Continuing Education Activity

Brain death is both a legal and clinical term. The term has been present in medical literature and texts for many years as part of the National Conference of Commissioners on Uniform State Laws in 1980 until the Uniform Determination of Death Act (UDDA) was drafted. This term was later adopted by the American Medical Association and the American Bar Association. The act was drafted in response to medical advances in life support in the late 1970s that allowed for complete respiratory and circulatory support despite the complete cessation of brain function. This activity reviews the criteria for brain death in adults and highlights the role of the interprofessional team in becoming familiar with the legal and clinical terms.

Objectives:

• Describe the etiology of brain death.
• Review the physical examination of a potentially brain-dead patient.
• Summarize the evaluations in a brain-dead patient.
• Review the importance of improving care coordination among interprofessional team members to ensure appropriate utilization of the legal and clinical definitions of brain dead.

Introduction

Brain death is both a legal and clinical term. The term has been present in medical literature and texts for many years, but as part of the National Conference of Commissioners on Uniform State Laws in 1980, the Uniform Determination of Death Act (UDDA) was drafted. These criteria were later adopted by the American Medical Association and the American Bar Association. The act was drafted in response to medical advances in life support in the late 1970s that allowed for complete respiratory and circulatory support despite the complete cessation of brain function. This act reads as follows regarding “Determination of Death: An individual who has sustained either (1) irreversible cessation of circulatory and respiratory functions or (2) irreversible cessation of all functions of the entire brain, including the brain stem, is dead. A determination of death must be made in accordance with accepted medical standards.”

Unfortunately, the UDDA did not go on to establish what “accepted medical standards’ were, only that they existed. The American Academy of Neurology (AAN) published the most current standards in 1995 and then updated them in 2010.[1]

Based on the published standards, three findings must be present to establish brain death. The AAN defines them as “coma (with a known cause), the absence of brainstem reflexes, and apnea.”[2][3][4]

Etiology

Brain death occurs after the destruction of enough neuronal cells in the brain that there is both an irreversible loss of consciousness (coma) and the absence of brainstem reflexes, including the inability of the lungs to inhale and exhale without external positive pressure support (apnea).[3]

In adults and children, the precipitant of brain death is either from an intracranial or extracranial cause. First, we have to establish an acute and irreversible cause. Intracranial injuries leading to brain death in adults are most commonly traumatic brain injuries or subarachnoid hemorrhage. However, in children, the most common cause is non-accidental trauma. The extracranial cause of brain death is most commonly cardiopulmonary arrest with inadequate cardiopulmonary resuscitation.[5]

One has to exclude the presence of any drugs or poisoning in the system. This can be accomplished by history, drug screen, etc. A thorough lab testing is to be done to exclude severe endocrine, acid-base, and electrolyte disturbances.

Epidemiology

The processes that lead to brain death are in order of frequency: cardiopulmonary arrest, traumatic brain injury, subarachnoid hemorrhage, and intracerebral hemorrhage.

For extracranial causes of brain death, in patients who present with cardiopulmonary arrest, 8.9% of those initially resuscitated will progress to brain death, and in those presenting with traumatic brain injury, 2.8% to 6.1% will die of brain death. For intracranial etiologies of brain death, in patients presenting with a subarachnoid hemorrhage, 8.5% to 10.7% will progress to brain death; and in those presenting with intracerebral hemorrhage, 6.1% to 9.6% will succumb to brain death.[6][7]

By definition, brain death carries 100% mortality.

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, 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, mainly 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 traumatic brain injuries or other intracranial injuries, the presence of increasing intracranial pressure as a result of injury beyond the mean arterial pressure will prevent adequate oxygenation of neuronal tissues. This situation will result in further injury, edema, and, eventually, the process initially described above.[8][7]

Histopathology

Microscopic evaluation of post-mortem 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.[9]

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 may be compatible with brain death and can include muscle stretch reflexes.[10] Additionally, the cause of the coma should be identified by neuroimaging, history, and physical examination or laboratory testing.

The following brainstem reflexes should be tested in the physical examination of a patient deemed for brain death evaluation.[11] They all must be absent for a patient to be diagnosed as brain dead:

• The pupillary reflex to light – must be fixed; pupil size is usually mid-position, around 4 to 6 mm, but may vary, and the exact size is unimportant. Of importance is that the pupils must not respond to light.
• Oculocephalic reflex – this is performed by rapidly turning the head after checking the integrity of the cervical spine.
• Oculovestibular reflex (cold caloric test) – an absence of eye movement for one minute when the head is held at 30 degrees and cold water (50 ml) is instilled in the ear canal.
• Corneal reflex–stimulate with a swab.
• Gag reflex–stimulate the posterior pharynx.
• Cough reflex–stimulated with endotracheal suctioning.
• The facial movement to noxious stimuli–apply noxious pressure to the supraorbital ridge; there should be no facial muscle response.

Evaluation

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

• Ensure no recent neuromuscular blocking agents have been administered. There must be a waiting period of five times the drug's half-life, or drug plasma levels should be below the therapeutic range.
• Drug screen to ensure no central nervous system (CNS) depressants are present. 
• Normal core temperature must be present greater than 36 C.
• Normal systolic blood pressure must be greater than 100 mmHg. Vasopressors may be administered if necessary.
• No severe electrolyte, acid-base, or endocrine disturbance must be present.
• Neurologic examination, in most US states, 1 attending physician examination is sufficient; however, some states require 2.

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 intracranial pressure (ICP) and could precipitate cerebral herniation. 

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

• Vasopressors should be adjusted to maintain a systolic blood pressure ≥100 mm Hg.
• Preoxygenate is given for at least 10 minutes with a 100% fraction of inspired oxygen (FiO2) to a partial pressure of oxygen, arterial (PaO2) greater than 200 mmHg.
• Reduce ventilator frequency to 10 breaths per minute.
• Reduce positive end-expiratory pressure to 5 cm H2O.
• If the peripheral capillary oxygen saturation (SPO2) remains greater than 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/min near the level of the carina through the endotracheal tube.
• Look for respiratory movements for 8 to 10 minutes.
• If no respiratory drive is observed, repeat blood gas at approximately 8 minutes.
• If no respiratory movements are observed, and PaCO2 is greater than 60 mmHg or 20 mm Hg increase in PaCO2 over a baseline PaCO2 (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:

• There is any respiratory movement (abdominal or chest excursions or brief gasp)
• Systolic blood pressure 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 T-piece, maintaining a continuous positive airway pressure (CPAP) of 10 cm water 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. These include electroencephalogram (EEG), cerebral angiography, nuclear scan, transcranial doppler, computed tomography angiography (CTA), and magnetic resonance imaging (MRI). These tests are used when apnea testing is inconclusive, or patients are too unstable to proceed with apnea testing.[2][8] Ancillary testing may also be beneficial in patients with severe facial trauma, where examination for brainstem reflexes may be difficult, and for those with severe metabolic abnormalities or other complicating conditions, such as hypotension, hypothermia, etc. 

In the case of cerebral angiography, there is no intracerebral filling noticed in the carotid or vertebral arteries at the skull entry-level and maintained blood flow in the external carotid artery. In the case of EEG, there is no electrographic reactivity noticed after intense stimuli, either somatosensory or audiovisual.[12] It is imperative to understand that there is no need to establish the death of every neuron in the brain to demonstrate brain death. For example, even after brain stem and cerebral hemispheres death, there may be preserved neuroendocrine function.[13] Magnetic Resonance Imaging (MRI) brain scan is not yet accepted as an ancillary test for brain death determination.

Treatment / Management

Once brain death has been diagnosed, the patient is clinically and legally declared deceased at the time of death after testing. At this time, depending on family and patient preference, cardiopulmonary support should be withdrawn, or arrangements for organ harvest should begin. 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 testing.[5]

Differential Diagnosis

Several conditions may mimic brain death. These include:

• Locked-in syndrome[14]
• Hypothermia
• Drug intoxication
• Guillan-Barre syndrome
• Delayed paralytic clearance

The clinicians should perform a clinical evaluation to ensure these conditions are not present and must be done before diagnosing brain death. It is essential to differentiate the difference 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.[5][15]

Prognosis

The prognosis of brain death, by definition, is 100% fatal.[16]

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 that was not brain dead.[17]

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.[15]

Pearls and Other Issues

Requirements for the diagnosis of brain death: 

• Coma with an identified cause
• The absence of brainstem reflexes
• Apnea

The diagnosis is best made by closely following the American Academy of Neurology guidelines.[18]

Enhancing Healthcare Team Outcomes

The designation of brain death will often involve an interprofessional team. Nurses, physicians, social workers, and clergy will play a vital role in working with families during the evaluation and once the diagnosis is made. Subspecialists, such as neurology, neurosurgery, and radiology, may be required to interpret ancillary testing if the clinical diagnosis is inadequate. 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 been made to ensure adequate protection for the team that cared for the patient until death.[19]