Brain Death (Clinical)

Overview and Pathophysiology

Definition^[1,2,4]

Brain Brain The part of central nervous system that is contained within the skull (cranium). Arising from the neural tube, the embryonic brain is comprised of three major parts including prosencephalon (the forebrain); mesencephalon (the midbrain); and rhombencephalon (the hindbrain). The developed brain consists of cerebrum; cerebellum; and other structures in the brain stem. Nervous System: Anatomy, Structure, and Classification death is the complete and permanent loss of all cerebral and brain Brain The part of central nervous system that is contained within the skull (cranium). Arising from the neural tube, the embryonic brain is comprised of three major parts including prosencephalon (the forebrain); mesencephalon (the midbrain); and rhombencephalon (the hindbrain). The developed brain consists of cerebrum; cerebellum; and other structures in the brain stem. Nervous System: Anatomy, Structure, and Classification stem functions, including the ability of the brain Brain The part of central nervous system that is contained within the skull (cranium). Arising from the neural tube, the embryonic brain is comprised of three major parts including prosencephalon (the forebrain); mesencephalon (the midbrain); and rhombencephalon (the hindbrain). The developed brain consists of cerebrum; cerebellum; and other structures in the brain stem. Nervous System: Anatomy, Structure, and Classification stem to regulate vegetative and respiratory activities. 

Definition of “complete and permanent loss” of brain Brain The part of central nervous system that is contained within the skull (cranium). Arising from the neural tube, the embryonic brain is comprised of three major parts including prosencephalon (the forebrain); mesencephalon (the midbrain); and rhombencephalon (the hindbrain). The developed brain consists of cerebrum; cerebellum; and other structures in the brain stem. Nervous System: Anatomy, Structure, and Classification function:

• Unresponsive coma Unresponsive Coma Brain Death with loss of capacity for consciousness
• Loss of brainstem reflexes Loss of Brainstem Reflexes Brain Death 
• Inability to breathe unassisted
• Loss of function Loss of Function Inflammation unable to resume spontaneously and unable to be restored through intervention
• Note: Cellular-level neuronal and neuroendocrine activity may still persist; their presence does not preclude the diagnosis.^[4]

Etiology^[1,3]

• Traumatic brain injury Traumatic brain injury A form of acquired brain injury which occurs when a sudden trauma causes damage to the brain. Le Fort Fractures 
• Hemorrhagic or ischemic stroke Ischemic Stroke An ischemic stroke (also known as cerebrovascular accident) is an acute neurologic injury that occurs as a result of brain ischemia; this condition may be due to cerebral blood vessel occlusion by thrombosis or embolism, or rarely due to systemic hypoperfusion. Ischemic Stroke
• Cardiopulmonary arrest Cardiopulmonary arrest Cardiac arrest is the sudden, complete cessation of cardiac output with hemodynamic collapse. Patients present as pulseless, unresponsive, and apneic. Rhythms associated with cardiac arrest are ventricular fibrillation/tachycardia, asystole, or pulseless electrical activity. Cardiac Arrest with inadequate CPR CPR The artificial substitution of heart and lung action as indicated for heart arrest resulting from electric shock, drowning, respiratory arrest, or other causes. The two major components of cardiopulmonary resuscitation are artificial ventilation and closed-chest cardiac massage. Cardiac Arrest
• Brain Brain The part of central nervous system that is contained within the skull (cranium). Arising from the neural tube, the embryonic brain is comprised of three major parts including prosencephalon (the forebrain); mesencephalon (the midbrain); and rhombencephalon (the hindbrain). The developed brain consists of cerebrum; cerebellum; and other structures in the brain stem. Nervous System: Anatomy, Structure, and Classification tumor Tumor Inflammation
• ↑ Intracranial pressure Intracranial Pressure Idiopathic Intracranial Hypertension ( ICP ICP Normal intracranial pressure (ICP) is defined as < 15 mm Hg, whereas pathologically increased ICP is any pressure ≥ 20 mm Hg. Increased ICP may result from several etiologies, including trauma, intracranial hemorrhage, mass lesions, cerebral edema, increased CSF production, and decreased CSF absorption. Increased Intracranial Pressure (ICP))
• CNS infection
• Sepsis Sepsis Systemic inflammatory response syndrome with a proven or suspected infectious etiology. When sepsis is associated with organ dysfunction distant from the site of infection, it is called severe sepsis. When sepsis is accompanied by hypotension despite adequate fluid infusion, it is called septic shock. Sepsis and Septic Shock leading to cerebral hypoperfusion and ischemia Ischemia A hypoperfusion of the blood through an organ or tissue caused by a pathologic constriction or obstruction of its blood vessels, or an absence of blood circulation. Ischemic Cell Damage
• Drug overdose

Pathophysiology^[1,3]

• Brain Brain The part of central nervous system that is contained within the skull (cranium). Arising from the neural tube, the embryonic brain is comprised of three major parts including prosencephalon (the forebrain); mesencephalon (the midbrain); and rhombencephalon (the hindbrain). The developed brain consists of cerebrum; cerebellum; and other structures in the brain stem. Nervous System: Anatomy, Structure, and Classification injury → brain Brain The part of central nervous system that is contained within the skull (cranium). Arising from the neural tube, the embryonic brain is comprised of three major parts including prosencephalon (the forebrain); mesencephalon (the midbrain); and rhombencephalon (the hindbrain). The developed brain consists of cerebrum; cerebellum; and other structures in the brain stem. Nervous System: Anatomy, Structure, and Classification edema Edema Edema is a condition in which excess serous fluid accumulates in the body cavity or interstitial space of connective tissues. Edema is a symptom observed in several medical conditions. It can be categorized into 2 types, namely, peripheral (in the extremities) and internal (in an organ or body cavity). Edema → ↑ ICP ICP Normal intracranial pressure (ICP) is defined as < 15 mm Hg, whereas pathologically increased ICP is any pressure ≥ 20 mm Hg. Increased ICP may result from several etiologies, including trauma, intracranial hemorrhage, mass lesions, cerebral edema, increased CSF production, and decreased CSF absorption. Increased Intracranial Pressure (ICP)
  • Edema Edema Edema is a condition in which excess serous fluid accumulates in the body cavity or interstitial space of connective tissues. Edema is a symptom observed in several medical conditions. It can be categorized into 2 types, namely, peripheral (in the extremities) and internal (in an organ or body cavity). Edema can occur by:
    • Vasogenic disruption of the blood-brain barrier Blood-brain barrier Specialized non-fenestrated tightly-joined endothelial cells with tight junctions that form a transport barrier for certain substances between the cerebral capillaries and the brain tissue. Systemic and Special Circulations → protein leakage from plasma Plasma The residual portion of blood that is left after removal of blood cells by centrifugation without prior blood coagulation. Transfusion Products to the brain Brain The part of central nervous system that is contained within the skull (cranium). Arising from the neural tube, the embryonic brain is comprised of three major parts including prosencephalon (the forebrain); mesencephalon (the midbrain); and rhombencephalon (the hindbrain). The developed brain consists of cerebrum; cerebellum; and other structures in the brain stem. Nervous System: Anatomy, Structure, and Classification
    • Cytotoxic Cytotoxic Parvovirus B19 modifications in cellular osmolality Osmolality Plasma osmolality refers to the combined concentration of all solutes in the blood. Renal Sodium and Water Regulation → neurons Neurons The basic cellular units of nervous tissue. Each neuron consists of a body, an axon, and dendrites. Their purpose is to receive, conduct, and transmit impulses in the nervous system. Nervous System: Histology lose the capacity to manage ionic gradients
  • Cerebral perfusion Cerebral Perfusion Syncope pressure ( CPP CPP Increased Intracranial Pressure (ICP)) equals mean arterial pressure Mean Arterial Pressure Mean arterial pressure (MAP) is the average systemic arterial pressure and is directly related to cardiac output (CO) and systemic vascular resistance (SVR). The SVR and MAP are affected by the vascular anatomy as well as a number of local and neurohumoral factors. Vascular Resistance, Flow, and Mean Arterial Pressure (MAP) minus ICP ICP Normal intracranial pressure (ICP) is defined as < 15 mm Hg, whereas pathologically increased ICP is any pressure ≥ 20 mm Hg. Increased ICP may result from several etiologies, including trauma, intracranial hemorrhage, mass lesions, cerebral edema, increased CSF production, and decreased CSF absorption. Increased Intracranial Pressure (ICP):
    • CPP CPP Increased Intracranial Pressure (ICP) autoregulates to ensure brain Brain The part of central nervous system that is contained within the skull (cranium). Arising from the neural tube, the embryonic brain is comprised of three major parts including prosencephalon (the forebrain); mesencephalon (the midbrain); and rhombencephalon (the hindbrain). The developed brain consists of cerebrum; cerebellum; and other structures in the brain stem. Nervous System: Anatomy, Structure, and Classification perfusion in normal circumstances.
    • Autoregulation Autoregulation Systemic and Special Circulations is lost with extremes of MAP or ICP ICP Normal intracranial pressure (ICP) is defined as < 15 mm Hg, whereas pathologically increased ICP is any pressure ≥ 20 mm Hg. Increased ICP may result from several etiologies, including trauma, intracranial hemorrhage, mass lesions, cerebral edema, increased CSF production, and decreased CSF absorption. Increased Intracranial Pressure (ICP).
    • ↑ ICP ICP Normal intracranial pressure (ICP) is defined as < 15 mm Hg, whereas pathologically increased ICP is any pressure ≥ 20 mm Hg. Increased ICP may result from several etiologies, including trauma, intracranial hemorrhage, mass lesions, cerebral edema, increased CSF production, and decreased CSF absorption. Increased Intracranial Pressure (ICP) → ↓ CPP CPP Increased Intracranial Pressure (ICP) → brain ischemia Brain Ischemia Localized reduction of blood flow to brain tissue due to arterial obstruction or systemic hypoperfusion. This frequently occurs in conjunction with brain hypoxia. Prolonged ischemia is associated with brain infarction. Ischemic Stroke
    • Severely ↑ ICP ICP Normal intracranial pressure (ICP) is defined as < 15 mm Hg, whereas pathologically increased ICP is any pressure ≥ 20 mm Hg. Increased ICP may result from several etiologies, including trauma, intracranial hemorrhage, mass lesions, cerebral edema, increased CSF production, and decreased CSF absorption. Increased Intracranial Pressure (ICP) → brain Brain The part of central nervous system that is contained within the skull (cranium). Arising from the neural tube, the embryonic brain is comprised of three major parts including prosencephalon (the forebrain); mesencephalon (the midbrain); and rhombencephalon (the hindbrain). The developed brain consists of cerebrum; cerebellum; and other structures in the brain stem. Nervous System: Anatomy, Structure, and Classification herniation Herniation Omphalocele
• Mitochondrial dysfunction due to cellular hypoxia Hypoxia Sub-optimal oxygen levels in the ambient air of living organisms. Ischemic Cell Damage → free radical Free Radical Highly reactive molecules with an unsatisfied electron valence pair. Free radicals are produced in both normal and pathological processes. They are proven or suspected agents of tissue damage in a wide variety of circumstances including radiation, damage from environment chemicals, and aging. Natural and pharmacological prevention of free radical damage is being actively investigated. Nitroimidazoles generation and reduction in cellular energy production → neuronal cell death Cell death Injurious stimuli trigger the process of cellular adaptation, whereby cells respond to withstand the harmful changes in their environment. Overwhelmed adaptive mechanisms lead to cell injury. Mild stimuli produce reversible injury. If the stimulus is severe or persistent, injury becomes irreversible. Apoptosis is programmed cell death, a mechanism with both physiologic and pathologic effects. Cell Injury and Death:
  • Initially in the cerebral hemispheres and basal ganglia Basal Ganglia Basal ganglia are a group of subcortical nuclear agglomerations involved in movement, and are located deep to the cerebral hemispheres. Basal ganglia include the striatum (caudate nucleus and putamen), globus pallidus, substantia nigra, and subthalamic nucleus. Basal Ganglia: Anatomy
  • Followed by the thalamus Thalamus The thalamus is a large, ovoid structure in the dorsal part of the diencephalon that is located between the cerebral cortex and midbrain. It consists of several interconnected nuclei of grey matter separated by the laminae of white matter. The thalamus is the main conductor of information that passes between the cerebral cortex and the periphery, spinal cord, or brain stem. Thalamus: Anatomy and brainstem

Clinical Presentation

History^[4,5]

• Establish the etiology of the coma Coma Coma is defined as a deep state of unarousable unresponsiveness, characterized by a score of 3 points on the GCS. A comatose state can be caused by a multitude of conditions, making the precise epidemiology and prognosis of coma difficult to determine. Coma (e.g., overdose, trauma, stroke).
• Evaluate for any confounding conditions mimicking irreversible brain Brain The part of central nervous system that is contained within the skull (cranium). Arising from the neural tube, the embryonic brain is comprised of three major parts including prosencephalon (the forebrain); mesencephalon (the midbrain); and rhombencephalon (the hindbrain). The developed brain consists of cerebrum; cerebellum; and other structures in the brain stem. Nervous System: Anatomy, Structure, and Classification injury:
  • Severe electrolyte abnormalities or acid-base disorders
  • Severe endocrine dysfunction
  • Hypothermia Hypothermia Hypothermia can be defined as a drop in the core body temperature below 35°C (95°F) and is classified into mild, moderate, severe, and profound forms based on the degree of temperature decrease. Hypothermia
  • Circulatory collapse (i.e., severe hypotension Hypotension Hypotension is defined as low blood pressure, specifically < 90/60 mm Hg, and is most commonly a physiologic response. Hypotension may be mild, serious, or life threatening, depending on the cause. Hypotension)
  • Blood alcohol level > 80 mg/dL
  • CNS depressants or paralytics 
• In the presence of hospital-administered sedative drugs and paralytics:
  • Discontinue medications for 5 elimination Elimination The initial damage and destruction of tumor cells by innate and adaptive immunity. Completion of the phase means no cancer growth. Cancer Immunotherapy half-life Half-Life The time it takes for a substance (drug, radioactive nuclide, or other) to lose half of its pharmacologic, physiologic, or radiologic activity. Pharmacokinetics and Pharmacodynamics periods before testing.
    • Note: The American College of Medical Toxicology recommends a longer period for a large drug exposure.^[7]
  • May need more time with hepatic or kidney dysfunction

Observation time prior to clinical testing^[4,5]

There is insufficient evidence to determine optimal timing for testing.

• Anoxic brain injury Anoxic Brain Injury Persistent Vegetative State after resuscitated cardiac arrest Cardiac arrest Cardiac arrest is the sudden, complete cessation of cardiac output with hemodynamic collapse. Patients present as pulseless, unresponsive, and apneic. Rhythms associated with cardiac arrest are ventricular fibrillation/tachycardia, asystole, or pulseless electrical activity. Cardiac Arrest: Wait a minimum of 24 hours.
• For other brain Brain The part of central nervous system that is contained within the skull (cranium). Arising from the neural tube, the embryonic brain is comprised of three major parts including prosencephalon (the forebrain); mesencephalon (the midbrain); and rhombencephalon (the hindbrain). The developed brain consists of cerebrum; cerebellum; and other structures in the brain stem. Nervous System: Anatomy, Structure, and Classification injuries: determined on a case-by-case basis

Clinical neurologic examination^[4,6]

The number of, and interval between, neurologic examinations required to establish brain Brain The part of central nervous system that is contained within the skull (cranium). Arising from the neural tube, the embryonic brain is comprised of three major parts including prosencephalon (the forebrain); mesencephalon (the midbrain); and rhombencephalon (the hindbrain). The developed brain consists of cerebrum; cerebellum; and other structures in the brain stem. Nervous System: Anatomy, Structure, and Classification death may vary depending on the practice location (number often ranges from 1 to 3). Additionally, many places require at least 2 clinician Clinician A physician, nurse practitioner, physician assistant, or another health professional who is directly involved in patient care and has a professional relationship with patients. Clinician–Patient Relationship evaluations. See your hospital’s designated protocol.

Requirements for assessment:

• Minimum core temperature of 36°C is required.
• Systolic blood pressure ( SBP SBP Ascites) > 100 mm Hg or MAP > 60 mm Hg:
  • Age-appropriate blood pressure targets should be met MET Preoperative Care in children.
  • Vasopressors Vasopressors Sepsis in Children may be required.

Determination of coma Coma Coma is defined as a deep state of unarousable unresponsiveness, characterized by a score of 3 points on the GCS. A comatose state can be caused by a multitude of conditions, making the precise epidemiology and prognosis of coma difficult to determine. Coma by the bilateral absence of motor Motor Neurons which send impulses peripherally to activate muscles or secretory cells. Nervous System: Histology responses to:

• Verbal stimulation Verbal Stimulation Coma: Call out the individual’s name.
• Tactile stimulation Tactile Stimulation Coma:
  • Shake or tap the individual. 
  • Noxious stimuli, including applying deep pressure to:
    • Supraorbital notch
    • Sternal angle Sternal angle Chest Wall: Anatomy
    • Condyles at the level of the temporomandibular joint (TMJ)
    • Proximal and distal locations on all limbs
• Responses consistent with brain Brain The part of central nervous system that is contained within the skull (cranium). Arising from the neural tube, the embryonic brain is comprised of three major parts including prosencephalon (the forebrain); mesencephalon (the midbrain); and rhombencephalon (the hindbrain). The developed brain consists of cerebrum; cerebellum; and other structures in the brain stem. Nervous System: Anatomy, Structure, and Classification death:
  • No grimacing or facial muscle movement
  • No motor Motor Neurons which send impulses peripherally to activate muscles or secretory cells. Nervous System: Histology response of the limbs other than spinal reflexes ( Lazarus sign Lazarus Sign Brain Death)

Pupillary light reflex Pupillary Light Reflex Constriction of the pupil in response to light stimulation of the retina. It refers also to any reflex involving the iris, with resultant alteration of the diameter of the pupil. Pupil: Physiology and Abnormalities:

• Shine light into each eye and examine for pupillary constriction.
• Measure pupil Pupil The pupil is the space within the eye that permits light to project onto the retina. Anatomically located in front of the lens, the pupil’s size is controlled by the surrounding iris. The pupil provides insight into the function of the central and autonomic nervous systems. Pupil: Physiology and Abnormalities diameter.
• Responses consistent with brain Brain The part of central nervous system that is contained within the skull (cranium). Arising from the neural tube, the embryonic brain is comprised of three major parts including prosencephalon (the forebrain); mesencephalon (the midbrain); and rhombencephalon (the hindbrain). The developed brain consists of cerebrum; cerebellum; and other structures in the brain stem. Nervous System: Anatomy, Structure, and Classification death:
  • Absence of ipsilateral and contralateral pupillary response
  • Pupils fixed in a midsize or dilated position (4–6 mm) bilaterally
  • Constricted pupils are not consistent with brain Brain The part of central nervous system that is contained within the skull (cranium). Arising from the neural tube, the embryonic brain is comprised of three major parts including prosencephalon (the forebrain); mesencephalon (the midbrain); and rhombencephalon (the hindbrain). The developed brain consists of cerebrum; cerebellum; and other structures in the brain stem. Nervous System: Anatomy, Structure, and Classification death.
• Notes:
  • Pupillary response may be affected by previous eye surgery or trauma.
  • Ensure that no ophthalmic medications may interfere with the test.

Oculocephalic reflex (OCR) and oculovestibular reflex (OVR):

• OCR: examined by quickly rotating the head horizontally to both sides:
  • Make sure there are no concerns about cervical spine Spine The human spine, or vertebral column, is the most important anatomical and functional axis of the human body. It consists of 7 cervical vertebrae, 12 thoracic vertebrae, and 5 lumbar vertebrae and is limited cranially by the skull and caudally by the sacrum. Vertebral Column: Anatomy integrity.
  • The term “doll’s eyes” refers to vintage dolls with eyes painted on and unable to move with the head.
  • Abnormal reflex: Eyes are fixed with head movement as if gazing at a fixed point.
• OVR:
  • Instill 50 mL of cold water into the ear with the head at a 30-degree elevation (for ≥ 60 seconds).
  • Test both sides.
  • Ensure auditory canals are patent and tympanic membranes are intact.
• Responses consistent with brain Brain The part of central nervous system that is contained within the skull (cranium). Arising from the neural tube, the embryonic brain is comprised of three major parts including prosencephalon (the forebrain); mesencephalon (the midbrain); and rhombencephalon (the hindbrain). The developed brain consists of cerebrum; cerebellum; and other structures in the brain stem. Nervous System: Anatomy, Structure, and Classification death: absent eye movement with both tests
• Note: Eye movement may be impacted by severe orbital or scleral edema Edema Edema is a condition in which excess serous fluid accumulates in the body cavity or interstitial space of connective tissues. Edema is a symptom observed in several medical conditions. It can be categorized into 2 types, namely, peripheral (in the extremities) and internal (in an organ or body cavity). Edema.

Corneal reflex:

• Examined by touching the cornea Cornea The transparent anterior portion of the fibrous coat of the eye consisting of five layers: stratified squamous corneal epithelium; bowman membrane; corneal stroma; descemet membrane; and mesenchymal corneal endothelium. It serves as the first refracting medium of the eye. Eye: Anatomy with a cotton swab or squirts of water/saline
  • Touch the external border of the iris.
  • Light pressure can be applied.
  • Be careful not to damage the cornea Cornea The transparent anterior portion of the fibrous coat of the eye consisting of five layers: stratified squamous corneal epithelium; bowman membrane; corneal stroma; descemet membrane; and mesenchymal corneal endothelium. It serves as the first refracting medium of the eye. Eye: Anatomy.
• Responses consistent with brain Brain The part of central nervous system that is contained within the skull (cranium). Arising from the neural tube, the embryonic brain is comprised of three major parts including prosencephalon (the forebrain); mesencephalon (the midbrain); and rhombencephalon (the hindbrain). The developed brain consists of cerebrum; cerebellum; and other structures in the brain stem. Nervous System: Anatomy, Structure, and Classification death: absent eyelid movement
• Note: Response may be impacted by orbital or scleral edema Edema Edema is a condition in which excess serous fluid accumulates in the body cavity or interstitial space of connective tissues. Edema is a symptom observed in several medical conditions. It can be categorized into 2 types, namely, peripheral (in the extremities) and internal (in an organ or body cavity). Edema, chemosis Chemosis Conjunctivitis, or previous corneal transplantation Corneal transplantation Partial or total replacement of the cornea from one human or animal to another. Organ Transplantation.

Gag reflex Gag Reflex Cranial Nerve Palsies:

• Examined by touching the posterior pharyngeal wall with a suction device or tongue Tongue The tongue, on the other hand, is a complex muscular structure that permits tasting and facilitates the process of mastication and communication. The blood supply of the tongue originates from the external carotid artery, and the innervation is through cranial nerves. Lips and Tongue: Anatomy depressor 
• Response consistent with brain Brain The part of central nervous system that is contained within the skull (cranium). Arising from the neural tube, the embryonic brain is comprised of three major parts including prosencephalon (the forebrain); mesencephalon (the midbrain); and rhombencephalon (the hindbrain). The developed brain consists of cerebrum; cerebellum; and other structures in the brain stem. Nervous System: Anatomy, Structure, and Classification death: absent gag

Cough reflex:

• Examined by stimulating the tracheobronchial wall through suctioning
• Response consistent with brain Brain The part of central nervous system that is contained within the skull (cranium). Arising from the neural tube, the embryonic brain is comprised of three major parts including prosencephalon (the forebrain); mesencephalon (the midbrain); and rhombencephalon (the hindbrain). The developed brain consists of cerebrum; cerebellum; and other structures in the brain stem. Nervous System: Anatomy, Structure, and Classification death: absent cough
• Note: Response may be impacted by injury to the phrenic nerve Phrenic nerve The motor nerve of the diaphragm. The phrenic nerve fibers originate in the cervical spinal column (mostly C4) and travel through the cervical plexus to the diaphragm. Diaphragm: Anatomy.

Common sequelae^[6]

Irreversible cessation of brainstem function is associated with the following abnormalities (which may arise during the clinical course):

• Hyponatremia Hyponatremia Hyponatremia is defined as a decreased serum sodium (sNa+) concentration less than 135 mmol/L. Serum sodium is the greatest contributor to plasma osmolality, which is very tightly controlled via antidiuretic hormone (ADH) release from the hypothalamus and by the thirst mechanism. Hyponatremia or hypernatremia Hypernatremia Hypernatremia is an elevated serum sodium concentration > 145 mmol/L. Serum sodium is the greatest contributor to plasma osmolality, which is very tightly controlled by the hypothalamus via the thirst mechanism and antidiuretic hormone (ADH) release. Hypernatremia occurs either from a lack of access to water or an excessive intake of sodium. Hypernatremia
• Diabetes Diabetes Diabetes mellitus (DM) is a metabolic disease characterized by hyperglycemia and dysfunction of the regulation of glucose metabolism by insulin. Type 1 DM is diagnosed mostly in children and young adults as the result of autoimmune destruction of β cells in the pancreas and the resulting lack of insulin. Type 2 DM has a significant association with obesity and is characterized by insulin resistance. Diabetes Mellitus insipidus
• Hypothermia Hypothermia Hypothermia can be defined as a drop in the core body temperature below 35°C (95°F) and is classified into mild, moderate, severe, and profound forms based on the degree of temperature decrease. Hypothermia
• Cardiac dysrhythmia
• Hemodynamic instability

Diagnosis

Outside the clinical examination, additional testing can vary depending on practice location. See your hospital’s designated protocol. The following information is based on US and UK guidelines for adult patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship.

Diagnostic requirements for brain Brain The part of central nervous system that is contained within the skull (cranium). Arising from the neural tube, the embryonic brain is comprised of three major parts including prosencephalon (the forebrain); mesencephalon (the midbrain); and rhombencephalon (the hindbrain). The developed brain consists of cerebrum; cerebellum; and other structures in the brain stem. Nervous System: Anatomy, Structure, and Classification death^[4,5]

• Known clinical etiology of brain Brain The part of central nervous system that is contained within the skull (cranium). Arising from the neural tube, the embryonic brain is comprised of three major parts including prosencephalon (the forebrain); mesencephalon (the midbrain); and rhombencephalon (the hindbrain). The developed brain consists of cerebrum; cerebellum; and other structures in the brain stem. Nervous System: Anatomy, Structure, and Classification death
• Absence of confounding conditions
• Abnormal brainstem reflexes on neurological examination Neurological examination A neurological exam is a systematic assessment of cognitive, sensory, and motor responses to identify pathologies of the nervous system. A neurological exam allows for the localization of neurologic lesions to narrow the differential diagnosis and focus on subsequent laboratory and imaging examinations. The exam should include assessments of the subject’s mental status, speech, cranial nerves, motor system, deep tendon reflexes, sensation, balance, and coordination. Neurological Examination
• Positive apnea test Apnea Test Brain Death
• Ancillary tests (when appropriate):
  • Recommended when:
    • Unable to perform all aspects of the clinical examination or apnea test Apnea Test Brain Death
    • Uncertainty about clinical response to clinical testing
    • Cannot completely rule out confounding conditions
  • May also bolster the clinical diagnosis for grieving families

Laboratory evaluation^[4,7]

Laboratory studies are often used to evaluate the etiology and identify confounding factors. The following may be considered (list is not exhaustive and should be guided by the clinical scenario):

• Electrolytes Electrolytes Electrolytes are mineral salts that dissolve in water and dissociate into charged particles called ions, which can be either be positively (cations) or negatively (anions) charged. Electrolytes are distributed in the extracellular and intracellular compartments in different concentrations. Electrolytes are essential for various basic life-sustaining functions. Electrolytes → rule out metabolic disorders and assess acid-base status
• CBC
• Arterial blood gas Arterial blood gas Respiratory Alkalosis (ABG) analysis: Assess acid-base status and ensure optimal ventilation Ventilation The total volume of gas inspired or expired per unit of time, usually measured in liters per minute. Ventilation: Mechanics of Breathing prior to apnea testing.
• Toxicology screen and alcohol level → rule out intoxication:
  • Specific drug testing should be guided by the patient’s history.
  • Consult a clinical toxicologist for guidance in cases where intoxication cannot be ruled out by standard testing (e.g., synthetic opioids Opioids Opiates are drugs that are derived from the sap of the opium poppy. Opiates have been used since antiquity for the relief of acute severe pain. Opioids are synthetic opiates with properties that are substantially similar to those of opiates. Opioid Analgesics, clonazepam Clonazepam An anticonvulsant used for several types of seizures, including myotonic or atonic seizures, photosensitive epilepsy, and absence seizures, although tolerance may develop. It is seldom effective in generalized tonic-clonic or partial seizures. The mechanism of action appears to involve the enhancement of gamma-aminobutyric acid receptor responses. Benzodiazepines).
• CSF analysis CSF analysis Meningitis → not routinely done, but may be performed in the diagnostic workup for an etiology (e.g., CNS infection, subarachnoid hemorrhage Subarachnoid Hemorrhage Subarachnoid hemorrhage (SAH) is a type of cerebrovascular accident (stroke) resulting from intracranial hemorrhage into the subarachnoid space between the arachnoid and the pia mater layers of the meninges surrounding the brain. Most SAHs originate from a saccular aneurysm in the circle of Willis but may also occur as a result of trauma, uncontrolled hypertension, vasculitis, anticoagulant use, or stimulant use. Subarachnoid Hemorrhage)

Apnea test Apnea Test Brain Death^[4–6]

This test is part of all protocols for determination of brain Brain The part of central nervous system that is contained within the skull (cranium). Arising from the neural tube, the embryonic brain is comprised of three major parts including prosencephalon (the forebrain); mesencephalon (the midbrain); and rhombencephalon (the hindbrain). The developed brain consists of cerebrum; cerebellum; and other structures in the brain stem. Nervous System: Anatomy, Structure, and Classification death. The following is based on US guidelines. The recommended protocol in the UK varies slightly and can be found here.

• Performed after all other criteria for brain Brain The part of central nervous system that is contained within the skull (cranium). Arising from the neural tube, the embryonic brain is comprised of three major parts including prosencephalon (the forebrain); mesencephalon (the midbrain); and rhombencephalon (the hindbrain). The developed brain consists of cerebrum; cerebellum; and other structures in the brain stem. Nervous System: Anatomy, Structure, and Classification death have been met MET Preoperative Care
• Before the test:
  • Ensure SBP SBP Ascites ≥ 100 mm Hg or MAP ≥ 60 mm Hg
  • Temperature should be ≥ 36℃.
  • Discontinue paralytic drugs.
  • Place arterial line for easy ABG sampling.
  • Adjust ventilator settings to a PaCO₂ between 35 and 45 mm Hg.
  • Preoxygenate with 100% O₂ for ≥ 10 minutes before the test.
• Cannot be done in:
  • The presence of high cervical spine Spine The human spine, or vertebral column, is the most important anatomical and functional axis of the human body. It consists of 7 cervical vertebrae, 12 thoracic vertebrae, and 5 lumbar vertebrae and is limited cranially by the skull and caudally by the sacrum. Vertebral Column: Anatomy lesions
  • Individuals with chronic CO₂ retention 
• Steps:
  • Discontinue ventilator for 10 minutes.
  • Provide 100% O₂ to a maximum PO₂ of 200 mm Hg or until PaCO₂ is > 40 mm Hg.
    • CPAP CPAP A technique of respiratory therapy, in either spontaneously breathing or mechanically ventilated patients, in which airway pressure is maintained above atmospheric pressure throughout the respiratory cycle by pressurization of the ventilatory circuit. Noninvasive Ventilation/ PEEP PEEP Pressure remaining in the distal airways of the patient at the end of expiration Invasive Mechanical Ventilation can prevent derecruitment and ↓ risk of cardiopulmonary instability.
    • Oxygen insufflation method via tracheal cannula may also be used.
  • After 10 minutes, ABG should be sent.
  • If no spontaneous respiratory efforts → test is terminated after 10 minutes
• Abort test if:
  • Spontaneous respirations witnessed
  • SBP SBP Ascites < 110 mm Hg or MAP < 60 mm Hg despite titration of fluid, inotropes Inotropes Hypoplastic Left Heart Syndrome (HLHS), and vasopressors Vasopressors Sepsis in Children
  • SpO₂ < 85%
  • Unstable arrhythmias
• Positive test:
  • No respiratory response to PaCO₂ ≥ 60 mm Hg, or ≥ 20 mm Hg above baseline values
  • Final arterial pH pH The quantitative measurement of the acidity or basicity of a solution. Acid-Base Balance < 7.30

Ancillary testing^[4–6]

• Brain blood flow studies Brain Blood Flow Studies Brain Death: Absent brain Brain The part of central nervous system that is contained within the skull (cranium). Arising from the neural tube, the embryonic brain is comprised of three major parts including prosencephalon (the forebrain); mesencephalon (the midbrain); and rhombencephalon (the hindbrain). The developed brain consists of cerebrum; cerebellum; and other structures in the brain stem. Nervous System: Anatomy, Structure, and Classification blood flow Blood flow Blood flow refers to the movement of a certain volume of blood through the vasculature over a given unit of time (e.g., mL per minute). Vascular Resistance, Flow, and Mean Arterial Pressure is consistent with brain Brain The part of central nervous system that is contained within the skull (cranium). Arising from the neural tube, the embryonic brain is comprised of three major parts including prosencephalon (the forebrain); mesencephalon (the midbrain); and rhombencephalon (the hindbrain). The developed brain consists of cerebrum; cerebellum; and other structures in the brain stem. Nervous System: Anatomy, Structure, and Classification death.
  • Conventional 4-vessel cerebral angiography Angiography Radiography of blood vessels after injection of a contrast medium. Cardiac Surgery/digital subtraction angiography Angiography Radiography of blood vessels after injection of a contrast medium. Cardiac Surgery:
    • Preferred testing method
    • Should demonstrate absent filling where the internal carotid and vertebral arteries Arteries Arteries are tubular collections of cells that transport oxygenated blood and nutrients from the heart to the tissues of the body. The blood passes through the arteries in order of decreasing luminal diameter, starting in the largest artery (the aorta) and ending in the small arterioles. Arteries are classified into 3 types: large elastic arteries, medium muscular arteries, and small arteries and arterioles. Arteries: Histology enter the skull Skull The skull (cranium) is the skeletal structure of the head supporting the face and forming a protective cavity for the brain. The skull consists of 22 bones divided into the viscerocranium (facial skeleton) and the neurocranium. Skull: Anatomy base
    • External carotid circulation Circulation The movement of the blood as it is pumped through the cardiovascular system. ABCDE Assessment should be patent.
  • Radionuclide studies (alternative)
  • Transcranial Doppler Doppler Ultrasonography applying the doppler effect, with frequency-shifted ultrasound reflections produced by moving targets (usually red blood cells) in the bloodstream along the ultrasound axis in direct proportion to the velocity of movement of the targets, to determine both direction and velocity of blood flow. Ultrasound (Sonography) (alternative):
    • If used, it is recommended to perform 2 examinations ≥ 30 minutes apart.
  • CTA CTA A non-invasive method that uses a ct scanner for capturing images of blood vessels and tissues. A contrast material is injected, which helps produce detailed images that aid in diagnosing vascular diseases. Pulmonary Function Tests and MRA MRA Imaging of the Heart and Great Vessels are not currently recommended to support the diagnosis of cerebral circulatory arrest Circulatory arrest Cardiac arrest is the sudden, complete cessation of cardiac output with hemodynamic collapse. Patients present as pulseless, unresponsive, and apneic. Rhythms associated with cardiac arrest are ventricular fibrillation/tachycardia, asystole, or pulseless electrical activity. Cardiac Arrest.
• EEG EEG Seizures:
  • Required to diagnose brain Brain The part of central nervous system that is contained within the skull (cranium). Arising from the neural tube, the embryonic brain is comprised of three major parts including prosencephalon (the forebrain); mesencephalon (the midbrain); and rhombencephalon (the hindbrain). The developed brain consists of cerebrum; cerebellum; and other structures in the brain stem. Nervous System: Anatomy, Structure, and Classification death in children
  • Should not be routinely used in adults unless legally mandated
  • Consistent with brain Brain The part of central nervous system that is contained within the skull (cranium). Arising from the neural tube, the embryonic brain is comprised of three major parts including prosencephalon (the forebrain); mesencephalon (the midbrain); and rhombencephalon (the hindbrain). The developed brain consists of cerebrum; cerebellum; and other structures in the brain stem. Nervous System: Anatomy, Structure, and Classification death if no potentials are recorded after 30 minutes
  • May be falsely negative or falsely positive
• Addition studies:
  • MRI or CT may:
    • Assist with determining an etiology (e.g., hemorrhage, mass Mass Three-dimensional lesion that occupies a space within the breast Imaging of the Breast lesion)
    • Demonstrate irreversible, devastating brain Brain The part of central nervous system that is contained within the skull (cranium). Arising from the neural tube, the embryonic brain is comprised of three major parts including prosencephalon (the forebrain); mesencephalon (the midbrain); and rhombencephalon (the hindbrain). The developed brain consists of cerebrum; cerebellum; and other structures in the brain stem. Nervous System: Anatomy, Structure, and Classification injury:
      • Evidence of severe edema Edema Edema is a condition in which excess serous fluid accumulates in the body cavity or interstitial space of connective tissues. Edema is a symptom observed in several medical conditions. It can be categorized into 2 types, namely, peripheral (in the extremities) and internal (in an organ or body cavity). Edema or herniation Herniation Omphalocele
      • If seen, brain Brain The part of central nervous system that is contained within the skull (cranium). Arising from the neural tube, the embryonic brain is comprised of three major parts including prosencephalon (the forebrain); mesencephalon (the midbrain); and rhombencephalon (the hindbrain). The developed brain consists of cerebrum; cerebellum; and other structures in the brain stem. Nervous System: Anatomy, Structure, and Classification edema Edema Edema is a condition in which excess serous fluid accumulates in the body cavity or interstitial space of connective tissues. Edema is a symptom observed in several medical conditions. It can be categorized into 2 types, namely, peripheral (in the extremities) and internal (in an organ or body cavity). Edema is suggestive of brain Brain The part of central nervous system that is contained within the skull (cranium). Arising from the neural tube, the embryonic brain is comprised of three major parts including prosencephalon (the forebrain); mesencephalon (the midbrain); and rhombencephalon (the hindbrain). The developed brain consists of cerebrum; cerebellum; and other structures in the brain stem. Nervous System: Anatomy, Structure, and Classification death.
  • If ICP ICP Normal intracranial pressure (ICP) is defined as < 15 mm Hg, whereas pathologically increased ICP is any pressure ≥ 20 mm Hg. Increased ICP may result from several etiologies, including trauma, intracranial hemorrhage, mass lesions, cerebral edema, increased CSF production, and decreased CSF absorption. Increased Intracranial Pressure (ICP) monitor is in place → measured ICP ICP Normal intracranial pressure (ICP) is defined as < 15 mm Hg, whereas pathologically increased ICP is any pressure ≥ 20 mm Hg. Increased ICP may result from several etiologies, including trauma, intracranial hemorrhage, mass lesions, cerebral edema, increased CSF production, and decreased CSF absorption. Increased Intracranial Pressure (ICP) ≥ MAP indicates no perfusion gradient for blood flow Blood flow Blood flow refers to the movement of a certain volume of blood through the vasculature over a given unit of time (e.g., mL per minute). Vascular Resistance, Flow, and Mean Arterial Pressure

Clinical and Ethical Considerations

Documentation Documentation Systematic organization, storage, retrieval, and dissemination of specialized information, especially of a scientific or technical nature. It often involves authenticating or validating information. Advance Directives required for determination of brain Brain The part of central nervous system that is contained within the skull (cranium). Arising from the neural tube, the embryonic brain is comprised of three major parts including prosencephalon (the forebrain); mesencephalon (the midbrain); and rhombencephalon (the hindbrain). The developed brain consists of cerebrum; cerebellum; and other structures in the brain stem. Nervous System: Anatomy, Structure, and Classification death^[4–6]

• Etiology of the coma Coma Coma is defined as a deep state of unarousable unresponsiveness, characterized by a score of 3 points on the GCS. A comatose state can be caused by a multitude of conditions, making the precise epidemiology and prognosis of coma difficult to determine. Coma 
• Absence of confounding conditions
• Full details and results of clinical testing performed
• Neuroimaging Neuroimaging Non-invasive methods of visualizing the central nervous system, especially the brain, by various imaging modalities. Febrile Infant results and timing in relation to clinical testing 
• Reason for and type of ancillary testing performed and results 
• Time of death 
• Identity of the practitioner(s) performing the evaluation

Somatic support after declaration of brain Brain The part of central nervous system that is contained within the skull (cranium). Arising from the neural tube, the embryonic brain is comprised of three major parts including prosencephalon (the forebrain); mesencephalon (the midbrain); and rhombencephalon (the hindbrain). The developed brain consists of cerebrum; cerebellum; and other structures in the brain stem. Nervous System: Anatomy, Structure, and Classification death^[4–7]

• Diagnosis made → individual is declared clinically and legally deceased
• Physiologic support should be discontinued unless:
  • Decedent is pregnant and support is needed for the fetus
  • Organ donation Organ Donation Brain Death is planned:
    • Notify the local organ procurement organization → notification required in many regions
    • Organ procurement coordinators review the medical chart.
    • If appropriate, the coordinators speak with the potential donor’s next of kin.
  • Family requests due to religious or moral beliefs:
    • Every effort should be made to address concerns.
    • Involvement of religious authorities or ethics Ethics Medical ethics are a set of moral values that guide the decision-making of health care professionals in their daily practice. A sense of ethical responsibility has accompanied the profession of medicine since antiquity, and the Hippocratic oath was the 1st document to codify its core ethical principles. Medical Ethics: Basic Principles committees may be helpful.
    • Treat every person and family with the utmost respect.
    • A multidisciplinary approach (e.g., social workers, psychologists, counselors) is advisable.
    • Prolongation of support > 48 hours should generally be avoided.

Differential Diagnosis

• Locked-in syndrome Locked-in syndrome Locked-in syndrome (LIS) is a rare neurological disorder in which patients are awake and conscious but are unable to move their limbs or speak. The disorder is a result of brain injury to the ventral aspect of the pons and caudal ventral midbrain; etiologies include brainstem stroke, tumors, intracranial bleeding, and demyelinating disorders. Locked-in Syndrome (also known as “ pseudocoma Pseudocoma Locked-in syndrome (LIS) is a rare neurological disorder in which patients are awake and conscious but are unable to move their limbs or speak. The disorder is a result of brain injury to the ventral aspect of the pons and caudal ventral midbrain; etiologies include brainstem stroke, tumors, intracranial bleeding, and demyelinating disorders. Locked-in Syndrome” or “de-efferented state”): a state of quadriplegia Quadriplegia Severe or complete loss of motor function in all four limbs which may result from brain diseases; spinal cord diseases; peripheral nervous system diseases; neuromuscular diseases; or rarely muscular diseases. The locked-in syndrome is characterized by quadriplegia in combination with cranial muscle paralysis. Consciousness is spared and the only retained voluntary motor activity may be limited eye movements. This condition is usually caused by a lesion in the upper brain stem which injures the descending corticospinal and corticobulbar tracts. Locked-in Syndrome and paralysis of the lower cranial nerves Cranial nerves There are 12 pairs of cranial nerves (CNs), which run from the brain to various parts of the head, neck, and trunk. The CNs can be sensory or motor or both. The CNs are named and numbered in Roman numerals according to their location, from the front to the back of the brain. The 12 Cranial Nerves: Overview and Functions leading to the inability to move, communicate, or show any facial expression (except for certain eye movements). Locked-in syndrome Locked-in syndrome Locked-in syndrome (LIS) is a rare neurological disorder in which patients are awake and conscious but are unable to move their limbs or speak. The disorder is a result of brain injury to the ventral aspect of the pons and caudal ventral midbrain; etiologies include brainstem stroke, tumors, intracranial bleeding, and demyelinating disorders. Locked-in Syndrome typically results from pontine hemorrhage or infarct Infarct Area of necrotic cells in an organ, arising mainly from hypoxia and ischemia Ischemic Cell Damage. Diagnosis is made clinically with individuals limited to blinking or performing vertical eye movements upon request. Management involves supportive care and prevention of immobilization Immobilization Delirium complications. Long-term physical therapy Physical Therapy Becker Muscular Dystrophy is essential. 
• Hypothermia Hypothermia Hypothermia can be defined as a drop in the core body temperature below 35°C (95°F) and is classified into mild, moderate, severe, and profound forms based on the degree of temperature decrease. Hypothermia: a drop in core body temperature Body Temperature The measure of the level of heat of a human or animal. Heatstroke below 35°C. Hypothermia Hypothermia Hypothermia can be defined as a drop in the core body temperature below 35°C (95°F) and is classified into mild, moderate, severe, and profound forms based on the degree of temperature decrease. Hypothermia is classified into mild, moderate, severe, and profound forms based upon the degree of temperature decrease. Populations of individuals with extremes of age, homelessness, mental illness, or substance use disorders may be more vulnerable to accidental hypothermia Accidental Hypothermia Hypothermia. Evaluation includes assessment for associated trauma and contributing medical conditions. Management involves rewarming the individual based on the severity of hypothermia Hypothermia Hypothermia can be defined as a drop in the core body temperature below 35°C (95°F) and is classified into mild, moderate, severe, and profound forms based on the degree of temperature decrease. Hypothermia.
• Drug intoxication: intoxication of CNS-suppressant medications or muscle relaxants/paralytics. The drugs may include opioids Opioids Opiates are drugs that are derived from the sap of the opium poppy. Opiates have been used since antiquity for the relief of acute severe pain. Opioids are synthetic opiates with properties that are substantially similar to those of opiates. Opioid Analgesics, tricyclics, baclofen Baclofen A gamma-aminobutyric acid derivative that is a specific agonist of gaba-b receptors. It is used in the treatment of muscle spasticity, especially that due to spinal cord injuries. Its therapeutic effects result from actions at spinal and supraspinal sites, generally the reduction of excitatory transmission. Spasmolytics, barbiturates Barbiturates A class of chemicals derived from barbituric acid or thiobarbituric acid. Many of these are gaba modulators used as hypnotics and sedatives, as anesthetics, or as anticonvulsants. Intravenous Anesthetics, paralytics, anticholinergics Anticholinergics Anticholinergic drugs block the effect of the neurotransmitter acetylcholine at the muscarinic receptors in the central and peripheral nervous systems. Anticholinergic agents inhibit the parasympathetic nervous system, resulting in effects on the smooth muscle in the respiratory tract, vascular system, urinary tract, GI tract, and pupils of the eyes. Anticholinergic Drugs, and organophosphates, which may significantly suppress consciousness and motor Motor Neurons which send impulses peripherally to activate muscles or secretory cells. Nervous System: Histology/ sensory Sensory Neurons which conduct nerve impulses to the central nervous system. Nervous System: Histology responses. The exposure may be either known or unrecognized. Diagnosis is based on history, review of medications, interviews with family, and toxicologic evaluations. Management is based on the diagnosis.
• High cervical spine Spine The human spine, or vertebral column, is the most important anatomical and functional axis of the human body. It consists of 7 cervical vertebrae, 12 thoracic vertebrae, and 5 lumbar vertebrae and is limited cranially by the skull and caudally by the sacrum. Vertebral Column: Anatomy injury: such injuries are associated with quadriparesis, loss of sensation below the level of the injury, inability to breathe, and reduced ability to speak. Although neurologic evaluation should easily distinguish the condition from brain Brain The part of central nervous system that is contained within the skull (cranium). Arising from the neural tube, the embryonic brain is comprised of three major parts including prosencephalon (the forebrain); mesencephalon (the midbrain); and rhombencephalon (the hindbrain). The developed brain consists of cerebrum; cerebellum; and other structures in the brain stem. Nervous System: Anatomy, Structure, and Classification death, the clinical picture may be confounded by a concurrent traumatic brain injury Traumatic brain injury A form of acquired brain injury which occurs when a sudden trauma causes damage to the brain. Le Fort Fractures or the effects of medications. Vigilance and repeated comprehensive neurologic evaluations in combination with neuroimaging Neuroimaging Non-invasive methods of visualizing the central nervous system, especially the brain, by various imaging modalities. Febrile Infant are helpful in establishing the correct diagnosis. Management may be medical or surgical.