Abstract
Brain death denotes the loss of function in both the cerebrum and the brain stem, leading to coma, absence of spontaneous respiration in the setting of adequate stimulus, and the cessation of all brain stem reflexes. Although spinal reflexes such as deep tendon, plantar flexion, and withdrawal reflexes may persist, recovery is not possible. The cessation of brain function qualifies as death because of its central role in coordinating vital bodily functions. Although brain death is largely determined by a clinical and neurologic examination, confounding variables may necessitate ancillary testing such as cerebral brain perfusion imaging.
Brain death, also referred to as death by neurologic criteria, denotes the irreversible cessation of all brain activity after a catastrophic brain injury. In 1995, the American Academy of Neurology established formal guidelines for determining brain death in adults. This guideline was revised in 2010. Additionally, the pediatric guideline, established by the American Academy of Pediatrics, the Child Neurology Society, and the Society of Critical Care Medicine, was updated in 2011 (1).
In October 2023, a new consensus practice guideline was published in the medical journal of the American Academy of Neurology, Neurology. Developed through collaboration between the American Academy of Neurology, the American Academy of Pediatrics, the Child Neurology Society, and the Society of Critical Care Medicine, this 2023 guideline integrates guidance for adults and children into a single comprehensive framework (1). It provides a practical approach for clinicians to evaluate patients who have sustained catastrophic brain injuries to determine whether they meet brain death criteria. Given that brain death is based on clinical assessment, ancillary testing is required only when the clinical assessment demonstrates uncertain neurologic examination results, when the assessment cannot be safely or fully completed, when confounding variables render the clinical examination unreliable, to shorten the duration of the observation period, or to encourage family member cooperation (1).
CLINICAL PREREQUISITES
Diagnosing brain death typically occurs with a clinical and neurologic assessment, necessitating specific conditions within the clinical setting and evidence indicating the absence of brain function on neurologic examination. Before brain death assessment is initiated, specific clinical prerequisites must be met as described in Table 1 (1,2). The apnea test will be performed once all other clinical and neurologic criteria have been met. Spontaneous breathing, absence of coma, intact brain stem reflexes, or motor activity beyond spinally mediated reflexes all indicate brain function and are inconsistent with brain death (1).
Clinical Prerequisites and Findings (2)
ANCILLARY TESTING
Although brain death determination relies primarily on clinical and neurologic examinations, certain clinical scenarios may arise in which a component of the neurologic assessment or the apnea test cannot be completed or the findings cannot be adequately interpreted. In such cases, ancillary testing may be necessary to ensure accurate brain death determination. It is important to note that ancillary testing does not replace careful clinical assessment but serves as a supplemental tool (1,2). Examples of situations in which ancillary testing may be warranted include fractures or trauma hindering cranial nerve assessment, the presence of neuromuscular paralysis or heavy sedation, an invalid apnea test, difficulties in interpreting the neurologic evaluation, or uncorrected metabolic disturbances (1,2). For infants less than 1 y old, and particularly those less than 2 mo old, 2 positive ancillary tests are typically required (1). The indications for ancillary tests and the selection of appropriate tests may be governed by hospital or state policies (1).
Several diagnostic imaging ancillary tests may be used as described in Table 2; however, this article will elaborate on only radionuclide brain perfusion scintigraphy, to include indications, contraindications and precautions, radiopharmaceutical dose and method of administration, imaging parameters, image interpretation, and image artifacts and sources of error.
RADIONUCLIDE BRAIN PERFUSION SCINTIGRAPHY
Indications
Brain death scintigraphy is recommended for assessing cerebral blood flow in patients suspected of brain death. This diagnostic tool becomes particularly valuable for clinical and neurologic assessments and may be less reliable if there are confounding variables such as severe hypothermia, coma induced by barbiturates, electrolyte or acid–base imbalances, endocrine or metabolic disturbances, drug intoxication, poisoning, or neuromuscular blockade. Moreover, this study often serves as a critical and decisive step for the patient’s family to provide their consent to withdraw care and harvest organs (3–5). Various events, such as head trauma, anoxia, cerebrovascular accidents, and edema, can cause fluid accumulation in the confined space of the calvarium. The resulting increased intracranial pressure causes cessation of cerebral blood flow, thus increasing the specificity of brain death scintigraphy (4,6).
Contraindications and Precautions
Brain death scintigraphy does not require the withdrawal of medical therapy, but specific precautions must be considered. Although some hospitals may possess a mobile γ-camera, brain death scintigraphy is typically conducted in the nuclear medicine department. Given the patient’s acute condition, collaboration with personnel responsible for monitoring and ensuring safe patient transport and imaging is essential (3,5). The patient should have stable blood pressure and be otherwise systemically stable. A halo with metal components, a breathing apparatus, or patient positioning may interfere with the examination protocol (5).
Radiopharmaceutical Dose and Method of Administration
Several 99mTc-labeled radiopharmaceuticals may be used, including 99mTc-bicisate (99mTc-ECD; 99mTc-ethyl cysteinate dimer), 99mTc-exametazime (99mTc-HMPAO; 99mTc-hexamethylpropylene amine oxime), and 99mTc-pentetate (99mTc-DTPA; 99mTc-diethylenetriaminepentaacetic acid) (3,5,6). 99mTc-DTPA is a nondiffusible, non–brain-specific radiopharmaceutical that does not cross the intact blood–brain barrier and therefore provides information only on low-resolution vascular flow. Some hospitals prefer to use diffusible, lipophilic, brain-specific radiopharmaceuticals such as 99mTc-HMPAO and 99mTc-ECD because image interpretation is less dependent on the quality of the bolus and relies more on the assessment of parenchymal uptake on delayed static imaging for determining the presence or absence of cerebral blood flow (3–7). Further brain-specific radiopharmaceuticals allow for the evaluation of regional brain tissue perfusion and permit the use of SPECT, which makes image interpretation even more straightforward (3,7). It is important to note that SPECT acquisition may not be feasible in unstable patients on life support equipment (3).
In adults, the bolus injection can be up to 1,110 MBq (30 mCi) administered in a peripheral vein as close to the access point as possible (3,5–7). Pediatric doses should be based on body weight and kept as low as reasonably achievable for diagnostic image quality. Typically, children receive a dose of 11.1 MBq/kg (0.3 mCi/kg), with a minimum dose of 185 MBq (5 mCi) for brain-specific radiopharmaceuticals (3,7).
Tables 3, 4, and 5 describe radiation dosimetry in adults, children (5 years old; normal renal function), and the pregnant or potentially pregnant patient, respectively.
Radiation Dosimetry: Adults (8)
Radiation Dosimetry: Children (5 Years Old; Normal Renal Function) (8)
Radiation Dosimetry in Pregnant or Potentially Pregnant Patient (8)
Imaging Parameters
Brain death scintigraphy routinely involves a cerebral angiogram, which evaluates dynamic blood flow in the brain’s vessels, and static planar images. Non–brain-specific radiopharmaceuticals such as 99mTc-DTPA are charged hydrophilic compounds that cannot normally localize in the brain parenchyma because of the intact blood–brain barrier (4,6). Instead, they are found in the overlying scalp soft tissues, calvarium, subarachnoid spaces outlining the cerebral hemispheres, and larger blood pools such as the sagittal and transverse sinuses (7). Non–brain-specific radiopharmaceuticals are able to enter the brain when the blood–brain barrier has been disrupted by some pathologic process (5,6). In contrast, 99mTc-HMPAO and 99mTc-ECD are lipophilic, allowing them to cross the intact blood–brain barrier and be retained in the brain parenchyma in proportion to regional cerebral blood flow. Because non–brain-specific radiopharmaceuticals such as 99mTc-DTPA do not show brain parenchymal uptake, dynamic blood flow images are crucial for interpretation. Conversely, with brain-specific radiopharmaceuticals, the absence of blood flow in dynamic images confirms brain death when delayed static images fail to show brain visualization (3–6).
The dynamic blood flow images are acquired at the time of radiopharmaceutical injection, with image acquisition commencing immediately before or immediately after injection (3–6). Since these patients are often receiving multiple medications, it is essential to determine the optimal venous access point and inject as close to the body as feasible. Injection technique with a high-quality bolus injection (0.5–1 mL) is more critical for non–brain-specific radiopharmaceuticals than for brain-specific radiopharmaceuticals, which rely more on the assessment of parenchymal uptake on static images for determining brain death (6). During blood flow imaging of the brain, a series of 1- to 3-s-per-frame anterior (or anterior and posterior) images of the head are acquired for 1–2 min (3,5,6). Static anterior or anterior/posterior and lateral blood pool images are acquired immediately after the dynamic images for non–brain-specific radiopharmaceuticals and at 20 min after injection for brain-specific radiopharmaceuticals (5). The static images should be acquired for long enough to permit 500,000–1,000,000 counts per view (3). Delayed static images may also be acquired at 1–4 h after injection (5).
The top 10 professional tips for performing radionuclide brain perfusion scintigraphy are listed below:
Coordinate with nursing, patient transport, respiratory therapy, and the nuclear pharmacy to ensure your dose arrives on time and there is a camera available when the patient arrives.
Do not blow the flow. Ensure a quality bolus injection and initiate imaging promptly. It is better to start too early than too late. If necessary, set the image acquisition to 120 s to ensure that imaging begins before the bolus reaches the carotid arteries and continues well after the venous phase.
Position the patient supine and head-in, with the camera anterior or anterior/posterior. Provided there is no trauma to the skull and there are no fixating devices, head-in positioning allows for the use of a head holder and strap, which help ensure that the head is positioned straight to allow for comparison of right and left carotid flow as well as visualization of the anterior and middle cerebral arteries. Additionally, head-in positioning facilitates the securement of all infusion lines and medical devices out of the field of view and outside the camera rotation range. Moreover, this positioning facilitates closer detector proximity for lateral statics and SPECT (if applicable).
Ensure proper patient positioning to visualize the carotid arteries and skull vertex in the field of view and to allow assessment of the symmetry of blood flow to both sides of the head and superior sagittal sinus activity. Prompt visualization of the carotid arteries serves as an assessment for a quality bolus injection with no infiltration.
Double-check the camera position, patient information, and that the correct image acquisition is being performed before moving the patient to the imaging table.
Ensure that the image acquisition can be initiated from the persistence scope or hand controller.
For the dynamic blood flow, consider placing a tourniquet or elastic band under the posterior protuberance of the skull, over the ears, and just above the orbits to minimize scalp circulation, which may be confused with cerebral perfusion. Avoid this step if the patient has head trauma.
Obtain at least one blood pool image in the same view as the dynamic blood flow images. Consider obtaining optional static images, including posterior and vertex.
Perform SPECT or SPECT/CT if using 99mTc-HMPAO or 99mTc-ECD to enhance visualization of perfusion to the posterior fossa and brain stem structures. However, SPECT acquisition may not be possible for unstable patients reliant on life support equipment.
Use zoom or magnification techniques if imaging pediatric patients.
Table 6 describes the benefits and drawbacks of radiopharmaceuticals, and Table 7 describes the image acquisition parameters.
Regarding the processing and display of images, scale static and blood flow images to provide the best visualization of the areas of interest and display in gray scale (3). SPECT and SPECT/CT images should be processed as per the manufacturer’s specifications and the interpreting physician’s requests (3,5). SPECT data should be filtered in 3 dimensions and reconstructed at the highest pixel resolution, 1 pixel thick. Three-dimensional filtering can be accomplished either by 2-dimensionally prefiltering the projection data or by applying a 3-dimensional postprocessing filter to the reconstructed data (5). The entire brain should be reconstructed to include the vertex and cerebellum, and images should be displayed in transverse, sagittal, and coronal slices (5).
Image Interpretation
The cerebral angiogram illustrates uptake in the arterial, capillary, and venous phases. After the injection of the radiopharmaceutical into a peripheral vein, prompt and symmetric visualization should occur in the subclavian, carotid, and cerebral arteries (5). Visualization of the anterior and middle cerebral arteries forms a trident appearance and indicates cerebral perfusion (Fig. 1). During the capillary phase, symmetric and diffuse activity is observed in both cerebral hemispheres (5). The venous phase reveals visualization of the sagittal sinus and jugular veins (5). If a patient is suspected of being brain-dead on the basis of clinical and neurologic evaluation and there is no evidence of cerebral perfusion on the cerebral angiogram, the diagnosis is confirmed (3).
Findings of persistence of blood flow on blood flow study using nonlipophilic radiopharmaceutical in 22-y-old man with ruptured aneurysm of left posterior inferior cerebral artery. (A) CT scan demonstrates intraventricular and subarachnoid hemorrhage. (B) Two-second flow images (top rows) after injection of 905 MBq of 99mTc-DTPA demonstrate excellent visualization of anterior (vertical arrows) and middle (horizontal arrows) cerebral arteries, forming trident appearance indicating presence of perfusion, which progresses into visualization of intracranial venous sinuses. On immediate anterior (Ant) and right lateral (R lat) static images (bottom row), radiopharmaceutical does not cross blood–brain barrier; however, activity is noted in venous sinuses. (Reprinted from (8).)
Interpretation of brain death when using non–brain-specific radiopharmaceuticals relies on the dynamic flow study because these radiopharmaceuticals do not cross the blood–brain barrier (6). In contrast, brain-specific radiopharmaceuticals can evaluate both dynamic flow and parenchymal uptake in the brain as they are lipophilic and diffuse across the blood–brain barrier. Diffuse radiopharmaceutical uptake in the brain parenchyma will accumulate over time if the brain perfusion is conserved (Fig. 2) (6).
Findings of persistence of blood flow on blood flow study using lipophilic radiopharmaceutical in 18-y-old man after motor vehicle accident followed by left-sided craniotomy to evacuate subdural hematoma. (A) CT indicates loss of white matter–to–gray matter differentiation in left posterior cerebral artery territory and right posterior parasagittal cortex territory. There is diffuse cerebral edema and transtentorial herniation with compression of basilar cisterns. (B) Two-second flow images (top rows) demonstrate excellent visualization of anterior (vertical arrows) and middle (horizontal arrows) cerebral arteries, resembling trident, with retention of activity within brain parenchyma, thereby indicating presence of blood flow. Anterior (Ant) and left lateral (L lat) parenchymal phase images (bottom row) demonstrate somewhat inhomogeneous though extensive brain perfusion. (Reprinted from (8).)
When brain death occurs, blood flow to the internal carotid artery ceases because of increased intracranial pressure or clotting (6). During the cerebral angiogram, blood flow halts at the level of the internal carotids and base of the skull, with no blush of activity observed in the anterior and middle cerebral arteries or pooling in the sagittal sinus. Subsequent to the cerebral angiogram, blood pool images will reveal soft-tissue uptake in facial structures, but no uptake will be evident in the sagittal or transverse sinuses (5). If using a brain-specific radiopharmaceutical, there will be an absence of uptake in the brain parenchyma that results in a light-bulb or hollow-skull phenomenon indicating a lack of brain perfusion and supporting the diagnosis of brain death (Fig. 3) (2). Blockage of the internal carotid arteries may redirect blood to the maxillary branch of the external carotid arteries, potentially resulting in increased accumulation of activity in the nasopharynx and the appearance of a hot nose (3,5–7). The hot nose sign does not specifically indicate brain death but may be used as a secondary sign when intracerebral perfusion is absent.
Findings of absence of blood flow on blood flow study using lipophilic radiopharmaceutical in 33-y-old man after hanging. (A) CT scan demonstrates diffuse cerebral edema with narrowing of lateral ventricles and bilateral infarction of lentiform nuclei. (B) Two-second flow images (top rows) after injection of 799 MBq of 99mTc-HMPAO demonstrate excellent visualization of common carotid arteries (arrows) but absence of flow into calvarium, consistent with brain death. Anterior (Ant) and left lateral (L lat) parenchymal phase images (bottom row) demonstrate complete lack of perfusion within boney skull (light-bulb or hollow-skull sign), including absence in posterior fossa and superior sagittal sinus. More technically demanding SPECT imaging is generally not performed in these critically ill patients. (Reprinted from (8).)
Image Artifacts and Sources of Error
Ensuring venous patency and using proper injection technique are critical for accurate image interpretation (3,5). The occurrence of radiopharmaceutical infiltration or prolonged infusion poses a risk to the assessment of cerebral angiogram results. Failure to promptly visualize the radiopharmaceutical in the carotid arteries may indicate complete dose infiltration (3,5). In such instances, obtaining an image of the injection site is advisable to confirm infiltration. Additionally, the presence of metal plates or life-support equipment such as respirators can cause attenuation, potentially compromising the clinical usefulness of planar imaging and SPECT procedures (3,5). Documenting head trauma, cerebrospinal fluid shunts, and intracranial pressure transducers is essential because of their potential to induce hyperemic blood flow, which could consequently produce false-negative cerebral angiography results (3,5,7).
CONCLUSION
Conducting brain death scintigraphy presents technical challenges, yet many complications can be preempted through careful planning and effective communication with the nuclear pharmacy, support staff, and interpreting physician. It is crucial to minimize distractions and meticulously configure the camera acquisition, ensuring that the persistence scope or hand controller is enabled to initiate the acquisition accurately. Patient positioning may be facilitated with a head-holder and strap. Additionally, when non–brain-specific radiopharmaceuticals such as 99mTc-DTPA are used, it is advisable to extend the blood flow dynamic image acquisition time and begin the image acquisition immediately before the injection to prevent blowing the flow.
DISCLOSURE
No potential conflict of interest relevant to this article was reported.
Footnotes
CE credit: For CE credit, you can access the test for this article, as well as additional JNMT CE tests, online at https://www.snmmilearningcenter.org. Complete the test online no later than September 2027. Your online test will be scored immediately. You may make 3 attempts to pass the test and must answer 80% of the questions correctly to receive 1.0 CEH (Continuing Education Hour) credit. SNMMI members will have their CEH credit added to their VOICE transcript automatically; nonmembers will be able to print out a CE certificate upon successfully completing the test. The online test is free to SNMMI members; nonmembers must pay $15.00 by credit card when logging onto the website to take the test.
Published online Aug. 13, 2024.
REFERENCES
- Received for publication April 8, 2024.
- Accepted for publication June 25, 2024.
