Continuing Education Activity

Brain death, both a legal and clinical term, has been present in medical literature and texts for many years and was defined by the Uniform Determination of Death Act (UDDA) in 1981. This course is designed to equip healthcare professionals with a deep understanding of the multifaceted aspects of brain death, from its pathophysiology to its ethical and legal ramifications. The course primarily focuses on three core areas: the etiology and progression to brain death, distinguishing brain death from other states such as coma or vegetative state, and the comprehensive criteria and protocols for the diagnosis of brain death.

This course explores the latest standards and practices in diagnosing brain death, emphasizing clinical assessments, brainstem reflex testing, and the uses of ancillary tests. This activity aims to enhance the competence of healthcare professionals across disciplines, fostering an interprofessional approach to managing this challenging aspect of patient care. This activity will equip the healthcare team with the necessary knowledge and skills to effectively navigate brain death's clinical, ethical, and legal complexities, ensuring high-quality, compassionate care for patients and their families.

Objectives:

• Identify the etiology of brain death.

• Interpret the physical examination of a patient with a potential diagnosis of brain death.

• Apply the appropriate evaluations to a patient with a potential diagnosis of brain death.

• Communicate the importance of improving care coordination among interprofessional team members to ensure appropriate utilization of the legal and clinical definitions of brain death.

Introduction

Death is defined in the United States by the Uniform Determination of Death Act (UDDA), proposed in 1981. A determination of death must be made in accordance with the accepted medical standards and must additionally include one of the following:

1. Irreversible cessation of circulatory and pulmonary functions.
2. Irreversible cessation of all functions of the entire brain, including the brainstem, is dead. 

The UDDA was drafted in the late 1970s in response to medical advances in life support that allowed for complete circulatory and respiratory support despite complete cessation of brain function. The UDDA did not establish what "accepted medical standards" were; instead, only that they existed. The American Academy of Neurology (AAN) published the initial standards in 1995 and updated them in 2010 to the current standards. 

AAN's recent position statement on brain death endorses UDDA's death definition as "irreversible cessation of all functions of the entire brain, including the brainstem, has been determined by the demonstration of complete loss of consciousness (coma), brainstem reflexes, and the independent capacity for the ventilatory drive (apnea), in the absence of any factors that imply possible reversibility."[1] Irreversibility in the definition of death refers to the impossibility of recovery, regardless of any medical intervention, which requires clear elaboration, as with the advancement of mechanical ventilation and life support technologies during the 20th century, patients who suffered severe brain damage could be maintained physiologically for prolonged periods in intensive care units (ICUs).[2][3] AAN, in addition, believes "preserved neuroendocrine function may be present despite irreversible injury of the cerebral hemispheres and brainstem and is not inconsistent with the whole brain standard of death."[1]

In 2012, the World Health Organization (WHO) partnered with an international forum to endorse brain death as the official diagnosis of death.[4] However, internationally and even within different states of the United States, there is no uniformity to certify brain death. Brain death criteria also differ based on the patient's age. Therefore, different standards are in effect when performing a document of brain death, and the provider should be aware of their country/state's criteria for a specific patient's age. 

Distinguishing the term "brain death" from "coma" to the public is essential, as coma may imply a limited form of life. The understanding that brain death is equivalent to death helps guide decision-making for both physicians and patients' families regarding the withdrawal of care and prevents the unnecessary expenditure of resources. An essential topic that evolved in parallel with brain death is obtaining organs for transplantation. According to the "dead donor rule," organ procurement can occur only after death has been declared. Therefore, for patients who are brain dead, the procurement of viable organs is allowed, even if a patient still has some circulatory and pulmonary function. This concept continues to result in some ongoing debate and controversy.[5][6]

Differentiating brain death from other forms of severe brain damage, including vegetative state and minimally responsive state, is crucial.[7] In a vegetative state and minimally responsive state, some brain functions are maintained, resulting in a chance of recovery, even occasionally after prolonged periods, especially in patients with traumatic brain injury (TBI).

Etiology

Brain death occurs as a result of an acute catastrophic brain injury. Abrupt loss of cerebral perfusion occurs if a concomitant elevation of intracranial pressure exceeds the mean arterial pressure. The formula is as follows: cerebral perfusion pressure (CPP) = mean arterial pressure (MAP) - intracranial pressure (ICP). This process was studied by monitoring brain tissue oxygenation in patients with brain death and can occur via 2 different mechanisms: 

• Intracranial causes: In adults, the predominant intracranial injuries leading to brain death are traumatic brain injuries (TBI) and subarachnoid hemorrhage. These injuries elevate intracranial pressure (ICP), impair cerebral perfusion, and reduce brain tissue oxygenation, leading to neuronal damage. In pediatric cases, nonaccidental trauma is a common cause, contributing to increased ICP and subsequent brain injury.[8][9]
• Extracranial causes: In both adults and children, a significant extracranial cause of brain death is cardiopulmonary arrest with delayed or inadequate resuscitation.[10] This leads to prolonged cessation of cerebral blood flow, resulting in anoxia, cellular membrane pump failure, disturbed osmoregulation, and severe brain edema. The increased ICP within the confined space of the skull further compromises cerebral perfusion, exacerbating neuronal injury.

Epidemiology

The most common processes leading to brain death, in order of frequency, are cardiopulmonary arrest, TBI, subarachnoid hemorrhage, and intracerebral hemorrhage. Among extracranial causes, patients who experience cardiopulmonary arrest show a progression to brain death in 8.9% of cases post-resuscitation. For those presenting with TBI, the rate of progression to brain death ranges from 2.8% to 6.1%. Regarding intracranial etiologies, patients with a subarachnoid hemorrhage progress to brain death in 8.5% to 10.7% of cases, while those with intracerebral hemorrhage progress at a rate of 6.1% to 9.6%.[11][12] Notably, by definition, brain death is associated with a 100% mortality rate.

Pathophysiology

The physiology of brain death is similar regardless of the etiology. Inadequate tissue oxygenation leads to a progressive cascade of further edema, increasing intracranial pressure (ICP), a further decrease in cerebral perfusion and eventual herniation, or complete cessation of blood flow and aseptic necrosis of brain tissue. In anoxic brain injuries, inadequate cardiopulmonary resuscitation following a cardiopulmonary arrest, tissue hypoxia leads to the release of cytotoxic material that leads to progressive cerebral edema and eventually the cascade described above.

For TBIs or other intracranial injuries, increasing ICP leads to a decrease in CPP and prevents adequate oxygenation of neuronal tissues. This situation will result in further injury, edema, and, eventually, the process initially described above.[3][12]

Histopathology

Microscopic evaluation of postmortem brain-dead patients reveals varying degrees of neuronal ischemic changes. The hemispheric lobes and basal ganglia are the most common areas to experience severe ischemic change, followed by the pons, medulla oblongata, midbrain, and thalamus, respectively. Autolysis of the cerebellum can also be appreciated in many autopsies.[13]

History and Physical

Once the decision to proceed with the brain death determination has been made, three conditions must be present: coma, the absence of brainstem reflexes, and apnea.

Coma should be evaluated by ensuring a lack of responsiveness to noxious stimuli; no eye or motor reflex should be present in response to stimuli. Spinal-mediated reflex movements, including muscle stretch reflexes, may be compatible with brain death.[14] Additionally, the cause of the coma should be identified by neuroimaging, history, and physical examination or laboratory testing.

The following cranial nerve (CN) and brainstem reflexes should be tested in the physical examination of a patient eligible for brain death evaluation.[15] They all must be absent for a patient to be diagnosed as brain dead:

• CN II and III (pupillary light reflex): Pupils should be fixed, mid-size/dilated (4-9 mm), and not reactive to light. A magnifying glass or pupillometer can be used to evaluate further if the results are equivocal.[16]
• CN III, VI, VIII (oculovestibular reflex): The oculovestibular reflex can be tested using the oculocephalic reflex or caloric testing. When the oculocephalic reflex is absent, the eyes will turn in the same direction in which the head is turning (Doll's eyes). Testing for the oculocephalic reflex should only be performed in a patient with a stable cervical spine. Cold caloric testing may be performed by irrigation of one ear with 50 to 60 mL of ice water. An absent oculovestibular reflex is indicated by a lack of movement of the eyes towards the irrigated side within 1 minute. The contralateral ear should be tested after 5 minutes.[17]
• CN V and VII (corneal reflex): Loss of corneal reflex is determined by using a cotton swab or drops of water/normal saline.[18]
• CN IX (gag reflex): Loss of gag reflex is confirmed after stimulation of bilateral posterior pharyngeal membranes without elevation of the palate.       
• CN X (cough reflex): Loss of cough reflex is confirmed after tracheal suctioning without reaction.[19]

Evaluation

Before deciding to proceed with the diagnosis of brain death, several conditions must be evaluated and met:

• Evidence of an etiology of coma should be known. Confounding conditions should be excluded, including severe metabolic, endocrinologic, and acid-base derangements.[16][17]
• If a drug intoxication is suspected or if recent neuromuscular blocking agents have been administered, then five half-lives of drug clearance should be waited, with adjustment to renal and hepatic functions.
• The core temperature must be >36 °C.
• Systolic blood pressure (SBP) >100 mm Hg. Vasopressors may be administered if necessary.
• Neurologic examination (ie, brainstem reflexes): in most states in the United States, 1 attending physician examination is sufficient; however, some states require 2 physicians.

If the above conditions are present and there is an identified cause of coma and complete lack of brainstem reflex, you may proceed with apnea testing. Apnea testing should be reserved for last and only once the diagnosis of brain death is reasonably determined since elevating partial pressure carbon dioxide in arterial blood (PaCO₂) increases ICP and could precipitate cerebral herniation. 

Apnea testing is performed using the following procedure as recommended by the AAN.

• Vasopressors should be adjusted to maintain a SBP ≥100 mm Hg.
• Preoxygenation is given for at least 10 minutes with a 100% FiO₂ to a PaO₂ >200 mm Hg.
• Reduce ventilator frequency to 10 breaths per minute.
• Reduce positive end-expiratory pressure to 5 cm H₂O.
• If the SpO₂ remains >95%, obtain baseline blood gas.
• Disconnect the patient from the ventilator and preserve oxygenation with oxygen delivered through insufflation tubing given at 100% FiO₂ at 6 L per minute near the level of the carina through the endotracheal tube.
• Look for respiratory movements for 8 to 10 minutes.
• Repeat blood gas at approximately 8 minutes if no respiratory drive is observed.
• If no respiratory movements are observed, and PaCO₂ >60 mm Hg or 20 mm Hg increase in PaCO₂ over baseline (such as in chronic obstructive pulmonary disease), the apnea test result is positive. 

If the above list is completed, and coma, the absence of brainstem reflexes, and a positive apnea test are present, the diagnosis of brain death can be made. This procedure is validated and supported by several professional organizations.

The apnea test has to be aborted if:

• Any respiratory movement (abdominal or chest excursions or brief gasp) exists.
• SBP decreases to <90 mm Hg.
• Oxygen saturation is less than 85% for more than 30 seconds. If so, the procedure has to be retried with a T-piece, maintaining a continuous positive airway pressure (CPAP) of 10 cm H₂O and administration of 100% oxygen at 12 L/min.

Although not required for the diagnosis of brain death, hospitals frequently have additional ancillary tests available to confirm the diagnosis of brain death. Ancillary tests are used when apnea testing is inconclusive or patients are too unstable to proceed with apnea testing.[16][3] These tests include:  

• Cerebral angiography: Four-vessel angiography is the gold standard for cerebral blood flow evaluation. Angiography can confirm brain death when it shows a cessation of blood flow to the brain. Cerebral angiography's limitations include the test's invasiveness and transferring the patient to the radiology suite. Also, the contrast may induce nephrotoxicity, affecting the donor's kidney. False-negative tests can occur when ICP becomes lowered by surgery, trauma, or ventricular shunts.         
• Transcranial ultrasound (US): US can be used to assess bilateral pulsations of the middle cerebral, vertebral, basilar, anterior cerebral, or ophthalmic arteries. The transcranial US can confirm brain death by showing small peaked systolic pulsations or the absence of diastolic pulsations. Test limitations include the examiner's expertise, unsuitable windows due to thick temporal bones, and lowered ICP by surgery or ventricular shunts giving false-negative tests. 
• Computed tomography and magnetic resonance angiography of the brain may be used to show cessation of cerebral blood flow.                  
• Radionuclide brain imaging: This can be done using a 99mTc-labeled hexamethyl propylene amine oxime (HMPAO) isotope tracer and then imaging by single-photon emission computed tomography (SPECT) brain scintigraphy. The absence of a tracer in cerebral circulation (the hollow skull phenomenon) is consistent with brain death. The test may show false-positive results if imaging is done in one plane only instead of two planes (anterior and lateral).[17]
• Somatosensory evoked potentials (SSEPs): Patients with brain death show no somatosensory evoked potentials in response to bilateral median nerve stimulation and no brain stem evoked potentials in response to auditory stimuli.[16] SSEPs can confirm EEG findings, as it is less affected by drug intoxication; however, they can still be affected by hypothermia.[20][21]

Treatment / Management

Once brain death has been diagnosed, the patient is clinically and legally declared deceased at the time of completion of brain death testing. At this time, depending on family and patient preference, cardiopulmonary support should be withdrawn, or arrangements for organ harvest should commence. Adequate documentation of all criteria of the diagnosis of brain death must be included in the patient's medical record. It is recommended that some form of checklist be used to ensure the completeness of brain death testing.[10]

Differential Diagnosis

Several conditions may mimic brain death, including those listed below. 

• Vegetative state
• Minimally responsive state
• Locked-in syndrome[22]
• Hypothermia
• Drug intoxication
• Guillan-Barre syndrome
• Delayed paralytic clearance

The clinicians should perform a clinical evaluation to exclude these conditions before proceeding with the brain death examination. It is essential to differentiate between coma and brain death. When the AAN guidelines are followed, there have been no misdiagnoses of brain death reported in the literature; of the reported misdiagnoses, at least one violation of the AAN guidelines was identified.[10][23]

Prognosis

The prognosis of brain death, by definition, is 100% fatal.[24]

Complications

Questioning the diagnosis of brain death only arises when AAN guidelines or protocols for brain death determination are not followed. These complications are limited to misdiagnosing a different neurologic condition as brain death and the ultimate death of a patient who was not brain dead.[25]

Deterrence and Patient Education

The diagnosis of brain death is difficult for families to accept. However, research supports asking the family to witness the clinical evaluation of brain death will help them understand the diagnosis. Multiple meetings with more than one provider, clergy, social workers, or ancillary staff may be necessary for the family's acceptance of the diagnosis.[23]

Pearls and Other Issues

Requirements for the diagnosis of brain death are coma with an identified cause, absence of brainstem reflexes, and apnea. The diagnosis is best made by closely following the American Academy of Neurology guidelines.[26]

Enhancing Healthcare Team Outcomes

The designation of brain death involves an interprofessional team. Nurses, physicians, social workers, and clergy will play a vital role in coordinating with families during the process of brain death examination and counseling after the diagnosis has been made. Subspecialists, such as intensivists, neurologists, or neurosurgeons, are required to interpret the physical examination findings, and radiologists may be necessary to interpret ancillary testing if the clinical diagnosis is inconclusive. While the diagnosis is considered, an interprofessional team specially trained in organ procurement should be involved; these specialty teams should handle all aspects of care only once the diagnosis of brain death has officially been made to ensure adequate protection for the team that cared for the patient until the diagnosis of brain death.[27] By adhering to the guidelines of clinical evaluation, ethical considerations, legal responsibilities, interprofessional collaboration, and effective communication, healthcare professionals can provide comprehensive and compassionate care in managing brain death scenarios. This approach ensures that patients and their families receive the highest standard of care significantly improves outcomes, and strengthens team performance in this complex and sensitive area of medical practice.