Monitoring anoxic depolarization at the bedside: A step closer to the 24th century

Abstract

Anoxic depolarization starts the clock for irreversible brain injury. Yet, this critical indicator has been highly elusive and notoriously difficult to capture using currently available clinical monitoring tools. Recent data suggest that it may be possible to detect anoxic depolarization at the bedside. Detection of such terminal events has far-reaching implications for diagnosis, prognostication, and neuroprotection, as well as the ethics of end-of-life decision-making in neurocritical care.

Mass neuronal depolarization in response to brain circulatory arrest was first discovered over 70 years ago by Leão, ¹ and subsequent studies showed that this “anoxic depolarization” is what triggers the well-known pathological changes in severely ischemic brain tissue. Often described generically as membrane ion pump failure, these changes include a steep rise in extracellular potassium and glutamate, intracellular calcium overload, mitochondrial depolarization, and cytotoxic edema—the swelling of cell bodies and beading of neuronal dendrites. Anoxic depolarization is the moment when critically ischemic tissue transitions from a relatively hyperpolarized and electrophysiologically silent (penumbra-like) state to near-complete loss of membrane potentials (a superdepolarization state) within a matter of seconds. As such, anoxic depolarization marks the time when the clock starts ticking for irreversible injury.

Dreier et al. recently reported the electrophysiological signature of anoxic depolarization in human cortex using intraparenchymal depth as well as subdural electrode arrays marking a milestone in the characterization of terminal events in the human brain. ² Their recordings also revealed non-spreading depression of activity preceding terminal spreading depolarization (SD), confirming the observations made only in experimental animals to date. This non-spreading depression of activity precedes the reduction of ATP to critical levels not compatible with cell survival, and therefore, is likely a preemptive protective shutdown. Recognition of anoxic depolarization as a standing, persistent wave is important because it develops in fact as a spreading wave, with essential characteristics in common with SD transients that repeatedly occur for days after acute injury and promote secondary injury.^3,4 For instance, the focal ischemic “core”—the diffusion lesion in clinical MRI imaging—is co-extensive with and defined by the region of anoxic depolarization. Stroke progression over time is thought to occur when numerous SDs gradually expand this terminally depolarized core in a stepwise fashion.^3,5–7

While a large body of work on SDs has been translated to the clinic in recent years, ⁴ evidence for anoxic depolarization in human brain has been elusive. It is not possible to monitor the human brain in the initial minutes after a stroke or cardiac arrest. Dreier et al. instead investigated electrophysiological onset of severe ischemia in another scenario—when there is a decision to withdraw life-sustaining therapy after devastating brain injury from trauma or aneurysm rupture in their cohort. They found that cortical electrical silence develops during the sharp decline in brain energy supply, but that brain ion homeostasis is preserved for a further period of seconds to minutes until the terminal, persistent wave of SD occurs. These demonstrations of anoxic depolarization strongly suggest that the same sequence of events also occurs in cases of survivable severe ischemia. Of importance to all these conditions is that terminal SD marks the onset of the toxic cellular changes that eventually lead to death, but is not a marker of death per se, since depolarization is reversible—up to a point—with restoration of the circulation.^1,3 The demonstration of this wave in the human brain thus has profound implications for diagnosis, prognostication, and neuroprotection, and also for the ethics of end-of-life procedures. For example, cessation of clinical brain function and spontaneous electroencephalography activity usually occurs within 30 s of circulatory arrest. In some countries, it is inferred from this that a 5-min period of circulatory arrest constitutes a valid indicator that awareness has fully ceased. This aligns with a 5-min no-touch time after the loss of arterial pulse, the current circulatory standard of death determination in non-heart-beating organ donation. ⁸ However, the front of SD represents an extreme form of neuronal excitation and activation. Dreier et al. ² found that this occurs minutes after cessation of the patient’s pulse. This warrants caution to guarantee complete loss of awareness to organ donors at 5 min after pulselessness.

On another cautionary note, while detecting the onset of anoxic depolarization at the bedside has important implications for outcome and survival, one should not rush into interpreting anoxic depolarization as marker of brain death. This is because what appears to be terminal anoxic depolarization can be reversible even after tens of minutes of ischemia. Although scattered neuronal death may ensue after such prolonged anoxic depolarization events (in part modulated by other factors such as brain temperature and glucose availability), the overall integrity of the bulk of the brain can often be preserved.

For these implications to be further explored and integrated into medical practice, less invasive methods for SD diagnosis are desperately needed. In this regard, I cannot help but recall Star Trek: The Next Generation, Season 1, Episode “Skin of Evil” (23 April 1988), set in the 24th century, when the young Lieutenant Yar was urgently beamed aboard the starship USS Enterprise and admitted to sick bay after being attacked and injured by a malicious entity. A medical technician monitored her brain with a non-invasive device and announced that “her synaptic network is breaking down” as the doctor’s attempts at resuscitation became more frantic. Moments later, the technician observed that “neurons are beginning to depolarize” and the lieutenant subsequently expired. It appears the scientific consultants for Star Trek had read Leão and understood perfectly the sequence of electrical silence followed by terminal SD, as now demonstrated by Dreier et al. in the human neocortex. Here’s hoping that such a non-invasive device is available before the 24th century.