Amir Halevy

Brain Death: Reconciling Definitions, Criteria, and Tests

The development of machines that mechanically sustain the life functions of respiration and circulation forced the medical community and society in general to re-evaluate the accepted definition, criterion, and tests of death. In certain cases, the classic definition of death as the permanent cessation of the flow of vital bodily fluids was no longer consonant with the classic criterion of death as the irreversible cessation of spontaneous respiration and circulation [1]. In addition, newly developed organ transplantation programs required a definition, criterion, and test of death that would facilitate the procurement of organs before they deteriorate. Thus, the medical community began to develop alternative, brain-based accounts of death. The Harvard Report [2], published in 1968, was the first formal attempt to meet this need. Continued efforts to reach a consensus regarding brain death culminated in a report from the Presidents Commission for the Study of Ethical Problems in Medicine and Biomedical and Behavioral Research [3] and in two resulting documents, the clinical report of the medical consultants to the Presidents Commission [4] and the Uniform Determination of Death Act [5]. These efforts were largely successful, although doubts about the appropriateness of this brain-based account continued to be expressed in some countries [6, 7] and in some religious communities [8]. The Presidents Commission considered three possible criteria for death: a nonbrain criterion, a whole-brain criterion, and a higher-brain criterion (Table 1). The first criterion was most consonant with the definition of death as the permanent cessation of the flow of vital bodily fluids, the second with the definition of death as the permanent cessation of the integrated functioning of the organism as a whole, and the third with the definition of death as the permanent loss of what is essential to the nature of man (consciousness). Although the Commission chose to emphasize legislation derived from criteria rather than from definitions [3], it did refer in its justification to the brains primacy in integrating body functions as well as in sponsoring consciousness. To quote the Commission: This view gives the brain primacy not merely as the sponsor of consciousness (since even unconscious persons may be alive), but also as the complex organizer and regulator of bodily functions. Only the brain can direct the entire organism [3]. Table 1. Alternative Definitions of Death The whole-brain criterion was selected for practical reasons as well. From a practical standpoint, the higher-brain criterion suffered because no agreement could be reached about what portions of the brain are required for cognition and consciousness and because even when the sites of certain aspects of consciousness can be found, their cessation often cannot be assessed with the certainty that would be required in applying a statutory definition [3]. Moreover, adoption of a higher-brain criterion was too radical a departure from the traditional criterion and one would desire much greater consensus than now exists before taking the major step of radically revising the concept of death [3]. The Uniform Determination of Death Act provided the legal articulation of the whole-brain criterion of death as irreversible cessation of all functions of the brain, including the brainstem [5]. The choice of the word functions rather than activity reflected the view that bodily parts, and the subparts that make them up, are important for the functions they perform [3]. The Presidents Commission explicitly recognized that electrical and metabolic activity of groups of cells within an organ may continue after that organ has ceased functioning. However, the Commission stipulated that cellular activity is considered functioning when it is organized and directed [3]. We consider below still stronger requirements for when activity is considered functioning. Less clear are the medical tests necessary to establish that the legal criterion is met. The Uniform Determination of Death Act stated that a determination of death must be made in accordance with accepted medical standards [4], but what are these standard tests? To meet the challenge of developing standard tests that clinicians could use to establish that the criterion of death had been met, the Presidents Commission created a panel of medical consultants. The standard tests proposed by the medical consultants to the Presidents Commission are clinically based. The brain functions considered are cerebral and brain stem functions. Cessation of cerebral function is attested by deep coma without clinical response to any physical stimuli. Brain stem function is assessed by testing for cranial nerve function, including pupillary, corneal, oculocephalic, oculovestibular, and oropharyngeal reflexes, and by carrying out an apnea test to determine respiratory function. Irreversibility is determined by identifying the cause of the coma to exclude drug intoxication and hypothermia and by observing the patient for a specified period of time. Such tests as an electroencephalogram, a brain stem evoked potentials study, or a cerebral blood flow study are considered desirable when objective documentation is needed to substantiate these clinical findings but are not generally necessary for the determination of brain death. We show that the standard clinical tests proposed by the advisors to the Presidents Commission do not ensure that all brain functions have actually ceased and do not therefore ensure that the whole-brain criterion of death has been met. We also show that many possible solutions to this discrepancy are unsatisfactory. We conclude by suggesting that an alternative approach is needed to deal with troubling cases. The Problem A review of published reports about brain death shows that many patients who meet the standard clinical tests for brain death still maintain some brain functioning and therefore do not satisfy the whole-brain criterion of death. Three areas of persistent functioning are neurohormonal regulation, cortical functioning as shown by significant nonisoelectric electroencephalograms, and brain stem functioning as shown by evoked responses. Neurohormonal Functioning The first evidence for continued brain functioning despite a patients meeting the standard clinical tests for brain death is found in analyses of neurohormonal regulation. Anterior pituitary hormone levels have been studied by several investigators; much of the research has been motivated by a desire to optimally manage brain-dead donors. In one of the earliest studies, by Schrader and colleagues [9], normal hormonal levels were found, although other studies [10] have reported different results. Provocative testing provides the best evidence of intact neurohormonal regulation. Schrader and coworkers [9] evaluated several patients with signs of brain death including the criteria set forth by the Ad Hoc Committee of Harvard. In two cases, an insulin-induced hypoglycemia test was done, and one of the patients showed a decrease in the glucose level that was associated with an immediate growth hormone response. Posterior pituitary function, specifically antidiuretic hormone secretion, provides the best documented evidence of preserved brain function. If the hypothalamus and neurohypophysis, structures on the brain side of the blood-brain barrier, were nonfunctional, then the patient should develop clinically apparent central diabetes insipidus because of the lack of antidiuretic hormone regulation. However, not all patients meeting the standard clinical criteria of brain death develop the syndrome. Mollaret and Goulon [11] in their original paper on coma depasse observed polyuria that behaved like diabetes insipidus in some of the cases. Grenvik and colleagues [12] reported that only 8.5% of their cases had the clinical manifestations of diabetes insipidus. Two series on the incidence of diabetes insipidus in children meeting the standard clinical tests of death showed clinical manifestations of diabetes insipidus in 87% [13] and in 38% [14] of patients. Further reducing the percentage of such patients with true central diabetes insipidus is evidence from two groups that assayed for antidiuretic hormone [15, 16]. Hohenegger and colleagues assayed antidiuretic hormone in 11 patients meeting the standard tests of brain death who had clinical manifestations of central diabetes insipidus and found normal-to-increased levels in all 11 cases, effectively excluding the diagnosis of central diabetes insipidus. This residual neurohormonal regulation is the most troubling of the three forms of functioning for three reasons. First, it is apparently found in most patients presumed to be brain dead using the standard tests. Moreover, this residual neurohormonal regulation clearly represents functioning and not merely activity. As noted above, the definition of functioning offered by the Presidents Commission was organized and directed cellular activity, and this regulation certainly meets that definition. Bernat [17] proposed that only clinically observable (as opposed to measurable in the laboratory) activity that contributes to the functioning of the whole organism counts as functioning. In another report [18], he has suggested that only neuronal activity that executes the functions of the organism as a whole counts as functioning. A failure of neurohormonal regulation of antidiuretic hormone secretion certainly presents itself clinically at the bedside, and the preservation of that regulation is certainly essential to the functioning of the whole organism; therefore, neurohormonal regulation is functioning, even according to the most demanding accounts of functioning, and not merely activity. Finally, it is a component of the integrative role of the brain in regulating the rest of the body, the very role that is emphasized in the whole-brain definition of death. C