Oxidative Stress Response and Delirium after Cardiac Surgery: Can Circulating Biomarkers Refine New Therapeutic Paradigms?

Although postoperative delirium afflicts as many as half of cardiac surgery patients and is associated with prolonged hospitalization, long-term cognitive decline, and mortality, we know little of the pathophysiologic mechanisms that subtend this common neurobehavioral syndrome. Delirium is an acute confusional state, generally viewed as a marker of increased brain vulnerability and an aberrant response to stress. As such, its neuropathogenesis depends on complex interrelationships between predisposing and precipitating factors, with a number of overlapping mechanistic theories involving neuronal aging, neuroinflammation, oxidative stress, neurotransmitter deficiency, neuroendocrine activation, circadian dysregulation, and breakdown in brain network connectivity. While anesthesia/surgery are clearly inciting factors for delirium, intraoperative strategies to reduce it are sorely lacking. This is in part because prevailing theories have focused on preoperative (older age, frailty, medical comorbidities, and preexisting cognitive impairment) and postoperative recovery factors (disrupted sleep, altered sensorium, pain, and sedating medication use/polypharmacy) as drivers of postoperative delirium. In this issue of Anesthesiology, Lopez et al. refocus our attention on intraoperative factors associated with delirium—namely, oxidative stress and blood–brain barrier breakdown. They report results from a subset of patients (n = 400) enrolled in a single-center randomized controlled trial of statin therapy to reduce acute kidney injury and delirium following cardiac surgery. The primary trial results revealed no statin effects on incident postoperative acute kidney injury as well as incidence or duration of postoperative delirium. Here, in a prespecified secondary analysis, the authors performed mass spectrometry–based plasma quantification of oxidative stress indicators F2-isoprostanes and isofurans, demonstrating clear associations with incident postoperative delirium. They also found that postoperative elevations of a putative marker of blood–brain barrier breakdown, S100 calcium-binding protein, are associated with delirium. Oxidative stress and blood–brain barrier breakdown markers were both associated with increases in ubiquitin carboxyl-terminal hydrolase isozyme L1, a plasma marker of neuronal injury, and the strength of the association between oxidative damage and neuronal injury was higher in patients with biomarker evidence of blood–brain barrier disruption. Overall, this biologically plausible triangle of elegant consecutive correlations between surrogate circulating biomarkers and delirium adds evidence in support of the oxidative stress hypothesis, which proposes that pathologic insults such as hypoxia and ischemia-reperfusion may lead to reduced cerebral oxidative metabolism and associated cognitive and behavioral symptoms of delirium. Readers might consider several factors in interpreting the potentially wide-ranging clinical and translational relevance of the study by Lopez et al. The first promising translational implication is the use of circulating biomarkers to predict, monitor, and assess therapeutic effectiveness for postoperative delirium. The Institute of Medicine has outlined a clear