Brain Hypoxia Is Associated With Neuroglial Injury in Humans Post-Cardiac Arrest
Circulation Research | July 21, 2021
Hoiland RL, Ainslie PN, Wellington CL, Cooper J, Stukas S, Thiara S, Foster D, Fergusson N, Conway EM, Menon DK, Gooderham PA, Hirsch-Reinshagen V, Griesdale D and Sekhon M
Circulation research. 2021
Rationale: Secondary brain hypoxia portends significant mortality in ischemic brain diseases, yet our understanding of hypoxic ischemic brain injury (HIBI) pathophysiology in humans remains rudimentary.
Objective: To quantify the impact of secondary brain hypoxia on injury to the neurovascular unit in patients with HIBI.
Methods and Results: We conducted a prospective interventional study of invasive neuromonitoring in 18 post-cardiac arrest patients with HIBI. The partial pressures of brain tissue O2 (PbtO2) and intracranial pressure were directly measured via intra-parenchymal micro-catheters. To isolate the cerebrovascular bed, we conducted paired sampling of arterial and jugular venous bulb blood and calculated the trans-cerebral release of biomarkers of neurovascular injury and inflammation in the HIBI patients and 14 healthy volunteers for control comparisons. Ten HIBI patients exhibited secondary brain hypoxia (PbtO2<20mmHg), while eight exhibited brain normoxia (PbtO2≥20mmHg). In the patients with secondary brain hypoxia, we observed active cerebral release of glial fibrillary acidic protein (-161[ -3695 – -75] pg/mL; P=0.0078), neurofilament light chain (-231[-370 – -11] pg/mL; P=0.010), total tau (-32[-310 – -3] pg/mL; P=0.0039), neuron specific enolase (-14890[-148813 – -3311] pg/mL; P=0.0039), and ubiquitin carboxy-terminal hydrolase L1 (-14.7[-37.7 – -4.1] pg/mL; P=0.0059) indicating de novo neuroglial injury. This injury was unrelated to the systemic global ischemic burden or cerebral endothelial injury but rather was associated with cerebral release of interleukin-6 (-10.3[-43.0 – -4.2] pg/mL; P=0.0039). No cerebral release of the aforementioned biomarkers was observed in HIBI patients with brain normoxia or the healthy volunteers. Hyperosmolar therapy in the patients with secondary brain hypoxia reduced the partial pressure of jugular venous O2-to-PbtO2 gradient (39.6[34.1-51.1] vs. 32.0[24.5-39.2] mmHg; P=0.0078) and increased PbtO2 (17.0[9.1-19.7] vs. 20.2[11.9-22.7] mmHg; P=0.039) suggesting improved cerebrovascular-to-parenchymal O2 transport.
Conclusions: Secondary brain hypoxia is associated with de novo neuroglial injury and cerebral release of interleukin-6. Mitigating cerebrovascular-to-parenchymal limitations to O2 transport is a promising therapeutic strategy for HIBI patients with secondary brain hypoxia.
This study was performed using the Quanterix HD-1 Analyzer.
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