Hypoxic-Ischemic Brain Injury in ECMO: Pathophysiology, Neuromonitoring, and Therapeutic Opportunities

Abstract

Extracorporeal membrane oxygenation (ECMO), in conjunction with its life-saving benefits, carries a significant risk of acute brain injury (ABI). Hypoxic-ischemic brain injury (HIBI) is one of the most common types of ABI in ECMO patients. Various risk factors, such as history of hypertension, high day 1 lactate level, low pH, cannulation technique, large peri-cannulation PaCO₂ drop (∆PaCO₂), and early low pulse pressure, have been associated with the development of HIBI in ECMO patients. The pathogenic mechanisms of HIBI in ECMO are complex and multifactorial, attributing to the underlying pathology requiring initiation of ECMO and the risk of HIBI associated with ECMO itself. HIBI is likely to occur in the peri-cannulation or peri-decannulation time secondary to underlying refractory cardiopulmonary failure before or after ECMO. Current therapeutics target pathological mechanisms, cerebral hypoxia and ischemia, by employing targeted temperature management in the case of extracorporeal cardiopulmonary resuscitation (eCPR), and optimizing cerebral O₂ saturations and cerebral perfusion. This review describes the pathophysiology, neuromonitoring, and therapeutic techniques to improve neurological outcomes in ECMO patients in order to prevent and minimize the morbidity of HIBI. Further studies aimed at standardizing the most relevant neuromonitoring techniques, optimizing cerebral perfusion, and minimizing the severity of HIBI once it occurs will improve long-term neurological outcomes in ECMO patients.

Keywords: extracorporeal membrane oxygenation; hypoxia-ischemia brain injury; neurological complication; neuromonitoring; outcome.

Figure 1

Harlequin syndrome. ECMO circuit induces hypercoagulable state due to a low-flow state and non-pulsatile blood flow. This leads to endothelial injury, microcirculation disruption, and differential hypoxemia. Over time, as the left ventricle regains its function, deoxygenated blood is pumped by the heart to the cerebral blood vessels leading to cerebral autoregulation impairment and global hypoxia. This clinically presents as HIBI. This figure is created with the BioRender software, with the assistance of Soorin Chung in finalizing the graphic design.

Figure 2

Pathogenesis of HIBI at the molecular level. Decreased cerebral perfusion impairs the function of Na⁺/K⁺ ATPase pump in the brain tissue due to decreased ATP production. This generates a hypoxic state which leads to a shift in metabolism from oxidative phosphorylation to anaerobic glycolysis. The resultant acidotic environment due to lactic acid accumulation impairs cell function. Furthermore, ischemia leads to an activation of NMDA receptor and influx of calcium ions. Calcium induces the release of excitotoxic neurotransmitter glutamate, which along with the reactive oxygen species and activation of degrative enzymes leads to neuronal cell death by necrosis, apoptosis, or autophagocytosis. This figure is created with the BioRender software, with the assistance of Soorin Chung in finalizing the graphic design.