Brain Death Diagnosis: Who And How?

Introduction

Case 1: A 78-year-old lady is being admitted to ICU. She was urgently intubated and put on ventilator for low GCS and respiratory depression. Her diagnosis turned out to be massive posterior circulation cerebral infarct and prognosis is guarded. GCS is 3, totally unresponsive and all brainstem reflexes are absent. Is she legally dead? And when can the ventilator be taken off?

Case 2: A 45-year-old man is in ICU for severe traumatic brain injury. He is unresponsive and pupillary and cornea reflexes are absent. He has an organ donor card. How should we proceed?

Depending on the clinical settings, death can be diagnosed based on 1) circulatory criteria: irreversible/permanent cessation of cardiac and respiratory functions; or 2) neurological criteria: irreversible cessation of the function of the central nervous system. Cardiopulmonary death by circulatory criteria is common and is already well-practiced. Less well-known but equally important to practice is brain death or death by neurological criteria (BD/DNC) which plays a role in patients on ventilators and/or in consideration of organ transplant. Brain death is irreversible and is an actual death (there is no chance of recovery). There is limited knowledge even among the healthcare professionals on determination of brain death: who, when and how.

Definition of Brain death/Death by Neurologic Criteria (BD/DNC)

BD/DNC is defined as complete and permanent loss of brain function as defined by an unresponsive coma with loss of capacity for

• consciousness (GCS 3)
• brainstem reflexes and
• the ability to breathe independently (Apnea)¹

This may result from permanent cessation of oxygenated circulation to the brain and/or after devastating brain injury such as massive ischemic or hemorrhagic stroke, traumatic brain injury, encephalitis, brain tumor, etc.

Who should perform the brain death diagnosis?

Brain death diagnosis is to be made by two doctors who have been registered for more than five years and must be competent in the procedure. At least one should be a specialist (defined as an anesthetist/intensivist, neurologist, neurosurgeon, emergency physician, general physician or general surgeon).2 At least one should be the doctor attending the patient/the doctor of the unit where the patient is admitted but neither doctor should be a member of the transplant team. If instrumental tests such as electroencephalogram (EEG), arteriography etc are required, these are best carried out and interpreted by specialists such as neurophysiologists and radiologists accordingly.

Steps in determining brain death

• Precondition (prerequisites)
• The clinical evaluation by neurological examination
  • Coma
  • Absence of brainstem reflexes.
  • Apnoea
• Ancillary tests

Precondition (prerequisites) (All preconditions must be met.)

• Patient must be deeply unconscious, apneic, and mechanically ventilated.
• Cause of brain damage (traumatic brain injury, stroke, brain tumour, anoxia, etc.) must be known, in order to establish the irreversibility of the process.
• Conditions that could simulate brain-dead must be excluded.
  • severe systemic arterial hypotension (SBP must be> 100, MAP > 60 mmHg)
  • severe hypothermia (minimum core temperature must be 36°C)
  • metabolic, acid-base, and endocrine disturbances such as hypothyroidism, panhypopituitarism, adrenal dysfunction, uremia, hepatic failure, electrolyte imbalance (After correction, sodium must be 115-160 mmol/L, potassium >2mmol/L, phosphate 0.5 – 3 mmol/L, magnesium 0.5 – 3 mmol/L, blood glucose 3.0 – 20 mmol/L).²
• effect of certain drugs (CNS depressants such as barbiturates, benzodiazepines, neuromuscular blockers, anticholinergic drugs, etc.) (To correct this, postpone till drug clearance which is 5 times the drug’s half-life for normal hepatic and renal function. If alcohol intoxication is suspected, the alcohol blood level must be < 80mg/dL. In the case of barbiturates/thiopentone (many days to metabolize), either blood levels to be < 10mg/l or demonstration of absent cerebral blood flow by ancillary test. To use appropriate drug antagonist as necessary eg. flumazenil in case of benzodiazepines if there is doubt about the persisting effects.²
• If any of above cannot be corrected or met, ancillary testing must be considered.

Observation period

Adequate observation period (the time thought necessary to exclude reversibility without any doubt) is needed prior to clinical testing for BD/DNC. It is determined on a case-by-case basis. It is generally a minimum of a 4-hour-observation if unresponsive coma (GCS 3), with pupils non-reactive to light, absent cough/tracheal reflex and no spontaneous breathing efforts prior to undertaking the first set of brain death tests. In cases of acute hypoxic – ischemic brain injury, it has to be delayed for at least 24 hours subsequent to the ROSC (restoration of spontaneous circulation). However, if BD/DNC determination is urgent for some reason prior to 24 hours, demonstration of absent cerebral blood flow by Ancillary test is required.²

How to do clinical examination for brain death determination?

BD/DNC determination requires clinical evaluation by neurological examination to confirm coma, absence of brainstem reflexes and apnea. There must be coma with lack of responsiveness to noxious stimuli. However, spinal reflexes (motor responses in a somatic distribution after non-cranial nerve territory stimulation and not after stimulus in the cranial nerve territory) may be present and acceptable although it is not common and its decision requires expertise. All brain-stem reflexes must be absent to determine brain death. These include pupillary light reflex, corneal reflex, facial movements and spontaneous muscle movements after stimulation at cranial nerve territory, oculovestibular reflex, oculocephalic reflex, gag reflex, trachea/cough reflex and apnea test.

Absent pupillary light reflex is the absence of change in size of pupils on stimulation by a bright light. Absent corneal reflex is no blinking on stimulation of cornea (avoid central cornea) with a cotton-tipped swab. On applying deep pain (supra-orbital ridge, temporomandibular joint, etc.), there must be no facial movements and spontaneous muscle movements. Oculovestibular reflex (cold caloric test) is done after eliminating earwax and ensuring the integrity of the tympanum membrane. With head up 30º, 50 ml of freezing/iced water is injected into the external auditory conduct with the eyelids open. There must be no ocular movement in brain death upon observation for 1 minute after ear irrigation. Both sides are tested with 5-minute-interval. Absent oculocephalic reflex is absence of eye movement in response to head movement (eyes follow the head movement) when head is turned abruptly from side to side (Normal response is deviation of the eyes to the opposite side of head turning). Gag reflex is done by stimulating the base of the tongue and the posterior wall of the pharynx with probe/tongue blade. Trachea/cough reflex, which is the last reflex to disappear in brain death, is done by introducing a probe/ ETT suctioning past end of ETT down the lower respiratory tract. For those reflexes where bilateral exist, at least one ear and one eye are to be done if the other side is affected by local injury or disease. In case, any one of the above brain stem reflexes cannot be done eg. facial trauma involving the auditory canal, petrous bone or skull base fracture inhibit cold caloric test, ancillary testing is required.

Apnea test (to be done by intensivist)

Prerequisites: (1) Normotension SBP at least 100 mmHg or MAP at least 60mmHg with use of vasopressors, and/or inotropes as needed(2) Normothermia at least 36 °C with use of a warming blanket, automated temperature regulation device, thermal mattress, warmed fluids, and/or warmed oxygen as needed) (3) Euvolemia (4) Eucapnia (PaCO2 35–45mmHg) (5) Absence of hypoxia (6) No prior evidence of CO2 retention (i.e., COPD, severe obesity, high cervical cord injury). If above prerequisites cannot be fulfilled, ancillary testing is required.²
Procedure:

• Preoxygenate at least for 10 minutes with 100% oxygen.
• Adjust baseline PaCO2 to be 40 mmHg prior and confirmed by basal arterial blood gas (ABG) testing.
• Disconnect the patient from the ventilator.
• Deliver 100% O2 (6 l/min) through endotracheal tube, via CPAP or resuscitation bag with a functioning PEEP valve or via the oxygen insufflation method via tracheal cannula.
• Allow PaCO2 increase (Average rate of rise is 2.5-3 mmHg per minute so it will take about 6 minutes).
• Observe for respiratory effort.
• Get ABG to determine PaCO2 > 60 mmHg, ≥20 mmHg over baseline
  Interpretation: Positive apnea test if respiratory movements are absent when arterial PCO2 is ≥ 60 mm Hg or 20 mm Hg increase over a baseline. If PCO2 target is not met, repeat longer test (10 -15 min) in hemodynamically stable patient. If spontaneous respiration is witnessed, abort the test and repeat after 24 hours. If hemodynamics become unstable during the test, abort the test and send ABG. If PaCO2 target is met, the apnea test positive (consistent with BD), and if PaCO2 target is not met, ancillary testing is required.

Number of Examinations

Clinical brainstem reflexes must be performed on two occasions. But only 1 positive apnea test is enough. Doctor A may perform the tests while Doctor B observes. Second set of clinical tests done by second pair of doctors without time interval between first and second (if prerequisite and observation period satisfied) but if same pair of doctors for the second set, an interval of 6 hours is needed. If first set of examination is inconclusive for brain death, same pair or different pair of doctors to repeat first set after 6 hours. When second set of clinical test is still not conclusive, ancillary testing is required. If the tests are still inconclusive, decision must be made by the team/committee for determination of brain death.²

Ancillary tests³

Ancillary testing is not always necessary. Choice of the test is according to the clinician’s sound judgment and availability. Different tests are with different purposes to assess.

• To assess cerebral circulatory arrest:
  • Transcranial Doppler (TCD)
  • Cerebral arteriography
• To assess absence of bioelectric activity:
  • Electroencephalogram (EEG)
  • Multimodal Evoked Responses to visual, auditory and somatosensory
• To assess decrease of cerebral aerobic metabolism:
  • Cerebral gammagraphy

Medical records documentation

A standardized checklist must be used for death determination and its documentation. Following evidences need to be documented;

• Aetiology and irreversibility of condition
• Absence of motor response to pain
• Absence of brain stem reflexes
• Absence of respiration with PCO2 ≥ 60mmHg
• Justification for ancillary test and result of ancillary test
• The time of brain death
  • when second set of examination is completed
  • the time arterial PCO2 reached the target value during the apnea test
  • when the ancillary test has been officially interpreted
  • identity of practitioners performing the evaluation.

    For a case to be confirmed brain death finally, brain death must be diagnosed following local protocol and legislation and the diagnosis of brain death or death by neurological criteria must be written in the medical record of the patient.³

Conclusion

For confirmation of brain death in case 1 with massive stroke affecting brain stem, with the absence brain stem reflexes, we had to proceed to apnea test and ancillary testing. We would recommend an ancillary testing which looks at absence of bioelectric activity of brain rather than TCD or cerebral arteriography which assess cerebral circulatory arrest in such case. If apnea test is positive and EEG shows electrocerebral inactivity, brain death is confirmed and all the life supports can be withdrawn. For case 2, after 4 hours’ observation from unresponsive coma and absent corneal and pupillary reflexes, we need to proceed to confirm absence of all brain stem reflexes and then positive apnea test. As soon as possible after brain death confirmation by 2 sets of doctors consecutively, subsequent steps are declaration of death, family counselling, donor management, organ allocation and recipient identification, and organ recovery procedures.

Disclosure

There is no conflict of interest and no financial grant from any organization or individual.

References

1. Greer, D.M., Shemie, S.D., Lewis, A. et al. (2020). Determination of brain death/death by neurologic criteria: The World Brain Death Project. JAMA, 324:1078.
2. Brain death guideline, University of Medicine 1, Myanmar. 2016.
3. Organ donation innovative strategies for Southeast Asia (ODISSeA). (2021). Postgraduate programme in organ donation. DTI donation & transplantation institute. https://odisseaproject.eu/about/

Author Information

Ohnmar¹, Yan Lynn Aung², Moe Moe Zaw³, Phyu Phyu Lay⁴, Win Min Thit⁵

1. Associate Professor, Department of Neurology, University of Medicine 1
2. Consultant Neurologist, Department of Neurology, Yangon General Hospital
3. Professor/Head, Department of Neurology, University of Medicine 2
4. Professor/Head, Department of Neurology, Yangon General Hospital
5. Former Professor/Head, Department of Neurology, Yangon General Hospital