The journal Nature recently published a report by Yale investigators showing the restoration of porcine brain cellular activity 4 hours after death.1 By restoring circulation to intact pig brains following decapitation using a normothermic, hemoglobin-based, acellular, cytoprotective perfusate, the investigators demonstrated brain cellular metabolic activity, synaptic activity, and preservation of cell architecture. They concluded that the intact large mammalian brain “possesses an underappreciated capacity for restoration of microcirculation and molecular and cellular activity after a prolonged postmortem interval.”1
A recent widely reported study demonstrated cellular metabolism in pig brains 4 hours after death. This commentary reviews that study in the context of the validity of determining death by neurologic criteria and after permanent absence of circulation.
These findings were widely reported by the media and frequently interpreted as a challenge to the well-established concept of death determination by irreversible cessation of brain functions (“brain death”) and thereby as a challenge to prevailing standards of death determination in organ donors.2 However, a critical analysis of this study shows these fears to be overstated.
The restoration of brain cellular and synaptic activity and of microcirculation is a stunning achievement and one that most neuroscientists and clinicians had assumed was impossible. However, despite the presence of restored cellular activity, the pig brains exhibited no functions at all. There was no recordable EEG or electrocorticogram, and no evidence of distributed neuronal networks that are necessary for brain functions. Specifically, there was no recovery whatsoever of the integrated brain functions necessary for consciousness. The authors clearly recognized this distinction and concluded that the restored metabolic activity in brain cells did not constitute the capacity for consciousness provided by a functional brain.1
The distinction between brain cellular activity and more macro level brain functions is highly relevant to the impact of this study on brain death determination. In their influential 1981 book Defining Death, the U.S. President’s Commission clarified the relationship of brain functions to brain cellular activities. They stated that the concept of brain death required the cessation of all brain functions, but did not require the cessation of all brain cellular activities.3 Numerous reports over the past several decades have described isolated brain cellular activities in brain dead patients despite no resulting brain functions.4 Thus, in the present study, the restoration of brain cellular activity without resulting brain functions should have no direct impact on prevailing practices of brain death determination (Table 1).
Nevertheless, the Yale study may have a potential impact on the emerging field of neuro-resuscitation. If the perfusate or other technologies developed by the investigators are found to be safe and effective in human trials, they may have a role in limiting brain damage from stroke, traumatic brain injury, and hypoxic-ischemic neuronal insults. This technology may add lifesaving and brain-saving emergency interventions to current interventional therapies that limit brain damage from stroke.
DONATION AFTER CIRCULATORY DEATH DETERMINATION
Our remarks about the practice of donation after circulatory death (DCD) are displayed in the accompanying algorithm (Figure 1) depicting the fate of comatose patients with a devastating brain injury. We acknowledge with appreciation the guidance of Beatriz Dominguez-Gil, Alexandra Glazier, and Nancy Ascher in the development of Figure 1.
The approach of organ donation through DCD is appropriately considered for comatose and ventilator-dependent patients who are not brain dead. The prognosis establishing the futility of further treatment is dependent upon the mechanism and extent of brain injury. Critical-care physicians apply outcome metrics (scores and scales) to determine prognosis for neurological recovery and may conclude that consciousness will not be restored, despite the presence of viable brain cells. The poor neurological prognosis may lead a lawful surrogate, following accepted standards of surrogate decision-making, to withdraw futile ventilator therapy resulting in the patient’s death, as illustrated in Figure 1.5
Such a prognosis is now commonly reached in proper end-of-life care independent of the consideration of organ donation. Once heartbeat ceases and the absence of all circulation to the brain is witnessed for 5 minutes, it is determined to be permanent because circulation to the brain will not be restored. The patient is then declared dead. Although some brain cells may remain potentially viable at the time of death declaration, the capacity of the brain to regain consciousness or any other integrated function is now permanently lost. Without circulation to the brain, brain function is lost within 60 seconds as evidenced by the absence of electroencephalographic activity. The permanent absence of brain circulation renders the cessation of brain functions permanent enabling the declaration of death.
Although DCD practices vary among countries on the length of the “no touch period” before death is declared, the absence of circulation for 5 minutes following mechanical asystole has become an international standard.6 The extension of the “no touch period” to 10 minutes (Ireland and Portugal) or 20 minutes (Italy) brings no further assurance that every cell of the brain has become nonviable, especially now that the Yale group has found revivable cells 4 hours after death. During the 5-minute period, there must be neither intervention that restores brain circulation nor spontaneous resumption (auto-resuscitation). Without circulation to the brain, the capacity for any brain function is lost permanently. The patient is declared dead because of the permanent absence of brain functions.7,8
Methodologies are currently being studied to determine whether in situ or ex situ perfusion of organs improves the function and outcome of transplanted organs (Figure 1). Scientific investigation of perfused organs now brings hope for an expansion of deceased donation to address the worldwide deficiency of organs needed for patients with end-stage organ failure. DCD remains an ethically appropriate approach for deceased donation that enables a declaration of death, irrespective of potentially viable brain cells, when a patient’s advance directive or surrogate decision-maker has determined that the patient would not want to survive in an unconscious state.
With appreciation to Emily Scaramella of New England Donor Services for her kind assistance in drafting the Figure to a PowerPoint and jpg file.
1. Vrselja Z, Daniele SG, Silbereis J, et al. Restoration of brain circulation and cellular functions hours post-mortem. Nature. 2019;568:336–343.
3. President’s Commission for the Study of Ethical Problems in Medicine and Biomedical and Behavioral Research. Defining Death. Medical, Ethical, and Legal Issues in the Determination of Death. 1981:Washington, DC: US Government Printing Office; 33–34.
4. Bernat JL. Ethical Issues in Neurology. 2008:3rd ed. Philadelphia, PA: Lippincott Williams & Wilkins; .
5. Smith M, Dominguez-Gil B, Greer DM, et al. Organ donation after circulatory death: current status and future potential. Intensive Care Med. 2019;45:310–321.
6. Del Mar Lomero M, Johnson R, Coll E, et al. Donation after circulatory death: an updated description of the European landscape. Transplantation 2018;102:S386.
7. Dalle Ave AL, Bernat JL. Using the brain criterion in organ donation after the circulatory determination of death. J Crit Care. 2016;33:114–118.
8. Dalle Ave AL, Bernat JL. Donation after brain circulation determination of death. BMC Med Ethics. 2017;18:15.