Death is commonly declared with the observation of a flat line or isoelectric EEG that is irreversible. Yet there are many caveats, challenges and ambiguities to defining brain death this way.
What defines death?
Traditionally a person was declared dead when there was an irreversible cessation of breathing and heartbeat. This cardiopulmonary standard of death was soon challenged by the advance of medical technology. For instance, what happens when you are kept alive by cardiopulmonary bypass (a heart-lung machine) during surgery? How then could you test for a heartbeat or breathing? What if you were in the process of getting a heart or lung transplant and for some time didn’t have one or the other organ? This made it necessary to rethink the definition of death.
In 1980, after two decades of debate, The National Conference of Commissioners on Uniform State Laws formulated the Uniform Determination of Death Act which reads as follows:
An individual who has sustained either (1) irreversible cessation of circulatory and respiratory functions, or (2) irreversible cessation of all functions of the entire brain, including the brain stem, is dead. A determination of death must be made in accordance with accepted medical standards’
On the face of it, it may seem straightforward but there are many issues of contention. Should it be the whole brain or higher brain? What is irreversible? How do you measure cessation of brain function?
Whole brain or higher brain?
What if there is irreversible cerebral damage and only the brain stem continues to show activity? Are you alive? A philosophical argument put forward by Robert Veatch in 1975 proposes that death is ‘the irreversible loss of that which is essentially significant to the nature of man’. The extension of this argument is that it is the higher functions of the brain such as memory and consciousness that are significant to the nature of man. Therefore, the irreversible loss of these functions should be treated as death. Others argue that since these functions are mediated by the cerebral cortex, that irreversible cessation of cortical activity should be a sufficient measure of death. While it is not the accepted formal definition of death, as we will see, the nature of measurement may ultimately deem it so.
Measuring cessation of brain activity
This is one of the rubs in the determination of death. What measurement assures us that there is no further activity in the brain? One of the most commonly used measurements of cessation of brain activity is the EEG. What should you look for? In 2015, the Société de Neurophysiologie Clinique de Langue Française presented a set of guidelines (at least for France). These guidelines state that:
Electrocerebral inactivity may be confirmed when a 30-minute good quality EEG recording shows complete electrocerebral silence, defined as no cerebral activity greater than 2 uV.
However, they also present multiple associated caveats. First, various drugs such as sedatives or anesthetics can also induce this condition. Similarly, there are other conditions such as metabolic disorders or hypothermia that can also result in flat line EEGs. They therefore indicate that all of these must first be ruled out first and if any of these conditions cannot be ruled out, a different criterion must be used to establish cerebral death such as CT brain angiography. These alternative methods measures blood flow, which although related represent an entirely different criteria of ‘brain activity’.
A second caveat is that even in the absence of cerebral death, newborns can sometimes exhibit periods of inactivity in the EEG, the utmost caution is indicated since electrocerebral inactivity can be observed in the absence of cerebral death.
Beyond the isoelectric line of EEG
Now even with all of these caveats there is another significant challenge to this definition. A flat line or isoelectric EEG may not really mean the cessation of activity.
A study in 2013 by Kroeger et al in PLOS One showed that electrical activity could be induced at levels of anesthesia that were higher than those required to produce an isoelectric EEG. Motivated by an observation of this phenomenon in one comatose patient, they undertook a study in cats where they carried out double simultaneous intracellular recordings in the cortex and hippocampus, combined with EEG. With the application of increasing doses of the anesthetic isoflurane they found that the EEG passed through different stages, reaching an isoelectric flat line to producing quasi-rhythmic sharp waves at higher doses. The authors called these waves Nu-complexes. The intracellular recordings demonstrated that Nu-complexes originated in the hippocampus and were subsequently transmitted to the cortex.
Figure 1 (from Kroeger et al PLOS One): A-C show EEG at increasing doses of isofluorane anesthesia. Nu Complexes shown in E arise at anesthetic doses greater than those used to achieve an isoelectric EEG.
The challenges of EEG as the primary tool of measurement are therefore several fold. First it does not tell you about whole brain activity and the interpretation of a flat line EEG as cessation of activity could be called into question with greater understanding of how underlying activity contributes to the structure of the EEG signal.
What is irreversible?
Finally, a crucial aspect of the definition of death of the brain is not just the cessation of activity but its irreversibility. Medical technology continues to challenge what is irreversible. Take the example of deep hypothermic circulatory arrest. In this paradigm, used during cardiac surgery where the heart must be stopped, the brain is cooled to a range typically between 16 and 28 degrees Celsius to the point when an isoelectric EEG is reached. This prevents ischemic damage and can be successfully reversed with rewarming within a period of 30 minutes. Interestingly, isoelectric EEG is reached at very different temperatures for different people. Some even continue to show activity at 14 degrees (profound hypothermia). This is the impetus for ideas like cryogenic freezing. What if freezing could make all brain death reversible in the future?
Human Brain Activity Patterns beyond the Isoelectric Line of Extreme Deep Coma Kroeger, D, Florea, B and Amzica F. PLOS One September 18, 2013
Consensus on hypothermia in aortic arch surgery Yan, TD et al Ann Cardiothorac Surg. 2013 Mar; 2(2): 163–168.