RESUMO
Extracorporeal membrane oxygenation (ECMO) is often associated with disturbances in acid/base status that can be triggered by the underlying pathology or the ECMO circuit itself. Extracorporeal membrane oxygenation is known to cause hypocapnia, but the impact of reduced partial pressure of carbon dioxide (pCO2) on biomarkers of tissue perfusion during veno-arterial (VA)-ECMO has not been evaluated. To study the impact of low pCO2 on perfusion indices in VA-ECMO, we placed Sprague-Dawley rats on an established VA-ECMO circuit using either an oxygen/carbon dioxide mixture (O2 95%, CO2 5%) or 100% O2 delivered through the oxygenator (n = 5 per cohort). Animals receiving 100% O2 developed a significant VA CO2 difference (pCO2 gap) and rising blood lactate levels that were inversely proportional to the decrease in pCO2 values. In contrast, pCO2 gap and lactate levels remained similar to pre-ECMO baseline levels in animals receiving the O2/CO2 mixture. More importantly, there was no significant difference in venous oxygen saturation (SvO2) between the two groups, suggesting that elevated blood lactate levels observed in the rats receiving 100% O2 were a response to oxygenator induced hypocapnia and alkaline pH rather than reduced perfusion or underlying tissue hypoxia. These findings have implications in clinical and experimental extracorporeal support contexts.
RESUMO
BACKGROUND: Factor XII (FXII) is a multifunctional protease capable of activating thrombotic and inflammatory pathways. FXII has been linked to thrombosis in extracorporeal membrane oxygenation (ECMO), but the role of FXII in ECMO-induced inflammatory complications has not been studied. We used novel gene-targeted FXII- deficient rats to evaluate the role of FXII in ECMO-induced thromboinflammation. METHODS: FXII-deficient (FXII-/-) Sprague-Dawley rats were generated using CRISPR/Cas9. A minimally invasive venoarterial (VA) ECMO model was used to compare wild-type (WT) and FXII-/- rats in 2 separate experimental cohorts: rats placed on ECMO without pharmacologic anticoagulation and rats anticoagulated with argatroban. Rats were maintained on ECMO for 1 hour or until circuit failure occurred. Comparisons were made with unchallenged rats and rats that underwent a sham surgical procedure without ECMO. RESULTS: FXII-/- rats were maintained on ECMO without pharmacologic anticoagulation with low resistance throughout the 1-hour experiment. In contrast, WT rats placed on ECMO without anticoagulation developed thrombotic circuit failure within 10 minutes. Argatroban provided a means to maintain WT and FXII-/- rats on ECMO for the 1-hour time frame without thrombotic complications. Analyses of these rats demonstrated that ECMO resulted in increased neutrophil migration into the liver that was significantly blunted by FXII deficiency. ECMO also resulted in increases in high molecular weight kininogen cleavage and complement activation that were abrogated by genetic deletion of FXII. CONCLUSIONS: FXII initiates hemostatic system activation and key inflammatory sequelae in ECMO, suggesting that therapies targeting FXII could limit both thromboembolism and inopportune inflammatory complications in this setting.