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, which were updated in 2010 to the current standards. 

AAN's recent position statement on brain death endorses UDDA's death definition as "irreversible loss of 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."

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 criteria are in effect to perform a document of brain death, and the provider should be cognizant of their country/state's criteria for a specific patient's age. 

It is essential to distinguish the term "brain death" from "coma" to the public, 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/or pulmonary function. This concept continues to result in some ongoing debate and controversy.[5][6]

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

Function

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 is more than mean arterial pressure (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 two different mechanisms:    

1. Extracranial brain injury, as seen in patients following cardiopulmonary arrest with delayed resuscitation, resulting in prolonged cessation of cerebral blood flow. The resultant anoxia leads to neuronal damage, resulting in cellular membrane pump failure, disturbed osmoregulation, and severe brain edema. As a result of the confined space of the skull, ICP increases, compromising cerebral perfusion and resulting in further neuronal injury.    
2. Intracranial brain injury, as seen in traumatic brain injury (TBI) and intracerebral hemorrhage, can cause an elevation in ICP and the resulting impairment of brain oxygenation, as mentioned above.[8][9]

Issues of Concern

The largest known study to date regarding brain death determination protocols worldwide was released in 2020 by Lewis A. et al. 136 corresponding countries' contacts (42% world) revealed high variability in the brain death criteria protocols internationally.[10] Eighty-three countries had brain death protocols, while 53 did not. Of the 83 countries with protocols, 78 had unique protocols. This study also determined a considerable difference between clinical exam components of the brain death examination. The pupillary light reflex was included in 70 (90%) of the 83 countries, 68 (87%) included the corneal reflex, 67 (86%) included the oculovestibular reflex, 64 (82%) included the gag reflex, 62 (79%) included the cough reflex, 58 (74%) included the oculocephalic reflex, 37 (47%) included noxious stimulation to the face, 22 (28%) included noxious stimulation to the limbs, and 22 (28%) included other reflexes. While the apnea test was a requirement in 91% of protocols, it is of interest that there were differences in the apnea testing technique and reference ranges for determining brain death, including target partial pressure of carbon dioxide in arterial blood (PaCO2). This ancillary test was deemed a requirement to pronounce brain death in 22% of protocols.[10] 

A previous international study of brain death criteria in 91 countries by Patel PV et al. showed that 22% of low-income vs. 97% of high-income countries had an institutional protocol for brain death determination.[11] The same study also showed variability in apnea test performance and concluded that countries with an organized transplant network were more likely to have a brain death provision when compared to countries without such provisions.

Another study evaluated brain death intranational standards practiced within the US's top 50 neurology/neurosurgery institutions, as reported in 2006. Results showed variability in the protocols between various health institutions, including the performance of the apnea and the ancillary tests. It was also found that the examiner had different requirements depending on the state, including if one or two physicians are required to determine brain death. Some states (Alaska) allow nurses to assess brain death with further certification by a physician. Another common requirement is that if the patient has the potential for organ procurement, the physician who declares brain death should not be a procurement team member.[11][12]

A recent study, "The World Brain Death Project," tried to achieve the minimum clinical criteria needed to determine brain death by performing a literature search of important databases from January 1, 1992, through April 2020.[13] The study proposed brain death with the exam demonstrating coma, brainstem areflexia, and apnea. Ancillary testing, including blood-brain flow studies and electroencephalogram, can be used if a clinical exam is non-yielding.

Clinical Significance

Specific prerequisites should be present before the determination of brain death.

Including: 

1. Evidence of an etiology of coma should be known. Confounding conditions should be excluded, including severe metabolic, endocrinologic, and acid-base derangements. If a drug intoxication is suspected, five half-lives of drug clearance should be waited, with adjustment to renal and hepatic functions.
2. Core body temperature should be greater than 36 °C for 24 to 72 hours. Warming blankets are optional to help achieve normothermia. 
3. Achieve systolic blood pressure (SBP) of or greater than 100 mm Hg, often accomplished using vasopressors. 
4. Sodium 110 to 160 mEq/L, serum osmolarity < 350 mOsm/kg, calcium < 12 mg/dL, glucose 70 to 300 mg/dL, pH >7.2, alcohol < 80 mg/dL.[14][15]

Physical examination, the apnea test, and ancillary tests can assess brain death.

I. Physical Examination

The physical examination includes the response to pain and assessment of brain stem reflexes. Loss of response to central pain occurs in brain death. Central pain assessment can be examined by applying noxious stimuli to certain areas, such as the supraorbital notch, the angle of the jaw, the upper trapezius, the anterior axillary fold, and the sternum. Neither eye response nor motor reflexes are detectable in brain death. It is important to note that some spinal reflexes can be present in patients with brain death. Saposnik et al. studied spinal reflexes in 107 patients with brain death and noted the following reflexes:

• Undulating toe flexion response, which is repetitive flexion and extension of toes triggered by plantar tactile stimulation
• Triple flexion reflex, which is flexion of the thigh, leg, and foot triggered by plantar tactile stimulation
• The plantar response, which is plantar flexion triggered by plantar stimulation
• Pronator extension reflex triggered by head-turning
• Quadriceps flexion triggered by local noxious stimuli
• Facial myokymia, which is repetitive twitching of facial muscles
• Lazarus sign, which is bilateral arm flexion, shoulder adduction, and hand raising to the chest/neck, triggered by head flexion and sternal stimulation
• Myoclonus of arm and leg
• Muscle fasciculations[16]

Brain death confirmation requires loss of brain stem reflexes, including:        

• CN II: Loss of pupillary reflex (light reflex): Pupils should be fixed in mid-size or dilated (4 to 9 mm) and not reactive to light; a magnifying glass or pupillometer can be used to evaluate further if results are equivocal.[14]
• CN III, IV, VI: Loss of pupillary light reflex as mentioned above (CN III). For cranial nerves IV, VI, and VIII, the oculocephalic reflex can be tested by holding a patient's eyelids open and turning their head from side to side. A positive oculocephalic reflex is present when the eyes reflexively look in the position opposite to that of the direction the head is turning. When the oculocephalic reflex is absent, the eyes will turn in the same direction in which the head is turning (Doll's eyes). It is imperative to only perform this examination maneuver in patients with a stable cervical spine who are not in cervical spine precautions. 
• CN V, VII: Loss of corneal reflex determined by using a cotton swab or drops of water/normal saline.[13]
• CN VIII: Loss of oculovestibular reflex (Caloric test). Irrigation of each ear by 50 to 60 mL of ice water won't move the eyes towards the irrigated side within 1 minute of the test performed. Each ear should be irrigated after a pause of a couple of minutes.[15]
• CN IX: Loss of gag reflex confirmed after stimulation of bilateral posterior pharyngeal membranes.         
• CN X: Loss of cough reflex confirmed after tracheal suctioning.[16]

II. Apnea Test

The apnea test is used to examine the brain's ability to drive pulmonary function in response to the rise of carbon dioxide (CO₂). Before performing the apnea test, the mechanical ventilator should be adjusted to obtain PaCO2 within 35 to 45 mmHg and partial pressure of oxygen within arterial blood (PaO2) above 200 mmHg, using a positive end-expiratory pressure (PEEP) of 5 to 8 cm of water (H2O). During the test, oxygen (O2) should be supplemented using a cannula connected to the endotracheal tube at 6 L/min, a T-piece at 12 L/min, or using continuous positive airway pressure (CPAP) of 5 to 10 cm H2O. In the case of the loss of respiratory drive, CO2 is expected to rise 5 mmHg every minute in the first 2 minutes, then by 2 mmHg every minute thereafter. Repeat arterial blood gas (ABG) after 8 to 10 minutes showing CO2 of 60 mmHg or the rise of CO2 by more than 20 mm Hg above baseline is consistent with brain death. If the patient develops hypotension with SBP below 90 mm Hg or cardiac arrhythmias, the test should be terminated, and arterial blood gases should be drawn. For patients on extracorporeal membrane oxygenation (ECMO) machines, oxygenation can be maintained while performing the apnea test by decreasing the gas sweep flow rate to 0.5 to 1.0 L/min and using an oxygenation source through the endotracheal (ET) tube.[15]

III. Ancillary Tests

Ancillary tests can be used as adjuncts if there is any uncertainty of the diagnosis of brain death or if the apnea test cannot be performed (as in cases of chronic CO2 retainers).

*Ancillary tests used for detection of cessation of cerebral blood flow:   

• Cerebral angiography: Four-vessel angiography is the gold standard for tests evaluating cerebral blood flow. It can confirm brain death when it shows cessation of blood flow to the brain. Limitations include the invasiveness of the test 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): Can be used to assess pulsations of middle cerebral arteries, vertebral and basilar arteries bilaterally, also anterior cerebral arteries or ophthalmic arteries if possible. 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, the presence of unsuitable windows due to thick temporal bones, as well as lowered ICP by surgery or ventricular shunts giving false-negative tests. 
• Computed tomogram (CT) brain angiography and MR angiography 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).[15]

*Ancillary tests used for detection of loss of bioelectrical activity of the brain:   

• 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.[14] SSEPs can confirm EEG findings, as it is less affected by drug intoxication; however, they can still be affected by hypothermia.[17][18]

Other Issues

In the United States, the physician's eligibility to perform a brain death examination varies from state to state and institution to institution. Most states and institutions legally allow any physician to perform brain death exams, while some only allow neurologists, neurosurgeons, and intensive care specialists.[14]

Time of death is also country and institutional guideline-based. As per AAN, the time of death is when PCO2 reaches the target value during the apnea test. For patients who underwent the ancillary examination, death is when the results are officially reported.[14] However, in the United Kingdom, although two exams are needed to diagnose the test formally, the legal time of death is when the first test confirms the absence of brainstem reflexes.[19]

Enhancing Healthcare Team Outcomes

The designation of brain death often involves an interprofessional team. Physicians, nurses, social workers, and clergy will play a vital role in working with family members during the evaluation and discussing the results of the brain death examination once the diagnosis has been made. Subspecialists in neurosurgery, neurology, and radiology may be required to interpret ancillary testing if the clinical diagnosis is inadequate. Simultaneously, while the possibility of brain death is considered, an interprofessional team specially trained in organ procurement and independent from the treating healthcare team should be involved; these specialty teams handle all aspects of the patient's care only once the diagnosis of brain death has been made.

Nursing, Allied Health, and Interprofessional Team Interventions

Nurses should continue to monitor and treat the patient until the confirmation of brain death. No patient should experience deprivation of any treatment until this notification. Upon determining brain death, the appropriate provider should document their findings in the chart and relay them to the patient's family. Accommodations for religious preferences should be made if desired. 

Nursing, Allied Health, and Interprofessional Team Monitoring

If there is any dispute with the family regarding brain death and treatment, nurses should not hesitate to call the ethics team to help with the situation. It is essential to be supportive of the family and their wishes during these difficult discussions with an understanding that once the patient has been declared brain dead, the patient is, by definition, dead without any chance of recovery. 

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Disclosure: Mostafa Aboubakr declares no relevant financial relationships with ineligible companies.

Disclosure: Muhammad Ismail Khalid Yousaf declares no relevant financial relationships with ineligible companies.

Disclosure: Luke Weisbrod declares no relevant financial relationships with ineligible companies.

Disclosure: Gustavo Alameda declares no relevant financial relationships with ineligible companies.