Objectives: Brain death is a state of irreversible loss of brain function in the cortex and brainstem. Diagnosis of brain death is established by clinical assessments of cranial nerves and apnea tests. Different conditions can mimic brain death. In addition, confirmatory tests may be falsely positive in some cases. In this study, we aimed to evaluate the role of positron emission tomography-computed tomography scan with 2-deoxy-2[18F]fluoro-D-glucose (18F-FDG-PET/CT) as an ancillary test in diagnosing brain death.
Materials and Methods: We analyzed 6 potential brain death donors for the confirmatory diagnosis of brain death using FDG-PET/CT. All 6 donors were brain dead by clinical criteria. All patients had electroen-cephalogram and brain computed tomography. Other than FDG-PET/CT, transcranial Doppler was performed in 1 patient, with other patients having no confirmatory ancillary imaging tests. Patients had nothing by mouth for 6 hours before imaging. Patients were supine in a semi-dark, noiseless, and odorless room with closed eyes. After 60 minutes of uptake, the brain PET/CT scan was performed with sequential time-of-flight-PET/CT (Discovery 690 PET/CT with 64 slices, GE Healthcare). The PET scan consisted of LYSO (Lu1.8Y0.2 SiO5) crystals with dimensions of 4.2 × 6.3 × 25 mm3. Three-dimen-sion images were with scan duration of 10 minutes.
Results: The PET scan confirmed brain death in 5 of the 6 cases. However, we ruled out brain death using PET/CT in a 3-year-old child, although all clinical tests confirmed brain death.
Conclusions: A PET scan illustrates a hollow skull phenomenon suggestive of brain death. It can be a powerful diagnostic tool to assess brain death.

Key words : Brain dead donor, Organ donation, PET scanning

Introduction

Brain death is a state of irreversible loss of brain function in the cortex and brainstem. Diagnosis of brain death is established by clinical assessments of cranial nerves and apnea tests. In the presence of conditions that can mimic brain death, ancillary tests may be needed for the confirmation of brain death diagnosis.¹

Various circumstances require ancillary tests of brain death. For example, the depletion of cranial nerve reflexes is observed in deep hypothermia.² Moreover, overdose of certain drugs or induction of sedative medications, including fentanyl, phenytoin, morphine, phenobarbital, and midazolam, in the hospital setting can prevent physicians from distinguishing brain death from overdose coma.³ The American Academy of Neurology suggests a normal hepatic and kidney clearance for a definitive diagnosis of such cases. Indeed, in the case of recent administration of sedative drugs, the clinical examination should be performed after 5 half-lives of the medications.⁴

In addition to interfering medications and hemodynamic instability, trauma to the face, neck, and peripheral nerves is a barrier to the precise examination of cranial nerves. In trauma patients, damage to the high cervical cord can result in apnea and loss of spontaneous breathing, which may incorrectly be attributed to an injury to the brainstem.⁵

The apnea test is the standard method to evaluate the respiratory control center in the medulla. There are particular prerequisites to consider before performing an apnea test. The hemodynamic state of the patient should be stable. Systolic blood pressure should be 100 mm Hg or higher. Normal temperature and normal arterial CO2 pressure are also necessary before performing an apnea test. Apnea test intolerance is another issue to consider. Certain conditions may make the apnea test intolerable and require stoppage, including O2 saturation drop under 85% for more than 30 seconds and systolic blood pressure drop below 90 mm Hg, among others.6 These limitations postpone the diagnosis of brain death and can result in the loss of potential donors. Therefore, an ancillary test is essential to diagnose brain death when a clinical diagnosis is not feasible.

In some instances, performing ancillary tests are inevitable for the final diagnosis of brain death. Electroencephalography (EEG) is a primary ancillary method that evaluates cortical activity by recording the electrical activity generated by the cortical neurons using electrodes placed on the scalp surface. The isoelectric electroencephalogram is in favor of approval of brain death. Notably, EEG does not assess brainstem activity and can be falsely positive in the case of overdoses or metabolic conditions.⁷

Other ancillary tests, including cerebral angiog-raphy, nuclear scan, transcranial Doppler (TCD) sonography, computed tomography (CT) angiography, and magnetic resonance angiography, evaluate cerebral blood flow rather than neural activity.^6,8 An absent brain uptake in radionuclide studies using Tc-labeled cerebral perfusion imaging agents and FDG favors brain death diagnosis.^6,9,10

Conventional 4-vessel cerebral angiography is the gold standard confirmatory test for diagnosing brain death by indicating the absence of blood circulation in the cerebrum and circle of Willis. However, it can be falsely negative when blood flow is decreased in certain conditions, such as trauma, postsurgery, ventricular shunts, and infants with pliable skulls. The contrast should be injected into the aortic arch at high pressure to perform the test correctly and reach anterior and posterior circulations. Intracerebral filling at the entry level of the carotid or vertebral artery to the skull should not be seen. In conventional angiography, it should be considered that the longitudinal sinus may be filled in the case of brain death.⁶

Computed tomography angiography and mag-netic resonance angiography are alternatives to conventional angiography. They are mostly preferred, as they do not require an expert operator and are more available. According to the American Academy of Neurology, although the nuclear scan is preferred to the aforementioned methods in the United States, there is insufficient evidence to prove their clinical superiority.¹¹ In an interesting case report of a 31-year-old woman with subarachnoid hemorrhage, the clinical examination and computed tomography angiography favored brain death. In contrast, TCD documented normal blood flow and anterograde flow in the left middle cerebral right ophthalmic arteries.¹² Here, we aimed to examine the use of the positron emission tomography (PET) scan with FDG as an ancillary test for diagnosis of brain death. We performed a PET scan on 6 patients with different etiologies of brain death. Furthermore, we ruled out brain death using PET/CT in a 3-year-old child, despite all clinical tests confirming brain death.

Materials and Methods

In this case series, we evaluated 6 potential brain-dead donors at the Organ Procurement Unit of Massih Daneshvari Hospital. Five patients were brain dead. However, ancillary testing in 1 patient ruled out brain death. The Iranian legal system requires the diagnosis of brain death to be approved by 5 specialists, including a neurologist, a neurosurgeon (or 2 neurologists), 1 internist, 1 anesthesiologist, and a forensic pathologist. Also, 2 EEGs, 6 hours apart, are obligatory. The Ethics Committee of the National Research Institute of Tuberculosis and Lung Diseases approved this study.

Positron emission tomography scan
2-Deoxy-2[18F]fluoro-D-glucose (18F-FDG) was produced by our in-site GE cyclotron in Masih Daneshvari Hospital (Tehran, Iran). The patients had nothing by mouth for 6 hours before imaging, and 4.6 MBq/kg 18-FDG was administered intravenously. The patients were supine in a semi-dark, noiseless, odorless room with closed eyes. After 60 minutes of uptake, the brain PET/CT scan was performed with sequential time-of-flight PET/CT (Discovery 690 PET/CT with 64 slices; GE Healthcare). The PET tomography consisted of LYSO (Lu1.8Y0.2 SiO5 [Ce]) crystals with dimensions of 4.2 × 6.3 × 25 mm³. Data were acquired in 3-dimen-sional mode with brain scan duration of 10 minutes. Two nuclear medicine specialists with 10 years of expertise in PET/CT reporting reviewed the images.

Results

Case 1
A 26-year-old man with methanol intoxication presenting with convulsions and drowsiness was taken to a hospital with emergency medical services (EMS). As his level of consciousness decreased, hemodialysis was performed. Three days after admission, he was clinically diagnosed with brain death. He was then transferred to the Masih Daneshvari Hospital Organ Procurement Unit (OPU) to confirm brain death. In clinical examination, the apnea test was not feasible. Hence, further ancillary testing was done. The patient’s EEGs displayed isoelectric activity of the brain in favor of brain death. Brain CT scan demonstrated ischemic encephalopathy. Two days after clinical diagnosis of brain death, a PET scan was performed. No FDG uptake was detected in the brain and brainstem. The PET findings confirmed brain death (Figure 1).

Case 2
A 39-year-old woman with a past surgical history of abdominoplasty and drug history of sertraline and alprazolam was transferred to the emergency room with a complaint of presumed poisoning. According to her companion, she was cyanotic and unconscious after the suspected consumption of various pain killers in the setting of her recent tooth implantations. On arrival, she had a Glasgow Coma Scale (GCS) of 3/15. She was intubated and transferred to a tertiary hospital; her pupils were mydriatic and nonreactive to light. In further evaluations, amphetamine, methamphetamine, and benzodiazepine were positive in the urine toxicology panel. Ethanol level was positive in the blood, indicating use of an alcohol-containing beverage. Brain CT revealed generalized edema. The patient’s EEG result was in favor of brain death with no epileptic waves. Chest CT revealed aspiration pneumonia. Later, her clinical examination indicated brain death. She was transferred to Masih Daneshvari OPU for further evaluation. Two other EEGs, 6 hours apart, were done to confirm brain death. She did not tolerate the formal apnea test. Therefore, on day 3 after intubation, PET/CT with FDG was performed. The PET findings confirmed brain death (Figure 2).

Case 3
A 22-year-old man with a past medical history of major depressive disorder and history of seizures and usage of valproic acid was taken to the emergency room by EMS after cardiac arrest. He had a GCS of 3/15 after successful cardiopulmonary resuscitation. His toxicology test was positive for tetrahydrocannabinol, tramadol, and methadone. Clinical examination suggested brain death. He was transferred to Masih Daneshvari Hospital for ancillary tests. Brain CT scan revealed generalized edema of the brain, and EEGs were isoelectric. Brain death was confirmed by negative FDG uptake in the brain (Figure 3).

Case 4
A 51-year-old woman with abrupt headache, convulsions, left hemiparesis, and loss of consci-ousness was taken to a private hospital. Subarachnoid hemorrhage was demonstrated in a head CT scan. Craniotomy and right temporal lobectomy were done, in addition to cranial angiography and coiling of the aneurysm. The patient’s level of consciousness did not change. After 3 days, clinical examinations, atropine tests, and apnea tests supported the diagnosis of brain death. She was transferred to Masih Daneshvari OPU to confirm brain death and possible organ donation. Two days after the initial assessment, a clinical examination was conducted again, including 2 EEGs at a 6-hour interval. On day 11 after her first symptom, a PET scan was conducted. Brain death was confirmed by PET findings (Figure 4).

Case 5
A 57-year-old man with a past medical history of hypertension, ischemic heart disease, and diabetes was taken to a hospital by EMS due to nausea and vomiting, bilateral hemiparesis, and loss of consciousness. Brain CT demonstrated intracranial hemorrhage, intraventricular hemorrhage, and cerebral edema following a low GCS score and no response to painful stimulants. Surgery was not indicated according to the neurosurgical consultation. One day after admission, clinical examination, including cranial nerve examinations, atropine test, and apnea test, supported a brain death diagnosis. Three days after admission, 2 EEGs with a 6-hour interval and a PET/CT scan of the brain were done in the Masih Daneshvari OPU. The PET scan verified no FDG uptake of the brain, in neither the cortex nor brainstem. Brain death was confirmed by PET (Figure 5).

Case 6: exclusion of brain death
A 3-year, 7-month-old boy with low GCS and no response in clinical examination of cranial nerves was suggested as a potential brain-dead donor. At admission to a pediatric hospital, physical examina-tion revealed generalized edema and a tracheostomy conducted 1.5 years previously because of foreign body aspiration, recurrent pneumonia, and asphyxia.
His consciousness gradually decreased for an unknown reason. His GCS dropped to 3/15. He had no response to clinical cranial nerves examination. The atropine test favored brain death, but he did not tolerate formal apnea testing. The next day, he was transferred to Masih Daneshvari OPU. The repetition of clinical tests suggested brain death. Two EEGs were recorded at a 6-hour interval. The patient’s EEGs
were isoelectric, affirming brain death. Transcranial Doppler sonography examinations were done on 2 consecutive days after the prior examinations. Blood flow was significantly decreased in intracranial arteries by both TCDs. The PET scan was performed to determine FDG uptake in the brain. Fluoro-deoxyglucose was accumulated in the brain, sug-gesting brain activity and preserved cerebral glucose metabolism. Despite clinical examinations, the clinical state of the patient, and EEGs showing brain death, the PET scans showed severe and generalized decreased metabolic activity of cortex confirming vegetative state. Therefore, the PET scan ruled out the diagnosis of brain death (Figure 6).

Discussion

Death by neurological criteria is described in 2 categories: “whole brain” death and “brainstem” death. Unlike whole brain death, in which inactivation in all parts of the brain is needed to make the diagnosis, brainstem death relies on the absence of brainstem activity. In case of brainstem death, the remaining brain function does not result in any degree of consciousness.¹³

In Iran, brain death diagnosis is based on whole brain death. Therefore, after clinical examination (including an apnea test), 2 EEGs, 6 hours apart, must be recorded. The legal diagnosis is finalized by judgment from Ministry of Health-approved specialists. These specialists include a neurologist, a neurosurgeon (or 2 neurologists), an internal medicine specialist, an anesthesiologist, and a forensic medicine specialist.^14,15

Brain death diagnosis is based on clinical examination. Several conditions mimic brain death, including hypothermia, locked-in syndrome, and drug intoxication. In the event of hypothermia, the brainstem clinical examination is disrupted. In the case of locked-in syndrome, the clinical examination must be in favor of brain death due to quadriplegia and anarthria. However, complementary vascular imaging is indicated to determine diagnosis of locked-in syndrome. Intoxications by drugs, such as opioids, barbiturates, tricyclic antidepressants, and benzodiazepines, interrupt brainstem reflexes and may culminate in falsely positive clinical examination results for brain death diagnosis.¹⁶

Time is invaluable for organ donation; therefore, it is critical to finalize the diagnosis of brain death as soon as possible. In circumstances where prerequisites for clinical examination are not fulfilled, ancillary tests become crucial.4 Brain death diagnosis in pediatric cases is another critical area to bear in mind. Precise and vigilant assessment is recommended to diagnose brain death in children. A minimum of 24 hours of observation for infants under 30 days old and 12 hours for older children is recommended with clinical examination, including an apnea test, done twice at the start and the end of the observation period. Given an emergency where observation is not feasible, ancillary tests permit the definitive diagnosis of brain death.¹⁷ Various factors determine the preferentiality of specific ancillary tests, including noninvasiveness, portability, operator friendliness,¹⁸ and operator independence.^19,20

Modalities such as CT scans and magnetic resonance imaging (MRI) reveal characteristic features in brain death cases. Nevertheless, these findings are not always detectable. Concerning brain CT scans, cerebral edema and a midline shift above 10 mm are the classic findings in brain death cases.²¹ Gray matter-to-white matter Hounsfield attenuation ratio is another indicator of brain death. The gray matter-to-white matter Hounsfield attenuation ratio of <1.18 is 100% predictive of brain death. Latency of these imaging findings is a weak point, as the brain death diagnosis may be clinically made, whereas the imaging findings would not indicate brain death.²² On MRI, brain herniation and edema along with narrowing of ventricles can commonly be seen in brain death cases.¹⁹ Magnetic resonance spectroscopy frequently delineates an accumulation of lactate and other metabolites in the event of brain death; however, these findings are not limited to brain death.²³

Transcranial Doppler as an ancillary test presents greater availability; according to a systematic review and meta-analysis, it has 89% sensitivity and 98% specificity. Transcranial Doppler evaluates the common carotid artery and basilar blood flow. It does not assess brainstem activity and therefore has to be done together with a clinical examination.²⁴ False positivity has been recorded in a previous study in which the TCD result favored brain death; nonetheless, the patient’s level of consciousness had raised after a few days.²⁵ Another study reported respiratory attempts during apnea test in a suspected brain death patient with a TCD result in favor of brain death.²⁶ The sensitivity of this method is affected by certain surgical procedures such as decompressive hemicraniectomy and external ventricular device placement.²⁷ These procedures are commonly conducted on patients with a high probability of brain death, such as patients with an intracranial hemorrhage diagnosis.

Cerebral angiography is the gold standard of brain death diagnosis and can best be exploited as an ancillary test when the clinical examination is not feasible.28 On the one hand, this method is specific and takes only 30 to 60 minutes to be completed.²⁹ On the other hand, it is an expensive and invasive test that only a neuroradiology specialist should perform. Moreover, it imposes the risk of vessel impairment during placement of the catheter. In addition, donatable organs such as kidneys may be damaged by the iodine contrast. Another major downside of this method is the need to transfer suspected brain-dead patients with unstable hemodynamics to the radio-interventional depart-ment for cerebral angiography. Although cerebral angiography has been verified as the “gold standard,” false negatives have been reported.²³ These false-negative cases include patients who have undergone various surgical procedures such as craniotomy with or without external ventricular drain placement and orthopedic procedures. False positives have also been reported in patients with persistent hypotension.³⁰

In contrast to cerebral angiography, CT angiog-raphy has been demonstrated as a promising ancillary test, especially in European countries, owing to its superior accessibility and noninvasiveness.10 Cellular damage is still possible in CT angiography. This is because of the use of iodine contrast material for this method.⁹ In addition, false-positive brain death diagnosis by CT angiography has been reported. In a notable recent case, a divergence of CT angiography and TCD results was reported con-cerning the diagnosis of brain death in a 31-year-old woman with subarachnoid hemorrhage.¹²

Magnetic resonance angiography detects intracra-nial arterial flow by detecting gadolinium.³¹ The contrast can damage the donatable kidneys. Insufficient data support this ancillary test for diagnosing brain death. Slow cerebral blood flow and intracranial pressure reduction procedures like craniotomy can affect the sensitivity of this test. The need to transfer hemodynamically unstable suspected brain-dead patients to interventional centers and the time-consuming scans are some of the other disadvantages.

Single-photon emission CT (SPECT) is another ancillary test that assesses brain metabolism and blood flow. Brain scintigraphy displays a “hollow skull” phenomenon as a result of no brain and cerebellum radionuclide (like technetium-99m hexamethyl propylene amine oxime) uptake.³²

This test can have high sensitivity in diagnosis of brain death, but its access is limited. A SPECT view can miss posterior fossa activity and therefore result in false positive outcomes. There are some other modalities that can evaluate brain death, but inadequate data are available to suggest them as ancillary tests. Radionuclide angiography assesses cerebral perfusion with radionuclide contrast that spares the kidneys.³³ This test is not widely available and is not an adequate ancillary test because it has limitations in analyses of the posterior fossa, brain stem function, and blood flow; in addition, clinical examination is always needed for a definite diagnosis. Another test is radionuclide perfusion scintigraphy, which evaluates brain metabolism by assessing isotope uptake. It requires patient transfer to an interventional center, and the test is not available in many centers. Magnetic resonance spectroscopy shows neuronal pathways and cells by detecting changes in lactate levels and also sodium- and phosphorus-based methods. These changes are not specified to brain death. Magnetic resonance spectroscopy does not count as an ancillary test because of the lack of studies done on this matter. A noninvasive CT scan with contrast is the xenon gas CT scan. Low-xenon cerebral blood flow can demonstrate brain death. However, further evaluation of this method is needed; in addition, only a few academic centers in North America have this facility.³³

Our study suggests that PET scans can be used as an ancillary method when prior diagnostic efforts have not been conclusive. Indeed, a PET scan evaluates the activity of all brain cells and can be a reliable test of choice in the diagnosis of whole brain death. This test has been proposed as an ancillary test in the relevant literature. In a previous case report, 18F-FDG PET/CT was done as an ancillary test to confirm brain death in an 8-year-old girl.³⁴ Clinical examination favored brain death, and a brain CT scan demonstrated diffuse cerebral edema. A Tc-99m diethylenetriaminepentaacetic acid scan (dynamic and static scintigraphic images) had been done 2 days before the 18F-FDG PET/CT was done. The latter showed a hollow skull phenomenon. This study stated that the absence of 18F-FDG collection in the brain is an alternative indirect way to reject the presence of intracranial circulation, thus confirming brain death. In another previous study of an 18-year-old woman with clinically diagnosed brain death and brain CT scan exhibiting general edema in the cerebrum, a lack of 18F-FDG uptake was shown in the brain.³⁵

The PET scan offers the possibility to differentiate brain death from other conditions that mimic brain death. Even in the case of hypothermia and drug intoxications where reflexes are feeble and clinical examination is not trustworthy, a PET scan holds promise to disclose brain activity and exclude brain death. In a recent study on locked-in syndrome patients, PET results showed brain activity and FDG accumulation. A low level of activity in the brainstem, cerebellum, and left thalamus and yet preserved activity in supratentorial parts were shown.³⁶ In our study, we reviewed brain death diagnosis processes in 6 different cases with various mechanisms. Pathophysiological mechanisms, such as intoxication, intracranial hemorrhage, and craniotomy procedure, may lead to deep coma and simultaneously interfere with clinical examination of brain death. We also assessed brain death in a pediatric case with significant diagnostic difficulties. Another aspect is the hemodynamic profile of patients with suspected brain death, where hemodynamic compromise may give rise to false and misleading results. Such patients are not eligible for the apnea test, which consists of a pivotal clinical examination section of brain death. The PET scan can be used as a powerful diagnostic tool to assess brain death in the face of such challenges. A PET scan illustrating a hollow skull phenomenon is strong evidence suggestive of brain death.¹⁶

Conclusions

False-negative and false-positive results have been reported by cerebral angiography. On the other hand, it is an expensive and invasive test that possibly can have harmful effects from iodine contrast.

The PET/CT scan is presently more readily available, especially in referral medical centers. In present study, we had no false-positive or false-negative results, indicating that it is a potential gold standard ancillary test in such centers, especially in OPUs. Nevertheless, there is ample ground for future research on the determination of sensitivity and specificity of this method as a gold standard ancillary test for brain death diagnosis.

References:

1. Greer DM, Shemie SD, Lewis A, et al. Determination of brain death/death by neurologic criteria: the world brain death project. Jama. 2020;324(11):1078-1097.
   CrossRef - PubMed
   
2. Danzl DF, Pozos RS. Accidental hypothermia. N Engl J Med. 1994;331(26):1756-1760. doi:10.1056/NEJM199412293312607.
   CrossRef - PubMed
   
3. Zanelli S, Buck M, Fairchild K. Physiologic and pharmacologic considerations for hypothermia therapy in neonates. J Perinatol. 2011;31(6):377-386. doi:10.1038/jp.2010.146
   CrossRef - PubMed
   
4. Machado C, Jeret JS, Shewmon DA, et al. Evidence-based guideline update: Determining brain death in adults: report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology. 2011;76(3):307-309. doi:10.1212/WNL.0b013e3181fe7359
   CrossRef - PubMed
   
5. Busl KM, Greer DM. Pitfalls in the diagnosis of brain death. Neurocrit Care. 2009;11(2):276-287.
   CrossRef - PubMed
   
6. Spinello IM. Brain death determination. J Intensive Care Med. 2015;30(6):326-337. doi:10.1177/0885066613511053
   CrossRef - PubMed
   
7. Buchner H, Schuchardt V. Reliability of electroencephalogram in the diagnosis of brain death. Eur Neurol. 1990;30(3):138-141. doi:10.1159/000117330
   CrossRef - PubMed
   
8. Ducrocq X, Braun M, Debouverie M, Junges C, Hummer M, Vespignani H. Brain death and transcranial Doppler: experience in 130 cases of brain dead patients. J Neurol Sci. 1998;160(1):41-46. doi:10.1016/s0022-510x(98)00188-9
   CrossRef - PubMed
   
9. Wijdicks EF. Brain death worldwide: accepted fact but no global consensus in diagnostic criteria. Neurology. 2002;58(1):20-25. doi:10.1212/wnl.58.1.20
   CrossRef: https://doi.org/10.1212/WNL.58.1.20
   PubMed: https://pubmed.ncbi.nlm.nih.gov/11781400/
10. Munari M, Zucchetta P, Carollo C, et al. Confirmatory tests in the diagnosis of brain death: comparison between SPECT and contrast angiography. Crit Care Med. 2005;33(9):2068-2073. doi:10.1097/01.ccm.0000179143.19233.6a
    CrossRef - PubMed
    
11. Wijdicks EF. The case against confirmatory tests for determining brain death in adults. Neurology. 2010;75(1):77-83. doi:10.1212/WNL.0b013e3181e62194
    CrossRef - PubMed
    
12. Greer DM, Strozyk D, Schwamm LH. False positive CT angiography in brain death. Neurocrit Care. 2009;11(2):272-275. doi:10.1007/s12028-009-9220-1
    CrossRef - PubMed
    
13. Wijdicks EF. The clinical determination of brain death: rational and reliable. Semin Neurol. 2015;35(2):103-104. doi:10.1055/s-0035-1547531
    CrossRef - PubMed
    
14. Nozary Heshmati B, Tavakoli SAH, Mahdavi?Mazdeh M, Zahra S. Assessment of brain death of organ donors in Iran. Transpl Int. 2010;23(5):e7-9. doi:10.1111/j.1432-2277.2010.01060.x
    CrossRef - PubMed
    
15. Ghods AJ. The history of organ donation and transplantation in Iran. Exp Clin Transplant. 2014;12(suppl 1):38-41.
    CrossRef - PubMed
    
16. Rizvi T, Batchala P, Mukherjee S. Brain death: diagnosis and imaging techniques. Semin Ultrasound CT MR. 2018;39(5):515-529. doi:10.1053/j.sult.2018.01.006
    CrossRef - PubMed
    
17. Nakagawa TA, Ashwal S, Mathur M, et al; Society of Critical Care Medicine; Section on Critical Care and Section on Neurology of the American Academy of Pediatrics; Child Neurology Society. Guidelines for the determination of brain death in infants and children: an update of the 1987 Task Force recommendations. Crit Care Med. 2011;39(9):2139-2155. doi:10.1097/CCM.0b013e31821f0d4f
    CrossRef - PubMed
    
18. Palmer S, Bader MK. Brain tissue oxygenation in brain death. Neurocrit Care. 2005;2(1):17-22. doi:10.1385/NCC:2:1:017
    CrossRef - PubMed
    
19. Young GB, Lee D. A critique of ancillary tests for brain death. Neurocrit Care. 2004;1(4):499-508. doi:10.1385/NCC:1:4:499
    CrossRef - PubMed
    
20. Bernat JL. The concept and practice of brain death. Prog Brain Res. 2005;150:369-379. doi:10.1016/S0079-6123(05)50026-8
    CrossRef - PubMed
    
21. Dominguez-Roldan JM, Jimenez-Gonzalez PI, Garcia-Alfaro C, Hernandez-Hazañas F, Murillo-Cabezas F, Perez-Bernal J. Identification by CT scan of ischemic stroke patients with high risk of brain death. Transplant Proc. 2004 Nov;36(9):2562-2563. doi:10.1016/j.transproceed.2004.11.071
    CrossRef - PubMed
    
22. Geraghty MC, Torbey MT. Neuroimaging and serologic markers of neurologic injury after cardiac arrest. Neurol Clin. 2006;24(1):107-121. doi:10.1016/j.ncl.2005.10.006
    CrossRef - PubMed
    
23. Monsein LH. The imaging of brain death. Anaesth Intensive Care. 1995;23(1):44-50. doi:10.1177/0310057X9502300109.
    CrossRef - PubMed
    
24. Chang JJ, Tsivgoulis G, Katsanos AH, Malkoff MD, Alexandrov AV. Diagnostic accuracy of transcranial Doppler for brain death confirmation: systematic review and meta-analysis. AJNR Am J Neuroradiol. 2016;37(3):408-414. doi:10.3174/ajnr.A4548
    CrossRef - PubMed
    
25. Nagai H, Moritake K, Takaya M. Correlation between transcranial Doppler ultrasonography and regional cerebral blood flow in experimental intracranial hypertension. Stroke. 1997;28(3):603-608. doi:10.1161/01.str.28.3.603
    CrossRef - PubMed
    
26. Dosemeci L, Dora B, Yilmaz M, Cengiz M, Balkan S, Ramazanoglu A. Utility of transcranial Doppler ultrasonography for confirmatory diagnosis of brain death: two sides of the coin. Transplantation. 2004;77(1):71-75. doi:10.1097/01.TP.0000092305.00155.72
    CrossRef - PubMed
    
27. Thompson BB, Wendell LC, Potter NS, et al. The use of transcranial Doppler ultrasound in confirming brain death in the setting of skull defects and extraventricular drains. Neurocrit Care. 2014;21(3):534-538. doi:10.1007/s12028-014-9979-6
    CrossRef - PubMed
    
28. Heiskanen O. Cerebral circulatory arrest caused by acute increase of intracranial pressure. A clinical and roentgenological study of 25 cases. Acta Neurol Scand Suppl. 1964;40:1-57.
    CrossRef - PubMed
29. Shemie SD, Doig C, Dickens B, et al. Severe brain injury to neurological determination of death: Canadian forum recommendations. CMAJ. 2006;174(6):S1-S13. doi:10.1503/cmaj.045142
    CrossRef - PubMed
    
30. Alvarez LA, Lipton RB, Hirschfeld A, Salamon O, Lantos G. Brain death determination by angiography in the setting of a skull defect. Arch Neurol. 1988;45(2):225-227. doi:10.1001/archneur.1988.0052026011703
    CrossRef - PubMed
    
31. Spears W, Mian A, Greer D. Brain death: a clinical overview. J Intensive Care. 2022;10(1):1-16. doi:10.1186/s40560-022-00609-4
    CrossRef - PubMed
    
32. Corrêa DG, de Souza SR, Nunes PG, Coutinho AC, da Cruz LC. The role of neuroimaging in the determination of brain death. Radiol Bras. 2022;55(6):365-372. doi:10.1590/0100-3984.2022.0016
    CrossRef - PubMed
    
33. Henderson N, McDonald M. Ancillary studies in evaluating pediatric brain death. J Pediatr Intensive Care. 2017;6(4):234-239. doi:10.1055/s-0037-1604015
    CrossRef - PubMed
    
34. Ozdemir S, Tan YZ, Ozturk FK, Battal F. Confirmation of brain death with positron emission tomography. J Pediatr Intensive Care. 2020;9(01):51-53. doi:10.1055/s-0039-1696652
    CrossRef - PubMed
    
35. Meyer MA. Evaluating brain death with positron emission tomography: case report on dynamic imaging of 18F-fluorodeoxyglucose activity after intravenous bolus injection. J Neuroimaging. 1996;6(2):117-119. doi:10.1111/jon199662117
    CrossRef - PubMed
    
36. Schnakers C, Perrin F, Schabus M, et al. Detecting consciousness in a total locked-in syndrome: an active event-related paradigm. Neurocase. 2009;15(4):271-277. doi:10.1080/13554790902724904
    CrossRef - PubMed