Aberrant brain-heart coupling is associated with the severity and prognosis of hypoxic-ischemic brain injury after cardiac arrest

Abstract

Background and Objectives: Approximately 50% of post-cardiac arrest survivors remain comatose after 72h, a substantial proportion of which will have a poor neurological outcome, predominantly due to irreversible hypoxic-ischemic brain injury. Recent findings in healthy subjects and patients suggested that autonomic nervous system activity measured by brain-heart interactions could be reliable markers of consciousness and cognitive processing. Thus, we hypothesized that brain-heart interactions are associated with the severity of hypoxic-ischemic brain injury and the prognosis of these patients. Methods: In post-cardiac arrest patients still comatose 48h after sedation weaning, brain-heart interaction markers were computed on 5 minutes of continuous EEG/ECG recording using a synthetic data generation model, gathering bidirectional interactions between EEG frequency bands (delta, theta and alpha) and heart-rate variability frequency bands (low and high frequency). The strength and complexity of the interactions were quantified using medians and refined composite multiscale entropy. Primary outcome was the severity of brain injury, assessed by: (i) standardized qualitative EEG classification, (ii) somatosensory evoked potentials (N20), and (iii) neuron-specific enolase levels. Secondary outcome was the 3-month neurological status, assessed by the Cerebral Performance Category score [good (1-2) vs. poor outcome (3-4-5)]. Results: Between January 2007 and July 2021, 181 patients [116 males (64%), median age 61 years, age range 49-72 years] were admitted to ICU for a resuscitated cardiac arrest (76% out-of-hospital, 69% non-shockable rhythm). Poor neurological outcome was observed in 134 patients (74%). Qualitative EEG patterns suggesting high severity were associated with a decreased sympatho-vagal balance. Severity of EEG changes were proportional to higher absolute values of brain-to-heart coupling strength (p<2x10-3 for all brain-to-heart frequencies) and lower values of complexity (all p-values<0.05 except for alpha-to-low frequency). Brain-to-heart coupling strength was significantly higher in patients with bilateral absent N20 and correlated with neuron-specific enolase levels at day 3. This aberrant brain-to-heart coupling (increased strength, decreased complexity) was also associated with 3-month poor neurological outcome. Discussion : Our results suggest that autonomic dysfunctions may well represent hypoxic-ischemic brain injury post-cardiac arrest pathophysiology. These results open avenues for integrative monitoring of autonomic functioning in critical care patients with potential prognostic applications.