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"Brain death: irreversible coma; irreversible brain damage as manifested by absolute unresponsiveness to all stimuli, absence of all spontaneous muscle activity, and an isoelectric electroencephalogram for 30 minutes, all in the absence of hypothermia or intoxication by central nervous system depressants."1
MOST MEDICAL dictionary definitions of brain death are very similar to the one quoted above. But in practice, this seemingly clear definition raises many unanswered questions. No true standardization of brain death criteria is accepted nationwide, and procedures and protocols vary significantly among facilities. Questions open to debate include the following.
* Who is qualified to perform a brain death assessment?
* What is the appropriate timing between clinical assessments?
* Are clinical assessments enough to diagnose brain death, or are confirmatory tests indicated?
* What confirmatory tests are acceptable?
This article reviews criteria for a brain death diagnosis in adult patients, complicating conditions that must be ruled out, the brain death exam, and various confirmatory tests used to determine brain death. It also incorporates some of the evidence-based research highlighted in the 2010 update of American Academy of Neurology (AAN) guidelines.
In 1980, the Uniform Determination of Death Act (UDDA) provided the following definition: "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 brainstem, is dead. A determination of death must be made with accepted medical standards."2 (See Defining brain death: An ongoing evolution.)
A persistent vegetative state (PVS), often confused with brain death by laypeople, is a distinctly different condition. According to a hallmark study by the Multi-Society Task Force on PVS, "the vegetative state is a clinical condition of complete unawareness of self and the environment, accompanied by sleep-wake cycles, with either complete or partial preservation of hypothalamic and brainstem autonomic functions. In addition, patients in a vegetative state show no evidence of sustained, reproducible, purposeful, or voluntary behavioral responses to visual, auditory, tactile, or noxious stimuli; show no evidence of language comprehension or expression; have bowel and bladder incontinence; and have variably preserved cranial-nerve and spinal reflexes."3 Further discussion of PVS is beyond the scope of this article.
Most institutions base their brain death criteria on the AAN's evidence-based guidelines for the determination of brain death, originally published in 1995.4 In June 2010, the guidelines were updated by the AAN's Quality Standards Subcommittee, which researched the evidence to explore five questions.5
* Do some patients who fulfill the clinical criteria for brain death recover brain function?
* What's an adequate observation period to ensure that cessation of neurologic function is permanent?
* Are complex motor movements that falsely suggest retained brain function sometimes observed in brain death?
* What is the comparative safety of techniques for determining apnea?
* Do new ancillary tests accurately identify patients with brain death?
In response to the first question, the committee concluded that recovery of brain function has never been reported in adult patients declared dead using AAN criteria outlined in the 1995 practice guidelines. The following discussion will include some of the committee's conclusions to the other provocative questions.
Although the UDDA requires diagnosing brain death in adults according to "accepted medical standards," it doesn't define these standards. Three important criteria are widely accepted: irreversible coma with a known cause, absence of brainstem reflexes, and apnea.6 But specific protocols for clinical determination of brain death vary from institution to institution.
The AAN identifies four prerequisites that should be met to establish a brain death diagnosis.5
1. coma of known cause as established by history, clinical exam, lab testing, and neuroimaging. The standard of care is a computed tomography scan or magnetic resonance imaging (MRI), the two most commonly used neuroimaging tests. Complicating conditions, including hypotension, hypothermia, and hypoxemia, must be ruled out or reversed before the brain death exam begins.
The patient must also be observed for a period to "exclude the possibility of recovery." The AAN subcommittee looked at what the observation period should be, but found insufficient evidence to recommend a specific observation period for determining that the loss of neurologic function is irreversible.
2. normal or near-normal core body temperature (higher than 36[degrees] C)
3. normal systolic BP (higher than or equal to 100 mm Hg)
4. at least one neurologic exam (some states and hospital protocols require two).
All complicating conditions must be ruled out or reversed before beginning the neurologic exam to confirm brain death. Many patients arriving at the ED with severe head injuries are endotracheally intubated in the field. Paralytics, sedatives, and other rapid-sequence medications given to facilitate intubation will complicate the patient's neurologic exam.
In addition, many ingested drugs can complicate the neurologic exam, including opioids, barbiturates, benzodiazepines, tricyclic antidepressants, aminoglycosides, anticholingerics, antiepileptic drugs, chemotherapy agents, alcohol, antipsychotics, stimulants, and many cardiac medications.6,7 Some medications can also cause acid-base abnormalities, resulting in metabolic and respiratory acidosis. If an overdose is suspected, determining the type of drug and administering the antidote, if one exists, is required to determine that the patient's current neurologic state isn't reversible.
If the type of ingestion is unknown, then a waiting period of at least 2 days is recommended to determine whether any brainstem reflexes return.6,7 At that time, if no brainstem reflexes have returned, a confirmatory test (such as electroencephalography [EEG] or cerebral angiography) may be obtained along with the brain death exam to diagnose brain death. Confirmatory test types and indications will be discussed in detail below.
Hypothermia can also mimic brain death. At body temperatures below 32[degrees] C (90[degrees] F), a patient may lose all brainstem reflexes, be tachycardic, and be unable to shiver, depending on the degree of hypothermia. Most healthcare professionals have heard the expression, "a patient is not dead until warm and dead." A brain death diagnosis can't be made until the patient's core body temperature rises to at least 32[degrees] C.7
Other complicating conditions include acute metabolic and endocrine crises that can mimic brain death. Usually these crises result in severe cerebral edema, anoxia, or demyelination, causing a profoundly devastating neurologic presentation. Examples of such crises include fulminant hepatic failure, ketoacidosis, hypo-/hypernatremia, hypo-/hyperglycemia, hypothyroidism, and pan-hypopituitarism. In most of these cases, however, complete loss of brainstem reflexes is rare unless cerebral edema is severe.7
In patients suffering severe facial trauma, pupillary assessments can be difficult or impossible to perform due to severe edema. Direct ocular trauma must be ruled out as the cause of pupillary abnormality when edema subsides.6
If all complicating conditions have been ruled out and the patient's neurologic status remains unchanged, a clinical neurologic exam is conducted to confirm the loss of all brain function, including the loss of brainstem reflexes and absence of spontaneous respirations after a CO2 challenge.5,8 In cases where certain complicating conditions can't be ruled out, most protocols require obtaining a confirmatory test and a detailed note in the patient's medical record documenting the patient's condition.
No national consensus has been reached on who's qualified to perform a brain death exam. Because it requires a thorough neurologic exam, including assessment of brainstem reflexes, most institutions utilize the expertise of a neurologist or neurosurgeon. However, critical care intensivists, with the proper training, are also capable of performing this type of exam.
A brain death exam is best performed using a head-to-toe approach. First, the practitioner assesses pupillary response. The pupillary light reflex must be absent in both eyes and pupils must be fixed "in a midsize or dilated position (4-9 mm)."5 (Cranial nerves II, III.) In patients with severe facial trauma with ocular injury or those with preexisting pupillary abnormalities where pupillary assessments may be unattainable or inconclusive, a confirmatory test is highly recommended and should be performed sometime after the completion of the brain death exam. Clear and detailed documentation by the examining practitioner regarding the limitations to performing a pupillary exam is required by most facility protocols.
An assessment of ocular movements includes oculocephalic and oculovestibular testing (Cranial nerves III, IV, VI).9 The oculocephalic reflex, also known as the doll's eye reflex, is assessed next. In the trauma patient, cervical spine injury or instability must be ruled out before this exam. If the patient has such an injury, this test isn't performed and a detailed explanation is documented in the medical record.
With the eyes held open, the patient's head is turned rapidly horizontally and vertically and eye movement is observed. If the oculocephalic reflex is present, the eyes move in the direction opposite to head movement. If the oculocephalic reflex is absent, which is consistent with brain death, the eyes remain midline with head movement.10
The next assessment is oculovestibular or cold caloric testing to assess the presence of the oculovestibular reflex. After tympanic membrane perforation has been ruled out and after any major cerumen deposit has been removed, the head of the bed is positioned at 30 degrees. Then, 30 to 50 mL of ice-cold (33[degrees] C) water is injected slowly (over 30 seconds) into each ear, with a 5-minute wait between injections into each ear. Once the water is injected, both eyes are held open to assess for ocular movement. In patients with an intact brainstem, you'll see a slow movement of the patient's eyes to the side of the ice-water irrigation, followed by a rapid corrective movement of the eyes.11
An alternative test for assessing vestibular function is bilateral irrigation with warm water (44[degrees] C). Normally the eyes move away from the side irrigated. Simultaneous bilateral irrigation with cold water normally causes downward deviation of the eyes; bilateral irrigation with warm water normally triggers upward deviation. In brain death, eye movement is absent for at least 1 minute of observation.5,11
Next is an assessment of facial sensory and motor responses. Assess the presence or absence of facial grimacing when the practitioner assesses for a jaw reflex. While the patient's mouth is held open, the practitioner uses a reflex hammer to lightly strike the face just below the midline of the bottom lip and just above the chin. Contraction of the masseter muscles is a normal response. No movement is abnormal, indicating loss of the jaw reflex. (Cranial nerve VII.)10
Assessment of corneal reflexes includes lightly brushing the cornea of each eye with a piece of tissue paper, cotton swab, or a squirt of water. A blink response indicates the corneal reflex is present; no movement of the eye or eyelid indicates an absent corneal reflex. (Cranial nerves V and VII.)5,10
Assessment of pharyngeal (gag) and tracheal reflexes (Cranial nerves IX, X) is next. A suction device or tongue blade is used to stimulate the back of the throat on each side to assess the gag reflex. No response bilaterally indicates that the gag reflex is absent.5,10
A cough response to tracheal suctioning indicates the tracheal reflex is intact. The suctioning catheter is advanced to the level of the carina and 1 or 2 suctioning passes are performed. No cough indicates loss of the tracheal reflex.5
The last physical assessment preceding an apnea test is the response to painful stimuli. Apply pain via a sternal rub, supraorbital pressure, pinching, or nail bed pressure and assess for grimacing or other facial movement. Absence of facial muscle movement indicates loss of the facial motor response.5
Interpreting motor responses may be a challenge because some patients demonstrate abnormal motor activity when stimulated due to spinal reflexes. These movements occur when a sensory stimulus arises from receptors in the muscle, joints, and skin, resulting in a motor response that is entirely contained within the spinal cord.12 The most common spinal reflex is plantar flexion in one or both lower extremities. Other spinal reflexes can cause upper extremity or finger movement, head movement, repetitive leg movements, pupillary changes, and facial twitching.5
The AAN subcommittee reviewed six Class III studies that looked at how spinal reflexes complicate the determination of brain death. They concluded that in some patients who meet the criteria for brain death, spinal reflexes may falsely suggest some retained brain function. One study cited in the updated guidelines documented plantar flexion and flexion synergy bilaterally that persisted for 32 hours after determination of brain death.5
Provide information about spinal reflexes and support family members, who may be extremely disturbed by these movements and think the patient is responding appropriately. Helping them understand that these movements aren't initiated by brain function is very important in helping them accept and cope with the death of a loved one.12
One of the most important parts of the brain death exam is the apnea test to confirm the loss of spontaneous respirations. Because various factors may trigger the ventilator and falsely suggest spontaneous breathing, the AAN has determined that the apnea test can be reliably performed only by disconnecting the patient from the ventilator.5 The patient may be taken off the ventilator for 10 or more minutes, so it's performed last, after the clinical exam is complete.
First, the patient's baseline PaCO2 level is determined via an arterial blood gas (ABG) analysis. If it's not within the normal range (35 to 45 mm Hg), mechanical ventilator settings are adjusted until eucapnia is achieved. Next, the patient is preoxygenated with 100% FiO2 for at least 10 minutes to reach a target PaO2 above 200 mg Hg.5 This is to eliminate stores of nitrogen and facilitate oxygen transportation.7
When the patient is hyperoxygenated and the PaCO2 level is within a normal range, the patient is disconnected from the ventilator. A cannula is inserted through the endotracheal tube and placed close to the level of the carina to provide the patient with a constant flow of oxygen (6 L/minute). The patient remains disconnected from the ventilator for 8 to 10 minutes and the chest and abdomen are observed for movement. If no movement is seen during this period, another ABG specimen is obtained and the patient is placed back on the ventilator. A rise in PaCO2 by 20 mm Hg over baseline or a PaCO2 of 60 mm Hg or more is considered a positive apnea test and supports the clinical diagnosis of brain death.5
During the apnea test, the patient's BP and oxygen saturation levels are continuously monitored. If the patient becomes hemodynamically unstable (for example, systolic BP below 90 mm Hg), the apnea test must be aborted and a confirmatory test obtained. The reason for stopping the test early must be clearly documented.
If the results are inconclusive but the patient is hemodynamically stable, the test may be repeated for 10 to 15 minutes after the patient is again preoxygenated.5
If the target increase in PaCO2 isn't obtained, a confirmatory test and written documentation of why the apnea test was inconclusive is required.
The AAN looked at four clinical studies that reviewed apnea test techniques and the safety of performing an apnea test. They found that the apnea test is safe, but that the evidence is inconclusive to determine the comparative safety of various techniques used for performing the apnea test.5
The AAN states that "a confirmatory test is not mandatory but is desirable in patients in whom specific components of clinical testing cannot be reliably performed or evaluated."4 Various confirmatory tests can be used in conjunction with a clinical brain death exam, but the AAN stresses that a brain death diagnosis is primarily based on clinical assessment: "In adults, ancillary tests are not needed for the clinical diagnosis of brain death and cannot replace a neurologic examination."5
In practice, specific confirmatory tests and the criteria for using them vary from institution to institution. Acceptable practice is one neurologic brain death exam, including an apnea test, and a confirmatory test. The confirmatory test should be performed after the neurologic exam has been completed and documented.
One of the most common and widely accepted tests is conventional cerebral angiography. In brain death, this invasive imaging study reveals no intracerebral filling at the level of the carotid bifurcation or circle of Willis.4
Conventional angiography is the gold standard for confirming the absence of cerebral blood flow, but it's a time-consuming, expensive, and invasive procedure that requires the patient to be transported out of the ICU to an angiography suite.
EEG, a noninvasive bedside test, is very reliable if it displays an isoelectric reading. To determine brain death, the EEG should show absence of electrical activity at a sensitivity of 2 mcV for at least 30 minutes.4,6,10
Drawbacks to an EEG are that it's prone to interference from its surroundings and it's susceptible to false positives. However, it remains a highly acceptable confirmatory test in many institutions.
Cerebral scintigraphy (technetium tc-99m brain scan), also known as a cerebral blood flow study, is a noninvasive nuclear medicine study involving I.V. administration of a radioisotope. In brain death, there's no uptake of the isotope in the brain parenchyma, referred to as the hollow skullphenomenon.4,5 This confirmatory test is widely used because of its noninvasive and portable nature, and results are extremely reliable.
Transcranial Doppler ultrasonography (TCD), another noninvasive bedside test, involves placing a probe at the temporal bone just above the zygomatic arch to measure the velocity of flow through the cerebral vasculature. Absence of diastolic flow, small peaks in systole, and lack of flow are consistent with brain death. Because TCDs have a 70% to 100% sensitivity with a specificity of 97% to 100%, they're becoming more widely accepted as a confirmatory test.6 A disadvantage to TCDs is the difficulty in finding the temporal window to perform the study.
Cerebral computed tomographic angiography (CTA), although noninvasive, requires the patient to be transported to the radiology department. In brain death, no intracerebral blood flow appears past the carotid and vertebral arteries entering the brain.13 The efficacy and reliability of this test hasn't yet been validated in the United States for the diagnosis of brain death, so it's not considered a first-line confirmatory test in many institutions. However, it is widely accepted and utilized in the brain death process in Europe and elsewhere.6,10,13
Somatosensory evoked potential (SSEP) is a newer study sometimes used to study the functional integrity of various parts of the brain. Evoked potentials are electrical signals generated by the nervous system in response to sensory stimuli.6 Bilateral absence of response to medial nerve stimulation is consistent with brain death. False positives are also possible.
Bispectral index (BIS) is a noninvasive bedside measurement of level of consciousness determined through an EEG-derived multivariant scale. The BIS value ranges from 0 to 100, with 0 being no brain activity and 100 being fully awake. In brain death, the BIS value is zero.7,14
According to the updated AAN guidelines, no evidence supports the use of newer tests such as cerebral CTA, cerebral MRI, cerebral magnetic resonance angiography, SSEP, and BIS as acceptable first-line confirmatory tests due to the "high risk of bias and inadequate statistical measures of efficiency in identifying brain death."5
Brain death remains a challenging clinical diagnosis. Understanding the brain death exam process is key to making the correct diagnosis. Eliminating complicating conditions and performing a thorough neurologic exam along with an apnea test is important in assuring the brain death diagnosis is accurate and accepted. Much of the evidence regarding brain death criteria is inconclusive or insufficient, warranting further research to achieve a widely accepted and consistent brain death protocol in the United States.
Brain death was first described in 1959 by Mollaret and Goullon, who used the term "depasse" to mean "a state beyond coma."15 They used this term to refer to neurologic conditions where recovery was impossible.
In 1968, an ad hoc committee on brain death at the Harvard Medical School published a landmark journal article defining brain death. They identified these criteria: unresponsiveness to even the most painful stimuli, no movement or breathing, loss of reflexes, and flat electroencephologram.16
The Uniform Determination of Death Act, which became law in 1980, defines brain death as death. It was supported in 1981 by a landmark report issued by the President's Commission for the Study of Ethical Problems in Medicine and Behavioral Research.17 Most state laws defining brain death are based on these sources. Even so, criteria for clinical determination of brain death vary among states and from institution to institution.
1. TheFreeDictionary. Brain death. http://medical-dictionary.thefreedictionary.com/brain+dead. [Context Link]
2. Uniform Determination of Death Act, 12 uniform laws annotated 589 (West1993 and West suppl 1997). [Context Link]
3. Medical aspects of the persistent vegetative state. The Multi-Society Task Force on PVS. N Engl J Med. 1994;330(21):1499-1508. [Context Link]
4. Practice parameters for determining brain death in adults (summary statement). The Quality Standards Subcommitte of the American Academy of Neurology. Neurology. 1995;45(5):1012-1014. [Context Link]
5. Wijdicks EF, Varelas PN, Gronseth GS, Greer DM, American Academy of Neurology. Evidence-based guideline update: determining brain death in adults: report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology. 2010;74(23):1911-1918. [Context Link]
6. Busl KM, Greer DM. Pitfalls in the diagnosis of brain death. Neurocrit Care. 2009;11(2):276-287. [Context Link]
7. http://Braindeath.org. http://www.braindeath.org/clinical.htm. [Context Link]
8. Doig CJ, Burgess E. Brain death: resolving inconsistencies in the ethical declaration of death. Can J Anaesth. 2003;50(7):725-731. [Context Link]
9. Blumenfeld H. Extraocular movements (CN III, IV, VI). In: Neuroanatomy Through Clinical Cases. 2nd ed. 2010. http://www.neuroexam.com/content_pf.php?p=20. [Context Link]
10. http://Braindeath.org. http://www.braindeath.org/confirm.htm. [Context Link]
11. Hickey JV. The Clinical Practice of Neurological & Neurosurgical Nursing. 6th ed. Philadelphia, PA: Wolters Kluwer Health/Lippincott Williams & Wilkins; 2009:150-151. [Context Link]
12. Saposnik G, Bueri JA, Maurino J, Saizar R, Garretto NS. Spontaneous and reflex movements in brain death. Neurology. 2000;54(1):221-223. [Context Link]
13. Yu SL, Lo YK, Lin SL, Lai PH, Huang WC. Computed tomographic angiography for determination of brain death. J Comput Assist Tomogr. 2005;29(4):528-531. [Context Link]
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15. Mollaret P, Goulon M. Le coma depasse (preliminary memoir). Rev Neurol (Paris). 1959;101:3-15. [Context Link]
16. A definition of irreversible coma. Report by the Ad Hoc Committee of the Harvard Medical School to examine the definition of brain death. JAMA. 1968;205(6):337-340. [Context Link]
17. Guidelines for the determination of death. Report of the medical consultants on the diagnosis of death to the President's Commission for the study of ethical problems in medicine and biomedical and behavioral research. JAMA. 1981;246(19):2184-2186. [Context Link]
18. Bickley LS, Szilagyi PG. Bates' Guide to Physical Examination and History Taking. 10th ed. Philadelphia, PA: Wolters Kluwer Health/Lippincott Williams & Wilkins; 2009:707. [Context Link]
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