A recent study gives insight into the #neurobiology of dying. Before the process of dying neurologists closely monitored patients with devastating #brain injuries following Do Not Resuscitate-Comfort Care orders. This gave key insights into the mechanisms and timing of events in the brain and the circulatory system during the dying process.
The objective of emergency treatment is to restore circulation to prevent #cerebral ischemia. #Cerebral ischemia is a condition that occurs when blood flow is restricted to the brain, which then causes the #death of brain tissue. Understanding the brain’s response to energy depletion can help us estimate how much time is available for resuscitation until irreversible damage has occurred. The goal is to develop methods that can prolong this window before irreversible damage takes place . Injury to central neurons begins only during the progressive and uncontrollable #depolarization of neurons called anoxic depolarization. This Anoxic depolarization “wave” is potentially reversible and typically starts 2 to 5 minutes after the emergence of severe ischemia. This marks the beginning of a toxic change within the neuron which eventually leads to irreversible brain injury.
Subdural electrode strips (n=4) or intraparenchymal electrode arrays (n = 5) were used to observe patients with devastating brain injuries. This was performed on patients with devastating brain injuries that resulted in the activation of a Do Not Resuscitate–Comfort Care order followed by terminal extubation.
When life-sustaining therapies were withdrawn several things happened:
- A decline in brain tissue partial pressure of oxygen (pti02) and circulatory arrest.
- Non spreading depression developed during the decline phase of pti02 (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.
“These results provide fundamental insight into the neurobiology of dying and have important implications for survivable cerebral ischemic insults.” Ann Neurol 2018;83:295–310”
The most vulnerable organ of the body to oxygen deprivation (hypoxia) and lack of blood flow (ischemia) is the brain. There are 6 layers in the neocortical pyramid. It was found that layer III, the hippocampal CA1 pyramidal cells (a major output pathway goes to layer V), layer IV, striatal cells (the principal neurons of the striatum, which is responsible for the reward and motor systems), and layer V, the Purkinje cells (the only output cells of the cerebellar cortex) showed the most vulnerability. After 10 minutes, when circulation completely ceases, such as after cardiac arrest, massive injury to these cells becomes irreversible. The pathophysiological processes resulting in this type of injury have been extensively investigated in various animal species for more than 50 years.
In humans, however, we only have had vague hints as to what happens in the brain when circulation ceases through the use of scalp electroencephalographic (EEG) recording. In clinical literature there are a wide variety of conclusions and interpretations of the data, including significant departure from the observations gleaned from animal models. One notion is that when there are no longer any measurable voltage fluctuations resulting from ionic currents within the neurons from within the brain through the use of EEG, then that is brain death. That’s one example. After EEG silence with acute, complete ischemia, neurons within the cortex of the human brain can remain polarized for several minutes. The failure of membrane pumps indicate that the tissue’s death is another notion as to when brain “death” occurs. Such failure in animal studies admits only to the cytotoxic processes leading to death and only occurs as a consequence of a terminal depolarization wave, a phenomenon that has not yet been documented in the human brain.
The complete idleness of electrical activity caused by global ischemia (ie, isoelectricity) in the affected gray matter happens within about 20-40 seconds within animals. Neuronal energy usage is suppressed by the shutdown of nonessential cell functions well before the depletion of the neuronal adenosine triphosphate (ATP) pool and the probability of tissue recovery vanish. This is considered an austerity program of neuronal energy and its purpose iscerebral silencing. Several mechanisms mediate between the correspondence of electrical inactivity and hyperpolarization of neurons, as reviewed recently. The spreading of electrical silencing simultaneously in the affected tissue after severe ischemia is its hallmark, which has been termed “nonspreading depression.” The release of Gibbs free energy causes sodium and calcium to leak into the cells and potassium to leak out. These movements happen regardless of this austerity program of neuronal energy. Na,K-ATPase fails to restore the leaking ions after the ATP becomes depleted. Once nonspreading depression starts after the ischemic tissue is rendered isoelectric, the threshold level of failure is typically reached within 1 to 5 minutes. Once this threshold has been reached neurons then undergo abrupt changes, creating the imbalance of input and output (nonlinear) rundown in the ionic gradients across the cellular membranes. The development of depolarization happens altogether and spreads organically in the tissue as a wave from either one or multiple focal points. The spreading depolarization (SD) which was initially termed “anoxic” or “asphyxia” depolarization ignites an excessive amount of toxic changes. Recent reviews show that the toxic changes include intracellular calcium and sodium loading, a steep rise in extracellular glutamate, and cytotoxic edema. It is important to consider that during the initial period of nonspreading depression that there is no development of cellular injury and that it only begins with a delay after SD starts.
Research in treatment strategies of cardiac arrest and stroke to supplement efforts in reestablishing circulation is dependent on the clear and concise understanding of this pathological process. It also opens up the debate about organ donation after cardiocirculatory death (DCD) is declared between 2 and 10 minutes following after the circulatory function ceases. The analysis of the sequences of the physiological events was therefore conducted in patience after the withdrawal of life-sustaining treatments during abrupt hypoxia-ischemia.
Neuromonitoring with intracranial electrodes during intensive care treatment following aneurysmal subarachnoid hemorrhage (aSAH) and clip ligation of the aneurysm, decompressive hemicraniectomy for malignant hemispheric stroke (MHS), or traumatic brain injury (TBI) was conducted. Following poor clinical course and family discussion, neuromonitoring was continued through the dying process after activation of a Do Not Resuscitate–Comfort Care (DNR-CC) order.
Haber, Suzanne N. “11 Neuroanatomy of Reward: A View from the Ventral Striatum.” Neurobiology of sensation and reward (2011): 235. Neurobiology of Sensation and Reward