Are Brain Death Findings Reversible?

Second, it was suggested that a need exists for ‘‘responsible scholarship in this field.’’ We agree. It is of concern that Shemie et al. provide no rationale to accept brain death as death, other than that it is accepted legally and medically. This does not convey the fact that brain death remains a conclusion in search of a justification [1]. We agree with the many authors who concluded that no rationale exists to accept brain death as equivalent to the state of death [1-12]. Some suggest that a promising strategy would involve finding ways to support organ donation without needing the ‘‘brain death is death’’ moral fiction [2]. Third, it was suggested that ‘‘many confounding conditions preclude brain-death testing,’’ and that therapeutic hypothermia after cardiac arrest can now be considered one of these until 24 hours after rewarming. This approach is problematic for several reasons. The list of vaguely specified confounding conditions grows as more exceptions are found and need to be explained away. This list includes metabolic (glucose, electrolytes, liver, and renal function), endocrine, and temperature abnormalities that are poorly specified, unvalidated, and often present in those with brain death; neuropathy and myopathy that are difficult to diagnose, poorly specified, and often complicate a critical illness that is present in brain death; and sedative/drug effects that again are poorly specified, and often used in patients diagnosed with brain death (without measuring levels or knowing what levels would confound testing). Cervical spinal cord injury is a confounding factor, and we recently described it as a common unrecognized reversible consequence of any brain-herniation event [13]. Regarding postcardiacarrest hypothermia, more clear specification of this possible confounding condition would be needed. For example, is 24 hours long enough after rewarming? Would other ischemia-reperfusion events present in most cases of brain death (such as sustained or recurrent hypotension) also be confounders for the same reason (progressive cerebral edema over days)? Does hypothermia protect the medullary respiratory center (the only brain structure to regain some clinical function in our case)? Is the American Academy of Neurology practice parameter [14] stating that an examination for brain death may occur when the temperature is at least 32 C (the lowest cooled temperature in our case) in need of revision? We suggest that to extend the interval before testing ‘‘according to physician judgment’’ in the face of vaguely specified confounders is not an adequate solution when one is to pronounce death. Moreover, the ancillary test of radionuclide brain blood flow has not been adequately validated to prove absent blood flow to some viable brain or brainstem in the setting of severe brain injury, because its specificity in this situation is unknown [15]. Fourth, it was suggested that the typical sequence of brain death is ‘‘progressive cerebral edema, and intracranial hypertension and herniation.’’ This may be true, but it renders some facts present in many patients with brain death difficult to explain. For example, electroencephalogram activity occurs in 20% of these patients, brain blood flow in 5-40%, hypothalamic function in over 50%, and lack of pathologic destruction of brain and/or brainstem in over 40% [16]. It was claimed that these functions of the brain are not relevant. Again, this may be true, but misses the point that if herniation occurs, the brain blood flow should stop, brain functions should then cease, brain tissue should die, and brain edema should not resolve for a long time (there is no blood flow to reabsorb it). It is likely that a significant number of patients with brain death have not undergone this ‘‘typical sequence.’’ Another relevant consideration, given this mechanism, is that apnea testing intentionally causes a rise in carbon dioxide in the blood, leading to a further increase in intracranial hypertension, potentially completing the herniation event, and resulting in a failed apnea test and irreversible brain death [17]. Fifth, Shemie et al. seem to imply that if one had considered hypothermia a confounding factor, one would not make the ‘‘diagnostic error’’ of thinking that findings of brain death can be

reversible. This view is problematic, given the other cases reviewed in our report. We think that two options are available, given these other cases: to search for confounding factors in each, and add them to the growing list; or to accept that the cases indicate that brain death can, however rarely, have reversible findings in neonates, infants, adults with multiple sclerosis, and likely other adults. The only data to suggest that the findings in brain death may be irreversible were reviewed in our report, and are extremely limited. We stand by our conclusion that brain death is, however rarely, not an irreversible state, and therefore not equivalent to the death of a patient. Ari R. Joffe, MD Hanna Kolski, MD Jon Duff, MD Allan deCaen, MD Department of Pediatrics University of Alberta and Stollery Children’s Hospital Edmonton, Alberta, Canada References [1] Shewmon DA. Brain death: Can it be resuscitated? Hastings Cent Rep 2009;39:18-24. [2] Miller FG, Truog RD. Rethinking the ethics of vital organ donations. Hastings Cent Rep 2008;38:38-46. [3] Potts M, Evans EW. Does it matter that organ donors are not dead? Ethical and policy implications. J Med Ethics 2005;31:406-9. [4] McMahan J. An alternative to brain death. J Law Med Ethics 2006;34:44-8. [5] Seifert J. Is ‘‘brain death’’ actually death? Monist 1993;76:175-202. [6] DeGrazia D. Identity, killing, and the boundaries of our existence. Phil Public Affairs 2003;31:413-42. [7] Kerridge IH, Saul P, Lowe M, McPhee J, Williams D. Death, dying and donation: Organ transplantation and the diagnosis of death. J Med Ethics 2002;28:89-94. [8] Zamperetti N, Bellomo R, Defanti CA, Latronico N. Irreversible apnoeic coma 35 years later: Towards a more rigorous definition of brain death? Intensive Care Med 2004;30:1715-22. [9] Veatch RM. The impending collapse of the whole-brain definition of death. Hastings Cent Rep 1993;23:18-24. [10] Karakatsanis KG. Brain death: Should it be reconsidered? Spinal Cord 2008;46:396-401. [11] Byrne PA, O’Reilly S, Quay PM, Salsich PW. Brain death: The patient, the physician, and society. Gonzaga Law Rev 1982;18:429-516. [12] Halevy A, Brody B. Brain death: Reconciling definitions, criteria, and tests. Ann Intern Med 1993;119:519-25. [13] Joffe AR, Anton N, Blackwood J. Brain death and the cervical spinal cord: A confounding factor for the clinical examination. Spinal Cord 2010;48:2-9. [14] Quality Standards Subcommittee of the American Academy of Neurology. Report of the Quality Standards Subcommittee of the American Academy of Neurology. Practice parameters for determining brain death in adults (summary statement). Neurology 1995;45:1012-4. [15] Joffe AR, Lequier L, Cave D. Specificity of radionuclide brain blood flow testing in brain death: Case report and review. J Intensive Care Med 2010;25:53-64. [16] Joffe AR. Are recent defenses of the brain death concept adequate? Bioethics 2010;24:47-53. [17] Coimbra CG. Implications of ischemic penumbra for the diagnosis of brain death. Braz J Med Biol Res 1999;32:1479-87.

Are Brain Death Findings Reversible? To the Editor: The diagnosis of brain death in children entails special medical complexity. The child’s brain is a developing organ, and the

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demonstration that a cessation of brain functions is irreversible is a very difficult task [1]. Joffe et al. recently reported on an infant who apparently recovered from a state of brain death [2]. Nonetheless, some drawbacks were evident in the case report. The boy, aged 10 months and 3 weeks, had undergone a near-drowning accident. The patient was first evaluated 42 hours after the event to confirm brain death. Some complaints may be in order about the report [2]. The infant manifested a probable seizure at 24 hours after the event, contradicting the diagnosis of brain death at that moment. He had undergone a systemic cooling for 24 hours, followed by a rewarming procedure that ended 32 hours after the event (10 hours before the first clinical examination for a diagnosis of brain death). His treatment included therapeutic dosing of phenobarbital for the suspected seizure. He was also treated with a 24-hour infusion of midazolam, which ended only 6 hours earlier than the first clinical examination. Most criteria recommend periods of observation for up to 24 hours when potential reversible causes of coma are present, such as hypoxic-ischemic encephalopathy, hypothermia, and central nervous system-depressor drugs [1]. The patient manifested hiccups only 15 hours after the first clinical examination. At that time, an electroencephalogram revealed preserved electrical activity, and a planar cerebral blood-flow study demonstrated preserved intracranial circulation, further contradicting a diagnosis of brain death at that time. The Canadian Neurological Determination of Death Forum stated specific recommendations for infants aged 30 days to 1 year old, i.e., ‘‘There is no recommended minimum time interval between determinations. Should uncertainty or confounding issues arise that cannot be resolved, the time interval may be extended according to physician judgment, or an ancillary test demonstrating absence of intracerebral blood flow may be used’’ [3]. I conclude that at the moment of the first clinical examination, the patient’s comatose state mimicked brain death. Fifteen hours after the first examination, when blood clearance of drugs had surely occurred and body temperature was finally corrected, brain functions progressively recovered. Moreover, it is crucial to consider the innate potential for neurologic restoration during infancy, and mainly when brain injury involves hypoxic-ischemic encephalopathy. In Cuba, when confounding factors are present, we recommend that the period of observation should be extended according to the physician’s judgment, or ancillary tests should be applied, both to assess cerebral circulatory arrest and to demonstrate a loss of bioelectric activity [1]. Calixto Machado, MD, PhD Department of Clinical Neurophysiology Institute of Neurology and Neurosurgery Havana, Cuba E-mail: [email protected] References [1] Machado C. Brain death. A reappraisal. New York: Springer; 2007:1-223. [2] Joffe AR, Kolski H, Duff J, et al. A 10-month-old infant with reversible findings of brain death. Pediatr Neurol 2009;41:378-82. [3] Shemie SD, Doig C, Dickens B, et al. Severe brain injury to neurological determination of death: Canadian Forum recommendations. Can Med Assoc J 2006;174(Suppl.):S1-12.

Response: We thank Dr. Machado for his thoughtful letter. We agree to some extent with the six major points that Dr. Machado raises. However, we disagree in regard to their implications.

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First, Dr. Machado questioned whether testing for brain death was indicated, based on the facts that the infant manifested a probable seizure 24 hours after the drowning, had undergone systemic cooling to 32-33  C for 24 hours followed by normothermia for 10 hours before testing for brain death, and had sustained a hypoxicischemic injury 42 hours before testing for brain death. Although we agree that guidelines suggest observation periods of up to 24 hours after potentially reversible causes of coma such as hypoxic-ischemic injury, these guidelines do not demand this interval, and the interval in our case was longer (42 hours). Further, these guidelines claim that after temperature has reached at least 34  C, testing for brain death is reliable [1,2]. We do not think that any of these factors can be raised as objections to testing for brain death in our patient. Second, Dr. Machado offered the suggestion that electroencephalogram (slow, very low-voltage activity) and cerebral blood flow testing ruled out brain death in our case. It is important to realize that in confirmed cases of brain death, in which the patients are pronounced deceased, electroencephalogram activity persists in at least 20% of patients [3]. In addition, in confirmed cases of brain death in which the patients are pronounced deceased, cerebral blood flow is evident in at least 5-40% of cases [3]. Therefore, current guidelines have retermed ‘‘confirmatory tests’’ as ‘‘ancillary tests’’ [1]. An ancillary test is not required if all clinical criteria can be completed. In these cases, the presence of ongoing electroencephalogram activity or cerebral blood flow is unimportant, and is said to represent surviving ‘‘nests of cells,’’ and not ongoing integrative activity of the brain [3]. We suggest that one cannot ‘‘have it both ways,’’ i.e., insist that brain death is a clinical diagnosis, but then insist that electroencephalogram and cerebral blood-flow findings invalidate the clinical diagnosis. In our patient, electroencephalogram and cerebral blood-flow findings were not required; the patient was brain-dead upon first examination. Third, the issue of drug clearance is important. The patient’s phenobarbital level was low-therapeutic in our case. The 24hour midazolam infusion of 2 mg/kg/minute had been discontinued 6 hours earlier. The clearance of midazolam can be variable in critically ill patients, even with normal renal and liver function, as in our patient [4]. Some authors have suggested measuring the midazolam level before testing for brain death [5]. However, what exact measured level of midazolam that would interfere with testing for brain death is unknown, and the availability of levels in a timely manner is rare. We speculate that most patients with brain death have been on sedative or analgesic drugs before testing for brain death. To require that blood levels meet some yet-undefined cutoff before testing for brain death would render a diagnosis infeasible in almost all cases. This issue is important for future studies, and would ideally preclude a diagnosis of brain death until adequate studies are performed. Fourth, Dr. Machado stressed that when confounding factors or clinical uncertainty enters into a diagnosis of brain death, the time interval should be extended according to the physician’s judgment. This point is important, and in our interpretation of it, a physician’s judgment is too vague and subjective. In a diagnosis with irreversible implications, leaving the application of vague guidelines to a physician’s judgment is problematic. This practice has led to problems (as documented in the literature) of variable guidelines regarding brain death, variable clinical practices regarding brain death, poor adherence to guidelines regarding brain death, and poor documentation of the diagnosis of brain death [6]. In our patient, several specialists did not think there were confounding factors. Fifth, Dr. Machado suggested that our cases ‘‘mimicked brain death,’’ because ‘‘brain functions progressively recovered.’’ Brain functions did not progressively recover; rather, only some breathing resumed, which was not effective enough to sustain life after extubation. This breathing was not, as claimed by defenders of