Mollart and Goulon first coined the term 'coma depasse,' meaning a state beyond coma, for brain death.[1] The Conference of Royal Medical Colleges in 1976  came to the consensus that brainstem death constitutes brain death. The revised memorandum in 1979 correlated brainstem death with death itself.[1] The American Academy of Neurology (AAN) has postulated brain death as a “coma, absence of brainstem reflexes, and apnea.”[2] Academy of Medical Royal Colleges Working Party has defined brainstem death as 'the irreversible loss of the capacity for gaining consciousness, and the capacity to spontaneously breathe.'

Persistent vegetative state- loss of only cortical functions with intact brain stem functions

Brain-stem death- absent brain stem reflexes but the presence of few cortical as well as hypothalamic integrity such as osmoregulation

Whole Brain death- biological death with absent cortical and brainstem functions

Death- Whole-brain death along with the cardiopulmonary arrest

The following brainstem reflexes should be carried out for evaluating the clinical integrity of the brainstem: [2][3][4]

• The corneal reflex: The blinking of eyelids after touching the cornea with a cotton wisp or small jet of water.
• The pupillary light reflex This constitutes brisk constriction of the pupils after exposure to bright light. However,  precautions are necessary to rule out any previous eye surgeries, concurrent cataract, and use of drugs such as atropine.
• Oculocephalic reflex: Turning of the eyes in the opposite direction of head movement when the head is turned from the mid position to both sides. This should not be attempted in patients with concern for cervical cord injuries. 
• Oculovestibular reflex: Lack of eye movements after 50 ml of ice-cold water is instilled into the external auditory meatus over one minute after assuring patency of the tympanic membrane.
• Gag reflex: Pharyngeal contraction after stimulating the pharynx with a spatula or tongue depressor.
• Cough reflex: Presence of cough after stimulation of the carina by a bronchial catheter.
• Response to noxious stimuli along the distribution of cranial nerves. For-example facial grimace after noxious stimulus applied on the supraorbital ridge supplied by the trigeminal nerve.  

However, following confounding factors that can impede upon correct evaluation of the brainstem function must first be ruled out:[2]

• No concurrent use of central nervous system depressant drugs or neuromuscular blocking agents
  • Must wait for at least five half-lives of the drug to attempt valid evaluation if such agents have been used
• Normal core body temperature 
• Normal systolic blood pressure 
• No severe electrolyte, acid-base or endocrine disturbances

If the patient fulfills the above criteria and evaluation reveals the absence of brainstem reflexes, the clinician should perform apnea testing per the AAN recommendation. [5]

Apnea Test:

• Connect a pulse oximeter, pre-oxygenate with 100% oxygen (O2), and disconnect the ventilator.
• Deliver 100% O2 at 6 L/min through a cannula placed at the level of the carina.
• If respiratory movements are absent despite arterial partial pressure of carbon dioxide (PCO2) of greater than or equal to 60 mmHg or a 20 mmHg increase in PCO2 over a normal baseline is noted, the apnea test is considered concluded. 

The test is terminated in instances wherein there is hypotension, hypoxemia, or cardiac arrhythmias.

The absence of brainstem reflexes and an apnea test negative for spontaneous respirations validate the brain death of the patient.

Ancillary tests that can be used to diagnose brain death include:

• Flat electrical activity on at least a 30-minute electroencephalogram (EEG)
• Absence of cerebral flow beyond the circle of Willis during angiography
• No uptake of isotope within the blood vessel or brain parenchyma during a nuclear scan
• Small systolic peaks in early systole without diastolic flow or reverberating flow on a transcranial doppler

These tests are only justified when apnea testing is inconclusive, or patients are too unstable to proceed with apnea testing, or when brainstem reflexes cannot be carried out (vestibulo-ocular reflex in cervical spine injuries).

Brainstem death is a clinical diagnosis made by an examiner. Ancillary tests are not essential for confirming brain death.[1]

 Brainstem death has to be certified by certified board members, which include:  

•  Medical superintendent (MS) - in-charge of the hospital
•  The treating medical or critical care specialist
•  A neurologist or a neurosurgeon

Members from the organ donation or the transplantation team cannot be involved in this certification. 

The clinical diagnosis of brain death should take place in three steps:

• Establishing the etiology
• Excluding possible reversible syndromes that may produce signs similar to brain death
• Demonstration of clinical signs of brain death including coma, brainstem areflexia, and apnea

However, when planning for organ donation, separate complete examinations by two physicians is recommended.[6]

Ethical morality - justifying the use of limited medical resources, adding up the financial burden, and maximizing emotional toll to relatives in a hopeless clinical scenario

The whole-brain death concept- It is more prudent for the application of brainstem death rather than the whole brain death concept. It requires emphasis that though the brain stem is dead, there may still be some cortical and the hypothalamic functions (osmoregulation) intact in the patient. It is also distinct from cortical death (persistent vegetative state) wherein the brainstem functions are intact.

Concerns with the apnea test- There are inherent confounding clinical factors that can invalidate the apnea test, such as hypoxia, hypotension, cervical cord injuries. Moreover, hypercarbia by causing cerebral vasodilation can further impede upon the cascade of impending cerebral herniation, thereby further complication the clinical scenario.

Public belief in brain death and organ procurement- There can be a significant concern among the relatives and the public that organ donation occurs when the patient heart is still beating, and the person is not entirely dead. There can be looming fear that death will be declared prematurely for the sake of organ and tissue retrieval.[7]

Is the brain dead person really dead? - Issues in defining biological death - certain pitfalls merit consideration while evaluating for brainstem death confirmation:[8][9]

• The inexperience of the performing physician
• Potential confounders - such as hypothermia, drugs, alcohol
• Inadequate consideration during apnea test- such as low pCO2, ventilator trigger settings
• False Positive Brain Death Determination in scenarios such as barbiturate coma, baclofen toxicity
• False Negative Brain Death Determination- spinal reflexes and automatisms, ventilator auto-triggering during the apnea test
• Brain Death in Children- From 37 weeks of gestational age to 30 days, two examinations 24 hours apart whereas in 30 days to 18 years child, two examinations 12 hours apart
• Limitations of Ancillary Tests- artifacts in EEG
• Concerns relating to families and potential Organ donation such as personal and religious beliefs
• Failure to Maintain adequate environment for Organ donation -Systolic blood pressure of 100 mm Hg, urine output of at least 0.5 ml/kg/h; normal serum electrolytes and a tidal volume, not more than 8 ml/kg

The diagnosis of brain death is primarily derived clinically.[6]

The first step in determining brainstem death is to notify the next of kin about the process.

The interval observation period of 6 hour period is usually considered sufficient in adults and children over one year age. A reliable interval period has not been established for children less than seven days old. For children between 7 days to two months, two examinations and electroencephalograms (EEGs) should be separated by at least 48 hours. In contrast, in children between two months to one year, two examinations and EEGs should be separated by at least 24 hours. 

Repeat the clinical assessment of brain stem reflexes.

The steps and all examinations require full documentation.

Confirmatory testing should only take place out when deemed necessary and include:

• Angiography: the absence of intracerebral filling at the level of the carotid bifurcation or circle of Willis.

• Electroencephalography:  absent electrical activity during at least 30 minutes of recording 

• Nuclear brain scan: the absence of uptake of isotope (“hollow skull phenomenon”)

• Somatosensory evoked potentials: Brain death confirmed by the bilateral absence of N20-P22 response with median nerve stimulation.

• Transcranial doppler ultrasonography: small systolic peaks confirm brain death in early systole without diastolic flow or reverberating flow.

Medical Record Documentation should include:

• Etiology and irreversibility of coma

• Absent motor response to pain

• Absent  brainstem reflexes during two separate examinations separated by at least 6 hours

• Absent respiration with pCO2 greater than or equal to 60 mmHg

• Justification for, and result of, confirmatory tests if applicable 

Clinical instances that can be observed but compatible with the diagnosis of brain death [6]:

• Spontaneous movements  other than pathologic flexion or extension response
• Respiratory-like movements
• Autonomic features such as sweating, flushing, tachycardia
• Normal or sudden increases in blood pressure
• Absence of diabetes insipidus
• Deep tendon reflexes; superficial abdominal reflexes; triple flexion response
• Babinski reflex