My name is Rajiv Garg, and I'm an Associate Professor of Neurologic Sciences in the Division of Critical Care Neurology and Section of Cognitive Neurosciences at Rush University Medical Center in Chicago. Over the next 20 minutes, I will be speaking to the audience on the declaration of brain death. As a neurointensivist, I am unfortunately faced with diagnosing brain death both in my own patients as well as patients in other intensive care units that have succumbed to their severe critical illness. What I hope to leave everyone with today are the essentials on the clinical assessment of death by neurologic criterion and potential pitfalls in approaching a patient you suspect is brain dead. With this in mind, we will achieve the following objectives with this talk. First, we will review the definition of brain death, which may seem to be intuitive. In reality, the definition of brain death can have significant variability depending on which country, state, or hospital you practice in. Second, we will review the bedside approach to the clinical assessment of a patient who is believed to be brain dead. This will be followed by the indications and the best evidence for the use of ancillary testing for the declaration of brain death. And finally, I would like to say some brief words on several special topics related to brain death that you may all face in your own practice. I do want to qualify that most of the talk will be based on best practice guidelines here in the United States. However, there is growing literature to standardize the approach to the declaration of brain death, so much of what I will present will hopefully be applicable to your own practice. With that said, I encourage all members of the audience to take this talk as a foundation that you can use within the rules and regulations of your own state, region, or country. It's important that we begin by discussing the definition of brain death. For critical care specialists, the definition of brain death is important both medically and legally. In 1981, the United States President's Commission for the Study of Ethical Problems in Medicine and Biomedical and Behavioral Research proposed a model statute to foster uniformity in the declaration of brain death. The commission was tasked with defining death so it could be applied to legal and medical practices. The commission defined two alternative physiologic standards of death. The first, which most will not dispute, is the irreversible sensation of circulatory and respiratory functions. The second is the irreversible sensation of all functions of the entire brain, including the brainstem. The second definition was needed given the advances in cardiopulmonary support in our field that could support a patient who was in fact dead. As you can imagine, this definition also had important implications for organ donation. And the second definition is particularly important in that the commission differentiated concepts of whole brain death versus brainstem death. In other words, a patient without evidence of brainstem function but intact cerebral cortical activity could not be considered brain dead. As we will discuss later, while the whole brain death concept is the standard used in the United States, several countries utilize the concept of brainstem death in the law for the declaration of brain death. Therefore, the legal definition of brain death, depending upon where you live, may not meet the currently accepted medical concept of a whole brain death in defining brain death. Most if not all of the guideline recommendations for the diagnosis of brain death stem from the American Academy of Neurology and their publication in 2010. Despite these guidelines, there continues to be much local, regional, and international variability in the diagnosis of brain death. An example here within the United States is that of a story of a young girl by the name of Jahi McMath, who was declared brain dead and therefore declared dead by California law. However, the family had the patient transferred to New Jersey where local state law allows for families to require, on religious grounds, that death can only be declared by cardiopulmonary arrest instead of brain death. This allowed the patient to be kept alive on life support in her apartment with 24-7 care until her eventual cardiopulmonary death five years later. Given this heterogeneity, a group of both adult and pediatric intensivists and investigators initiated the World Death Project, which was an attempt to formulate consensus guidelines for the determination of brain death. The World Death Project was an international consensus statement of five world federations and 27 medical societies. If there's one take-home point I can make for this lecture, that would be to get a copy of the World Death Project, which was published in JAMA 2020, and review it. Despite relatively broad medical consensus, the diagnosis of brain death still is subject to legal considerations that will likely take longer to resolve. Moving on to the clinical assessment for the determination of brain death, performing the brain death examination requires a working knowledge of neuroanatomy, neuroimaging, and the bedside neurologic examination. And this is another important take-home point, that despite all of our technological advances, the neurologic examination still remains the gold standard for the determination of brain death. Therefore, it is imperative that a proper and thorough neurologic examination is conducted prior to the declaration of brain death. There is limited training amongst critical care specialists on the clinical approach to declaring brain death, and that largely depends on the scope of one's practice and how often they perform brain death evaluations. Most of what is learned about brain death is through didactics, simulations, and direct supervision by senior faculty during one's training. Pre-education, however, is key for providers who may not be performing brain death assessments on a regular basis. Recently, the Neurocritical Care Society created a brain death determination toolkit, which has been endorsed by the American Academy of Neurology, to supplement the clinical training obtained by clinicians who are involved in brain death testing. In addition, it remains important for healthcare providers to be knowledgeable of the rules and regulations and laws that govern this topic both at the institutional, state, and country. When brain death is suspected in a patient, several prerequisites need to be met before proceeding with formal brain death testing. First and foremost, the patient must be comatose due to an irreversible and proximate cause with continued cardiac and pulmonary function. This assessment is based on a combination of the clinical history, the presenting illness or injury, and supportive neuroimaging. Therefore, a patient who is comatose with normal neuroimaging needs to be re-evaluated as to the reason for the patient's coma. An example is a patient who develops Fulminum Guillain-Barre. While the patient may have no findings on neurologic examination, as well as an absent respiratory function, the imaging of their brain will be normal since this is an acute polyneuropathy. Therefore, this patient would not meet prerequisite criteria for brain death or brain death testing. Similarly, it is important that patients who might have received a neuromuscular blocking agent for management are appropriately tested via peripheral nerve stimulation to ensure return of normal muscular function. In addition, underlying causes for coma can be confounded by toxic, metabolic, or hemodynamic derangements. Even low doses of as-needed sedatives, severe electrolyte derangements, and poor perfusion may have profound effects on the level of consciousness of a brain-injured patient. Therefore, it is important to exclude these confounders since they may alter the patient's examination and your clinical outcome. Once a patient is found to be in coma due to a neurologic injury with supportive neuroimaging, it is also important to evaluate the patient for several other factors that may preclude further brain death testing and require ancillary testing. High cervical spine injury would prevent one from testing the oculocephalic reflex or raise the possibility that the patient's inability to breathe during their apnea challenge is due to a cervical spine injury rather than brainstem dysfunction. The patient's temperature has to be a minimum of 36 degrees Celsius or 96.8 degrees Fahrenheit since this can influence the patient's mentation and blunt neurologic reflexes. It is not uncommon that patients that are being tested for brain death have external warming applied in order to raise their core body temperature to meet this target. The patient's systolic blood pressure and mean arterial pressure need to be adequate enough to ensure appropriate cerebral perfusion if present. While the American Academy of Neurology guidelines suggest a systolic blood pressure of 100 mmHg, the World Brain Death Project guidelines suggest either this target or a mean arterial pressure greater than 60 mmHg. And finally, the patient should be made euvolemic with fluid resuscitation if necessary. Brain death patients may experience central DI with significant volume loss, hypovolemia, and hypotension, complicating adequate cerebral perfusion, and further provoking hemodynamic instability during the apnea challenge. After the necessary prerequisites are met, formal brain death testing can begin. We begin the neurologic examination with the evaluation of the pupillary reflex to assess cranial nerve 2 or the ophthalmic nerve. The goal is to evaluate for direct and consensual response to bright light. Using a bright and focused light, a single eye is evaluated with both eyes held open to see if there is a pupillary response with either direct pupillary constriction and or consensual response. The same procedure is done with the opposite eye. Infrared pupillometry has become a modern bedside tool to evaluate for pupillary response and may detect subtle responses that are not visible to the examiner. It is important to take your time with this test since pupillary reflexes can be delayed in patients with brain injury. In addition, the presence of corneal or lenticular classification may obscure accurate assessment of the pupillary light reflex. If a pupillary response cannot be established in one eye, then a patient cannot be declared dead by physical examination alone, and ancillary testing is warranted. Following this, one has to assess cranial nerve 3, the oculomotor nerve, cranial nerve 6, the abducens nerve, and cranial nerve 8, the vestibulocochlear nerve. This is done by performing the oculocephalic reflex or doll's eyes maneuver. As an aside, for historical reasons, the reflex should be more appropriately referred to as the cephaloocular reflex, but most of the literature continues to refer to this as the oculocephalic reflex, which we will utilize for purposes of this talk. Again, we have to ensure that the patient does not have any concerns for cervical spine injury. Suspicion for cervical spine injury precludes the use of this exam maneuver. In this test, the patient's head is held by one hand over the forehead, using your thumb and index finger to open both eyelids. The other hand is used to secure the endotracheal tube to prevent accidental dislodgement. The head is turned rapidly to the left and right in the horizontal plane to assess for ocular movement. An intact oculocephalic reflex would produce conjugate eye movement in the direction opposite the movement of the head. Movement of one eye would suggest partial preservation of the brainstem pathways. Absence of movement would support diagnosis of brain death. Here is a visual schematic that shows the normal response to the oculocephalic maneuver. The patient's eyes deviate in the direction opposite to the direction of the head being turned. As a matter of personal practice, I also assess vertical oculocephalic reflexes by moving the head vertically to see if the eyes move conjugately in the vertical plane opposite the head movement. While this is not required in the guidelines for brain death testing, the absence of vertical eye movements reduces the likelihood of missing a patient who has locked-in syndrome, which may appear similar to brain death if the patient's level of consciousness is affected by unknown factors. The oculovestibular reflex, also referred to as cold clorox, is an additional maneuver used to ensure the accuracy of the oculocephalic response. It is a more potent stimulus to horizontal conjugate eye movement. In addition, it is the test of choice to utilize when concerned about cervical spine injury. A patient's external auditory canal should be inspected to ensure there is no obstruction from cerumen. The absence of tympanic membrane integrity does not preclude testing for cold clorox, but it may increase the risk for introducing an inner ear infection. Basilar skull fractures may also impact the integrity of this test and may require the use of ancillary supportive testing. The patient's head of bed should be raised to 30 degrees to place the horizontal semicircular canals in a vertical position. In cold ice water, a syringe is used to instill anywhere from 30 to 60 cc's of fluid into the ear, holding the eyelids open to examine for ocular movements. A normal response is a deviation of the eyes towards the direction of the cold stimulus. A period of 5 minutes should be given before injecting the contralateral ear to allow the temperature to normalize in the ear just injected. The same test should be repeated in the contralateral ear with visualization of response. Of note, ocular response may be delayed by several minutes, so time should be given before considering these reflexes are absent, which is defined as no movement of the eyes. Given the importance of the inner ear in eliciting this reflex, the absence of cold clorox response but preservation of oculosyphallics may be due to otolith dysfunction and would not be consistent with the diagnosis of brain death. Cranial nerve 5, the trigeminal nerve, and cranial nerve 7, the facial nerve, are assessed through several different examination maneuvers. The most well-known is the corneal reflex, where a gentle stimulus is placed across the cornea of each eye to assess for a blink response. Cotton swabs are commonly used, but as a matter of personal practice, I'll distill a drop of cold saline into the eye to avoid the risk of corneal abrasion. It has been argued that cotton swabs provide a more important stimulus and therefore should be the tool of choice, however examination of CGRP activity, which coordinates nociception of the cornea, appears similar between saline and tactile stimulation. In addition, the assessment of jaw jerk by striking the examiner finger placed on the chin to look for jaw closure, or pressure placed on the supraorbital or temporomandibular joint to look for facial grimace, provide assessment of trigeminal and facial nerves. Finally, cranial nerve 9, the glossopharyngeal nerve, and cranial nerve 10, the vagus nerve, are assessed through the gag and cough reflex. The gag reflex is done by stimulation of the posterior pharyngeal wall bilaterally with a tongue depressor or suction catheter. For the cough reflex, deep inline suctioning via the endotracheal tube to the level of the crina is utilized to evaluate for a cough response. The absence of a gag or cough reflex is supportive of the diagnosis of brain death. Next, we examine the presence of motor response in the patient by providing noxious stimulation to the upper and lower extremities. In my practice, I will always apply noxious stimuli both proximally and distally to avoid a distal sensory peripheral neuropathy confounding this examination. In addition, pressure on the superorbital notch bilaterally, the sternal notch, and the temporomandibular joint can also be assessed to evaluate for movement to noxious stimulus. It is important to differentiate reflexes produced at the level of the spinal cord, which are often stereotypical, versus movements that may localize to the cerebral cortex. The absence of cerebral-mediated reflexes is supportive of the diagnosis of brain death. After performing a detailed neurologic examination without evidence of neurologic function, one can state that the patient's examination is supportive but not conclusive for the diagnosis of brain death. In addition, the apnea challenge cannot be done alone to declare someone is brain dead. One must proceed to apnea testing after a complete neurologic examination to confirm death by neurologic criterion. It is recommended to place an arterial line since rapid and timely blood gasses are needed. This also serves as a way to monitor the patient's hemodynamics during the challenge. The patient should be pre-oxygenated with 100% Fi2 for approximately 10 minutes to allow for prolonged apnea. In addition, one should have a source of continuous O2 to provide the patient once they are disconnected from the ventilator. The patient is then placed on CPAP or disconnected from the ventilator with oxygen sufflation at 100% FiO2. When kept on the ventilator, it is important to ensure that chest wall movement due to cardiac pulsation does not inadvertently trigger a supported ventilator breath. The goal is to observe for spontaneous respiration for 8-10 minutes. In addition, arterial blood gasses are obtained every 2-3 minutes until reaching the following criteria, either a PaCO2 greater than 60 mmHg or a greater than or equal to 20 mmHg increase in PaCO2 from baseline. New per the World Death Project is also criteria for a pH of less than 7.30, which should trigger ventilation centrally at the level of the medulla. The absence of spontaneous respiration along with meeting of the above pH and or PaCO2 criteria would suggest apnea. In the setting of a neurologic examination that is supportive of brain death, an apnea challenge without spontaneous respiration would be confirmatory. Occasionally, the apnea challenge has to be aborted due to evidence of spontaneous respiration or cardiopulmonary instability that prevents continuation of the apnea challenge. Contraindications include hypotension, which sometimes can be managed with vasopressors, hypoxemia or cardiac arrhythmias. If any of these do occur during the apnea challenge, then the challenge must be aborted. It is up to the clinician to address the underlying issues and decide whether repeating the apnea challenge versus proceeding with ancillary testing is warranted. In cases where the declaration of brain death cannot be made solely based on the neurologic examination or the apnea challenge, clinicians have several ancillary tests available that can help confirm the diagnosis. Ancillary testing is supplemental to the neurologic examination, which still should be completed to the greatest extent possible. Ancillary testing does not replace the neurologic examination. However, it is worth noting that in some countries, ancillary testing is still required even if the neurologic examination and apnea challenge are consistent with brain death. Blood flow based methodology including digital subtraction angiography, radionuclide studies and transcranial dopplers are currently recommended. Radial subtraction angiography is considered the gold standard but does require patient stability and other resources including an anesthesiologist and endovascular team. Radionuclide studies are limited depending on availability and patient stability. SPECT imaging requires patient transport to a scanner. Essentially for both SPECT and planar scintography, a radioactive isotope is administered that indicates brain activity. Since cerebral blood flow is coupled to cerebral metabolic activity, care must be taken in using the study when given to a patient that's received a medication such as pentobarbital that can cause electrocerebral silence. Transcranial dopplers continue to remain a tool to assess for the absence of cerebral perfusion. However, they are highly operator dependent and select patients such as elderly female patients may not have acoustic windows to allow for appropriate blood flow assessment. While previously supported by the American Academy of Neurology, CTA and MRA has recently been removed from the World Death Project guidelines given the limited data on their sensitivity and specificity in brain death. More research in determining the agility in ancillary brain death testing is still needed. Electroencephalography, while supported by the American Academy of Neurology, has been removed from the World Death Project guidelines. It predominantly assesses cortical activity with limited information on brain stem activity. There's also concerns about electromagnetic interference from the ICU environment that can erroneously suggest cerebral electrical activity. And finally, EEG findings can be confounded by a whole host of toxins and metabolic arrangements that may make interpretation difficult in a patient with limited history. Finally, there are regional differences in how EEGs are interpreted with respect to brain death. Despite this, some regions require EEG to be part of the brain death assessment regardless of the neurologic examination and apnea challenge. In these situations, it is recommended that EEG be done in conjunction with somatosensory evoked potentials and brain stem auditory evoked potentials to evaluate brain stem. And finally, I would like to highlight a few special situations in brain death that in and of themselves be separate lectures. Brain death determination and the apnea challenge can be performed on patients on ECMO. During brain death and ECMO, patients is approached similarly with respect to the neurologic examination, but special attention and knowledge needs to be given to the workings of ECMO as it relates to apnea testing. The timing of brain death determination needs to be carefully considered in patients who have sustained cardiac arrest and require therapeutic temperature management. Normalization of neurologic reflexes can be delayed in patients that undergo therapeutic temperature management after cardiac arrest. Therefore, timing of a brain death evaluation needs to be carefully assessed. Patients with acute respiratory distress syndrome can be particularly challenging with respect to the apnea challenge. However, the use of recruitment maneuvers, PEEP, and proper CPAP settings has been described in the literature in order to perform an apnea challenge safely. Also important is the critical care support that needs to be provided to patients after declaration of brain death, specifically for patients of consented organ donation. The development of catastrophic brain injury protocols provide hemodynamic support to patients, help in organ preservation until procurement. And finally, pediatric criteria for determination of brain death, while similar, are different given children may potentially have delayed recovery. For this subject matter, I defer to my pediatric intensive care colleagues who can speak about this topic at a much more precise level than myself as an adult practitioner. In conclusion, the declaration of brain death requires a careful assessment of the patient's history, laboratory data, and neuroimaging to exclude potential confounders to brain death. The neurologic examination, along with the apnea challenge, remain the gold standard for the declaration of brain death. And finally, an understanding of the various ancillary tests and their limitations is important in order to utilize them in the assessment of brain death. As the World Death Project continues to publish on this topic, my hope is that it will harmonize international guidelines and allow for a more consistent approach to these patients. These are my references. I thank you for your time and attention, and I will be happy to take any of your questions.

brain death

neurologic examination

gold standard

ancillary testing

ECMO

organ donation