It is time to abandon apneic-oxygenation testing for brain death

For decades the apneic-oxygenation test has been used as a key component of clinical testing to determine if a potential organ donor has sustained irreversible loss of the ability to breathe spontaneously in the context of a hypercarbic challenge. When no respiratory effort is observed in association with irreversible unresponsive coma due to severe brain injury the victim is concluded to be “brain dead” and is an eligible organ donor. However, there is a growing clinical and legal opposition to performance of this test.


It is time to abandon apneic-oxygenation testing for brain death
For decades the apneic-oxygenation test has been used as a key component of clinical testing to determine if a potential organ donor has sustained irreversible loss of the ability to breathe spontaneously in the context of a hypercarbic challenge. When no respiratory effort is observed in association with irreversible unresponsive coma due to severe brain injury the victim is concluded to be "brain dead" and is an eligible organ donor. However, there is a growing clinical and legal opposition to performance of this test.
The apneic-oxygenation test is essential to satisfy the requirements of the second section of Uniform Determination of Death Act (UDDA), proposed in 1981, to defi ne death in which: An individual who has sustained either 1) irreversible cessation of circulatory and respiratory functions or 2) irreversible cessation of all functions of the entire brain, including the brainstem, is dead. A determination of death must be made in accordance with accepted medical standards." The UDDA in this form or slight variations has been adopted by most States and has been adopted in other countries, again with slight variations such as that in section 41 of the Human Tissue Act 1982 in the State of Victoria in Australia: "For the purposes of the law of Victoria, a person has died when there has occurred -(a) irreversible cessation of circulation of blood in the body of the person; or (b) irreversible cessation of all function of the brain of the person." Such legislation does not stipulate how brain death should be determined but the apneic-oxygenation test is an integral part of death determination. of the New York State Department of Health [2] advise that the test is conducted only when all other brainstem refl exes have been extinguished, tacitly conceding that hypercarbia may depress brain function. Essentially the test is conducted by allowing the carbon dioxide content of arterial blood to increase, without hypoxemia, to a level which would be expected to generate a respiratory effort. In the United States, Canada, Australia and New Zealand, that level is a PaCO 2 of at least 60 mmHg (8 kPa), or 20 mmHg above resting level while in Britain the required minimum level is 50 mmHg (6.7 kPa).
The test is a diagnostic one, that is to determine if the patient's respiratory center is functional or not. The main argument against using the test is that it may cause brain death, if the patient's brain is not already dead. That is, it is a selffulfi lling test which by causing brain death yields a positive result [3][4][5]. It is well known in neuro-intensive care that any rise in blood carbon dioxide causes a rise in intracranial pressure, and that hyperventilation may acutely reduce intracranial pressure. These changes in intracranial pressure are the consequences of vasoconstriction and vasodilation.
Of course, these effects are irrelevant if the patient is already dead, but since the test is a diagnostic one to determine if death is present or not, it is fl awed, even when conducted without adverse events such as hypoxemia which are not uncommon [3][4][5].
Another problem with the test is that it may be unreliable and may yield a false positive result. The minimum limit of hypercarbia to stimulate respiration is scientifi cally unknown.
Indeed, a number of case reports [6-10] in children, otherwise fulfi lling the criteria for death, document the onset of spontaneous breathing at PaCO 2 levels well above the minimum required to diagnose death (60 mmHg). At this minimal PaCO 2 level these children could have been diagnosed dead when they were in fact alive.
That the conduct of the apneic-oxygenation test for brain death exacerbates intracranial hypertension and compromises brain perfusion was documented in a case series of adults with severe brain injury [11]. In 13 patients with severe brain injuries, testing with a range of PaCO 2 60-81 mmHg caused mean intracranial pressure to rise from 87 +/-23 to 95 +/-28 mmHg which settled to 84 +/-21 mmHg after the test. Simultaneously the mean arterial pressure increased from 95 +/-22 to 109 +/-21 mmHg during the test and settled to 86 +/-16 mmHg after the test. Importantly, the cerebral perfusion pressure before the test was low (8 +/-16 mmHg) but lower after the test (1 +/-16 mmHg) suggesting that if there was cerebral perfusion before the test, the conduct of the test caused a signifi cant decrease (P=0.006). In jurisdictions where the test must be performed twice, it is likely that the outcome of a second test will be infl uenced by prior testing and yield a positive result.

Legal opposition to the apneic-oxygenation test
Recently, a number of high profi le legal cases in the US have controversially challenged the use of the test, with plaintiffs (or their legal guardians) claiming that the test (with other tests) does not determine death, for example Jahi McMath [12][13][14][15] and Israel Stinson [16] in the US and Ibrahim [17] in Australia.
However, Courts have ruled that the diagnosis of brain death does constitute death. Of more concern are several cases in which plaintiffs have claimed that performance of the apneicoxygenation test has in fact caused harm. Another key issue is whether the performance of the test is a medical procedure which requires informed consent from legal guardians. These issues are illustrated by the following few selected legal cases.

Case of alex pierce
In 2016, Sabrina Pierce, petitioned the Superior Court of California for an order to prevent Loma Linda Medical Centre performing brain death deaths on her son, Alex, a minor who had nearly drowned at a school party. Paramedics gave cardiopulmonary resuscitation CPR with restoration of a pulse.
He was subsequently transported with mechanical ventilation to Loma Linda Medical Center. He had spontaneous movement, eye opening and electroencephalographic (EEG) activity.
However, onset of convulsions treated with anticonvulsant medication abolished spontaneous movement. Physicians planned to perform clinical brain death testing and a brain blood fl ow study but were refused consent by his mother who believed that the apneic-oxygenation test would cause further brain damage. Loma Linda maintained a right to conduct brain function tests without consent and to cease treatment if brain death was established. The Court issued a temporary restraining order [18] preventing Loma Linda performing an apnea test, removing mechanical ventilation, withholding nutrition and necessary medical care, utilizing medication which could infl uence neurological testing and ordered an independent assessment by a physician not affi liated with Loma Linda including a repeat EEG and brain blood fl ow study.

Case of allen calloway
Another case in 2016 concerned a child of almost 6 years who nearly drowned in a Montana Lake. He was rescued and with CPR regained spontaneous circulation and some respiratory effort but thereafter his neurological condition worsened. After 5 days, brain stem herniation was suspected. Clinical tests, including an apneic-oxygenation test were conducted with consent on the basis that they would determine brain function, not brain death. During the 10 minute apneic-oxygenation test, the PaCO 2 increased from 39 mmHg to 100 mmHg with no respiratory effort observed. The physicians believed the test confi rmed their suspicion of brain death but Allen's guardian perceived that he had struggled to breathe and had experienced pain, distress and harm. A neurologist opined that because an conduct of brain function tests was a medical procedure and as such a guardian had the right to autonomously choose or refuse treatment under privacy guarantees of Montana's constitution [19]. This includes the right to decide whether or not to conduct a brain death examination -a medical procedure with considerable repercussions. In addition, the Court ruled that it was unwilling to grant the medical profession the sole and exclusive authority to conduct brain death examinations, with the Judge remarking that such public policy was the role of legislature, not the Court.

Alternative tests for brain death
Guidelines for organ donation make provision for ancillary testing if clinical tests cannot be performed or they are confounded [1,2], but they should be routine. The preferred test is scanning with lipophilic diffusible radionuclides including Technetium Tc 99m Exametazine or Technetium Tc 99m -ECD.
Brain death testing by radioisotope scanning is more practical and more easily accomplished with one test [21] compared with clinical testing which must be performed twice before organ procurement [1,2]. In addition, scanning is much less invasive compared to apneic-oxygenation testing and not injurious to the brain or other organs and is not infl uenced by brain depressive medication, muscle relaxants, hypothermia, metabolic and endocrine derangements, electrolyte abnormalities, spinal cord injury and automatism which may be present in severe brain injury and confound clinical testing. Radioisotope brain scanning can be used in all ages [22]. It need not be deferred until medication, which may confound clinical test, to be metabolized or excreted [23]. The only clinical requirements are for adequate blood pressure to ensure delivery of the radionuclide to the brain and suffi cient oxygenation and glucose supply to enable absorption of the radionuclide if any brain function is present. While absence of brain blood fl ow is considered to be the "gold-test" of brain death [24], scanning with lipophilic radionuclides are considered to be the "gold-tests" of blood fl ow [25][26][27] because they are taken up and metabolized by functioning brain tissue. Absence of intracranial radioactivity proves absence of brain blood fl ow.
Other tests of brain blood fl ow such as scanning with nonlipophilic radioisotopes, angiography, and Doppler ultrasound are less suitable for assessing brain function because they yield once-only angiographic data and nothing about brain function.
A few logistical prerequisites exist to perform appropriate radionuclide scanning. Brain blood fl ow detection is within the capabilities of any institution with a nuclear medicine service.
The cost of the radiopharmaceutical is minimal. Unless a portable gamma camera is available, transport of the patient from the critical care area is required but poses very little risk in hospitals already skilled in organ procurement. Singlephoton emission computed tomography (SPECT) is superior to planar imaging for detecting brainstem blood fl ow and both anterior and lateral views are required, the latter to optimally detect cerebellar fl ow [28].

Possible impact of foregoing the apneic-oxygenation test
A test for absence of brain blood fl ow may be a more stringent test for brain death than the apneic-oxygenation test because some brain blood fl ow may still remain when brain stem refl exes are absent [29][30][31]. Consequently, the rate of organ donation as a percentage of deaths may decrease.
However, this is only a theoretical risk. Scanning images showing complete absence of brain blood fl ow may be more convincing and less distressing for guardians to know that the patient is truly dead [32,33] and may contribute to the organ donation rate.

Proposals for legislative reform
Several authors have called for a reform of the UDDA [34,35].
If reform does occur, it may be opportune to specify that the absence of brain blood fl ow is a requirement to diagnose brain death. This could be accomplished by incorporating changes into medical guidelines or directly into legislation.
Lewis and colleagues [34] propose that the defi nition of brain death be modifi ed to "irreversible cessation of functions of the entire brain, including the brainstem, leading to unresponsive coma with loss of capacity for consciousness, brainstem arefl exia and the inability to breathe spontaneously".
Secondly, they urge that all US States follow the example of Nevada which specifi es that the determination of death by "accepted medical standards" be those of the American Academy of Neurology for adults and those of the Society of Critical Medicine, American Academy of Pediatrics and Child Neurology Society for children. Thirdly, these authors urge that the UDDA specify that ongoing hormonal function be exempted in requiring cessation of "all functions of the entire brain, including the brainstem". In addition, these authors urge that the UDDA specify that consent is not required from guardians for the performance of tests for brain death. However, abolition of informed consent is a retrogressive step in development of law and is most unlikely to be widely adopted. Of note is that the State of Nevada has adopted legislation to abolish the long-Citation: Tibballs J (2020) It is time to abandon apneic-oxygenation testing for brain death. Arch Organ Transplant 5(1): 006-0010. DOI: https://dx.doi.org/10.17352/2640-7973.000015 standing legal requirement of consent for testing [36,37]. While agreeing that the UDDA needs revision, Nguyen [35] maintains that the suggestions of Lewis and colleagues neither address the root cause of the litigations (harm caused by testing) nor the controversies about the neurological declaration of brain death.
Instead, Nguyen advocated for informed consent for testing and proposed that reform of the UDDA accommodate personal religious, cultural or moral convictions, as exemplifi ed in the New Jersey Declaration of Death Act 1991 [37] which provides for religious exemption to neurological declaration of death.

Conclusions
There is a need for legislative and policy reform in this contentious area. The apneic-oxygenation test should be abandoned because it is fl awed, harmful and may exacerbate a brain injury if the patient is not already dead. Better tests, in particular radionuclide scanning with lipophilic radionuclides, are available. Brain scanning is reliable, not harmful, easily accomplished and may be more convincing and less distressing to loved ones that the patient is dead.