ECPR. \u003c/strong\u003eLeft panel: box plots show variations from the baseline in pressure reactivity index (\u003cstrong\u003eΔ\u003c/strong\u003ePRx) values for control (blue), rapid CO₂ correction (red), and slow CO₂ correction (yellow) groups across four experimental phases: fibrillation and ECMO phases I–III (0–5, 5–10, and 10–15 min). Right panel: corresponding histograms illustrate the distribution of PRx values at each phase. The rapid group demonstrates a rightward shift in PRx values during ECMO, indicating progressive CVAR impairment. Statistically significant and clinically meaningful differences are marked (***).\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-6559635/v1/2feb67e147988037e4486d67.png"},{"id":82307107,"identity":"968e56fc-57da-4fdf-8363-6b18bedf7054","added_by":"auto","created_at":"2025-05-09 01:15:40","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":119359,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eABG Trends During ECMO in Control, Rapid, and Slow CO₂ Correction Groups. \u003c/strong\u003eThe left panels show subject-level line plots; the right panels display corresponding group-averaged heatmaps for pH, PaCO₂, PaO₂, HCO₃\u003csup\u003e-\u003c/sup\u003e, and BE at pre-ECMO, ECMO start, and post-cannulation timepoints (5 and 10 minutes). Groups include control (blue), rapid CO₂ correction (red), and slow CO₂ correction (yellow). Trends reflect CO₂ removal effects on PaCO₂ and HCO₃\u003csup\u003e-\u003c/sup\u003e with stable pH and higher PaO₂ in control and rapid groups.\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-6559635/v1/586383d0a35f859f27f05f5e.png"},{"id":82307400,"identity":"b723e3af-ea72-4540-b4c9-c7db942001d8","added_by":"auto","created_at":"2025-05-09 01:23:40","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":223102,"visible":true,"origin":"","legend":"\u003cp\u003eschematic representation of the analyzed regions for neurohistopathological assessment. A: coronal section of the left hemisphere at the level of basal ganglia. The caudate nucleus is outlined in pink, the putamen nucleus is outlined in blue, and the temporal cortex is outlined in yellow. B: sagittal section of the brain with hypothalamus outlined in pink. C: sagittal section of the cerebellum with Purkinje cell layer outlined in pink. D: coronal section of the hippocampal formation. CA-4 is outlined in blue medial to the dentate gyrus, CA-3 is outlined in pink, CA-2 in yellow, and CA-1 in green. E: coronal section of the mesencephalus with bilateral CN3 nucleus outlined in blue.\u003c/p\u003e","description":"","filename":"4.png","url":"https://assets-eu.researchsquare.com/files/rs-6559635/v1/d9c14422bdfd01f797af557f.png"},{"id":82307110,"identity":"ba7976f5-b91f-4295-be1a-5712f617af77","added_by":"auto","created_at":"2025-05-09 01:15:40","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":1066700,"visible":true,"origin":"","legend":"\u003cp\u003eSignificant increase on neuronal injury to rapid CO2 correction in the basal ganglia. Caudate results are evidenced in figure A and B. A corresponds to one specimen from the control group whereas B is a specimen from the rapid CO2 correction group. Highlighted is evidenced an example of a healthy vs injured neuron in the outer squares. Putamen results are evidenced in images C and D corresponding to a specimen from the control group and rapid CO2 correction group respectively.\u003c/p\u003e","description":"","filename":"5.png","url":"https://assets-eu.researchsquare.com/files/rs-6559635/v1/6e183eced4493be30f03394a.png"},{"id":82307116,"identity":"a04c3b90-31d0-45bb-ade5-dfb434df42f3","added_by":"auto","created_at":"2025-05-09 01:15:40","extension":"png","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":534596,"visible":true,"origin":"","legend":"\u003cp\u003eeffect of rapid CO2 correction in the temporal cortex (B) compared to control (A). Highlighted in the squares is shown the healthy vs injured morphology considered for cellurar counting in neurons from the external pyramidal layer.\u003c/p\u003e","description":"","filename":"6.png","url":"https://assets-eu.researchsquare.com/files/rs-6559635/v1/ace6ec290a08d297b51e6e51.png"},{"id":89310535,"identity":"be4295a4-6d55-422b-b5c7-0308d0818fef","added_by":"auto","created_at":"2025-08-18 16:07:17","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":3619144,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6559635/v1/69b725c7-a916-4186-b3d8-53361a50e260.pdf"},{"id":82307139,"identity":"228276e2-8ed1-4f4e-9990-ecd2e5f90e82","added_by":"auto","created_at":"2025-05-09 01:15:45","extension":"docx","order_by":0,"title":"","display":"","copyAsset":false,"role":"supplement","size":34756653,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementaryMaterials.docx","url":"https://assets-eu.researchsquare.com/files/rs-6559635/v1/9f39d88897130afb9fbbfda2.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Rapid CO₂ Correction Impairs Cerebrovascular Autoregulation and Exacerbates Neuronal Injury in a Porcine Model of Extracorporeal Resuscitation","fulltext":[{"header":"Introduction","content":"\u003cp\u003eExtracorporeal cardiopulmonary resuscitation (ECPR), which combines venoarterial extracorporeal membrane oxygenation (VA-ECMO) with conventional cardiopulmonary resuscitation (CPR), has become a critical rescue strategy for patients experiencing refractory cardiac arrest. ECPR significantly improves survival rates and neurological outcomes in select patient populations by rapidly restoring cerebral blood flow (CBF) and minimizing prolonged ischemic injury\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e. Despite these notable benefits, ECMO is associated with a substantial risk of acute brain injury (ABI), driven by mechanisms such as ischemia-reperfusion injury, hemodynamic instability, and metabolic derangements\u0026mdash;including dysregulated arterial partial pressure of carbo dioxide (PaCO₂) and oxygen (PaO₂)\u003csup\u003e\u003cspan additionalcitationids=\"CR3 CR4\" citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003ePaCO₂ is critical for maintaining adequate cerebral perfusion and autoregulatory function, primarily through its potent influence on cerebrovascular tone. Hypercapnia induces cerebral vasodilation, increasing CBF, whereas hypocapnia prompts vasoconstriction, reducing cerebral perfusion\u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e,\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e. Prior experiments suggested that decreases in PaCO\u003csub\u003e2\u003c/sub\u003e can cause dose-dependent vasoconstriction\u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e. Normally, cerebrovascular autoregulation (CVAR) mechanisms buffer acute fluctuations in PaCO₂, stabilizing cerebral perfusion across a wide range of blood pressures\u003csup\u003e\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u003c/sup\u003e. However, abrupt large decreases in PaCO₂ such as those commonly observed immediately after ECMO cannulation may overwhelm CVAR function and subsequently CBF and perfusion.\u003c/p\u003e \u003cp\u003eRetrospective observational clinical studies indicated an association between rapid, large magnitude decreases in PaCO₂ during ECMO initiation and higher frequency of seizure, ischemic stroke, intracranial hemorrhage (ICH), or brain death\u003csup\u003e\u003cspan additionalcitationids=\"CR9\" citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e. A rapid decrease of PaCO₂ in hypercapnia immediately after ECMO initiation has been proposed to increase ABI risk by impairing CVAR, leading to cerebral vasoconstriction and subsequent ischemic injury\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e,\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u003c/sup\u003e. One large multicenter analysis of nearly 12,000 adult ECMO patients (VA, VV or hybrid) demonstrated that a\u0026thinsp;\u0026gt;\u0026thinsp;50% drop in PaCO₂ within the first 24 hours of cannulation was associated with neurological complications (adjusted OR\u0026thinsp;=\u0026thinsp;1.73; p\u0026thinsp;\u0026lt;\u0026thinsp;0.001)\u003csup\u003e8\u003c/sup\u003e. A single-center retrospective observational study on VA-ECMO patients (n\u0026thinsp;=\u0026thinsp;129) similarly found that a greater PaCO₂ decrease during ECMO peri-cannulation period was associated with an increased risk of intracranial hemorrhage (odds ratio\u0026thinsp;=\u0026thinsp;2.69)\u003csup\u003e11\u003c/sup\u003e. These clinical \u0026ldquo;association\u0026rdquo; studies led to the hypothesis that rapid PaCO₂ correction may impair CVAR, contributing to ABI occurrence, especially early during ECMO support. However, several studies also reported that rapid CO2 correction was not associated with ABI in VA-ECMO (Shou, et al n\u0026thinsp;=\u0026thinsp;3125; Yu, et al n\u0026thinsp;=\u0026thinsp;323) and VV-ECMO (Yu, et al n\u0026thinsp;=\u0026thinsp;295)\u003csup\u003e4,12\u003c/sup\u003e. Yu et al. (2024) explicitly contradicted the rapid correction hypothesis, concluding that rapid PaCO₂ correction did not directly cause brain injury in their cohort (both VV and VA-ECMO)\u003csup\u003e\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u003c/sup\u003e. Diehl et al. (2020) suggested neurological injury was associated with large reductions (greater than 20 mmHg) in PaCO2 over 24 hours, without considering the rate of PaCO₂ correction itself in patients treated with VA-ECMO\u003csup\u003e\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u003c/sup\u003e. Hong et al. (2022) emphasize hypercapnia and extreme hyperoxia as problematic factors during VA-ECMO but did not find significant evidence directly implicating the rapid correction of hypercapnia toward normocapnia as causative in ABI\u003csup\u003e\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u003c/sup\u003e. This conflicting evidence underscores a critical lack of knowledge regarding the role of PaCO₂ dynamics in ABI pathogenesis during ECMO.\u003c/p\u003e \u003cp\u003eTo address this critical knowledge gap and overcome limitations inherent to retrospective observational clinical research with many confounding factors, we conducted a controlled experimental study evaluating the impact of PaCO₂ correction rate on CVAR function and neuronal injury following ECPR. Employing a porcine cardiac arrest model, we rigorously compared rapid (200%), slow (25%), and standard (100%) CO₂ correction strategies, integrating continuous physiological data with detailed histopathological analysis of brain tissue susceptible to ischemia during circulatory shock such as the hippocampus, basal ganglia, thalamus, and cerebellum\u003csup\u003e\u003cspan additionalcitationids=\"CR16\" citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u003c/sup\u003e. We hypothesized that rapid PaCO₂ correction would acutely disrupt CVAR function and exacerbate neuronal injury, particularly in ischemia sensitive brain regions. Conversely, we anticipate that gradual CO₂ correction would better preserve CVAR integrity and mitigate neuronal damage. By illuminating the interplay between CO₂ correction rate, CVAR function, and neuronal outcomes in the ECPR context, our study aims to inform safer ECMO initiation strategies and improve neurological recovery in cardiac arrest patients.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eExperimental Procedures\u003c/h2\u003e \u003cp\u003e Procedures were approved by the Johns Hopkins University Animal Care and Use Committee (Protocol SW21M451) and adhered to the Animal Welfare Act regulations and Public Health Service Policy. Porcine subjects were anesthetized with intramuscular ketamine (4.5 mg/kg), xylazine (88 \u0026micro;g/kg), and telazol (1.1 mg/kg), followed by maintenance with intravenous propofol (12\u0026ndash;20 mg/kg/hr). Animals were intubated and ventilated with a tidal volume of 8 mL/kg, PEEP of 5 cm H₂O, a respiratory rate of 10 breaths/min, and an FiO₂ of 40%. Ventilation and ECMO settings aimed to maintain PaO₂ at 65\u0026ndash;200 mmHg.\u003c/p\u003e \u003cp\u003eBilateral femoral arteries and veins were accessed percutaneously for medication administration, monitoring, and ABG sampling. ABG samples were collected at 5 minutes before ECMO initiation, followed by at 5 and 10 minutes after ECMO, including blood pH, PaCO\u003csub\u003e2\u003c/sub\u003e, PaO\u003csub\u003e2\u003c/sub\u003e, HCO₃⁻, and base excess (BE). Mean arterial pressure (MAP), ECMO Flow, and intracranial pressure (ICP) were continuously monitored throughout the experiment. The return of spontaneous circulation (ROSC) was attempted at 20 minutes of ECMO support via one 200 J shock. If the first 200J shock was unsuccessful, additional shocks were delivered at 2-minute intervals. After 2 hours of ECMO, animals were euthanized with potassium chloride and cold saline perfusion.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eCranial Access and ICP Monitor Placement\u003c/h3\u003e\n\u003cp\u003eBilateral cranial burr holes were performed to place the ICP monitor (Integra LifeSciences Production Corporation, Mansfield, MA). The pig was positioned laterally, and a 6 cm rostral-to-caudal incision was made, centered at the intersection of lines drawn from the external acoustic meatus to the contralateral pupil. The incision was created with a 10-blade scalpel and hemostasis was achieved using a Bovie cauterizing instrument. The skin flap was retracted with a Weitlaner retractor, and the Galea was cleared to visualize landmarks.\u003c/p\u003e \u003cp\u003eA burr hole was drilled in each hemisphere using a 2.7-mm bit, positioned\u0026thinsp;~\u0026thinsp;2 cm lateral to the sagittal suture and 1 cm anterior to the coronal suture. Dural punctures were made with an 18-gauge needle using room-temperature saline irrigation for hemostasis. Monitoring leads were positioned to a depth of 2 cm. The skin was closed with Vicryl sutures. Heparin (150 units/kg) was then administered to achieve activated clotting time\u0026thinsp;\u0026gt;\u0026thinsp;300 seconds. The left femoral artery received a 15\u0026ndash;17F arterial cannula, and the right femoral vein received a 19\u0026ndash;21F venous cannula for ECMO.\u003c/p\u003e\n\u003ch3\u003eCardiac Arrest and ECPR Protocol\u003c/h3\u003e\n\u003cp\u003eVentricular fibrillation was induced through a fibrillation pad placed on the chest. After 15 minutes of arrest without intervention, ECPR was initiated with a pump flow set between 60 mL/kg/min. Sweep gas percent oxygen was set to 60%, with ECMO sweep flow adjusted to assess 4 different CO2 concentrations, hypocapnia (25\u0026ndash;30 mmHg), normocapnia (35\u0026ndash;45 mmHg), mild hypercapnia (50\u0026ndash;55 mmHg), and severe hypercapnia (\u0026gt;\u0026thinsp;60 mmHg), as part of the experimental protocol. During ECMO, circuit flow rates were advanced to 80\u0026ndash;100 mL/kg/min, targeting a Mean Arterial Pressure (MAP)\u0026thinsp;\u0026gt;\u0026thinsp;45 mmHg. Lactated Ringer\u0026rsquo;s (LR) boluses were administered to optimize preload, and norepinephrine was used to maintain adequate perfusion pressure.\u003c/p\u003e\n\u003ch3\u003eCO Correction Protocol\u003c/h3\u003e\n\u003cp\u003eCO₂ removal was adjusted by modifying the sweep gas flow rate within the ECMO oxygenator. For this study, two of the six animals were assigned to each of the three CO₂ correction strategies: 1) Control Group with 100% sweep gas flow rate; 2) Rapid CO₂ Correction Group in which a 200% sweep gas flow rate was applied to induce accelerated CO₂ removal; and 3) Slow CO₂ Correction Group where a 25% sweep gas flow rate was used to promote gradual CO₂ correction over time. Sweep gas flow adjustments were continuously monitored to ensure the target CO₂ removal rate was achieved while maintaining physiological stability.\u003c/p\u003e\n\u003ch3\u003eTissue Preparation\u003c/h3\u003e\n\u003cp\u003eBrain tissue was initially stored in 10% Formalin. For each specimen, 1 cm slabs from the midbrain, cerebellum, diencephalon, basal ganglia including temporal cortex, and hippocampus, were collected, preserved in Peripheral Blood Smear (PBS), sectioned into 10-\u0026micro;m coronal sections and stained with hematoxylin and eosin (H\u0026amp;E).\u003c/p\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eCounting and Injury Assessment\u003c/h2\u003e \u003cp\u003eAll slides were examined under light microscopy, and anatomical regions were identified and validated according to the Stereotaxic atlas of the pig brain\u003csup\u003e\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003e. Target regions included the bilateral oculomotor nuclei (midbrain), Purkinje cells (cerebellum), hypothalamus, caudate and putamen nuclei at the striatal level, external pyramidal layer of the temporal cortex, and pyramidal neurons in hippocampal subregions CA-1 through CA-4.\u003c/p\u003e \u003cp\u003eTo ensure rigorous and reproducible histological analysis, neuronal counts were consistently compared within matched anatomical regions on the same slide, thus minimizing variability due to slide preparation and staining. For the midbrain, neuronal counts were performed bilaterally in both oculomotor nuclei. In the cerebellum and hypothalamus, neurons were counted bilaterally within matched coronal sections, labeled as side 1 (S1) and side 2 (S2). For all other structures (caudate, putamen, temporal cortex, and hippocampal subregions CA-1 through CA-4), neuronal counting was conducted across three to five non-overlapping fields aligned longitudinally with the neuroanatomical axis. Images were acquired at standardized magnifications (10x or 20x) appropriate to the anatomical region, ensuring consistent neuron identification and counting accuracy.\u003c/p\u003e \u003cp\u003eWithin each defined counting area, neurons were manually classified as injured or healthy based on standardized morphological criteria. Healthy neurons were defined as cells with a round or oval cell body (8\u0026ndash;10 \u0026micro;m in diameter) with an open nucleus and often with a nucleolus; preserved nuclear and cell membranes; and no apoptotic or ischemic morphology\u003csup\u003e\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u003c/sup\u003e. Injured neurons were characterized by shrunken or angular cell bodies, cytoplasmic vacuolization or condensation, chromatin fragmentation or nuclear disintegration, pyknotic nuclei, loss of perinuclear pallor, and absent nucleoli\u003csup\u003e\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e,\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eThe healthy neurons were outlined as green and the injured cells in red, to calculate the ratio of abnormal cells related to the total. Neurons where the nucleus or nucleolus could not be visualized were excluded from the counting, as well as granular neurons in the hippocampus, cortex, and cerebellum. Counts of injured versus healthy neurons were aggregated per brain region per animal, and the proportion of injured neurons relative to the total neuronal count (injured plus healthy) was calculated. The counting technique was validated, and the results were reviewed in 3 different moments: first, blind to the interventions performed on the specimens; second, after the disclosure of the groups and interventions; and third, all images were systematically retaken and meticulously counted from the beginning to validate the proportions that were initially analyzed.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003ePressure Reactivity Index (PRx) and CVAR assessment\u003c/h3\u003e\n\u003cp\u003eWe quantified real-time CVAR by the PRx, a moving correlation between MAP and ICP\u003csup\u003e\u003cspan additionalcitationids=\"CR23\" citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e\u003c/sup\u003e; with PRx values above ~\u0026thinsp;0.2 indicating impaired CVAR\u003csup\u003e\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e,\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e\u003c/sup\u003e. Signal processing employed a 1-minute sliding window with 50% overlap. A 7-second time lag was introduced from ICP to MAP to accommodate physiological delays in cerebrovascular pressure responses. The PRx was computed continuously throughout the experiment, and values were binned into experimental phases for group-level comparison. We defined PRx\u0026thinsp;\u0026gt;\u0026thinsp;0.2 as an indication of impaired CVAR in this study, while values near zero or negative suggest preserved cerebrovascular reactivity.\u003c/p\u003e\n\u003ch3\u003eBaseline Correction\u003c/h3\u003e\n\u003cp\u003eTo account for inter-subject variability at baseline, MAP, ICP, and PRx were baseline-corrected for each subject. Baseline correction was performed by calculating the mean value of each parameter during the Baseline phase and subtracting this value from subsequent measurements across all later time phases (Fibrillation; ECMO I: 0\u0026ndash;5 min after onset; ECMO II: 5\u0026ndash;10 min; ECMO III: 10\u0026ndash;15 min). This approach enabled the analysis of relative changes (ΔMAP, ΔICP, ΔPRx) over time, emphasizing variations from each subject's own physiological starting point rather than absolute values. Variation from baseline was demonstrated as the primary outcome metric throughout the study to focus on dynamic physiological responses to the experimental interventions. The results in absolute values were included in the Supplementary Materials.\u003c/p\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eStatistical Analysis\u003c/h2\u003e \u003cp\u003eFor MAP, ICP, ECMO flow, and PRx, a two-step statistical approach was employed to compare physiological parameters across experimental groups (Control, Rapid, and Slow) and time phases (Baseline; Fibrillation; ECMO I; ECMO II; ECMO III).\u003c/p\u003e \u003cp\u003eFirst, data were preprocessed by removing outliers within each signal and phase using an interquartile range (IQR) method. A one-way analysis of variance (ANOVA) was then conducted for each phase to determine whether significant differences existed between groups. Following a significant ANOVA result, Tukey\u0026rsquo;s Honestly Significant Difference (HSD) post hoc test was performed to assess pairwise group differences. To correct for multiple comparisons, a Bonferroni adjustment was applied, setting the significance threshold at α\u0026thinsp;=\u0026thinsp;0.0167 (0.05/3 comparisons).\u003c/p\u003e \u003cp\u003eSince we used continuous MAP and ICP data to represent each subject across experimental phases, there was a risk of inflating statistical significance. To address this, effect size was calculated using Cohen\u0026rsquo;s d, and only comparisons that met both the Bonferroni-corrected significance threshold and demonstrated a strong effect size (|d| \u0026ge; 0.8) were considered biologically meaningful. Due to the limited number of data points available, no statistical analysis was carried out on ABG measurements.\u003c/p\u003e \u003cp\u003eTo further assess distributional changes in PRx across time phases within each group, a two-sample Kolmogorov\u0026ndash;Smirnov (K-S) test was applied. The K-S test compares the empirical cumulative distribution functions (ECDFs) of two samples and identifies the maximum vertical distance between them (KS statistic) to detect differences in distribution shape, location, and spread. To avoid overinterpreting small, statistically significant differences, a KS statistic\u0026thinsp;\u0026ge;\u0026thinsp;0.4 threshold was applied.\u003c/p\u003e \u003cp\u003eFor histological data, neuronal injury was expressed as the proportion of injured neurons relative to total neurons counted in each region. Tukey\u0026rsquo;s multiple comparison test was chosen for histological data as it allows for pairwise comparisons between the Control, Rapid, and Slow CO₂ correction groups while controlling for family-wise error. To identify specific group differences in neuronal viability, p-values\u0026thinsp;\u0026lt;\u0026thinsp;0.05 were considered significant.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003ePhysiological results\u003c/h2\u003e \u003cdiv id=\"Sec14\" class=\"Section3\"\u003e \u003ch2\u003eContinuous Monitoring of MAP, Flow, and ICP\u003c/h2\u003e \u003cp\u003eSix female porcine subjects (50.75\u0026thinsp;\u0026plusmn;\u0026thinsp;1.89 kg) were evenly assigned to control, rapid, and slow CO₂ correction groups. Figure\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e and Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e summarize the temporal changes in ΔMAP, ΔICP, and ECMO flow across experimental phases and groups. During fibrillation, ΔMAP was higher in the rapid group compared to the slow group (d\u0026thinsp;=\u0026thinsp;1.31). ΔICP was significantly smaller in the rapid group compared to both the control (d\u0026thinsp;=\u0026thinsp;3.09) and the slow (d\u0026thinsp;=\u0026thinsp;2.21) group. Following ECMO initiation, ΔMAP showed no significant differences between groups, while ΔICP of the rapid group remains lower than both the control and the slow groups during ECMO I (d\u0026thinsp;=\u0026thinsp;1.63; d\u0026thinsp;=\u0026thinsp;2.24), ECMO II (d\u0026thinsp;=\u0026thinsp;1.08; d\u0026thinsp;=\u0026thinsp;2.02), and ECMO III (d\u0026thinsp;=\u0026thinsp;1.20; d\u0026thinsp;=\u0026thinsp;0.96). All pairwise comparisons of ΔMAP did not yield strong effect sizes at ECMO I, II, and III. Flow measurements revealed that ECMO circuit output was higher in the rapid group compared to control during ECMO I (d\u0026thinsp;=\u0026thinsp;0.88). No meaningful differences were observed between groups at later timepoints (all d\u0026thinsp;\u0026lt;\u0026thinsp;0.8). The results of MAP and ICP in terms of absolute values were included in \u003cb\u003eFigure \u003cspan refid=\"MOESM1\" class=\"InternalRef\"\u003eS1\u003c/span\u003e\u003c/b\u003e and \u003cb\u003eTable \u003cspan refid=\"MOESM1\" class=\"InternalRef\"\u003eS1\u003c/span\u003e\u003c/b\u003e.\u003c/p\u003e \u003cp\u003e\u003cstrong\u003eTable 1. Pairwise Comparisons of \u0026Delta;MAP, \u0026Delta;ICP, and Flow Between Groups\u003c/strong\u003e\u003c/p\u003e\n\u003cdiv\u003e\n \u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 125px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eParameter\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 103px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ePhase\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 180px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eAlternative Hypothesis\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 108px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ep-value\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 108px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eCohen\u0026apos;s d\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"12\" style=\"width: 125px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026Delta;MAP (mmHg)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"3\" style=\"width: 103px;\"\u003e\n \u003cp\u003eFibrillation\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 180px;\"\u003e\n \u003cp\u003eControl \u0026lt; Rapid\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 108px;\"\u003e\n \u003cp\u003e\u0026lt; 0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 108px;\"\u003e\n \u003cp\u003e0.34 (ns)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 180px;\"\u003e\n \u003cp\u003eControl \u0026lt; Slow\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 108px;\"\u003e\n \u003cp\u003e\u0026lt; 0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 108px;\"\u003e\n \u003cp\u003e0.14 (ns)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 180px;\"\u003e\n \u003cp\u003eRapid \u0026gt; Slow\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 108px;\"\u003e\n \u003cp\u003e\u0026lt; 0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 108px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e1.31 ***\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"3\" style=\"width: 103px;\"\u003e\n \u003cp\u003eECMO I\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 180px;\"\u003e\n \u003cp\u003eControl \u0026gt; Rapid\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 108px;\"\u003e\n \u003cp\u003e\u0026lt; 0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 108px;\"\u003e\n \u003cp\u003e0.48\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e(ns)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 180px;\"\u003e\n \u003cp\u003eControl \u0026gt; Slow\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 108px;\"\u003e\n \u003cp\u003e\u0026lt; 0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 108px;\"\u003e\n \u003cp\u003e0.29 (ns)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 180px;\"\u003e\n \u003cp\u003eRapid \u0026lt; Slow\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 108px;\"\u003e\n \u003cp\u003e\u0026lt; 0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 108px;\"\u003e\n \u003cp\u003e0.56 (ns)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"3\" style=\"width: 103px;\"\u003e\n \u003cp\u003eECMO II\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 180px;\"\u003e\n \u003cp\u003eControl \u0026gt; Rapid\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 108px;\"\u003e\n \u003cp\u003e\u0026lt; 0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 108px;\"\u003e\n \u003cp\u003e0.32 (ns)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 180px;\"\u003e\n \u003cp\u003eControl \u0026gt; Slow\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 108px;\"\u003e\n \u003cp\u003e\u0026lt; 0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 108px;\"\u003e\n \u003cp\u003e0.47 (ns)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 180px;\"\u003e\n \u003cp\u003eRapid \u0026gt; Slow\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 108px;\"\u003e\n \u003cp\u003e\u0026lt; 0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 108px;\"\u003e\n \u003cp\u003e0.60 (ns)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"3\" style=\"width: 103px;\"\u003e\n \u003cp\u003eECMO III\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 180px;\"\u003e\n \u003cp\u003eControl \u0026gt; Rapid\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 108px;\"\u003e\n \u003cp\u003e\u0026lt; 0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 108px;\"\u003e\n \u003cp\u003e0.47 (ns)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 180px;\"\u003e\n \u003cp\u003eControl \u0026gt; Slow\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 108px;\"\u003e\n \u003cp\u003e\u0026lt; 0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 108px;\"\u003e\n \u003cp\u003e0.48 (ns)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 180px;\"\u003e\n \u003cp\u003eRapid \u0026gt; Slow\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 108px;\"\u003e\n \u003cp\u003e\u0026lt; 0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 108px;\"\u003e\n \u003cp\u003e0.19 (ns)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"12\" style=\"width: 125px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026Delta;ICP (mmHg)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"3\" style=\"width: 103px;\"\u003e\n \u003cp\u003eFibrillation\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 180px;\"\u003e\n \u003cp\u003eControl \u0026gt; Rapid\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 108px;\"\u003e\n \u003cp\u003e\u0026lt; 0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 108px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e3.09 ***\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 180px;\"\u003e\n \u003cp\u003eControl \u0026gt; Slow\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 108px;\"\u003e\n \u003cp\u003e\u0026lt; 0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 108px;\"\u003e\n \u003cp\u003e0.69 (ns)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 180px;\"\u003e\n \u003cp\u003eRapid \u0026lt; Slow\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 108px;\"\u003e\n \u003cp\u003e\u0026lt; 0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 108px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e2.21 ***\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"3\" style=\"width: 103px;\"\u003e\n \u003cp\u003eECMO I\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 180px;\"\u003e\n \u003cp\u003eControl \u0026gt; Rapid\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 108px;\"\u003e\n \u003cp\u003e\u0026lt; 0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 108px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e1.63 ***\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 180px;\"\u003e\n \u003cp\u003eControl \u0026lt; Slow\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 108px;\"\u003e\n \u003cp\u003e\u0026lt; 0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 108px;\"\u003e\n \u003cp\u003e0.22 (ns)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 180px;\"\u003e\n \u003cp\u003eRapid \u0026lt; Slow\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 108px;\"\u003e\n \u003cp\u003e\u0026lt; 0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 108px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e2.24 ***\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"3\" style=\"width: 103px;\"\u003e\n \u003cp\u003eECMO II\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 180px;\"\u003e\n \u003cp\u003eControl \u0026gt; Rapid\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 108px;\"\u003e\n \u003cp\u003e\u0026lt; 0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 108px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e1.08 ***\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 180px;\"\u003e\n \u003cp\u003eControl \u0026lt; Slow\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 108px;\"\u003e\n \u003cp\u003e\u0026lt; 0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 108px;\"\u003e\n \u003cp\u003e0.34 (ns)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 180px;\"\u003e\n \u003cp\u003eRapid \u0026lt; Slow\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 108px;\"\u003e\n \u003cp\u003e\u0026lt; 0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 108px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e2.02 ***\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"3\" style=\"width: 103px;\"\u003e\n \u003cp\u003eECMO III\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 180px;\"\u003e\n \u003cp\u003eControl \u0026gt; Rapid\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 108px;\"\u003e\n \u003cp\u003e\u0026lt; 0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 108px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e1.20 ***\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 180px;\"\u003e\n \u003cp\u003eControl \u0026gt; Slow\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 108px;\"\u003e\n \u003cp\u003e\u0026lt; 0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 108px;\"\u003e\n \u003cp\u003e0.10 (ns)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 180px;\"\u003e\n \u003cp\u003eRapid \u0026lt; Slow\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 108px;\"\u003e\n \u003cp\u003e\u0026lt; 0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 108px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.96 ***\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"9\" style=\"width: 125px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eFlow (L/min)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"3\" style=\"width: 103px;\"\u003e\n \u003cp\u003eECMO I\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 180px;\"\u003e\n \u003cp\u003eControl \u0026lt; Rapid\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 108px;\"\u003e\n \u003cp\u003e\u0026lt; 0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 108px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.88 ***\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 180px;\"\u003e\n \u003cp\u003eControl \u0026lt; Slow\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 108px;\"\u003e\n \u003cp\u003e\u0026lt; 0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 108px;\"\u003e\n \u003cp\u003e0.52\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e(ns)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 180px;\"\u003e\n \u003cp\u003eRapid \u0026gt; Slow\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 108px;\"\u003e\n \u003cp\u003e\u0026lt; 0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 108px;\"\u003e\n \u003cp\u003e0.17 (ns)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"3\" style=\"width: 103px;\"\u003e\n \u003cp\u003eECMO II\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 180px;\"\u003e\n \u003cp\u003eControl \u0026gt; Rapid\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 108px;\"\u003e\n \u003cp\u003e\u0026lt; 0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 108px;\"\u003e\n \u003cp\u003e0.75\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e(ns)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 180px;\"\u003e\n \u003cp\u003eControl \u0026lt; Slow\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 108px;\"\u003e\n \u003cp\u003e\u0026lt; 0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 108px;\"\u003e\n \u003cp\u003e0.19 (ns)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 180px;\"\u003e\n \u003cp\u003eRapid \u0026lt; Slow\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 108px;\"\u003e\n \u003cp\u003e\u0026lt; 0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 108px;\"\u003e\n \u003cp\u003e0.34 (ns)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"3\" style=\"width: 103px;\"\u003e\n \u003cp\u003eECMO III\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 180px;\"\u003e\n \u003cp\u003eControl \u0026gt; Rapid\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 108px;\"\u003e\n \u003cp\u003e\u0026lt; 0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 108px;\"\u003e\n \u003cp\u003e0.38 (ns)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 180px;\"\u003e\n \u003cp\u003eControl \u0026gt; Slow\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 108px;\"\u003e\n \u003cp\u003e\u0026lt; 0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 108px;\"\u003e\n \u003cp\u003e0.48 (ns)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 180px;\"\u003e\n \u003cp\u003eRapid \u0026gt; Slow\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 108px;\"\u003e\n \u003cp\u003e\u0026lt; 0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 108px;\"\u003e\n \u003cp\u003e0.16 (ns)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003ePairwise comparisons were conducted using one-way ANOVA followed by Tukey\u0026rsquo;s Honestly Significant Difference post hoc test. Cohen\u0026rsquo;s d was calculated to assess effect size. Values marked with (***) indicate statistically significant and clinically meaningful differences (p \u0026lt; 0.0167 and |d| \u0026ge; 0.8) after Bonferroni correction for multiple comparisons. Abbreviations: MAP: Mean Arterial Pressure; ICP: Intracranial Pressure; ECMO: Extracorporeal Membrane Oxygenation; ANOVA: Analysis of Variance.\u003c/p\u003e \u003cp\u003eRapid CO\u003csub\u003e2\u003c/sub\u003e Correction Impaired CVAR During ECMO Support\u003c/p\u003e\u003cp\u003eGroup-wise comparisons of ΔPRx values are presented in Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e and detailed in Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e. ΔPRx of the slow group (median\u0026thinsp;=\u0026thinsp;0.018, IQR=-0.13, 0.25) was significantly larger than the control group (median=-0.131, IQR=-0.33, 0.02) during the fibrillation period (d\u0026thinsp;=\u0026thinsp;0.81), while no significant differences were observed between rapid vs control and rapid vs slow groups. During ECMO I and ECMO II, there were only small-to-moderate effect sizes (d\u0026thinsp;\u0026lt;\u0026thinsp;0.8) for all comparisons, but ΔPRx became significantly larger in the rapid group (median\u0026thinsp;=\u0026thinsp;0.577, IQR\u0026thinsp;=\u0026thinsp;0.44, 0.67) during ECMO III compared to both the control (median=-0.034, IQR=-0.35, 0.26, d\u0026thinsp;=\u0026thinsp;1.77) and the slow groups (median\u0026thinsp;=\u0026thinsp;0.192, IQR=-0.01, 0.30, d\u0026thinsp;=\u0026thinsp;1.83).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003ePhase-wise Group Comparisons of ΔPRx (Tukey HSD\u0026thinsp;+\u0026thinsp;Cohen\u0026rsquo;s d)\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePhase\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAlternative Hypothesis\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003ep-value\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eCohen's d\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"2\" rowspan=\"3\"\u003e \u003cp\u003eFibrillation\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eControl\u0026thinsp;\u0026lt;\u0026thinsp;Rapid\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003ep\u0026thinsp;\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.23 (ns)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eControl\u0026thinsp;\u0026lt;\u0026thinsp;Slow\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003ep\u0026thinsp;\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e0.81 (***)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eRapid\u0026thinsp;\u0026lt;\u0026thinsp;Slow\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003ep\u0026thinsp;\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.68 (ns)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"2\" rowspan=\"3\"\u003e \u003cp\u003eECMO I\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eControl\u0026thinsp;\u0026gt;\u0026thinsp;Rapid\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003ep\u0026thinsp;=\u0026thinsp;0.556\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.06 (ns)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eControl\u0026thinsp;\u0026lt;\u0026thinsp;Slow\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003ep\u0026thinsp;\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.18 (ns)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eRapid\u0026thinsp;\u0026lt;\u0026thinsp;Slow\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003ep\u0026thinsp;\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.34 (ns)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"2\" rowspan=\"3\"\u003e \u003cp\u003eECMO II\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eControl\u0026thinsp;\u0026lt;\u0026thinsp;Rapid\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003ep\u0026thinsp;\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.25 (ns)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eControl\u0026thinsp;\u0026gt;\u0026thinsp;Slow\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003ep\u0026thinsp;\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.11 (ns)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eRapid\u0026thinsp;\u0026gt;\u0026thinsp;Slow\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003ep\u0026thinsp;\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.44 (ns)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"2\" rowspan=\"3\"\u003e \u003cp\u003eECMO III\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eControl\u0026thinsp;\u0026lt;\u0026thinsp;Rapid\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003ep\u0026thinsp;\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e1.77 (***)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eControl\u0026thinsp;\u0026lt;\u0026thinsp;Slow\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003ep\u0026thinsp;\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.59 (ns)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eRapid\u0026thinsp;\u0026gt;\u0026thinsp;Slow\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003ep\u0026thinsp;\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e1.83 (***)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003eVariations from baseline in Pressure Reactivity Index (\u003cb\u003eΔ\u003c/b\u003ePRx) values were compared across experimental groups (Control, Rapid, Slow) and time intervals using Tukey\u0026rsquo;s HSD test. Cohen\u0026rsquo;s d was calculated to evaluate effect size. A significance threshold of p\u0026thinsp;\u0026lt;\u0026thinsp;0.0167 and |d| \u0026ge; 0.8 was applied to denote both statistical and clinical relevance. Significant comparisons are marked (***); non-significant comparisons are marked (ns).\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eThe absolute values of PRx across experimental phases showed a similar pattern (\u003cb\u003eFigure S2\u003c/b\u003e and \u003cb\u003eTable S2\u003c/b\u003e). By ECMO II (5\u0026ndash;10 min), the rapid correction group exhibited significantly elevated PRx (median\u0026thinsp;=\u0026thinsp;0.063, IQR=-0.09, 0.61) compared to the slow group (median=-0.021, IQR=-0.08, 0.03, d\u0026thinsp;=\u0026thinsp;1.03, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). This divergence intensified at ECMO III (10\u0026ndash;15 min), where the rapid group showed markedly higher PRx values (median\u0026thinsp;=\u0026thinsp;0.617, IQR=[0.49, 0.72]) than both the control (median\u0026thinsp;=\u0026thinsp;0.002, IQR=-0.30, 0.28, d\u0026thinsp;=\u0026thinsp;1.64) and slow groups (median\u0026thinsp;=\u0026thinsp;0.078, IQR=-0.06, 0.21, d\u0026thinsp;=\u0026thinsp;2.37).\u003c/p\u003e \u003cp\u003eHistogram distributions of ΔPRx and PRx values further confirm this pattern: the rapid group demonstrated a pronounced rightward shift, indicating elevation of ΔPRx and PRx with more PRx values clustering above the critical threshold (0.2) during ECMO II and III, consistent with loss of autoregulatory function (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e, S2). In contrast, the control and slow groups maintained ΔPRx and PRx distributions centered near zero, indicating preserved CVAR throughout the ECMO phases. The differences between both ΔPRx and PRx distributions in ECMO II and ECMO III showed significance (KS statistics\u0026thinsp;=\u0026thinsp;0.528) in the K-S test (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e, S3).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eK-S Test for ΔPRx Distribution Shifts Across Phases\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGroup\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eComparison\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003ep-value\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eKS Statistic\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"2\" rowspan=\"3\"\u003e \u003cp\u003eControl\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eFibrillation vs ECMO I\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003ep\u0026thinsp;\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.204 (ns)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eECMO I vs ECMO II\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003ep\u0026thinsp;\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.162 (ns)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eECMO II vs ECMO III\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003ep\u0026thinsp;\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.151 (ns)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"2\" rowspan=\"3\"\u003e \u003cp\u003eRapid\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eFibrillation vs ECMO I\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003ep\u0026thinsp;\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.236 (ns)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eECMO I vs ECMO II\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003ep\u0026thinsp;\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.367 (ns)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eECMO II vs ECMO III\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003ep\u0026thinsp;\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e0.528 (***)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"2\" rowspan=\"3\"\u003e \u003cp\u003eSlow\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eFibrillation vs ECMO I\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003ep\u0026thinsp;\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.077 (ns)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eECMO I vs ECMO II\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003ep\u0026thinsp;\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.118 (ns)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eECMO II vs ECMO III\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003ep\u0026thinsp;\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.250 (ns)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003ePhase-to-phase comparisons of ΔPRx distributions were conducted within each experimental group (Control, Rapid, and Slow) using two-sample Kolmogorov\u0026ndash;Smirnov tests. To minimize false-positive significance from large sample sizes, only comparisons meeting both a p-value\u0026thinsp;\u0026lt;\u0026thinsp;0.01 and a KS statistic\u0026thinsp;\u0026ge;\u0026thinsp;0.4 were considered biologically meaningful.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv id=\"Sec15\" class=\"Section2\"\u003e \u003ch2\u003eABG Dynamics Across Groups\u003c/h2\u003e \u003cp\u003eFigure \u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e shows subject-level trends and group-averaged heatmaps for ABG parameters. pH remained stable across all groups during ECMO. PaCO₂ and HCO₃\u003csup\u003e\u0026minus;\u003c/sup\u003e levels changed in accordance with CO₂ removal speed: the slow group showed higher PaCO₂ at ECMO start with a gradual decline, while rapid and control groups showed early reductions. HCO₃\u003csup\u003e\u0026minus;\u003c/sup\u003e dropped more sharply in the slow group. PaO₂ was higher in the rapid and control groups throughout, while BE decreased similarly across groups at ECMO initiation and then stabilized.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec16\" class=\"Section2\"\u003e \u003ch2\u003eHistopathological Results\u003c/h2\u003e \u003cdiv id=\"Sec17\" class=\"Section3\"\u003e \u003ch2\u003eHistological findings and regional analysis\u003c/h2\u003e \u003cp\u003eSchematic representation from the analyzed regions: midbrain, cerebellum, hypothalamus, basal ganglia (caudate and putamen), temporal cortex, and hippocampal regions (CA-1 through CA-4) are illustrated in Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eHigh-resolution photomicrographs (20x magnification) were acquired from 3\u0026ndash;5 non-overlapping fields per brain region per specimen, generating over 400 images. Neuronal viability was rigorously quantified, and neuronal injury was determined by evaluating the morphological integrity of neurons. Counting technique for all the specimens is evidenced in \u003cb\u003eFigure S3.\u003c/b\u003e During morphology evaluation, we found that one specimen from the rapid CO₂ correction group and one from the slow CO₂ correction group exhibited cortical hemorrhages (Figure S4).\u003c/p\u003e \u003cp\u003eHistological evaluation revealed that neuronal injury was most pronounced in the basal ganglia (Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003e), cortex (Fig.\u0026nbsp;\u003cspan refid=\"Fig6\" class=\"InternalRef\"\u003e6\u003c/span\u003e), and hippocampus in the rapid CO₂ correction group. These regions, known for their vulnerability to ischemia, displayed a high proportion of pyknotic neurons, nuclear fragmentation, and cytoplasmic vacuolization. In contrast, the cerebellum, hypothalamus, and hippocampal CA-1 region did not show apparent differences across experimental groups. Examples from these findings are evidenced in \u003cb\u003eFigures S5, S6 and S7.\u003c/b\u003e\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eTukey\u0026rsquo;s multiple comparison test (Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e) demonstrated that rapid CO₂ correction significantly increased neuronal injury compared to the control group in the caudate nucleus (Mean difference = -32.5, 95% CI: -63.64 to -1.361, p\u0026thinsp;=\u0026thinsp;0.041), putamen (Mean difference = -42.7, 95% CI: -64.50 to -20.90, p\u0026thinsp;=\u0026thinsp;0.003), temporal cortex (Mean difference = -26, 95% CI: -45.67 to -6.325, p\u0026thinsp;=\u0026thinsp;0.013), and hippocampal CA-3 region (Mean difference = -13.33, 95% CI: -24.82 to -1.851, p\u0026thinsp;=\u0026thinsp;0.026). Borderline trends were observed in the rapid CO2 removal group for the midbrain (p\u0026thinsp;=\u0026thinsp;0.087), cerebellum (p\u0026thinsp;=\u0026thinsp;0.075), and hippocampal regions CA-4 (p\u0026thinsp;=\u0026thinsp;0.123) and CA-2 (p\u0026thinsp;=\u0026thinsp;0.07).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab4\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eTukey Test Summary for Histological Findings and Regional Analysis\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"8\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRegion\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eComparison (Slices\u0026thinsp;=\u0026thinsp;N)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eMean 1\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eMean 2\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eMean Diff\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eSE Diff\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003e95.00% CI of diff.\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c8\"\u003e \u003cp\u003ep-value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"2\" rowspan=\"3\"\u003e \u003cp\u003eMidbrain\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eControl (4) vs. Rapid (4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e23.25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e16.25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e6.183\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e-2.726 to 35.23\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e\u003cb\u003e0.087\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eControl (4) vs. Slow (4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e23.25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e17\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e6.25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e6.183\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e-12.73 to 25.23\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e0.597\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eRapid (4) vs. Slow (4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e17\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e6.272\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e-29.24 to 9.243\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e0.318\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"2\" rowspan=\"3\"\u003e \u003cp\u003eCerebellum (S1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eControl (6) vs. Rapid (6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e46\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e13.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e32.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e12.13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e-3.689 to 68.69\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e0.075\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eControl (6) vs. Slow (6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e46\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e6.833\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e39.17\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e11.73\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e3.051 to 75.28\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e\u003cb\u003e0.037\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eRapid (6) vs. Slow (6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e13.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e6.833\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e6.667\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e5.757\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e-9.336 to 22.67\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e0.505\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"2\" rowspan=\"3\"\u003e \u003cp\u003eCerebellum (S2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eControl (6) vs. Rapid (5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e12.17\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e27.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-15.23\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e8.702\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e-42.23 to 11.77\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e0.266\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eControl (6) vs. Slow (6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e12.17\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e24.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-12.33\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e9.31\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e-39.90 to 15.23\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e0.428\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eRapid (5) vs. Slow (6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e27.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e24.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e2.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e11.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e-29.48 to 35.28\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e0.966\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"2\" rowspan=\"3\"\u003e \u003cp\u003eHypothalamus (S1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eControl (6) vs. Rapid (6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e36.67\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e47.83\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-11.17\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e17.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e-64.17 to 41.83\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e0.812\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eControl (6) vs. Slow (6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e36.67\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e33.33\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e3.333\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e13.05\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e-33.39 to 40.06\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e0.965\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eRapid (6) vs. Slow (6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e47.83\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e33.33\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e14.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e19.69\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e-40.84 to 69.84\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e0.749\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"2\" rowspan=\"3\"\u003e \u003cp\u003eHypothalamus (S2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eControl (6) vs. Rapid (6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e29.17\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e32.67\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-3.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e10.65\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e-32.70 to 25.70\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e0.943\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eControl (6) vs. Slow (6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e29.17\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e31.17\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e15.55\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e-46.76 to 42.76\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e0.991\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eRapid (6) vs. Slow (6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e32.67\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e31.17\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e15.63\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e-43.36 to 46.36\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e0.995\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"2\" rowspan=\"3\"\u003e \u003cp\u003eCaudate\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eControl (10) vs. Rapid (10)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e10.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e43.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-32.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e11.27\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e-63.64 to -1.361\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e\u003cb\u003e0.041\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eControl (10) vs. Slow (10)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e10.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e17.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-7.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e4.373\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e-18.82 to 4.219\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e0.253\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eRapid (10) vs. Slow (10)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e43.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e17.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e25.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e11.77\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e-6.506 to 56.91\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e0.126\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"2\" rowspan=\"3\"\u003e \u003cp\u003ePutamen\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eControl (10) vs. Rapid (5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e23.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e66.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-42.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e6.65\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e-64.50 to -20.90\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e\u003cb\u003e0.003\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eControl (10) vs. Slow (10)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e23.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e29.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-5.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e4.347\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e-17.18 to 5.582\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e0.401\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eRapid (5) vs. Slow (10)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e66.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e29.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e36.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e7.375\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e15.20 to 58.60\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e\u003cb\u003e0.004\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"2\" rowspan=\"3\"\u003e \u003cp\u003eTemporal Cortex\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eControl (8) vs. Rapid (8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e8.875\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e34.88\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-26\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e7.056\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e-45.67 to -6.325\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e\u003cb\u003e0.013\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eControl (8) vs. Slow (10)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e8.875\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e17.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-8.525\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e5.143\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e-21.99 to 4.944\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e0.256\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eRapid (8) vs. Slow (10)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e34.88\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e17.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e17.48\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e7.95\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e-3.553 to 38.50\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e0.109\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"2\" rowspan=\"3\"\u003e \u003cp\u003eCA-4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eControl (10) vs. Rapid (10)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e10.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-4.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e2.108\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e-10.09 to 0.6893\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e0.094\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eControl (10) vs. Slow (10)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e10.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-4.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e2.067\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e-9.580 to 0.9795\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e0.123\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eRapid (10) vs. Slow (10)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e10.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e10.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e2.205\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e-5.227 to 6.027\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e0.982\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"2\" rowspan=\"3\"\u003e \u003cp\u003eCA-3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eControl (6) vs. Rapid (6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e18\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e4.667\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e13.33\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e3.938\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1.851 to 24.82\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e\u003cb\u003e0.026\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eControl (6) vs. Slow (6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e18\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e9.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e8.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e4.559\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e-4.079 to 21.08\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e0.201\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eRapid (6) vs. Slow (6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4.667\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e9.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-4.833\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e3.371\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e-14.41 to 4.742\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e0.369\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"2\" rowspan=\"3\"\u003e \u003cp\u003eCA-2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eControl (10) vs. Rapid (10)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e12.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e6.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e6.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e4.273\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e-5.088 to 17.29\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e0.354\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eControl (10) vs. Slow (10)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e12.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e9.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e3.777\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e-0.7880 to 20.19\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e\u003cb\u003e0.070\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eRapid (10) vs. Slow (10)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e3.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e2.103\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e-2.171 to 9.371\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e0.249\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"2\" rowspan=\"3\"\u003e \u003cp\u003eCA-1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eControl (10) vs. Rapid (10)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e3.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e2.078\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e-1.697 to 9.497\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e0.190\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eControl (10) vs. Slow (10)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e2.014\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e-1.520 to 9.520\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e0.166\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eRapid (10) vs. Slow (10)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.8333\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e-2.053 to 2.253\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e0.992\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"8\"\u003eTukey\u0026rsquo;s multiple comparison test was used to compare the percentage of injured neurons across experimental groups and brain regions. The table includes mean injury percentages, mean difference, standard error (SE) of the difference, 95% confidence intervals (CI), and p-values. Statistically significant findings (p\u0026thinsp;\u0026lt;\u0026thinsp;0.05) are shown in bold. Abbreviations: SE: Standard Error; CI: Confidence Interval; CA: Cornu Ammonis region of the hippocampus; HSD: Honestly Significant Difference; ECMO: Extracorporeal Membrane Oxygenation.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eWhen comparing rapid vs. slow CO₂ correction, neuronal injury in the putamen was significantly higher (Mean difference\u0026thinsp;=\u0026thinsp;36.9, 95% CI: 15.20 to 58.60, p\u0026thinsp;=\u0026thinsp;0.004), highlighting the protective effect of gradual CO₂ removal in this region. The cerebellum (S1) showed a significant difference in neuronal viability when compared slow vs control groups (Mean difference\u0026thinsp;=\u0026thinsp;39.17, 95% CI: 13.051 to 75.28, p\u0026thinsp;=\u0026thinsp;0.037), suggesting a neuroprotective effect, however no other region suggested that effect. No significant differences were observed in the hypothalamus, cerebellum (S2) and hippocampal CA-1 region.\u003c/p\u003e \u003cp\u003eOverall, high-resolution imaging confirmed distinct neuronal injury patterns in the most affected regions, with a notable distinction between rapid and slow CO₂ correction groups.\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eIn this porcine model of ECPR, we demonstrate for the first time that the rate of CO₂ correction immediately following ECMO initiation significantly impacts CVAR and neuronal injury. Rapid correction of PaCO₂ markedly impaired CVAR \u0026ndash; as evidenced by a sustained increase in ΔPRx and PRx values above the critical threshold during ECMO II and III \u0026ndash; and led to significantly greater neuronal insult in ischemia-vulnerable brain regions, including the putamen, caudate nucleus, temporal cortex, and hippocampal CA-3 region. In contrast, gradual controlled PaCO₂ reduction preserved CVAR function (PRx near zero) and was associated with minimal neuronal damage. Nevertheless, given the small sample size (n\u0026thinsp;=\u0026thinsp;2 per group), results should be interpreted with caution and viewed as hypothesis-generating.\u003c/p\u003e \u003cp\u003eThese findings align with prior pre-clinical animal-model studies, indicating that PaCO₂ modulates cerebral perfusion via direct effects on vascular tone and influences cellular bioenergetics and inflammation\u003csup\u003e\u003cspan additionalcitationids=\"CR28 CR29 CR30\" citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e\u003c/sup\u003e. Rapid removal of CO₂ likely induces abrupt cerebral vasoconstriction, reducing CBF when reperfused brain tissue requires optimal blood flow. This hemodynamic disruption is compounded by respiratory alkalosis, which shifts the oxyhemoglobin dissociation curve to the left, impairing oxygen delivery at the tissue level despite adequate arterial saturation\u003csup\u003e\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e\u003c/sup\u003e. The net effect is a perfusion\u0026ndash;metabolism mismatch that exacerbates neuronal stress and injury during reperfusion of the brain\u003csup\u003e\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e,\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e,\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e\u003c/sup\u003e. At the cellular level, several animal studies have demonstrated that both hypocapnia and hypercapnia can impair mitochondrial function, deplete ATP and phosphocreatine reserves, and activate apoptotic pathways through upregulation of pro-apoptotic markers such as Bax and DNA fragmentation\u003csup\u003e\u003cspan additionalcitationids=\"CR28\" citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e\u003c/sup\u003e. Hypercapnia, in particular, has been associated with activation of the NLRP3 inflammasome and pyroptosis in hypoxemic conditions, suggesting that dysregulated CO₂\u0026mdash;whether too high, too low, or rapidly changing\u0026mdash;can amplify neuroinflammatory cascades\u003csup\u003e\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e,\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e\u003c/sup\u003e. Our data support this mechanistic framework by showing that rapid correction, rather than PaCO₂ level per se, may be the critical driver of neurological injury in ECMO.\u003c/p\u003e \u003cp\u003eHistological analysis revealed distinct regional susceptibilities or selective vulnerabilities. The basal ganglia, especially the putamen and caudate, were the most severely affected by rapid CO₂ correction. These structures are known to be metabolically active, with limited collateral blood supply, and particularly vulnerable to fluctuations in perfusion and oxygenation\u003csup\u003e\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e,\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e\u003c/sup\u003e. Injuries in these regions were consistent and pronounced, reinforcing their role as sentinel sites of ischemic vulnerability. Our findings corroborate this selective vulnerability of basal ganglia as a common area of ischemic insult, supporting our hypothesis that the rapid CO\u003csub\u003e2\u003c/sub\u003e correction leads to subsequent cerebral ischemia mediated by vascular and cellular level changes\u003csup\u003e\u003cspan additionalcitationids=\"CR38 CR39\" citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e\u003c/sup\u003e. In contrast, slow correction was associated with preserved neuronal integrity in most regions, including the cerebellum, which showed significantly less damage compared to both rapid-correction and control groups. Previous studies have also demonstrated that slow CO₂ correction facilitates a controlled adjustment in CBF, mitigating ischemia-reperfusion injuries and maintaining metabolic homeostasis\u003csup\u003e\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e,\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e,\u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e\u003c/sup\u003e. Furthermore, studies by other authors have also confirmed the beneficial effects of slow PaCO₂ correction in stabilizing intracellular calcium metabolism and mitochondrial function, which are critical factors for neuronal survival\u003csup\u003e\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e,\u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e,\u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eClinical studies of ECMO patients frequently report intracranial hemorrhage (ICH) as a major neurological complication in patients undergoing both VV and VA-ECMO\u003csup\u003e\u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e,\u003cspan citationid=\"CR46\" class=\"CitationRef\"\u003e46\u003c/span\u003e\u003c/sup\u003e. According to a systematic review by Sutter et al., the median frequency of ICH in adults on ECMO is approximately 5%, a life-threatening complication with high mortality rates\u003csup\u003e\u003cspan citationid=\"CR47\" class=\"CitationRef\"\u003e47\u003c/span\u003e\u003c/sup\u003e. Nevertheless, our histopathological findings predominantly reflected ischemic injury. Only two specimens in our study\u0026mdash;one from the slow correction group and one from the rapid correction group\u0026mdash;demonstrated cortical hemorrhages, and no consistent pattern of hemorrhagic transformation was observed across groups. This discrepancy likely reflects the intentionally short duration of ECMO support in our model, which was designed to capture early perfusion-related injury while minimizing confounding factors such as coagulopathy and anticoagulant-induced bleeding that typically emerge during prolonged runs. In clinical settings, the risk of hemorrhagic complications increases over time due to systemic anticoagulation, platelet dysfunction, and endothelial injury\u003csup\u003e\u003cspan additionalcitationids=\"CR49\" citationid=\"CR48\" class=\"CitationRef\"\u003e48\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR50\" class=\"CitationRef\"\u003e50\u003c/span\u003e\u003c/sup\u003e. Our findings are consistent with previous literature underscoring the importance of early detection of cerebral injury and the urgent need for standardized neuromonitoring protocols that can identify evolving neurological insults\u0026mdash;ischemic or hemorrhagic\u0026mdash;during the most vulnerable period following ECPR initiation\u003csup\u003e\u003cspan citationid=\"CR51\" class=\"CitationRef\"\u003e51\u003c/span\u003e,\u003cspan citationid=\"CR52\" class=\"CitationRef\"\u003e52\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eThe observed loss of CVAR with rapid PaCO₂ reduction likely plays a central role in mediating neuronal injury. As PRx values rise above the critical threshold, the brain's ability to maintain stable cerebral blood flow becomes impaired, making perfusion highly dependent on systemic blood pressure. In the vulnerable period following cardiac arrest, this loss of autoregulation can amplify even minor blood pressure fluctuations into periods of hypoperfusion, exacerbating ischemic damage\u003csup\u003e\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e,\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e\u003c/sup\u003e. In addition, the rapid development of respiratory alkalosis associated with CO₂ removal may reduce oxygen unloading at the tissue level and adversely affect intracellular homeostasis\u003csup\u003e\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e\u003c/sup\u003e. Specifically, abrupt alkalosis and vasoconstriction have been shown to impair calcium handling and mitochondrial function in neurons, increasing the risk of oxidative stress and promoting apoptosis. Prior experimental studies in animal models confirm that rapid shifts in PaCO₂\u0026mdash;both toward hypocapnia and hypercapnia\u0026mdash;can reduce ATP production, compromise mitochondrial membrane potential, and activate pro-apoptotic signaling cascades in the cerebral cortex\u003csup\u003e\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e,\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e,\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eSeveral limitations of this study warrant consideration. First, the small sample size limited statistical power, potentially obscuring subtle or region-specific effects and rare adverse outcomes. To account for multiple comparisons across continuous physiological recordings, we emphasized effect size thresholds alongside statistical significance testing to reduce false-positive findings driven by large numbers of datapoints per subject. Nevertheless, the limited cohort size constrained our ability to fully characterize inter-subject variability. While we observed robust and consistent changes in CVAR and neuronal injury using continuous physiological monitoring and histological analysis across multiple brain regions, a larger cohort would allow for better characterization of inter-subject variability and increased confidence in negative or borderline findings, particularly in regions with less pronounced injury. Second, an abnormal increase in ICP was observed in the Control and Slow correction groups during the fibrillation phase. Only the Rapid correction group demonstrated the anticipated ICP drop. This unexpected ICP elevation in the Control and Slow groups, and corresponding ICP drop in the Rapid group, suggests differences in cerebral perfusion during fibrillation that may confound the interpretation of subsequent outcomes. Specifically, the greater ICP drop in the Rapid group could indicate more severe ischemic injury during arrest itself, independently impairing CVAR and increasing neuronal vulnerability before any CO₂ correction was initiated. Third, the acute nature of this study (2-hour ECMO support) enabled us to capture early perfusion and injury dynamics, but it precludes insight and assessment of chronic neurological outcomes. We could not assess, for example, whether the damage observed would translate into permanent neurological deficits, or if some injuries might evolve (either worsen or partially recover) over time. Longer-duration studies or survival models will be important to determine whether gradual CO₂ correction confers lasting neuroprotective benefits and to identify any delayed effects of reperfusion injury. Future studies in larger cohorts with longer observation period are needed to validate these findings and better delineate the optimal timing for PaCO₂ correction.\u003c/p\u003e \u003cp\u003eTaken together, our findings highlight that the rapidity of PaCO₂ normalization is a critical and modifiable factor during the early ECMO period. While restoration of normocapnia is a therapeutic goal, our data suggest that how quickly this is achieved may determine whether the intervention is protective or harmful. These results support a paradigm in which slow, controlled PaCO₂ correction helps preserve autoregulation, stabilize oxygen delivery, and reduce metabolic stress, ultimately improving neuronal survival. Clinically, our findings suggest that CO₂ correction speed is a critical, modifiable factor that could be optimized to protect the brain during ECPR and this evidence strongly supports adopting a more gradual, controlled CO₂ correction approach during the initial ECMO stabilization period.\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003eRapid correction of severe hypercapnia upon ECMO initiation can destabilize cerebral autoregulation and exacerbate neuronal injury, whereas a slow, stepwise correction of PaCO₂ avoids this insult and better preserves neurovascular integrity. These results suggest that meticulous control of PaCO₂ rise and fall rates should be considered in ECMO management as a potential neuroprotective strategy.\u003c/p\u003e "},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAnimal Ethics Declaration\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll animal procedures were conducted in accordance with the Animal Welfare Act regulations and the Public Health Service Policy on Humane Care and Use of Laboratory Animals. The study protocol was reviewed and approved by the Johns Hopkins University Animal Care and Use Committee (Protocol Number SW21M451).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding Declaration\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eDr. Cho is funded by NIH (1K23HL157610; 1R21NS135045). This study is funded by Johns Hopkins Magic That Matters foundation grant.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflicts of Interest\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no conflict of interest.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor Contribution\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eCamila S. Contreras-Rojas contributed to study conceptualization, methodology development, data acquisition, and drafting of the manuscript. Mingfeng Cao contributed to study conceptualization, methodology development, data acquisition, formal data analysis, visualization, and drafting of the manuscript. Qihong Wang critically reviewed the manuscript. Jessica B. Briscoe provided support in surgical procedures, animal care, and experimental logistics. Carlos A. Pardo validated the histological assessment protocols. Hannah Rando contributed to animal preparation and assisted with experimental data collection. Jin Kook Kang provided assistance with experimental design. Glenn Whitman contributed to resource provision and study support. Steve Keller provided consultation on experimental design. Tito Porras supervised animal studies and participated in data acquisition. Sung-Min Cho oversaw study conceptualization, funding acquisition, project supervision, critical revision of all manuscript drafts, and final approval of the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData Availability\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ePlease directly contact the first author Mingfeng Cao or the corresponding author Sung-Min Cho to request for raw data.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eCai J, Abudou H, Chen Y, et al. The effects of ECMO on neurological function recovery of critical patients: A double-edged sword. 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Front Med. 2021;8:731106. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.3389/fmed.2021.731106\u003c/span\u003e\u003cspan address=\"10.3389/fmed.2021.731106\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCho SM, Ziai W, Mayasi Y, et al. Noninvasive Neurological Monitoring in Extracorporeal Membrane Oxygenation. ASAIO J. 2020;66(4):388\u0026ndash;93. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1097/MAT.0000000000001013\u003c/span\u003e\u003cspan address=\"10.1097/MAT.0000000000001013\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCho SM, Choi CW, Whitman G, et al. Neurophysiological Findings and Brain Injury Pattern in Patients on ECMO. Clin EEG Neurosci. 2021;52(6):462\u0026ndash;9. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1177/1550059419892757\u003c/span\u003e\u003cspan address=\"10.1177/1550059419892757\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"translational-stroke-research","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"trsr","sideBox":"Learn more about [Translational Stroke Research](http://jcmr-online.biomedcentral.com)","snPcode":"12975","submissionUrl":"https://submission.nature.com/new-submission/12975/3","title":"Translational Stroke Research","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"ECPR, ECMO, CVAR, histology, PaCO2","lastPublishedDoi":"10.21203/rs.3.rs-6559635/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6559635/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003ePrior clinical research demonstrated that rapid reduction in arterial carbon dioxide (PaCO\u003csub\u003e2\u003c/sub\u003e) 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.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eIn this prospective preclinical experimental study, six female pigs (mean weight: 50.75\u0026thinsp;\u0026plusmn;\u0026thinsp;1.89 kg) were subjected to 15 minutes of ventricular fibrillation and were supported by ECMO. Then, they were randomly assigned to three CO\u003csub\u003e2\u003c/sub\u003e 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\u0026thinsp;\u0026gt;\u0026thinsp;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.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eIn the rapid group, PaCO₂ correction caused a steep drop in PaCO₂\u0026mdash;from 60 to approximately 30 mmHg within 5 minutes\u0026mdash;and was associated with impaired CVAR, as indicated by ΔPRx became significantly larger in the rapid group (median\u0026thinsp;=\u0026thinsp;0.577, IQR\u0026thinsp;=\u0026thinsp;0.44, 0.67) during ECMO III compared to both the control (median=-0.034, IQR=-0.35, 0.26, d\u0026thinsp;=\u0026thinsp;1.77) and the slow groups (median\u0026thinsp;=\u0026thinsp;0.192, IQR=-0.01, 0.30, d\u0026thinsp;=\u0026thinsp;1.83). PRx values were elevated above 0.2 at 10\u0026ndash;15 minutes post-ECMO (median\u0026thinsp;=\u0026thinsp;0.617, interquartile range (IQR)\u0026thinsp;=\u0026thinsp;0.49, 0.72). In contrast, the slow correction group showed significantly lower PRx (median\u0026thinsp;=\u0026thinsp;0.078, IQR =-0.06, 0.21, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001, \u003cem\u003ed\u003c/em\u003e\u0026thinsp;=\u0026thinsp;1.64), and the control group remained near baseline (median\u0026thinsp;=\u0026thinsp;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, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.041), putamen (66.6% vs. 23.9%, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.003), temporal cortex (34.9% vs. 8.9%, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.013), and hippocampal CA-3 region (4.7% vs. 18.0%, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.026). Compared to rapid correction, the slow correction group demonstrated improved gas stability (PaCO₂ decline of ~\u0026thinsp;10 mmHg over 10 min), preserved PRx (mean PRx\u0026thinsp;\u0026lt;\u0026thinsp;0.2), and significantly reduced neuronal injury in the putamen (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.004).\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003eRapid 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.\u003c/p\u003e","manuscriptTitle":"Rapid CO₂ Correction Impairs Cerebrovascular Autoregulation and Exacerbates Neuronal Injury in a Porcine Model of Extracorporeal Resuscitation","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-05-09 01:15:35","doi":"10.21203/rs.3.rs-6559635/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-05-30T16:41:14+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-05-30T16:29:04+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-05-25T15:53:52+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"334695685191425578931413505381769439804","date":"2025-05-14T09:26:58+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-05-11T21:10:36+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"127923470711895005003451348612160243545","date":"2025-05-10T14:44:07+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"15391421030152522753401636381003036672","date":"2025-05-10T09:57:39+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"56888316848801643838336647090268727215","date":"2025-05-08T09:05:01+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"59305510961693579991701351306849966067","date":"2025-05-06T04:48:55+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-05-06T00:38:19+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-05-06T00:33:01+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-05-05T03:43:39+00:00","index":"","fulltext":""},{"type":"submitted","content":"Translational Stroke Research","date":"2025-04-29T22:08:35+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"translational-stroke-research","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"trsr","sideBox":"Learn more about [Translational Stroke Research](http://jcmr-online.biomedcentral.com)","snPcode":"12975","submissionUrl":"https://submission.nature.com/new-submission/12975/3","title":"Translational Stroke Research","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"7556a515-c25b-4e87-9ae3-4984ad310991","owner":[],"postedDate":"May 9th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2025-08-18T16:00:39+00:00","versionOfRecord":{"articleIdentity":"rs-6559635","link":"https://doi.org/10.1007/s12975-025-01376-8","journal":{"identity":"translational-stroke-research","isVorOnly":false,"title":"Translational Stroke Research"},"publishedOn":"2025-08-12 15:56:58","publishedOnDateReadable":"August 12th, 2025"},"versionCreatedAt":"2025-05-09 01:15:35","video":"","vorDoi":"10.1007/s12975-025-01376-8","vorDoiUrl":"https://doi.org/10.1007/s12975-025-01376-8","workflowStages":[]},"version":"v1","identity":"rs-6559635","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6559635","identity":"rs-6559635","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}