Neurological examination is considered as the gold standard to diagnose brain death and therefore must be performed accurately [7] [8]. It is essential to document presence of apnea, absence of brainstem reflexes and coma. The brainstem reflexes are lost in a rostral-to-caudal direction, with the medulla oblongata to be the last one to cease functioning in the event of brain death. Medullary function usually lasts for several hours as other functions of the brainstem are being lost [9]. If the medulla oblongata does not cease functioning, administration of 1 mg atropine will cause tachycardia, tracheal suctioning will lead to cough reflex and the blood pressure will be normal. The depth of coma can be assessed based upon the motor response to a standardized pain stimulation, done by pressing on temporomandibular joint, supraorbital nerve or finger nail bed. Next step is the evaluation of brainstem reflexes, which if absent, should show mid dilated non reactive round/oval pupils on ocular exam with absence of oculocephalic reflex. Presence of a spinal injury makes the interpretation of oculocephalic reflex challenging.

• Hypothermia

  We strongly recommend caution in the determination of brain death after cardiac arrest when induced hypothermia is used. [ncbi.nlm.nih.gov]

• Gagging

  Such criteria include deep coma with a known cause, absence of any brainstem functions (e.g., spontaneous respiration, pupil reactions, gag and cough reflexes), and exclusion of hypothermia, drugs, and poison as causes. [britannica.com]

  After rewarming to 36.5°C, neurologic examination showed no eye opening or response to pain, spontaneous myoclonic movements, sluggishly reactive pupils, absent corneal reflexes, and intact gag and spontaneous respirations. [ncbi.nlm.nih.gov]

  Oculovestibular and gag reflexes are absent. The patient is intubated due to loss of spontaneous respirations. After further workup, an apnea test is performed, which shows no respiratory response with a PaC O 2 > 60 mm Hg. [step2.medbullets.com]

  […] hypothermia) If the person doesn't have one of those problems, doctors do a physical exam to look for signs of brain activity including: Trying to breathe if the ventilator is turned off Flinching or moving if the person is pinched or poked by a needle Gagging [msdmanuals.com]

• Nausea

  After hospitalization, he complained of nausea and his consciousness level decreased immediately. [ncbi.nlm.nih.gov]

  Headache together with nausea is sometimes the first sign. The headache can be generalized or localized in one part of the head, and the pain is usually intense. Vomiting can be significant if it is sudden and without nausea. [medical-dictionary.thefreedictionary.com]

• Vomiting

  A patient who is brain dead will have no response to this type of stimuli, but an individual who has brain function will have a response, which can range from eye movement to vomiting. [surgery.about.com]

  Symptoms include fever, malaise, irritability, severe headache, convulsions, vomiting, and other signs of intracranial hypertension. [medical-dictionary.thefreedictionary.com]

• Hypotension

  Vasopressin, a catecholamine-sparing vasopressor and antidiuretic agent, may be an effective agent in the treatment of refractory hypotension after brain death prior to organ transplantation. [ncbi.nlm.nih.gov]

  Note: The apnea test should be done with extreme caution to minimize risks of hypoxia and hypotension, particularly in potential organ donors. [merckmanuals.com]

  Blood product replacement as indicated by hospital policy For hypotension unresponsive to fluid bolus: Consider vasopressor support to maintain either a MAP > 60 or a SBP >90mmHg (7 years-adult), >80mmHg (6 months-2 years), >60 (0-6 months) Preferred [pntb.org]

• Tachycardia

  If the medulla oblongata does not cease functioning, administration of 1 mg atropine will cause tachycardia, tracheal suctioning will lead to cough reflex and the blood pressure will be normal. [symptoma.com]

  Patients with marked hypothermia have lost the ability to shiver, feel as cold as a toad, often display tachycardia, and may have lost all brain stem reflexes when the temperatures dip into the 28°C range. [braindeath.org]

  The rhythms that coincide with cardiac arrest are asystole, ventricular tachycardia, and ventricular fibrillation, which may be seen on the ECG. However, a patient may appear to have normal electrical activity but have no pulses. [journals.lww.com]

  […] brainstem function: spontaneous movements of limbs other than pathologic flexion or extension response respiratory-like movements (shoulder elevation and adduction, back arching, intercostal expansion without significant tidal volumes) sweating, flushing, tachycardia [ncbi.nlm.nih.gov]

• Pupillary Abnormality

  Other situations possibly requiring confirmatory testing include severe facial trauma where determination of brainstem reflexes will be difficult, pre-existing pupillary abnormalities, and patients with severe sleep apnea and/or pulmonary disease. [en.wikipedia.org]

  Other variables that are correlated with a poor outcome include an advanced age, pupillary abnormalities, and a low score on a test of motor responses 47. [doi.org]

• Withdrawn

  Risk management should be involved early in the decision process, if life support is withdrawn without the family's assent. [ncbi.nlm.nih.gov]

  Once brain death is confirmed, all life support is withdrawn. [symptoma.com]

  After doctors declared there was no more hope for him, they ordered a 'terminal wean' - whereby life support is slowly withdrawn to end a life. [dailymail.co.uk]

  Here, the family insisted she be taken off life support, while the hospital refused, citing a Texas law that states such support cannot be withdrawn from a pregnant patient. We tend to think of brain death and a coma as the same thing. [bigthink.com]

• Grieving

  Defining brain death should allow families to begin the grieving process and protect providers from having to perform futile care. [chestnet.org]

  Death by standard criteria is easily accepted by grieving families who appreciate the lack of a heart beat, pulse, breathing and the change in skin pallor that accompanies circulatory arrest. [healthcare.utah.edu]

  Such a policy would state how much time would be allowed for the family to grieve with the deceased family member or to find another place to transfer, he says. [news.nationalgeographic.com]

  Physicians say it is difficult for many grieving families to understand that a person is dead, even when their heart is still beating. [bigthink.com]

  All team members must be clear about the patient's death so that the family can grieve properly. Family members may not understand brain death. [journals.lww.com]

• Denial

  But the ethical lag means that there are a lot of dark corners and niches that cause waste, deceit, denial, and harm. How we move forward in these instances, and what motivations are involved must also be considered. To learn more click here: -- [bigthink.com]

  Other factors include mixed information from team members, depictions of recovery from brain death on TV shows, the denial stage of grief, and emotional shock due to the acuteness of the event. [journals.lww.com]

• Confusion

  A case is reported in which procurement was delayed because ventilator self-cycling was confused for brainstem-mediated respiratory effort. [ncbi.nlm.nih.gov]

  Although the Act had a prescribed set of rules, doctors were confused about what needed to be done if they were faced with a medico-legal case or otherwise. The SOPs would put an end to this, Dr. Bhandari said. [thehindu.com]

  When anguish, fear, and confusion trample the spirit of those we love and those we mourn, true justice is but a dream. [thedailybeast.com]

• Stroke

  MATERIALS AND METHODS: We conducted a prospective observational 5-year follow-up on 29 transplanted organs from 14 brain-dead donors after acute stroke (7 subarachnoid and 4 intracerebral hemorrhages, 3 ischemic strokes). [ncbi.nlm.nih.gov]

  Often, for the patient with a non-traumatic brain injury like a stroke, there is no outward sign that their loved one has suffered a devastating and non-survivable injury to the brain. [donorrecovery.org]

• Fixed Pupils

  A 28-year-old man was admitted following a road traffic accident with a Glasgow Coma Score (GCS) of 3/15 and fixed pupils. [ncbi.nlm.nih.gov]

  Reflexes include pupillary response (fixed pupils), oculocephalic reflex, corneal reflex, no response to the caloric reflex test, and no spontaneous respirations. [en.wikipedia.org]

  Usually the pupils are fixed in a midsize or dilated position (4–9 mm). Constricted pupils suggest the possibility of drug intoxication. When uncertainty exists, a magnifying glass should be used. [neurology.org]

• Areflexia

  Brain death must be determined by careful neurologic examination showing apnea, cranial nerve areflexia, and unresponsiveness that is irreversible and caused by a structural lesion that accounts for the clinical findings. [medlink.com]

  All international brain codes follow the same step‐by‐step procedure of establishing aetiology, exclusion of potentially reversible syndromes, and demonstrating the clinical signs of brain death—coma, brainstem areflexia, and apnoea. [bja.oxfordjournals.org]

• Guillain-Barré Syndrome

  Guillain-Barré syndrome resembling brainstem death in a patient with brain injury. J Neurol 2001 ; 248 : 430 –432. Rivas S, Douds GL, Ostdahl RH, Harbaugh KS. [neurology.org]

In order to diagnose a patient with brain death, the first step is to rule out potential influence of paralyzing or sedating agents. The possibility of self administration of such agents should also be considered. In case status epilepticus is suspected, an electroencephalogram (EEG) must be performed. Hypothermia, defined by a core body temperature  of < 35°C should be increased gradually to > 36°C. The patient should be routinely evaluated for 6-24 hours. Ocular examination, with emphasis on brainstem reflexes and apnea testing must be performed with every examination. If the absence of brainstem reflexes is noted, apnea test must be performed.

To reduce the chances of misdiagnosing an individual with brain death, several countries have made a second clinical examination as a mandatory requirement, despite the absence of any evidence suggesting a possible benefit with this practice. On the contrary, it has been demonstrated that this practice, in fact delays the diagnosis of brain death. To determine the cause of brain death, a computed tomography (CT) scan of the head may be performed to look for pathologies such as hemispheric lesions, edema, mass, or herniation of the brain. Evaluation of the cerebrospinal fluid (CSF) is diagnostic where a central nervous system (CNS) infection is suspected. 

The following tests are indicated when only one clinical examination is desired (in a scenario where organ procurement needs to be done for transplantation) or if the apnea test is not tolerable hemodynamically:

• EEG, that shows complete absence of brain activity despite intense somatosensory and/or audiovisual stimulation in the presence of brain death.
• CT Angiography (cerebral), that shows absence of intracranial filling at the level of entry of vertebral and carotid arteries into the skull [11] in the presence of brain death. 

The current recommendations state that confirmatory testing must be performed in all children less than one year of age [10]. Several countries across the world have made confirmatory testing compulsory. However, it is for the physician to decide the battery of tests to be performed in the United States, where most physicians prefer bedside testing. Cerebral angiography is the only required confirmatory test in Sweden. 

Determination of brain death

Prerequisites (all prerequisites should be met)

• Coma that is irreversible and the cause is known
• Neuroimaging that can explain the reason for coma
• Systolic blood pressure greater than 100 mmHg
• Mild hypothermia or normothermia with a core body temperature greater than 36°C
• Absence of any evidence that suggests influence of paralytic agents (electrical stimulation may be performed if any use of a paralytic agent is suspected or known)
• Absence of the influence of any drug that can lead to CNS depression (toxicology screening may be performed, and if the patient was administered barbiturates, the serum level must be below 10 μg/ml)
• Absence of acid-base, endocrine or electrolyte abnormality that may lead to obtundation
• Absence of spontaneous respirations

Examination (all findings must be present)

• Non-reactive pupils when exposed to bright light
• Absence of corneal reflex
• Absence of gag reflex
• Absence of oculovestibular reflex
• Absence of oculocephalic reflex
• Absence of facial movements when a painful stimulus is applied at the temporomandibular joint or the supraorbital nerve
• Absence of any motor response when a painful stimulus is applied to any of the four limbs (spinal reflexes may be present; all four limbs should be tested)

Apnea testing (all findings must be present)

• Patient should be hemodynamically stable
• Patient should have normocarbia (achieved by adjusting the ventilator settings)
• Patient must have PaO2 >200 mmHg prior to disconnecting the ventilator, which is achieved by pre-oxygenation using 100% FiO2 for at least ten minutes
• Patient must be well oxygenated, with a positive end expiratory pressure (PEEP) of 5 cms H2O
• Oxygenate the patient by using a suction catheter inserted to the level of carina at a rate of 6 L/min or by attaching a T-piece with continuous (CPAP) at 10 cm H2O
• Disconnect the ventilator 
• Absence of spontaneous respirations noted
• After 8-10 minutes, an arterial blood gas sample is drawn and the ventilator is connected again with the patient
• The PCO2 should be ≥60 mmHg or must increase by a minimum of 20 mmHg from normal baseline

Or:

• Apnea test aborted

There are several alternative methods to support a diagnosis of brain death, in case if the apnea test is not conclusive or there are limitations due to patient factors that will not allow a complete clinical examination. These include:

• Cerebral angiogram
• EEG
• HMPAO SPECT
• TCD

• Isoelectric EEG

  An isoelectric EEG is not mandatory, but when used in conjunction with the clinical criteria for brain death, it provides confirmatory evidence of brain death. [clevelandclinic.org]

  EEG ( Ad Hoc Committee 1968 ). [medlink.com]

  One Class III study evaluated bispectral index monitoring in 54 patients and noted a gradual decline in bispectral index values to 0 in 9 patients, implicating isoelectric EEG. [neurology.org]

  EEG and CBF studies may not show abnormalities that are described in older patients. An observation period of 24 to 48 hours is recommended. If the EEG is isoelectric or if CBF is absent, the observational period can be shortened. [nature.com]

  There have been occasional reports of isoelectric EEGs in patients in a vegetative state 37,58,76,81,82. [doi.org]

• Flat-Line EEG

  An EEG will therefore be flat, though this is sometimes also observed during deep anesthesia or cardiac arrest. Although in the United States a flat EEG test is not required to certify death, it is considered to have confirmatory value. [en.wikipedia.org]

The criteria for diagnosing brain death are firm. Using the practice parameters published in 1995 by the AAN as a criteria for diagnosis, there is no data since 1995 that shows recovery of neurological deficits after a diagnosis of brain death was made [12].

The state of brain death is equivalent to the death of the person since it is irreversible. Once brain death is confirmed, all life support is withdrawn. It must be noted that as the whithdrawl of ventilatory support after brain death will result in terminal arrythmias and terminal apnea may provoke spinal reflexes, which should not be interpreted as signs of life. 

Traumatic brain injury and subarachnoid hemorrhage are the most important causes for brain death in adults [5]. Abuse is a common cause for brain death in children, others being asphyxia and motor vehicle collisions [6].

The epidemiology of brain death is in direct association with the epidemiology of the two main causes for brain death. namely traumatic brain injury and subarachnoid hemorrhage. Traumatic brain injury leads to almost 52,000 deaths every year in United States alone. Mortality rate is significantly lower in the patients that are hospitalized (6/100,000 persons) versus those who do not receive hospitalization (17/100,000 persons).

In order to maintain cerebral perfusion pressure, the arterial blood pressure increases in response to an elevated intracranial pressure. If the cerebral perfusion remains inadequate, pontine ischemia may develop leading to Cushing's reflex, consisting of bradycardia and hypertension. Ischemic injury rapidly progresses to involve other parts of the brain leading to an autonomic storm that is characterized by peripheral vasoconstriction, hypertension and tachycardia. It is frequently associated with an elevated amount of catecholamines in circulation and myocardial dysfunction (due to increased oxygen demand and arrythmias). During the hypertensive phase, the vasomotor nuclei in the brainstem suffer irreversible damage which leads to loss of sympathetic outflow and as a consequence, hypotension ensues.

Prevention of brain death is not possible, however, various steps can be taken to decrease the risk for the causes of brain death, most important of them being subarachnoid hemorrhage. Good control of blood pressure and smoking cessation may help decrease the risk of subarachnoid hemorrhage.

Brain death is the complete cessation of integrated functions of the cerebrum and brainstem and constitutes the death of person. This concept is accepted in both legal and cultural aspects throughout the world. The need to develop this concept arose because certain drugs and medical equipment like a ventilator could maintain basic functions of the body such as cardio-pulmonary activity for an indefinite period of time even after cessation of all brain activity. 

The Uniform Determination of Death Act (UDDA) was formed based off a report on "guidelines for determination of death" by the president's commission [1]. The act states:

"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 with accepted medical standards" [2].

In the year 1995, the American Academy of Neurology (AAN) put forth a practice parameter in order to outline the medically acceptable standards to determine brain death [3]. They stated that for diagnosing brain death, the patient must have absence of brainstem reflexes, apnea and in a state of coma for which the cause is known.

Inspite of the practice parameter made available by the AAN, there is significant variation in practice at different medical institutions. A study conducted in US hospitals identified the points of variations [4]. The most important points of variation were:

1. The number of examinations necessary
2. The prerequisites
3. The lowest acceptable body temperature

Brain activity is lost permanently in brain death. The patient loses the ability to breathe and perform other important functions, along with complete loss of capacity to think and be aware of surroundings. The patient will not respond to any stimulus. Once a diagnosis of brain death is made, no further treatment can be of any help and the patient is legally dead. 

Various advances in medical science can help maintain some vital functions like beating of the heart and breathing even after the brain stops working completely. However, even with the use of such devices and drugs, the organs will stop working eventually. 

Brain death is diagnosed based on a strict criteria. Some of these criteria are:

• The patient does not try to breathe
• The eyes are not reacting to light
• The patient shows no movement when specific reflexes and responses are checked

The doctors will also check certain reflexes elsewhere in the body to confirm brain death. The doctors will notify the next of kin about the diagnosis.

Doctors will not confirm a diagnosis of brain death until they check for and treat all problems that can possibly affect the brain function. These problems include, but are not limited to low blood pressure, low body temperature, abnormal levels of normally found substances in the blood, ingestion of toxic drugs and sedative overdose.

The above criteria are checked for at least one more time in 6-24 hours to confirm the presence of these criteria. Once the criteria have been confirmed two times, no further testing is needed and a diagnosis of brain death can be confirmed. In case if the diagnosis needs to be performed in a shorter time, the doctors may run certain tests to do so, thus eliminating the need to recheck the patient 6-24 hours later.

Individuals who have been diagnosed with brain death do not recover. Once the diagnosis is confirmed, all life supporting treatment is withdrawn. Family members may be allowed to be with the patient at the time of withdrawing life support. It is important to note that the patient might move his/her limbs or may even sit up when the device that assists in breathing is withdrawn.

1. 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 biochemical and behavioral research. JAMA1981; 246:2184–2186.
2. Uniform Determination of Death Act, 12 uniform laws annotated 589 (West 1993 and West suppl 1997).
3. The Quality Standards Subcommittee of the American Academy of Neurology. Practice parameters for determining brain death in adults (summary statement). Neurology 1995; 45:1012–1014.
4. Greer DM, Varelas PN, Haque S, Wijdicks EFM. Variability of brain death determination guidelines in leading US neurologic institutions. Neurology 2008; 70:284–289.
5. Wijdicks EF. Determining brain death in adults. Neurology. 1995;45: 1003-11. 
6. Ashwal S, Schneider S. Brain death in children. Pediatric Neurology. 1987; 3: 5-11. 
7. The Quality Standards Subcommittee of the American Academy of Neurology. Practice parameters for determining brain death in adults. Neurology. 1995;45:1012-4. 
8. Van Norman GA. A matter of life and death: what every anesthesiologist should know about the medical, legal, and ethical aspects of declaring brain death. Anesthesiology. 1999; 91:275-87.
9. Wijdicks EFM, Atkinson JLD, Okazaki H. Isolated medulla oblongata function after severe traumatic brain injury. J Neurol Neurosurg Psychiatry. 2001; 70:127-9.
10. American Academy of Pediatrics Task Force on Brain Death in Children. Report of special task force: guidelines for the determination of brain death in children. Pediatrics. 1987; 80:298-300. 
11. Bradac GB, Simon RS. Angiography in brain death. Neuroradiology. 1974; 7:25-8
12. Wijdicks EF, Varelas PN, Gronseth GS, Greer DM. Evidence-based guideline update: determining brain death in adults: report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology. 2010; 74:1911-8.