Determination of brain death and management of the brain-dead organ donor

Introduction

The diagnosis of death using neurologic criteria is recognized as the complete and irreversible loss of capacity for consciousness and all brain function as a consequence of catastrophic brain injury.

Historically and in many countries, this diagnosis is called “brain death.” Some countries and academic papers have moved away from this term, which can be a source of confusion, especially in the media. Although supportive of this move, for the purposes of this chapter, the historic and shorthand “brain death” is used.

The pathophysiologic sequelae of brain death include hemodynamic changes, activation of inflammatory and coagulation pathways, metabolic and endocrine effects, and loss of autoregulatory brain functions, all of which can affect multiple organ systems.

The physiologic care and management of the patient with brain death are important for optimizing donation and transplantation outcomes. Approximately 80% of worldwide organ donation after death occurs in individuals determined deceased using neurologic criteria.

Determination of brain death

The concept and definition of brain death

Brain death is accepted as death throughout most of the world, although there exists international variability in both the definition and process of determining brain death. There is general consensus regarding brain death as the complete and irreversible loss of brain function resulting from a devastating brain injury with the features of unresponsive coma, brainstem areflexia, and apnea.

Before the 1950s, catastrophic brain injury would inevitably lead to inadequate spontaneous respiration and rapid cardiorespiratory arrest. The advent of mechanical ventilation and cardiopulmonary resuscitation disrupted the interdependent linkage between these three functions. Complete cessation of brain function could occur and yet by intensive care support, respiration and circulation could be maintained.

Published case series from France in the 1950s first described ventilator-dependent patients in an irreversible state of apneic coma with absent brainstem reflexes and absence of electroencephalographic (EEG) activity, and the term “le coma dépassé” (a state beyond coma) was used. ^, In 1968 a committee of Harvard University faculty proposed criteria to diagnose this state, which they called “irreversible coma,” and asserted that despite the presence of mechanically supported respiration, and consequent circulation and organ function, people with permanent loss of all functions of the entire brain were dead. The Harvard report heralded the successive worldwide acceptance of brain death and the clinical approach to its determination.

The Harvard report described the requirement for “whole brain death,” inclusive of the cerebral hemispheres, cerebellum, and brainstem, and this approach was accepted within the United States and most other countries. At a similar time in the United Kingdom (UK) the “brainstem death” concept was evolving, with a focus on the vital role of the brainstem in consciousness and respiration. This became the legally accepted standard in the UK and in some other countries with historical colonial links. Despite these differences, in practice, the occurrence and process for determining death are very similar in both circumstances. ^,

Recent publications have sought to move from an historical and anatomic focused view of brain death to definitions that attempt to unify all diagnoses of human death (both neurologic and circulatory) around a concept of the permanent loss of brain function. ^, ^,

The vast majority of brain death arises from severe cerebral injury culminating in increased intracranial pressure (ICP), rostral-caudal herniation, reduced cerebral perfusion pressure, and finally the absence of brain blood flow. The loss of brainstem function is caused by ischemia and compression through uncal herniation.

The most common etiologies are hemorrhage (e.g., subarachnoid or intracerebral hemorrhage), ischemic stroke, traumatic brain injury, and hypoxic-ischemic brain injury after a resuscitated cardiac arrest. Other causes include central nervous system infection (e.g., bacterial meningitis, viral encephalitis, brain abscesses); neoplasms (primary brain tumors or metastases); obstructive hydrocephalus; and cerebral edema from hyponatremia, liver failure, or other metabolic conditions. The pathophysiology of raised ICP with loss of brain blood flow and perfusion is facilitated by the rigid nonexpanding nature of the skull and thus can be less likely or slower in onset in patients post-craniectomy and children younger than 2 years with nonfused skull sutures.

In the uncommon circumstance of an isolated brainstem or cerebellar injury, jurisdictions that require whole brain death need to ensure loss of supratentorial blood flow, as it cannot be presumed that “whole brain” death criteria have been met through clinical examination alone. Of note the majority of patients with posterior fossa lesions will with time go on to lose cerebral blood flow through the development of hydrocephalus or by other mechanisms.

Given the linkage between brain and cardiorespiratory function, with cessation of the latter in the setting of devastating brain injury, the development of brain death requires, at a minimum, the provision of mechanical ventilatory support. The setting for brain death is therefore almost exclusively in-hospital and usually within intensive care units.

The fundamentals of the clinical examination for brain death are relatively consistent throughout the world. Most variability in the process of brain death determination relates to aspects such as the qualifications of the examiners and number of examinations; time intervals between examinations; and the prerequisites for blood pressure, temperature, and drug levels, in addition to the indications and recommended techniques for ancillary testing. Healthcare providers should be knowledgeable about jurisdictional laws and guidelines and ensure their practice is consistent with local requirements.

Making a diagnosis of brain death has benefits irrespective of the potential for organ donation, as it establishes whether a patient is alive or dead. This can eradicate doubt for the family and hospital staff and allow futile and/or inappropriate treatment to cease. Brain death should therefore be determined whenever it has occurred and regardless of whether donation is being considered.

Process for determining brain death

Although individual jurisdictional requirements may vary, the general principles outlined here do not.

The consideration of brain death requires there to be definite clinical and neuroimaging evidence of acute brain pathology sufficient to result in the complete and irreversible loss of brain function. In countries that require “whole brain death,” evidence of sufficient cerebral pathology to cause loss of all brain function must be present.

The patient must have observed unresponsive coma, brainstem areflexia, and lack of spontaneous breathing effort in the absence of reversible conditions. Some conditions other than a devastating brain injury may result in reversible loss of brain function mimicking brain death, such as severe Guillain-Barré syndrome, snake bite, and botulism. The diagnosis of brain death must not be entertained in such situations.

Even in jurisdictions that require ancillary investigations, the diagnosis of brain death requires a clinical examination to demonstrate the absence of brainstem function.

Preconditions to clinical examination

The absence of confounders is important to ensure that the clinical examination accurately reflects the absence or presence of brainstem function. If confounding factors are present (e.g., inability to exclude sedative effects), or if a portion of the examination cannot be adequately undertaken (e.g., inability to adequately examine all brainstem reflexes or perform apnea testing), a clinical examination that is as complete as possible should be conducted, as evidence of residual brain function will exclude the presence of brain death. Where confounders exist, ancillary testing will be necessary in addition to the clinical examination to determine brain death (see later).

The following preconditions should be met before and throughout the clinical examination:

Exclusion of hypothermia (e.g., temperature ≥35°C).
Exclusion of hypotension (e.g., mean arterial pressure [MAP] 70–100 mm Hg in an adult and age-appropriate blood pressure in children).
Exclusion of effects of sedative medications (self-administered or otherwise). The time taken for plasma concentrations of sedative medications to fall below levels with clinically significant effects depends on the dose and pharmacokinetics of medications used and on hepatic and renal function, especially in the case of barbiturates, which take many days to metabolize. Measurement of blood levels to ensure they are below that of clinically significant effects may be necessary. Particular care should be taken to ensure the absence of continued sedative medication effect in patients who have been hypothermic (e.g., therapeutic hypothermia post cardiac arrest). If there is any doubt about the persisting effects of opioids or benzodiazepines, an appropriate medication antagonist should be administered at the time of examination, or ancillary investigations must be carried out.
Absence of severe electrolyte, metabolic, or endocrine disturbances. These include marked derangements in plasma concentrations of glucose, sodium, phosphate, magnesium, and urea and severe endocrine dysfunction (e.g., severe hypothyroidism or hypoadrenalism).
Absence of acute liver failure or decompensated chronic liver disease.
Absence of neuromuscular-blocking drugs. A peripheral nerve stimulator should be used to confirm that neuromuscular conduction is normal unless it is certain that neuromuscular-blocking medications have not been administered.
Ability to adequately examine the brainstem reflexes (e.g., may not be possible if major facial trauma prevents eye and/or ear examination).
Absence of a cervical spinal cord injury. This may preclude apnea testing that is reflective of brainstem function.
Absence of severe cardiopulmonary injury or disease, which may preclude the safe undertaking of apnea testing.

Observation period and establishing irreversibility

It must be established that the loss of brain function is constant over time and irreversible. This is achieved by knowledge of the mechanism and natural history of the devastating brain injury and a period of observation (e.g., a minimum of 4–6 hours of features consistent with brain death). When brain death is suspected after a resuscitated cardiac arrest, a longer period of 24 hours observation is recommended before brain death testing, as there can be slow recovery of brainstem function after successful resuscitation. Similarly, after prolonged hypothermia, such as therapeutic cooling post cardiac arrest, a period of 24 hours post-rewarming is recommended because of the effects of hypothermia on neurologic function and the impact cooling may have on drug metabolism, as demonstrated by case reports that support a more conservative approach in such circumstances. ^,

In patients who are unresponsive with nonreactive pupils but appear to be spontaneously breathing, care must be taken that the ventilator is not autocycling/autotriggering on a spontaneous mode secondary to cardiac pulsations.

Situations requiring extra caution

The UK has identified “red flag” categories where additional diagnostic caution is advised :

1.
Testing <6 hours of the loss of the last brainstem reflex
2.
Testing <24 hours of the loss of the last brainstem reflex, where the etiology is primarily anoxic damage
3.
Hypothermia—24-hour observation period after rewarming to normothermia recommended
4.
Patients with any neuromuscular disorders
5.
Steroids given in space-occupying lesions such as abscesses
6.
Prolonged fentanyl infusions
7.
Etiology primarily located to the brainstem or posterior fossa
8.
Therapeutic decompressive craniectomy.

Clinical examination

The following three clinical criteria need to be established for the neurologic determination of death:

Unresponsive coma
Absent brainstem reflexes
Apnea (absence of spontaneous breathing)

A generic process for undertaking the clinical examination is suggested in Table 159.1 . A number of countries have published education videos to assist clinicians.

TABLE 159.1

Process for the Clinical Examination in the Determination of Brain Death

Test	Response Consistent With Brain Death	Considerations
Responsiveness
There should be unresponsive coma with no evidence of arousal or movement after noxious stimulation, other than spinal-mediated reflexes.
Noxious stimuli should be applied in the cranial nerve distribution and all four limbs and trunk, observing for centrally mediated motor responses (e.g., pressure over the supraorbital nerve, sternal rub, and deep nail bed pressure).	There should be no motor response within the cranial nerve distribution or any response in the limbs secondary to cranial nerve stimulation. This equates to a Glasgow Coma Score (GCS) of 3.	Spinal reflexes may be present in patients with brain death (see later) and are not to be confused with a pathologic flexion or extension response.
Brainstem Reflexes The cranial nerves should be examined sequentially and bilaterally . All testable brainstem reflexes must be absent for brain death to be determined . The presence of a brainstem reflex means brain death is not present and testing is then ceased.
Pupillary light reflex—cranial nerves II and III Shine a bright light into the eye and look for a pupillary constrictor response.	There should be absence of ipsilateral and contralateral pupillary response, with pupils fixed in a midsize or dilated position (~4–6 mm), in both eyes.	Constricted pupils are not consistent with brain death and suggest the possibility of drug intoxication or locked-in syndrome. Pupils can be any shape (round/oval/irregular). Ancillary testing is recommended if eye trauma or anophthalmia limits examination.
Corneal reflex—cranial nerves V and VII Touch the corneas, applying light pressure with sterile soft cotton wool or gauze, and examine the eyes for blinking or other response.	No eyelid movement should be seen.	Touching the sclera is not sufficient. Care should be taken to avoid damaging the cornea. Ancillary testing is recommended if eye trauma, anophthalmia, severe orbital edema, or prior corneal transplantation limits examination.
Reflex response to pain in the trigeminal distribution—cranial nerves V and VII Apply pain over the trigeminal distribution (e.g., pressure over the supraorbital nerve).	No facial or limb movement should be seen.	Ancillary testing is recommended in the presence of severe facial trauma and swelling that may preclude evaluation.
Oculovestibular reflex—cranial nerves III, IV, VI, and VIII Inspect the external auditory canal with an otoscope to confirm that the eardrum is visible. If the eardrum is not visible, the canal must be cleared before testing can occur. Elevate the head to 30 degrees to place the horizontal semicircular canals in the true vertical position. Irrigate with ≥30 mL of ice water using a syringe or a syringe attached to a catheter placed inside the auditory canal. Hold eyelids open and observe for eye movement for a minimum of 60 seconds. Test both sides separately.	No eye movement should occur in response to the cold water.	A ruptured eardrum does not preclude the test. Ancillary testing is recommended in the setting of severe eye trauma, anophthalmia, or a fracture of the base of the skull or petrous temporal bone that may obliterate the response. Testing for the oculocephalic reflex (rotating the head briskly horizontally to both sides) examines the same reflex pathways and is not required in addition to the oculovestibular reflex and should not be undertaken in the presence of a cervical spine injury.
Gag reflex—cranial nerves IX and X Touch the posterior pharyngeal wall, on both sides, with a tongue depressor or cotton swab. A laryngoscope or video laryngoscope may assist in obtaining a good view of the pharynx for stimulation.	No gag response should be seen.	If the patient is orally intubated, the gag reflex may be difficult to discern.
Cough/tracheal reflex—cranial nerve X Stimulate the tracheobronchial wall to the level of the carina with deep endotracheal placement of a soft suction catheter.	No cough response should be seen.	The efferent limbs for this reflex are the phrenic nerve and the nerves of the thoracic and abdominal muscles. Therefore it cannot be assessed in patients with high cervical cord injury; in this setting, ancillary testing is recommended.
Apnea Testing
The test seeks to demonstrate a lack of spontaneous breathing in the setting of a sufficient respiratory center stimulus. Many guidelines suggest reaching a partial pressure of carbon dioxide in arterial blood (PaCO ₂ ) of ⩾60 mm Hg (8 kPa) . Apnea testing should be undertaken ONLY if all the earlier reflexes are absent.
Preoxygenate (inspired oxygen concentration 100%) for >5 minutes to prevent hypoxemia during the test, and adjust the ventilator settings such that the PaCO ₂ normalizes at 40–45 mm Hg (5.3–6 kPa). Throughout the procedure, monitor the patient’s percentage blood oxygenation saturation (SpO ₂ ) . Disconnect the endotracheal tube (ETT) from the ventilator, with or without the provision of oxygen. Common methods for providing oxygen include the use of a self-inflating bag with attached continuous positive airway pressure (CPAP) valve to prevent atelectasis or inserting a small cannula via the ETT to approximately the level of the carina to deliver oxygen at 4–6 L/min . Expose the chest and abdomen and observe continuously for any spontaneous breathing. End-tidal CO ₂ monitoring can be very helpful . An arterial blood gas (ABG) is taken after approximately 8–10 minutes to document the rise in PaCO ₂ to above 60 mm Hg (8 kPa). If the patient is stable and point-of-care ABG testing is available, await the return of the result before reconnecting the ventilator in case the required change in PaCO ₂ has not been achieved . At the end of testing, return the patient to mechanical ventilation.	If any respiration attempts are seen (that is, abdominal or chest excursions or activity of accessory respiratory muscles, or if there is end-tidal CO ₂ evidence of a breath), the test is ceased and the patient is reconnected to the ventilator, as the criteria for brain death have not been met.	Usually PaCO ₂ rises by ~3 mm Hg (0.4 kPa) for every minute of apnea. Some protocols require that a pH goal is also met, (e.g., <7.30) and/or that in the setting of prior CO ₂ retention that a rise (e.g., increase of >20 mm Hg = 2.7 kPa) above a known chronic baseline is achieved. If starting from normocapnia, the PaCO ₂ is likely to be >60 mmHg (8 kPa) after 8–10 minutes. Patients may become hypoxic or develop hemodynamic instability. If hypoxia (SpO ₂ <88%) occurs, give 1–2 mandatory breaths and continue apnea testing. Vasopressors may be adjusted to support blood pressure. If the test cannot be completed due to cardiorespiratory instability, it should be ceased and an alternative approach to undertaking the test be used or, alternatively, an ancillary test may be needed. Alternative approaches to achieving the PaCO ₂ goal while maintaining oxygenation include providing oxygen via a self-inflating bag with CPAP valve, preapnea recruitment maneuvers, and induction of hypercarbia with CO ₂ or carbogen before disconnecting from the ventilator. Care must be taken if a tracheal catheter is used, as wedging, trauma, or a size that is large relative to the tracheal diameter may result in barotrauma. High oxygen flow rates can cause CO ₂ washout with failure of the PaCO ₂ to rise. If the CPAP circuit on the ventilator is used, care must be taken to identify autotriggering/autocycling, which may be misinterpreted as spontaneous breathing.

Protocols vary in the requirement of whether it must be possible to reliably test each of the brainstem reflexes bilaterally, or at a minimum unilaterally. Ancillary testing is required if it is not possible to meet the local standard because of inability to adequately examine at least one or both eyes and ears.

Family presence during the clinical examination should be offered, with appropriate explanation and support, as family members may find witnessing the testing useful to their acceptance and understanding of death, especially the apnea test component. Diagrams, the use of nationally endorsed testing forms, and viewing neuroimaging and reports may also assist the family in their understanding of the patient’s prognosis and the concept of brain death.

When preconditions are satisfied, then clinical examination alone is preferable for the routine determination of brain death without reliance on ancillary testing (see later).

Number of examinations

A single clinical examination, including apnea testing, is the minimum standard for determination of brain death in adults. Most jurisdictions require two examinations. If two examinations are performed, an intervening period is unnecessary because the prerequisite of irreversibility will have already been demonstrated by knowledge of the mechanism and natural history of the devastating brain injury, along with a suitable observation period before initiating testing. All that may be required is enough time to allow for physiologic stabilization between tests. Many clinicians will use this time to update the family and invite them to witness the second examination.

Spinal reflexes

The preservation of spinal reflexes after brain death has been described for decades. Spinal reflexes can be either spontaneous or provoked by noxious stimuli such as pain, passive neck movement, hypotension, and hypoxemia after terminal removal of the ventilator or during the apnea test. They never involve the brainstem cranial nerves.

Prevalence is up to 50% of patients with brain death and is the result of a functioning spinal arc with loss of higher center inhibitory control.

Spinal reflexes can be simple or complex and may be upsetting when observed by family members and staff. It is essential that these movements are explained and forewarned to families and staff.

The most common movements described are finger and toe jerks, the undulating toe reflex, triple flexion response, pronation-extension reflex, facial myokymia, and myoclonus. ^, Rarely, marked upper extremity and torso movements may occur, such as the Lazarus sign, in which there is bilateral arm flexion; shoulder adduction; and sometimes flexion of the trunk, hips, and knees.

Other physiologic signs that are compatible with brain death include sweating, blushing, tachycardia, normal blood pressure without the need for pharmacologic support, and an absence of diabetes insipidus.

Observations that are incompatible with brain death include decerebrate or decorticate posturing, true extensor or flexor motor responses to painful stimuli, seizures, and limb movement elicited by stimulation of the cranial sensory nerves or facial movement elicited by stimulation of the body or limbs.

Ancillary testing

Ancillary testing is required if the preconditions for clinical examination alone to determine brain death cannot be met. This may include the presence of confounding conditions that cannot be resolved or the inability to complete all aspects of the clinical examination, including the apnea test. Ancillary tests may also be required if there is uncertainty in the interpretation of aspects of the clinical examination, including whether movements are centrally or spinal-mediated. Other reasons for undertaking ancillary tests include a desire to determine brain death earlier than the required observation period allows, if national policies or practices require them, and, for some families, ancillary tests may assist in providing greater understanding and certainty of brain death, especially if they have not witnessed the clinical examination. It is recommended that the clinical examination be completed to the fullest extent possible before undertaking an ancillary test.

Most ancillary testing is on the premise that demonstrating absence of cerebral blood flow and/or perfusion in a person with a supported somatic circulation correlates with permanent loss of brain function. An exception is EEG, which measures brain activity. The ideal test would have no false positives (incorrect diagnosis of brain death) or false negatives (incorrect ruling out of brain death). Various techniques have been described and validated, generally against clinical brain death testing. Local availability and preferences tend to guide use :

1.
Digital subtraction angiography (three- or four-vessel cerebral angiography)—Long regarded as the gold-standard ancillary test for this purpose, cerebral angiography in brain death demonstrates flow obstruction at the level of the carotid siphon and the foramen magnum. ^, Even cerebral angiography is subject to interoperator variability because of, for example, the vigorousness of contrast injection, but it is widely accepted as specific and sensitive.
2.
Radionuclide imaging (cerebral scintigraphy)—Radiotracer uptake should not occur in brain parenchyma in the setting of brain death. Intravenous injection of an agent such as Tc-99m labeled hexamethylpropyleneamine oxime (HMPAO), which normally crosses the blood-brain barrier and persists in brain parenchyma, together with planar or single-photon emission computed tomography (SPECT) detection is used. Although there have been case reports of false-positive tests, the specificity is thought to be high.
3.
Computed tomography (CT) angiography/perfusion—Being relatively easily available and noninvasive, CT has obvious appeal as an ancillary modality. It was evaluated initially using a 7-point and then a more sensitive 4-point scoring system. ^, A Cochrane review identified only moderate sensitivity and therefore could not recommend CT angiography as a mandatory investigation.
4.
Transcranial Doppler (TCD)—Although portable and noninvasive, TCD is operator dependent and reliant on detection of a suitable acoustic window. A systematic review and meta-analysis reported very high sensitivity and specificity when compared with clinical brain death testing.
5.
Magnetic resonance imaging (MRI)—Various techniques involving MRI have been evaluated in brain death (e.g., diffusion-weighted imaging [DWI], susceptibility-weighted imaging [SWI], gradient-recalled echo [GRE], magnetic resonance angiography [MRA]), but techniques suffer from uncertain specificity and the logistic impediments of transporting ventilated patients to the MRI scanner.
6.
EEG—In contrast to the aforementioned techniques, EEG is a test of cerebral function and not blood flow. It is a common mandatory test in algorithms for brain death determination in some jurisdictions and importantly requires clinical preconditions to be met (e.g., normothermia and absence of confounding sedative or metabolic effects). ^, Because of its limited utility and case reports where overreliance upon it has contributed to misdiagnosis, some countries now advise against its use. , ^, ^,

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