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Pathophysiology of brain death: What does the brain do and what is lost inbrain death

Lori Shutter MD, FCCM, FNCS

PII: S0883-9441(14)00154-3DOI: doi: 10.1016/j.jcrc.2014.04.016Reference: YJCRC 51508

To appear in: Journal of Critical Care

Received date: 14 April 2014Accepted date: 20 April 2014

Please cite this article as: Shutter Lori, Pathophysiology of brain death: What doesthe brain do and what is lost in brain death, Journal of Critical Care (2014), doi:10.1016/j.jcrc.2014.04.016

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Pathophysiology of brain death:

What does the brain do and what is lost in brain death

Lori Shutter, MD, FCCM, FNCS

Lori Shutter, MD, FCCM, FNCS

Vice Chair of Education, Critical Care Medicine

Professor, Departments of Critical Care Medicine, Neurology & Neurosurgery

University of Pittsburgh School of Medicine

Office phone: 412-647-3143

Email: shutterla@upmc.edu

The brain is the most eloquent and complicated organ in the body. On average it

weighs 1.5 kg and is comprised of 86 billion neurons, of which only 19% are located in

the cerebral cortex. In addition, there are 85 billion non-neuronal cells that provide

integral support activities for the neuron. [1] Entire texts have been devoted to

describing what the brain does, but for the purpose of this discussion the focus will be

on three central functions: cognitive, hormonal balance, and integrative. Almost every

function performed by the brain can be categorized into one of these activities, and

these components are crucial to any discussion of brain death.

Cognitive Function

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Cognition is the process of gaining knowledge, problem solving and decision making. It

requires awareness, perception, sensory input, reasoning and judgment, and is affected

by memories, emotions, attitudes, and social influences. The first requirement for any

cognitive processing is awareness, and the loss of awareness will prevent cognitive

development. In a discussion of brain death, we must be cognizant of the difference

between awareness and arousal. Arousal is the physical and psychological state that

allows a being to react to stimuli. A being can experience arousal without awareness,

but awareness cannot be achieved without arousal to allow for reactions to sensory

input. Patients who sustain a brain injury and demonstrate arousal without awareness

meet the definition of a vegetative state. They exhibit arousal through sleep-wake

cycles and perceived responsiveness through reflex movements, but in reality there is

no reliable demonstration of personal or environmental awareness. This loss of

cognition and higher cortical function has been proposed to represent “higher brain

death”, as the attributes of intellect and ‘humanness’ are lacking. While loss of cortical

function is a component of current brain death testing, “higher brain death” alone has

never gained acceptance by medical organizations or society.

Hormonal Function

Hormonal balance is controlled through a feedback loop between the brain and

endocrine system. Neurons in the brain have receptors for hormones, which act to

influence neuronal function and gene regulation that control the hypothalamic-pituitary

axis. The hypothalamus produces releasing factor hormones that drive the pituitary

gland to subsequently release hormones that drive activity of the endocrine glands.

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Activity of the endocrine glands is also influenced by environmental factors such as

stress and seasonal changes. This feedback system helps to demonstrate the

capability of the brain to respond to environmental factors, but it is not mandatory for

survival. An injury to the hypothalamic-pituitary axis can be compensated for through

the use of medications that serve as exogenous replacements for pituitary factors. In

addition, endocrine glands can continue to release hormones independent of brain

function, although there may be variations in hormonal levels. The term “whole brain

death” has been used when there is loss of higher cortical function, brainstem reflexes,

and regulation of the hypothalamic-pituitary axis. This concept has also not gained

widespread acceptance since the feedback loop system of hormonal control is not

completely dependent on brain functionality.

Integrative Function

The brain controls interactions with the environment by processing and reacting to both

external stimuli and internal signals. Any activity a person performs requires processing

of some information, whether it is reflexive, sensorimotor, cognitive or psychological.

The loss of integrative function prevents a person from maintaining the physiological

responses that allow maintenance of homeostasis, protective reflexes and life. The

cortex integrates higher sensorimotor and cognitive functions, while the brainstem

integrates the most basic reflexive protective responses. The loss of brainstem reflexes

results in the inability for an organism to maintain cardiopulmonary function. The

medical community recognized the loss of brainstem integrative functions as death by

neurological criteria, or brain death, in the Uniform Declaration of Death Act. [2] The

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American Academy of Neurology has published a practice parameter to guide the

process of determining death by neurological criteria. This document provides

information on the prerequisites for determination of brain death, as well specific steps

for testing all components of brainstem integrative function. [3]

Determination of Brain Death

Prerequisites for determination of brain death

Certain prerequisites must be met prior to assessing for death based on neurological

criteria. First and foremost, a known neurologic process must have occurred that would

be compatible with the loss of brain function. This is typically demonstrated by

computerized tomography (CT) or magnetic resonance imaging (MRI). In addition,

there cannot be any medication effects, metabolic or electrolyte abnormality that could

significantly impair brain responsiveness (Table 1). Hypothermia and impaired renal or

hepatic function may delay metabolism and clearance of central nervous system (CNS)

depressants, which may confound the neurologic exam and thus must be taken into

consideration when drug levels are not available. For this reason, calculation of drug

clearance should be performed using a minimum of 5 times the drug’s half-life, and

adjustments then made based on the patient’s liver and renal function. [3] Finally, the

systolic blood pressure must be greater than 100 mm Hg and core body temperature

greater than 36°C. Vasopressors and warming devices may be used to achieve these

requirements. Extreme caution should be used in the setting of therapeutic

hypothermia due to the effect of that intervention on medication clearance and the

physical exam, thus a minimum of 24 hours and up to 72 hours after achieving a core

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body temperature of greater than 36oC is recommended unless a confirmatory test to

demonstrate absent cerebral blood flow is performed. [4]

Insert Table 1

Assessing Integrative Function

Once all prerequisites have been reviewed and death by neurological criteria is

suspected, then confirmation of loss of integration between the brain and external

sensory stimuli must be demonstrated. This is done through a clinical examination that

assesses for reaction to central pain, responsiveness of cranial nerves II through X, and

apnea testing. Cranial nerves I, XI and XII cannot be assessed due to the absence of

involuntary observable motor reactions to stimulation.

Central Pain

Central pain is the application of noxious deep pressure to core body structures.

Appropriate locations include the supraorbital notch, mandible at the ankle of the jaw,

upper trapezius, anterior axillary fold, and sternum. Pain should not be applied to

peripheral locations such as nail beds, as this may produce a spinal reflex that could be

misinterpreted by those without appropriate expertise in performance of the neurological

exam. Noxious stimulation of central structures specifically tests responsiveness of the

corticospinal, rubrospinal and vestibulospinal motor pathways. In brain death there will

be no eye opening or motor response (volitional or reflexive) to pain.

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Cranial Nerve II: Pupillary reflex

A bright light should be shined into each eye to assess for any reaction of CN II, the

optic nerve. In brain death the pupils are usually mid-position, dilated (4 – 9 mm), and

non-reactive to this stimulation.

Cranial Nerve III, IV & VI: Oculocephalic reflexes

Assessment of the oculocephalic reflex, also known as “Doll’s Eyes”, evaluates the

responsiveness of CN III (oculomotor), IV (trochlear), and VI (abducens) to head

movement. Once the cervical spine has been cleared of any injury, the eyes are held in

an open position and the head is rotated rapidly in a side to side motion. If the cranial

nerves are functional, the eyes will move relative to the head to maintain a forward

gaze. In brain death, there will not be any eye motion relative to the head.

Cranial Nerve V & VII: Corneal reflex

The corneal reflex is elicited by touching the cornea with an edge of a piece of gauze or

cotton swab to stimulate the trigeminal nerve (CN V). A normal integrative response

would be the facial nerve activating the obicularis oculi muscle to produce eyelid

closure, or a blink response. In brain death, each eye is tested individually and there

will be no eyelid response to corneal stimulation.

Cranial Nerve VIII: Oculovestibular reflex

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The vestibular nerve (CN VIII) is tested through the oculovestibular reflex, or ‘cold

calorics’. The head of the bed should be placed at a 30° angle in order to provide

maximum stimulation of the semicircular canals, and the tympanic membrane should be

visualized to confirm patency of the external auditory canal. The eyes are held open,

then each ear is irrigated individually with 60 ml of ice water and observed for one

minute. If there is a normal integrative response, a slow movement of the eyes towards

the irrigated ear will occur. Both eyes need to be tested, and the examinations should

be separated by a few minutes. In brain death, there will be no movement of the eyes.

Cranial Nerve IX: Gag reflex

The glossopharyngeal nerve (CN IX) is assessed through the pharyngeal, or gag, reflex.

The posterior pharynx is stimulated with a tongue blade, suction device, or by

movement of the endotracheal tube (ETT), which will produce a gag response if the

brainstem is functioning. In brain death, the gag reflex is absent.

Cranial Nerve X: Cough reflex

The cough reflex assesses responsiveness of the vagus nerve (CN X). A suction

catheter is introduced down the ETT to the level of the carina for one – two passes, or

the ETT can be moved forcibly. These movements would produce a cough response

with a functioning brainstem. In brain death, the cough reflex is absent.

Apnea Testing

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Apnea testing is the final component of the brain death examination, and is essentially a

clinical confirmatory test. After demonstration that the brain is no longer integrating any

external stimulation to produce any basic protective brainstem responses, then an

assessment of the brain’s ability to drive pulmonary function is undertaken by

performing a CO2 challenge to document a rise in the PaCO2 above a specified target

value.

Prior to performing an apnea test the ventilator must be adjusted to achieve a normal

CO2 level of 35 – 45 mm Hg (or the patient’s baseline if they are known to have a

pulmonary disease causing CO2 retention) with a positive end-expiratory pressure of 5

– 8 cm H2O. Pre-oxygenation with 100% FiO2 should be provided for a minimum of 10

minutes to achieve a target PaO2 of greater than 200 mm Hg. An inability of the patient

to tolerate ventilator changes necessary to achieve these goals should raise concerns

about the patient’s ability to tolerate apnea testing.

Once these goals are demonstrated by obtaining a baseline arterial blood gas (ABG),

the patient is removed from the ventilator, placed on supplemental oxygen, and

observed for demonstration of any effective abdominal or chest wall respiratory

movements. Effective supplemental oxygen is be provided by delivering 6 L/min O2 by

cannula into the ETT, using a T-piece system at 12 L/min O2, or providing continuous

positive airway pressure (CPAP) at 10 cm H20. [5] Duration of the apnea test

necessary to achieve an adequate rise in CO2 can be calculated using the general rule

that the PaCO2 will rise by 5 mm Hg in the first 2 minutes off the ventilator, and then

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increase by another 2 mm Hg for every additional minute without respiratory function.

In patients undergoing extracorporeal membrane oxygenation (ECMO), the sweep

speed and oxygen delivery can be adjusted to allow accumulation of CO2 with

maintained oxygenation during apnea testing. [6] After an adequate time has passed

without respiratory effort, a repeat ABG is drawn and the patient is placed back on the

ventilator. A PaCO2 level greater than 60 mm Hg, or more than 20 mm Hg above

baseline PaCO2 levels in patients with known CO2 retention, supports a diagnosis of

brain death.

Some common complications that may occur during apnea testing include hypotension,

hypoxia, and cardiac arrhythmias. Factors associated with these complications are

listed in table 2. The use of supplemental oxygen and vasopressors may are

encouraged to avoid these complications. If the patient becomes hemodynamically

unstable during apnea test, an ABG should be drawn, the test aborted and the patient

placed back on the ventilator. The apnea test is considered indeterminate if the PaCO2

is less than 60mm Hg. In that situation, other confirmatory studies should be

considered (table 3).

Insert Table 2

Role of ancillary testing

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Ancillary studies are not mandatory and should not replace clinical testing, but may be

desirable in patients in whom specific components of clinical testing cannot be reliably

performed or evaluated. Examples of situations in which ancillary testing may be

considered include trauma to the face, persistent hypoxia and hemodynamic instability

after adequate resuscitation, after therapeutic hypothermia, or with refractory metabolic

or electrolyte abnormalities. Accepted studies for this purpose are listed in table 3. [3,

7-8]. Appropriate interpretation of these studies in this clinical setting requires expertise

in determination of brain death and awareness of the potential pitfalls of each option.

Insert Table 3

Conclusion

The determination of death by neurological criteria (brain death) is based on a clinical

examination that demonstrates the loss of integrative functions of the brain – body

connection in response to stimuli. The loss of this capability prevents the body from

maintaining protective responses, respiratory drive and independent cardiopulmonary

function. Expertise in death based on neurological criteria is needed for interpretation of

examination findings, particularly in relation to use of therapeutic hypothermia. The use

of ancillary studies should be reserved for clinical settings where any component of the

examination either cannot be performed or is felt to be unreliable.

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References

1. Azevedo FA, Carvalho LR, Grinberg LT, Farfel JM, Ferretti RE, Leite RE, Jacob

Filho W, Lent R, Herculano-Houzel S. Equal numbers of neuronal and

nonneuronal cells make the human brain an isometrically scaled-up primate

brain. J. Comp. Neurol. 2009:513, 532–541

2. Determination of Death Act. National Conference of Commissioners on Uniform

State Laws Annual Conference 1980.

http://www.uniformlaws.org/shared/docs/determination%20of%20death/udda80.p

df (accessed 4-6-14)

3. Wijdicks EFM, 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;74:1911-1918.

4. Webb A, Samuels O. Reversible brain death after cardiopulmonary arrest and

induced hypothermia. Crit Care Med 2011;39:1538-42.

5. Lévesque S, Lessard MR, Nicole PC, Langevin S, LeBlanc F, Lauzier F, Brochu

JG. Efficacy of a T-piece system and a continuous positive airway pressure

system for apnea testing in the diagnosis of brain death. Crit Care Med

2006;34:2213-6.

6. Smilevitch P, Lonjaret L, Fourcade O, Geeraerts T. Apnea test for brain death

determination in a patient on extracorporeal membrane oxygenation. Neurocrit

Care 2013;19:215-7.

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7. Ducrocqa X, Hasslerb W, Moritakec K, Newelld DW, von Reuterne GM, Shiogaif

T, Smithg RR. Consensus opinion on diagnosis of cerebral circulatory arrest

using Doppler-sonography: Task Force Group on cerebral death of the

Neurosonolgy Research Group of the World Federation of Neurology. J Neurol

Sci 1998;159:145–150.

8. Escudero D, Otero J, Marqués L, Parra D, Gonzalo JA, Albaiceta GM, Cofiño L,

Blanco A, Vega P, Murias E, Meilan A, Roger RL, Taboada F. Diagnosing brain

death by CT perfusion and multislice CT angiography. Neurocrit Care

2009;11:261-71.

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Table 1: Prerequisite laboratory values for declaration of death by neurological criteria

Sodium Range = 110 – 160 mEq/L

Serum osmolarity Less than 350 mOsm/kg

Calcium Less than 12 mg/dL

Glucose Range = 70 – 300 mg/dL

pH Greater than 7.2

CNS Depressants Levels should be in a low to sub-therapeutic range that would allow maintenance of protective responses

Alcohol Less than 0.08% (or 80 mg/dL)

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Table 2: Factors associated with complications during apnea testing

pH less than 7.3 or greater than 7.5

Plasma Na less than 120 or greater than 170 mEq/L

Serum potassium less than 3.0 or greater than 6.0 mEq/L

Calcium less than 8.0 or greater than 10.5 mEq/L

Pretest hypotension or administration of vasopressors

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Table 3: Ancillary studies for determination of brain death

Preferred Tests Test parameters Findings / Concerns

Cerebral angiography

Injection of contrast in both

anterior & posterior circulation

No intracranial flow of carotid or vertebral

circulation should be seen

Electroencephalography

Duration: minimum of 30

minutes

Channels: 16- or 18

Sensitivity: 2µV/mm

Electrocerebral inactivity

Cannot detect subcortical function

Sensitive to drug effects, sedation,

hypothermia, toxic/metabolic factors, and

artifacts

Cerebral Nuclear Medicine

Scan

Injection of isotope followed by

image acquisition at multiple

time points (immediately, at 30 –

60 minutes, and 2 hours)

Lack of cerebral uptake of isotope “Hollow

skull phenomenon”

Transcranial Dopplers

Must have baseline study

showing flow

Perform bilateral insonation with

assessment of at least one artery

on each side

Oscillating flow or low amplitude (<50

cm/s)

Brief (<200ms) spikes in early systole

without diastolic flow

Absent intracranial flow (with

known temporal windows)

CT Angiography

64-detector multi-slice scanner

Image from aortic arch to vertex

Non-opacification of cortical arteries and

deep cerebral veins