Implications of ischemic penumbra for the diagnosis of brain death:
Apnea testing may induce rather than diagnose death 

Concluding remarks

Reversible synaptic inactivation is clearly a characteristic response of the general brain tissue to circulatory levels within 35 and 10-15 ml.100g^-1.min^-1, rather than an exclusive attribute of the outer zone of focal ischemia. Sustained global reduction of BBF to the penumbra range should therefore bring about the same clinical manifestations nowadays restrictively ascribed to brain death. Obviously, patients with progressive ICH cannot reach BBF levels lower than those of ischemic penumbra without reaching such intermediary range. To date no study has addressed the question of how long these patients may remain in GIP. Hence, irreversibility of brain damage cannot be affirmed based on current standards. Patients sustaining absence of encephalic synaptic activity secondary to ICH or basilar artery occlusion should be rather treated with moderate hypothermia or thrombolysis, respectively, than allocated for organ donation. As an exceedingly important ethical issue, harvesting transplantable organs should require both exhausting available therapeutic resources to donors and indisputable irreversibility of brain damage, and neither of these requirements are fulfilled by current criteria for diagnosis of brain death.

Due to characterization of hypothermia as the most powerful neuroprotectant so far identified ^54-56, the circumstances that led hypothermia to be elected as a criterion of exclusion from the diagnosis of brain death by Beecher and co-workers in 1968¹ deserve attentive analysis. Hypothermia may result from cold exposure prior to rescue of unconscious victims of severe TBI, and synapse-dependent encephalic functions may become clinically undetectable in these patients either due to hypothermia-induced metabolic depression and/or GIP. Recovery may occur respectively as a consequence of resumption of normal temperature, or because hypothermia effectively treats severe brain damage equivocally presumed to be irreversible. Although these alternatives are not mutually exclusive, the robust neuroprotective effects of hypothermia evidently favor the latter.

However, dominant attention to the claims of transplantation may have led the Harvard Ad Hoc Committee to neglect any alternative to the former. As Mita Giacomini clearly demonstrated in a recent historical review ⁵⁷, the Committee was not charged to the question whether brain death ought to be defined, or who should define it, but how best to define it" ⁵⁷. Accordingly, criteria of exclusion (nervous system depressants and hypothermia) were added to the diagnosis of brain death to rule out cases such as 5 recoveries among 600 comatose patients with flat EEG reported in a preliminary study by the American EEG Society, supplied to Henry K. Beecher by Robert Schwab - members of the Committee⁵⁷.

Such approach for establishing diagnostic criteria clearly manifests misconceptions about dying and dead (prognosis and diagnosis of death) ^{12, 14, 34, 57}. Avoiding such conceptual error is fundamental, not simply a semantic issue. As already emphasized, patients previously regarded as hopeless (or "dying") - such as those with absent synapse-dependent brain functions, may be recovered by employing more effective therapeutic resources (such as moderate hypothermia) developed as a consequence of higher knowledge of the pathophysiology of their conditions (achieved, for instance, by recognizing the GIP situation). In contrast, as dead patients are obviously not considered for novel therapeutic approaches, the equivocal redefinition of death put forward in 1968¹ may have caused a 30-year delay in the therapeutic progress of GIP by disregarding the potential benefit of hypothermia.

To strengthen the safety of clinical criteria for diagnosing brain death, the identification of a known cause of irreversible damage has been required: "there must be definite clinical or neuroimaging evidence of an acute CNS catastrophe that is compatible with brain death" ³. However, the neuroscientific progress demonstrates that certain clinical situations formerly considered as "known causes of death" may have been incorrectly regarded as irreversible. For instance, in 1981 the long held false postulate that brain damage would become irreversible after 3-5 min. of intracranial circulatory arrest led the President's commission to enunciate: "Complete cessation of circulation to the normothermic adult brain for more than ten minutes is incompatible with survival of brain tissue. Documentation of this circulatory failure is therefore evidence of death of the entire brain" ². Contrastingly, careful studies aimed at detailing features of ischemic penumbra have demonstrated that the brain tissue evolves to irreversible injury within one hour or less after terminal depolarization ⁹. Furthermore, moderate hypothermia induced hours after 10 minutes of global ischemia remarkably reduced neuronal death in all forebrain structures analyzed ^{40, 42}. Clearly, the point of no return for neuronal damage has been repeatedly displaced during the last decades by both experimental and clinical data.

As from the point of view of ethics organ removal is to be linked to absolute intolerance to false positives, death cannot be conventionally defined as unlikely recovery through clinical studies or anecdotal medical experience ¹⁴. Affirmations such as "…medical centers with substantial experience in diagnosing death neurologically report no cases of brain functions returning following a six-hour cessation, documented by clinical examination and confirmatory EEG"² or "brain death is a clinical diagnosis"³ can no longer be seriously considered. The phenomenon of ischemic penumbra has invalidated the theoretical support for current criteria used to establish the diagnosis of brain death. More than ever, the diagnosis of brain death still lacks scientific validation and technical feasibility, and is to be urgently reconsidered.