Continuing Education Activity
Brain death accounts for about 2.06% of deaths in the United States and is often caused by traumatic brain injury. Criteria of Brain death determination were published in the American Academy of Neurology guidelines, but they're still a topic of ongoing debate. This article discusses the definition and the criteria of brain death determination and the role of the interprofessional team.
- Review the historical background of the brain death definition.
- Identify the pathophysiology of brain death.
- Summarize the physical examination findings, including the apnea test and other ancillary tests used to diagnose brain death.
- Explain the importance of having a standardized protocol for brain death diagnosis.
Death is defined in the United States by the Uniform Determination of Death Act (UDDA), proposed in 1981, as:
- Irreversible cessation of circulatory and pulmonary functions.
- Irreversible cessation of all functions of the whole brain, which means brain death.
Landmark article to define "irreversible coma" in order to determine death was released by the Ad Hoc Committee of the Harvard Medical School, led by Beecher HK, on 5th August 1968. This article focused on comatose patients with "no discernible central nervous system activity." This definition was also endorsed by World Medical Assembly, helping the global medical community to propose Brain death/Death by neurological criteria (BD/DNC) as the standard equivalent to diagnosing death. American Academy of Neurology (AAN) guidelines of brain death determination released in 1995 are retired, and AAN's evidence-based guidelines updated in 2010 are the current standards of BD/DNC.
AAN's recent position statement on BD/DNC 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."  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, World Health Organisation (WHO) partnered with an international forum to endorse BD as the official diagnosis of death.
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).
It is essential to distinguish the term "brain death" from "coma" to the public, as coma may imply a limited form of life. Understanding that brain death is equivalent to death helps both the physicians and patients' families to decide about the withdrawal of care and prevents the unnecessary expenditure of resources. Another 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. So for patients who are brain dead, the procurement of viable organs is allowed, even if they still have some circulatory and pulmonary functions. This concept is still causing an ongoing debate and controversy.
It is also crucial to differentiate brain death from other forms of severe brain damage, including vegetative state (VS) and minimally responsive state (MRS). In VS and MRS, some of the brain functions are maintained, and chances of recovery are there even after prolonged periods, especially in patients with traumatic brain injuries .
However, internationally and even within different states of the United States, there is no uniformity to certify brain death. Therefore, different standards are in effect to perform a brain death examination and document brain death.
Brain death occurs as a result of an acute catastrophic brain injury. Abruption of cerebral perfusion occurs if a concomitant elevation of intracranial pressure is more than mean arterial pressure (cerebral perfusion pressure = mean arterial pressure - intracranial pressure). This process was studied by monitoring brain tissue oxygenation in patients with brain death and can occur via two different mechanisms:
- Extracranial brain injury, as seen in patients post cardiopulmonary arrest with delayed resuscitation causing prolonged cessation of brain blood flow. The resultant rain anoxia leads to neuronal damage, resulting in cellular membrane pump failure and disturbed osmoregulation, which ends with severe brain edema. As a result of the confined space of the skull, intracranial pressure increases, compromising cerebral perfusion and may cause brain herniation. In some circumstances, as patients with decompressive craniotomy or ventricular shunts, it is important to note that an increment of intracranial pressure (ICP) may not be high enough to cause a complete cessation of cerebral blood flow. However, cerebral oxygenation is still severely impaired by the catastrophic injury at the cellular level leading to brain death.
- Intracranial brain injury, as seen in traumatic brain injury and intracerebral hemorrhage, can cause an elevation in intracranial pressure and impairment of brain oxygenation, as mentioned above.
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 country's contacts (42% world) revealed high variability in the BD/DNC protocols internationally. Eighty-three countries had BD/DNC protocols, while 53 did not. 78/83 of countries with protocols had unique protocols. This study also determined a considerable difference between BD determining clinical exam components. 70 (90%) included the pupillary reflex, 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. Though the apnea test was a requirement in 91% of protocols, what's interesting is that there was also dissimilarity in the apnea testing technique and reference ranges to determine BD, including target PaCO2. The ancillary test was deemed a requirement to pronounce BD in 22% of protocols.
A previous international study of BD criteria in 91 countries by Patel PV et al. showed 22% of low-income vs. 97% of high-income countries had an institutional protocol for brain death determination. 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 compared with countries without such provisions.
Another study evaluated BD/DNC 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. Also, different states had different requirements for the examiner, including one or two physicians required to determine brain death. Some states (as Alaska) allow nurses to assess brain death with further certification by a physician. Another common requirement is that if the patient is the potential for organ procurement, the physician who declares brain death should not be a procurement team member.
A recent study, "The World Brain Death Project," tried to achieve the minimum clinical criteria needed to determine BD/DNC by performing a literature search of important databases from January 1, 1992, through April 2020. The study proposed BD/DNC 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.
Specific prerequisites should be present before the determination of brain death.
- Evidence of an etiology of coma should be known. Confounding conditions should be excluded, including severe metabolic, endocrinal, 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.
- Core body temperature should be greater than 36 degrees Celcius for 24 to 72 hours. Warming blankets are an option.
- Achieve systolic blood pressure (SBP) of or greater than 100 mm Hg, often accomplished using vasopressors or vasopressin.
- Sodium 110-160 mEq/L, serum osmolarity < 350 mOsm/kg, calcium < 12 mg/dL, glucose 70 to 300 mg/dL, pH >7.2, alcohol < 80 mg/dL.
Brain death can be assessed by physical examination, the apnea test, and ancillary tests.
I. Physical Examination
This 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 by applying noxious stimuli to certain areas as the supraorbital notch, the angle of the jaw, 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 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
Brain death confirmation needs 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 can be used to evaluate further.
- CN III, IV, VI: Eye motion is lost in reaction to head movement "doll's eye").
- CN V, VII: Loss of corneal reflex determined by using a cotton swab or drops of water/normal saline.
- CN VIII: Loss of oculovestibular reflex (Caloric test). The test requires a cervical spine integrity check and head elevation at 30 degrees. 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.
- CN IX: Loss of gag reflex confirmed after stimulation of bilateral posterior pharyngeal membranes.
- CN X: Loss of cough reflex confirmed after tracheal suctioning.
II. Apnea Test
The apnea test is used to assess the brain's ability to drive pulmonary function in response to the rise of CO2. Before performing the apnea test, the mechanical ventilator should be adjusted to obtain PCO2 within 35 to 45 mmHg and Pao above 200 mmHg, using a positive end-expiratory pressure (PEEP) of 5 to 8 cm H2O. During the test, oxygen should be supplemented using a cannula connected to the endotracheal tube at 6 L/min, or T piece at 12 L/min, or using CPAP of 5 to 10 cm H2O. In the case of loss of respiratory drive, CO2 is expected to rise 5 mmHg every minute in the first 2 minutes, then by 2 mmHg every minute after. Repeat arterial blood gas (ABG) after 8 to 10 minutes showing CO2 of 60 mmHg or the rise of CO2 more than 20 mmHg above baseline is consistent with brain death. If the patient develops hypotension with SBP below 90 mmHg or cardiac arrhythmias, the test should terminate, 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.
III. Ancillary Tests
These tests are considerations if there is any uncertainty of 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 considered the gold standard for tests that evaluate cerebral blood flow. It can confirm brain death when it shows cessation of blood flow to the brain. Limitations include 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: 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 then imaging by single-photon emission computed tomography (SPECT) brain scintigraphy. The absence of a tracer in the brain 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).
*Ancillary tests used for detection of loss of bioelectrical activity of the brain:
- Somatosensory evoked potentials: 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. SSEPs can confirm EEG findings, as it is less affected by drug intoxication; however, it can still be affected by hypothermia.
In the US, a brain death exam performing physician's expertise 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.
Time of death is also country and institutional guideline-based. Time of death, as per AAN, is when PCO2 reaches the target value during the apnea test. While patients who underwent the ancillary examination, death is when the results are officially reported. 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.
Enhancing Healthcare Team Outcomes
Criteria of brain death determination is still a topic of controversy and debate. A clear approach to brain death diagnosis is crucial, as mentioned in the following points:
- Confirm the presence of prerequisites before assessing brain death.
- Using a standardized protocol for the determination of brain death in different health institutions based on the AAN guidelines.
- Proper and precise documentation of physical examination, apnea test, and ancillary test findings performed to diagnose brain death.
- A physician who has sufficient expertise should assess brain death.
- The patient’s family should be engaged in the process of brain death determination through effective and continuous communication.
Nursing should be supportive and continue to provide standard care until released by the diagnosis of brain death. The interprofessional healthcare team will function normally until making such a determination.
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 it in the chart. The nurse should call the family and make all possible accommodations for religious preferences. It is also important to ask the patient's family wishes regarding the autopsy if the law allows.
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. The key is to be supportive of the family and their wishes.