Terminal spreading depolarization and electrical silence in death of human cerebral cortex

Abstract

ObjectiveRestoring the circulation is the primary goal in emergency treatment of cerebral ischemia. However, better understanding of how the brain responds to energy depletion could help predict the time available for resuscitation until irreversible damage and advance development of interventions that prolong this span. Experimentally, injury to central neurons begins only with anoxic depolarization. This potentially reversible, spreading wave typically starts 2 to 5 minutes after the onset of severe ischemia, marking the onset of a toxic intraneuronal change that eventually results in irreversible injury.MethodsTo investigate this in the human brain, we performed recordings with either subdural electrode strips (n = 4) or intraparenchymal electrode arrays (n = 5) in patients with devastating brain injury that resulted in activation of a Do Not Resuscitate–Comfort Care order followed by terminal extubation.ResultsWithdrawal of life‐sustaining therapies produced a decline in brain tissue partial pressure of oxygen (ptiO2) and circulatory arrest. Silencing of spontaneous electrical activity developed simultaneously across regional electrode arrays in 8 patients. This silencing, termed “nonspreading depression,” developed during the steep falling phase of ptiO2 (intraparenchymal sensor, n = 6) at 11 (interquartile range [IQR] = 7–14) mmHg. Terminal spreading depolarizations started to propagate between electrodes 3.9 (IQR = 2.6–6.3) minutes after onset of the final drop in perfusion and 13 to 266 seconds after nonspreading depression. In 1 patient, terminal spreading depolarization induced the initial electrocerebral silence in a spreading depression pattern; circulatory arrest developed thereafter.InterpretationThese results provide fundamental insight into the neurobiology of dying and have important implications for survivable cerebral ischemic insults. Ann Neurol 2018;83:295–310

Oxygen and brain death; back from the brink

“…Beyond limits; the unexpected resilience of the brain. The traditional notion that the mammalian brain is irreversibly damaged soon after blood stops circulating, owing to limited energy stores, has been challenged by two landmark studies in particular [(Vrselja et al., ; Dreier et al, ), both marked by a gold star], sparking widespread debate over the clinical diagnosis of brain death and organ transplantation. (a) Neuronal, electrophysiological and metabolic recovery has been observed after global cerebral ischaemia or after a prolonged post‐mortem interval in the animal brain.…”

“…A recent study in patients suffering from devastating brain injuries, in whom life‐sustaining therapy was withdrawn while neuromonitoring continued as they died, is especially revealing (Dreier et al., ). Neurons were shown to shift into an energy‐saving standby mode after 20–40 s of O 2 deprivation; electrical activity stopped, and the brain flatlined and became ‘silent’ (termed non‐spreading depression), which would traditionally have been taken to reflect irreversible progression towards neuronal death.…”

“…A recent study in patients suffering from devastating brain injuries, in whom life-sustaining therapy was withdrawn while neuromonitoring continued as they died, is especially revealing (Dreier et al, 2018).…”

“…Equally fascinating, the 'high-fliers' , including Ruppell's griffon, Gyps rueppellii, and the bar-headed goose, Anser indicus, have been observed at altitudes of 9000-11,278 m, with the former capable of achieving the high metabolic rates required for flapping flight and running even when exposed to a simulated P aO 2 equivalent to that encountered on F I G U R E 4 Beyond limits; the unexpected resilience of the brain. The traditional notion that the mammalian brain is irreversibly damaged soon after blood stops circulating, owing to limited energy stores, has been challenged by two landmark studies in particular [ (Vrselja et al, 2019;Dreier et al, 2018), both marked by a gold star], sparking widespread debate over the clinical diagnosis of brain death and organ transplantation. (a) Neuronal, electrophysiological and metabolic recovery has been observed after global cerebral ischaemia or after a prolonged post-mortem interval in the animal brain.…”

Death: An Evolving, Normative Concept

“…6 In the study, nine people in Berlin, Germany, and Cincinnati, Ohio, had the electrical signals in their brain monitored as they died. Even five minutes after a person's heart stops beating, their brain cells may still function, according to recent findings published in the Annals of Neurology.…”