A 10-Month-Old Infant With Reversible Findings of Brain Death

A 10-Month-Old Infant With Reversible Findings of Brain Death Ari R. Joffe, MD, Hanna Kolski, MD, Jonathan Duff, MD, and Allan R. deCaen, MD Death has occurred when there is irreversible loss of integration of the organism as a whole, and brain death is said to be a criterion for death. In the present case, a 10-month-old boy was found submerged in a bathtub and was given cardiopulmonary resuscitation for 37 minutes. He had received therapeutic dosing of phenobarbital and midazolam up to 5 hours prior to a brain death examination. He fulfilled all criteria for brain death according to Canadian Neurological Determination of Death Forum recommendations on an examination 42 hours after the drowning event, but started breathing another 15 hours later. Eleven previously published cases of purported reversal of findings of brain death are discussed here, including two infants who fulfilled all criteria for brain death for more than 24 hours. Recommendations for brain death determination may require revision for infants, to more clearly define a time interval between examinations and to incorporate consideration of confounding sedative drug effects. Together with previous reports, the present case calls into question the assumption that brain death as currently diagnosed is irreversible, and therefore equivalent to death of the patient. Ó 2009 by Elsevier Inc. All rights reserved. Joffe AR, Kolski H, Duff J, deCaen AR. A 10-month-old infant with reversible findings of brain death. Pediatr Neurol 2009;41:378-382.

From the Department of Pediatrics, University of Alberta and Stollery Children’s Hospital, Edmonton, Alberta, Canada.

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Introduction Death is defined conceptually as the irreversible loss of integration of the organism as a whole [1-3]. When death has occurred, the organism is irreversibly in this disintegrated state. In the state of brain death, it is argued that the supreme regulator of the body, the brain, has irreversibly stopped functioning, with the body left as a nonintegrated corpse [1-3]. Reported here is the case of a 10-month-old boy who was found submerged in a bathtub and who fulfilled criteria for brain death after 42 hours, but started breathing 15 hours later. The case indicates that brain death as currently diagnosed may not always be irreversible. Case Report A boy, 10 months 3 weeks old, was found face down under water in a bathtub after being left with a 2-year-old sibling without adult supervision for only a few minutes. He was given cardiopulmonary resuscitation for 37 minutes. The heart rhythm between 7 and 34 minutes was asystolic. After intubation and two doses of intraosseous epinephrine, the heart rhythm was sinus and a palpable pulse was present. The first arterial blood gas (46 minutes after the drowning event) was pH 6.59, bicarbonate 5.2 mmol/L, and base excess # 30 mmol/L. He was admitted to the pediatric intensive care unit. His treatment included therapeutic dosing of phenobarbital for a suspected seizure (an episode of twitching of the right fifth finger at 24 hours after the event, lasting for 29 minutes and without change in vital signs), systemic cooling to 32 C to 33 C rectal for 24 hours followed by rewarming over 8 hours to 36 C to 37 C, and maintenance of normal blood pressure (without vasopressors) and partial pressure of CO2 at 35 to 40 mmHg. There was no diabetes insipidus. A computed tomogram of the head 38 hours after the event indicated moderate cerebral edema. Forty-two hours after the event, the patient had his first examination for brain death. He had good train of four responses with hand muscle twitching to electrical stimulation over the forearm, confirming no residual pharmacologic paralysis from the rocuronium given to facilitate ventilation during the first 24 hours in intensive care. His body temperature was 36.2 C; blood pressure, 98/36 (mean 60) mmHg; heart rate, 166 beats per minute; and oxygen saturation, 99%. Levels of electrolytes and glucose and liver enzymes were normal; there was absence of seizures on the electroencephalogram. His phenobarbital level drawn 5 hours earlier (and last dosed 2.5 hours before this level) was 104 mmol/L (therapeutic range, 65-170 mmol/L), and a 24-hour midazolam infusion of 2 mg/kg per minute had ended 6 hours earlier. Two pediatric intensivists together documented absent corneal, gag, cough to deep suctioning, oculocephalic, and oculovestibular reflexes, with fixed dilated 4 mm pupils and a Glasgow Coma Score of 3 without response to pain applied above the clavicles. An apnea test done on the ventilator with continuous positive airway pressure of +6 cm H2O and fraction of inspired oxygen concentration of 100% for

Communications should be addressed to: Dr. Joffe; Department of Pediatrics; 3A3.07 Stollery Children’s Hospital; 8440 112 Street; Edmonton, AB, T6G 2B7, Canada. E-mail: [email protected] Received January 26, 2009; accepted May 28, 2009.

Ó 2009 by Elsevier Inc. All rights reserved. doi:10.1016/j.pediatrneurol.2009.05.007  0887-8994/08/$—see front matter

more than 4 minutes indicated no respiratory efforts; the arterial blood gas evaluation indicated pH 7.28, PaCO2 38 mmHg, and PaO2 121 mmHg at baseline; PaCO2 73 mmHg and pH 7.08 at 3.25 minutes; and pH 7.04, PaCO2 74 mmHg, and PaO2 60 mmHg at 4 minutes. According to Canadian consensus guidelines, this first examination was compatible with brain death [4]. Fifteen hours after this examination for brain death (and 57 hours after the event), hiccups were noted, which would lead to some tidal ventilation. An electroencephalogram showed substantial generalized slowing but not electrocerebral silence (Fig 1). A planear cerebral blood flow study done with technetium Tc-99 m hexamethylpropyleneamine oxime indicated cerebral blood flow; test was repeated the next day and again indicated cerebral blood flow. A complete examination for brain death 86 hours after the event was identical to the first examination, except that on the apnea test breathing was noted. His breathing pattern documented 90 hours after the drowning event documented a rate of about 20 breaths/minute, with tidal volumes 20-80 mL (2-8 mL/kg). This breathing pattern was observed while the patient was ventilated, with pH 7.35, PaCO2 34 mmHg, and PaO2 65 mmHg. After 6 minutes of spontaneous breathing, his arterial blood gas showed pH 7.08, PaCO2 81 mmHg, and PaO2 366 mmHg. After discussion with the family, life support was withdrawn, and 8 minutes later cardiocirculatory death occurred. The parents requested no autopsy. The mother signed informed consent to allow publication of this case report.

Discussion This case is important because it reveals that the findings of brain death were reversible, and therefore were not compatible with the state of death. According to Canadian Neurological Determination of Death Forum recommendations, this 10-month-old fulfilled all criteria for brain death on a first brain death examination, 42 hours after drowning (Table 1) [4]. According to these recommendations, for children 1 year of age and older there is no need for an interval of time between examinations by two physicians for brain death; that is, the two examination may be performed concurrently. Nonetheless, in infants from 30 days to 1 year of age the forum recommended ‘‘a repeat examination at a different time . . . there is no recommended minimum time interval between the determinations’’ [4]. No second brain death examination had been performed before hiccup-like breaths were noted 15 hours after the first examination. This breathing precluded the confirmed diagnosis of brain death. We think it likely that if a second brain death examination had been done within hours after the first, it would have confirmed brain death. Other authors have reported cases of brain death being reversible (Table 2) [5-15]. In some cases, the details are unclear regarding whether an acceptable apnea test was performed. In two infants aged 3 months, apnea testing was adequately described, and brain death confirmed for >24 hours, with later return of some brainstem function [12,14]. Together with the present report in an infant aged 10 months, these cases illustrate that brain death as currently diagnosed can be reversible. The outcome in these three cases with a confirmed apnea test and reversal of brain death was dismal, with profound brain injury, and ultimate death. The point to emphasize, however, is that the loss of critical brain functions (such as breathing) was not irreversible. Although the prognosis was dismal, the patient’s

Figure 1. The electroencephalogram recorded 84 hours after the drowning event is remarkable for very low amplitude activity (although greater than 2 mV), of cerebral origin. Average (AVG) reference montage: C = central, F = frontal, O = occipital, P = parietal, T = temporal head regions. Odd numbers indicate the left hemisphere, even numbers indicate the right hemisphere, and z indicates the midline.

diagnosis was not death. Debate exists as to whether the apnea test itself could result in irreversibility of brain failure by terminally raising the intracranial pressure due to high PaCO2, resulting in irreversible loss of cerebral perfusion [16]. For this reason, the cases with unclear apnea testing (Table 2) are important, in that they also suggest brain death may not be an irreversible state. In two adults reported with brain death but unclear apnea testing, there was a good outcome [6,11]. The evidence for the irreversibility of brain death is limited. First, it is claimed that the diagnosis has withstood the test of time. This is a flawed argument for several reasons. There are reported cases of brain death being reversible (Table 2) [5-15]. A diagnosis of brain death inevitably leads to withdrawal of life support, leading to a self-fulfilling prophecy of irreversibility. Even today there is variability in the diagnostic criteria for brain death reported between hospitals, leading to the concern that because ‘‘brain death is considered a legal definition of death, [then] inappropriately labeling a patient as dead by brain criteria could subject them to inappropriate treatment, including withdrawal of care. [17].’’ This same ethical concern suggests that the self-fulfilling prophecy of irreversibility has been occurring. Second, major studies on brain death outcomes have serious limitations. The Cerebral Survival Study, the largest and the only prospective study to describe brain death outcomes, led to clarification of the criteria currently used to

Joffe et al: Reversible Brain Death 379

Table 1. Criteria for brain death fulfilled by a 10-month-old boy, 42 hours after drowning Criterion or test [4] Established etiology capable of causing neurologic death Deep unresponsive coma Absent brain stem reflexes

Absent respiratory efforts on the apnea test

Absent confounding factors

At least 2 licensed physicians with skill and knowledge in the management of infants with severe brain injury and brain death Ancillary test of cerebral blood flow when it is impossible to complete the minimum clinical criteria Ancillary test of electroencephalogram to document electrocerebral silence

Computed tomography scan of the head showing brain herniation

Description Drowning with cardiopulmonary resuscitation for asystole for 37 minutes. Glasgow Coma Score 3 with no response to pain. Absent gag, cough, corneals, and vestibulo-ocular responses and fixed dilated pupils. Absent oculocephalic reflexes for age 30 days-1 year. Absent respiratory efforts over 4 minutes with PaCO2 rising from 38 to 74 (rising >20) mmHg and pH 7.04, and PaCO2 > 70 mmHg for over 1 minute. Absent shock, hypothermia (temperature 36.2 C rectal), metabolic disorder (including glucose, electrolytes, liver and renal dysfunction), peripheral nerve or muscle dysfunction or neuromuscular blockade, or clinically significant drug intoxications (recent therapeutic dosing of phenobarbital and midazolam do not preclude the diagnosis*). Testing delayed for >24 hours subsequent to a cardiorespiratory arrest. Two experienced pediatric intensivists. Not necessary. Not recommended: ongoing EEG activity (present in 20% of correctly diagnosed brain death patients) is said to reflect nonsignificant activity of nests of brain cells [26]. Not necessary: if there is a clear clinical event to account for the brain injury, such as a prolonged cardiopulmonary arrest as in our case, then neuroimaging is not necessary.†

* Therapeutic phenobarbital level of 104 mmol/L at 5 hours prior to testing. Therapeutic dosing of midazolam was stopped for 6 hours, in the setting of normal renal and liver function. Measuring midazolam levels prior to brain death testing is not feasible in most centers, and what level would confound examination for brain death is unknown. † In correctly diagnosed brain death, there is ongoing cerebral blood flow in 5-40% of cases, ongoing electroencephalogram activity in 20% of cases, and lack of brain and brainstem pathologic destruction in >15% and 60% of cases. respectively [27]. This spared brain blood flow, electroencephalographic function, and brain structure are compatible with lack of complete brain herniation. Abbreviations: EEG = Electroencephalography PaCO2 = Partial pressure of arterial carbon dioxide

diagnose brain death [18]. Limitations of this study, however, make it impossible to determine whether brain death is irreversible. The study was done from 1970 to 1972, with 501 patients (a further 115 ‘‘additional patients’’ were excluded [19]) admitted with deep unresponsive coma and apnea (defined as no effort to override the respirator for at least 15 minutes); mortality was 91.2% [19]. Of the 501 patients, 185 met criteria for brain death (apnea, coma, electrocerebral silence, and absence of drug intoxication). All of these patients died within 7 days, supposedly confirming the irreversibility of brain death [19]. However, of these 185 patients, 114 had withdrawal of life support at 24 hours for clinician diagnosed brain death [19], and 75% of the remainder died before day 2.9 on the ventilator [20]. In those who had an autopsy after brain death for more than 24 hours, so-called respirator brain (i.e., pathologic brain destruction) was found in only 27/35 cases (77%) [10]. When electrocerebral silence was diagnosed, the systolic blood pressure was <80 mmHg in 55-60% of the patients [10]. Respiratory efforts were seen in approximately 2% of the patients after withdrawal of life support on the basis

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of brain death [21]. Furthermore, how many of the 185 patients had absent brainstem reflexes is not stated; for example, >24% with brain death had nondilated pupils [10], and of the entire 501 patients, only 102 (all from the same center) had enough information on cephalic reflexes to provide data for analysis [10]. In a large series reported from the United Kingdom of 609 brain death patients from 1962 to 1974, none survived, supposedly showing that brain death is irreversible [22]. In that retrospective study, however, 56% of brain death patients had life support withdrawn, and the median time on a ventilator before withdrawal of life support or cardiac arrest was 30-40 hours (>72 hours in 14%) [22]. Due to these limitations, these studies cannot support the claim that brain death is irreversible. The present case suggests that the Canadian consensus guidelines may be too vague on determination of brain death in infants. The American Task Force for the Determination of Brain Death in Children in 1987 published recommendations that, in infants, two examinations separated by 24 hours and confirmed by isoelectric electroencephalography are suggested to pronounce brain death [23]. It should

Table 2. Reported cases in the literature of brain death being reversible Reference

Age

Apnea test

EEG

CBF

Green et al., 1972 [5]

6 wk

Unclear*

ECS

Bolton et al., 1976 [6] Ashwal et al., 1977 [7]

60 yr

1 min

4d

Unclear*

Burst — suppression ECS Absent

Pasternak et al., 3 d 1979 [8]

Unclear*

Not ECS

Thompson et al., 1986 [9] Allen et al., 1980 [10]

Unclear*

ECS

3 mo

—

Present

Adult Unclear*

Not ECS

52 yr

No

Not ECS

Kohrman et al., 3 mo 1990 [12]

Yes

ECS

Kato et al., 1991 [13]

Unclear*

ECS

Yes

ECS

Ringel et al., 1988 [11]

8 mo

Okamoto et al., 3 mo 1995 [14]

Newburg et al., Adult Unclear* 2002 [15] Present case 10 mo Yes

—

? Not ECS

—

Imaging

Details

Multiple Seizures and apneas with brain death day 4. Moved spontaneously and porencephaly pupils reactive the next day. Breathing, eye movements, suck, and EEG activity for 3 weeks until death. — Anoxic from asthma. At 12 hours brain death; 24 hours later, pupils reactive and corneal reflexes present. Full recovery. — Neonatal asphyxia. Day 4 brain death with absent radionuclide cerebral blood flow and ECS. Day 5 respirations and movements present. Survived with ‘‘severe neurologic impairment.’’ Intraventricular Born at 35 weeks gestation at 2300 g weight. At 35 hours had hemorrhage intraventricular hemorrhage resulting in coma, apnea, and absent brainstem reflexes at 72 hours. Clinically unchanged until 120 hours, when pupils were reactive and spontaneous respiratory effort returned. Subsequent good outcome. Compatible Survived in persistent vegetative state.

—

Coma and absent cephalic reflexes for 36 hours, with return of respirations in last 24 hours prior to cardiac death. Pathology report: ‘‘only a primary brainstem hemorrhage.’’ — — Respiratory arrest with multiple sclerosis. Examination at 12, 24, and 48 hours showed absent brain-stem and pupillary reflexes. Exam at 72 hours found that he followed commands, and at 96 hours was fully alert. — Diffuse Found apneic in crib, requiring CPR. On day 4 and 5 (24 hours after cerebral the day 4 examination) all brain death criteria fulfilled. Four hours edema after the second brain death examination she developed sucking movements. Over the next 3 days she regained eye opening, facial grimacing, eye movements, and corneal reflexes for 30 days until death. Present Done Severe asphyxia after motor vehicle collision. Met criteria for brain death at 3 weeks. Persistent vegetative state after 2 months, with ‘‘voluntary movement.’’ Present on Severe atrophy Hypoglycemia and apnea requiring CPR. On day 3 and day 5 she day 19 day 19 met all criteria for brain death. She regained spontaneous respirations on day 43 until death day 71. Present ? A patient discharged from the hospital in a ‘‘persistent vegetative state.’’ Present Cerebral edema Found drowning and given CPR for 37 minutes. At 42 hours met all criteria for brain death. At 57 hours noted to have breathing until death at 93 hours.

* Apnea test unclear in seven reports. Green et al. [5] write ‘‘no spontaneous respirations.’’ Ashwal et al. [7] write ‘‘absence of spontaneous respiration: this was demonstrated by observing the patient’s inability to spontaneously trigger the respirator or by taking the patient off the respirator for a brief period of time until a drop in heart rate was observed.’’ Pasternak et al. [8] and Thompson et al. [9] write only ‘‘apnea.’’ Kato et al. [13] write ‘‘an apnea test.’’ Newberg et al. [15] write ‘‘patients in both groups met all clinical criteria for brain death.’’ The Allen et al. [10] report is from the cerebral survival study in which apnea was defined as ‘‘the lack of any observed effort of the patient to override the respirator or by ventilatory effort or movement other than that induced by the respirator’’ (page 96). Abbreviations: CBF = Cerebral blood flow CPR = Cardiopulmonary resuscitation ECS = Electrocerebral silence EEG = Electroencephalography

be noted that in most cases of children pronounced brain dead these guidelines are not followed [24,25]. A recent study from California documented that the majority of infants declared brain dead did not have the age-appropriate examination interval (median, 1.6 hours; range, 10 minutes to 14.4 hours), apnea testing, electroencephalography, or cerebral blood flow study [25]. Even outside of Canada,

this raises the concern that brain death, as currently diagnosed, may not be equivalent to death itself. In conclusion, a 10-month-old boy had findings of brain death according to Canadian consensus guidelines 42 hours after drowning and cardiac arrest, but then developed spontaneous respirations 15 hours later. This case, along with others discussed here, calls into question the claim that

Joffe et al: Reversible Brain Death 381

brain death as currently diagnosed is irreversible and equivalent to death of the patient.

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[14] Okamoto K, Sugimoto T. Return of spontaneous respiration in an infant who fulfilled current criteria to determine brain death. Pediatrics 1995;96:518-20. [15] Newberg A, Alavi A, van Rhijn S, Cotter A, Reilly P. Radiologic diagnosis of brain death. JAMA 2002;288:2121-2. [16] Coimbra CG. Implications of ischemic penumbra for the diagnosis of brain death. Braz J Med Biol Res 1999;32:1479-87. [17] Greer DM, Varelas PN, Haque S, Wijdicks EFM. Variability of brain death determination guidelines in leading US neurologic institutions. Neurology 2008;70:284-9. [18] Report of the Medical Consultants on the Diagnosis of Death to the President’s Commission for the Study of Ethical Problems in Medicine and Biomedical and Behavioral Research. Guidelines for the determination of death. JAMA 1981;246:2184-6. [19] Molinari GF. The NINCDS Collaborative Study of Brain Death: a historical perspective. In The NINCDS Collaborative Study of Brain Death. NINCDS Monograph 24 (NIH Publication 81-2286). Bethesda, MD: U.S. Department of Health and Human Services, 1980:1-32. [20] Walker AE. Neuropathological findings in the brains of patients admitted to the collaborative study. In The NINCDS Collaborative Study of Brain Death. NINCDS Monograph 24 (NIH Publication 81-2286). Bethesda, MD: U.S. Department of Health and Human Services, 1980:33-76. [21] Walker AE, Molinari GF. Criteria of cerebral death: a critique, The NINCDS Collaborative Study of Brain Death. NINCDS Monograph 24 (NIH Publication 81-2286). Bethesda, MD: U.S. Department of Health and Human Services, 1980:181-203. [22] Jennett B, Gleave J, Wilson P. Brain death in three neurosurgical units. Br Med J (Clin Res Ed) 1981;282:533-9. [23] American Academy of Pediatrics. Task Force on Brain Death in Children. Report of Special Task Force: guidelines for the determination of brain death in children. Pediatrics 1987;80:298-300. [24] Mejia RE, Pollack MM. Variability in brain death determination practices in children. JAMA 1995;274:550-3. [25] Mathur M, Petersen L, Stadtler M, et al. Variability in pediatric brain death determination and documentation in southern California. Pediatrics 2008;121:988-93. [26] Bernat JL. A defense of the whole-brain concept of death. Hastings Cent Rep 1998;28:14-23. [27] Joffe AR, Anton N, Mehta V. A survey to determine the understanding of the conceptual basis and diagnostic tests used for brain death by neurosurgeons in Canada. Neurosurgery 2007;61:1039-45; discussion 1046-1047.