Coma

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Coma
ICD-10 R40.2
ICD-9 780.01

In medicine, a coma (from the Greek κῶμα koma, meaning "deep sleep") is a state of unconsciousness lasting more than six hours, in which a person: cannot be awakened; fails to respond normally to painful stimuli, light, or sound; lacks a normal sleep-wake cycle; and, does not initiate voluntary actions.[1] A person in a state of coma is described as being comatose.

A comatose person exhibits a complete absence of wakefulness and is unable to consciously feel, speak, hear, or move.[2] For a patient to maintain consciousness, two important neurological components must function. The first is the cerebral cortex—the gray matter that covers the outer layer of the brain. The other is a structure located in the brainstem, called reticular activating system (RAS).[3] [4] Injury to either or both of these components is sufficient to cause a patient to experience a coma.[citation needed] The cerebral cortex is a group of tight, dense, "gray matter" composed of the nucleus of the neurons whose axons then form the "white matter", and is responsible for perception, relay of the sensory input (sensation) via the thalamic pathway, and many other neurological functions, including complex thinking.

RAS, on the other hand, is a more primitive structure in the brainstem that is tightly in connection with reticular formation (RF). The RAS area of the brain has two tracts, the ascending and descending tract. Made up of a system of acetylcholine-producing neurons, the ascending track, or ascending reticular activating system (ARAS), works to arouse and wake up the brain, from the RF, through the thalamus, and then finally to the cerebral cortex.[5] A failure in ARAS functioning may then lead to a coma.[citation needed] It is therefore necessary to investigate the integrity of cerebral cortex as well of the reticular activating system (RAS) in a comatose patient.[citation needed]

Video of a man at beginning of documented 3 month coma.[6]
Video of the man still nonresponsive to stimuli.[7]

Signs and symptoms[edit]

Generally, a person who is unable to voluntarily open the eyes, does not have a sleep-wake cycle, is unresponsive in spite of strong tactile (painful), or verbal stimuli and who generally scores between 3 to 8[8] on the Glasgow Coma Scale is considered in a coma.[1] Coma may have developed in humans as a response to injury to allow the body to pause bodily actions and heal the most immediate injuries - if at all - before waking. It therefore could be a compensatory state in which the body's expenditure of energy is not superfluous. The severity and mode of onset of coma depends on the underlying cause. For instance, severe hypoglycemia (low blood sugar) or hypercapnia (increased carbon dioxide levels in the blood) initially cause mild agitation and confusion, but progress to obtundation, stupor and finally complete unconsciousness. In contrast, coma resulting from a severe traumatic brain injury or subarachnoid hemorrhage can be instantaneous. The mode of onset may therefore be indicative of the underlying cause.

Causes[edit]

Coma may result from a variety of conditions, including intoxication (such as drug abuse, overdose or misuse of over the counter medications, prescribed medication, or controlled substances), metabolic abnormalities, central nervous system diseases, acute neurologic injuries such as strokes or herniations, hypoxia, hypothermia, hypoglycemia or traumatic injuries such as head trauma caused by falls or vehicle collisions. It may also be deliberately induced by pharmaceutical agents during major neurosurgery, to preserve higher brain functions following brain trauma, or to save the patient from extreme pain during healing of injuries or diseases.[9]

Forty percent of comatose states result from drug poisoning.[10] Drugs damage or weaken the synaptic functioning in the ARAS and keep the system from properly functioning to arouse the brain.[5] Secondary effects of drugs, which include abnormal heart rate and blood pressure, as well as abnormal breathing and sweating, may also indirectly harm the functioning of the ARAS and lead to a coma. Seizures and hallucinations have shown to also play a major role in ARAS malfunction. Given that drug poisoning causes a large portion of patients in a coma, hospitals first test all comatose patients by observing pupil size and eye movement, through the vestibular-ocular reflex.[5]

The second most common cause of coma, which makes up about 25% of comatose patients, occurs from lack of oxygen, generally resulting from cardiac arrest.[10] The Central Nervous System (CNS) requires a great deal of oxygen for its neurons. Oxygen deprivation in the brain, also known as hypoxia, causes neuronal extracellular sodium and calcium to decrease and intracellular calcium to increase, which harms neuron communication.[11] Lack of oxygen in the brain also causes ATP exhaustion and cellular breakdown from cytoskeleton damage and nitric oxide production.

Twenty percent of comatose states result from the side effects of a stroke.[10] During a stroke, blood flow to part of the brain is restricted or blocked. An ischemic stroke, brain hemorrhage, or tumor may cause such cessation of blood flow. Lack of blood to cells in the brain prevents nutrients and oxygen from getting to the neurons, and consequently causes cells to become disrupted and eventually die. As brain cells die, brain tissue continues to deteriorate, which may affect functioning of the ARAS.

The remaining 15% of comatose cases result from trauma, excessive blood loss, malnutrition, hypothermia, hyperthermia, abnormal glucose levels, and many other biological disorders.

Diagnosis[edit]

Diagnosis of coma is simple, but diagnosing the cause of the underlying disease process is often challenging. The first priority in treatment of a comatose patient is stabilization following the basic ABCs (standing for airway, breathing, and circulation). Once a person in a coma is stable, investigations are performed to assess the underlying cause. Investigative methods are divided into physical examination findings and imaging (such as CAT scan, MRI, etc.) and special studies (EEG, etc.)

Diagnostic steps[edit]

When an unconscious patient enters a hospital, the hospital utilizes a series of diagnostic steps to identify the cause of unconsciousness. According to Young,[5] the following steps should be taken when dealing with a patient possibly in a coma:

  1. Perform a general examination and medical history check
  2. Make sure the patient is in an actual comatose state and or is not in locked-in state (patient is either able to voluntarily move his eyes or blink) or psychogenic unresponsiveness (caloric stimulation of the vestibular apparatus results in slow deviation of eyes towards the stimulation followed by rapid correction to mid-line. This response can't be voluntarily suppressed—so if the patient doesn't have this response, psychogenic coma can be ruled out.)
  3. Find the site of the brain that may be causing coma (i.e., brain stem, back of brain…) and assess the severity of the coma with the Glasgow coma scale
  4. Take blood work to see if drugs were involved or if it was a result of hypoventilation/hyperventilation
  5. Check for levels of “serum glucose, calcium, sodium, potassium, magnesium, phosphate, urea, and creatinine”
  6. Perform brain scans to observe any abnormal brain functioning using either CT or MRI scans
  7. Continue to monitor brain waves and identify seizures of patient using EEGs

Initial assessment and evaluation[edit]

In the initial assessment of coma, it is common to gauge the level of consciousness by spontaneously exhibited actions, response to vocal stimuli ("Can you hear me?"), and painful stimuli; this is known as the AVPU (alert, vocal stimuli, painful stimuli, unresponsive) scale. More elaborate scales, such as the Glasgow Coma Scale, quantify an individual's reactions such as eye opening, movement and verbal response on a scale; Glasgow Coma Scale (GCS) is an indication of the extent of brain injury varying from 3 (indicating severe brain injury and death) to a maximum of 15 (indicating mild or no brain injury).

In those with deep unconsciousness, there is a risk of asphyxiation as the control over the muscles in the face and throat is diminished. As a result, those presenting to a hospital with coma are typically assessed for this risk ("airway management"). If the risk of asphyxiation is deemed high, doctors may use various devices (such as an oropharyngeal airway, nasopharyngeal airway or endotracheal tube) to safeguard the airway.

Physical examination findings[edit]

Decorticate posturing, indicating a lesion at the red nucleus or above. This positioning is stereotypical for upper brain stem, or cortical damage. The other variant is Decerebrate posturing, not seen in this picture.

Physical examination is critical after stabilization. It should include vital signs, a general portion dedicated to making observations about the patient's respiration (breathing pattern), body movements (if any), and of the patient's body habitus (physique); it should also include assessment of the brainstem and cortical function through special reflex tests such as the oculocephalic reflex test (doll's eyes test), oculovestibular reflex test (cold caloric test), nasal tickle, corneal reflex, and the gag reflex.

Vital signs in medicine are temperature (rectal is most accurate), blood pressure, heart rate (pulse), respiratory rate, and oxygen saturation. It should be easy to evaluate these vitals quickly to gain insight into a patient's metabolism, fluid status, heart function, vascular integrity, and tissue oxygenation.

Respiratory pattern (breathing rhythm) is significant and should be noted in a comatose patient. Certain stereotypical patterns of breathing have been identified including Cheyne-Stokes a form of breathing in which the patient's breathing pattern is described as alternating episodes of hyperventilation and apnea. This is a dangerous pattern and is often seen in pending herniations, extensive cortical lesions, or brainstem damage.[3] Another pattern of breathing is apneustic breathing, which is characterized by sudden pauses of inspiration and is due to a lesion of the pons.[1][3] Ataxic breathing is irregular and is due to a lesion (damage) of the medulla.

Assessment of posture and body habitus is the next step. It involves general observation about the patient's positioning. There are often two stereotypical postures seen in comatose patients. Decorticate posturing is a stereotypical posturing in which the patient has arms flexed at the elbow, and arms adducted toward the body, with both legs extended. Decerebrate posturing is a stereotypical posturing in which the legs are similarly extended (stretched), but the arms are also stretched (extended at the elbow). The posturing is critical since it indicates where the damage is in the central nervous system. A decorticate posturing indicates a lesion (a point of damage) at or above the red nucleus, whereas a decerebrate posturing indicates a lesion at or below the red nucleus. In other words, a decorticate lesion is closer to the cortex, as opposed to a decerebrate cortex that is closer to the brainstem.

Oculocephalic reflex also known as the doll's eye is performed to assess the integrity of the brainstem. Patient's eyelids are gently elevated and the cornea is visualized. The patient's head is then moved to the patient's left, to observe if the eyes stay or deviate toward the patient's right; same maneuver is attempted on the opposite side. If the patient's eyes move in a direction opposite to the direction of the rotation of the head, then the patient is said to have an intact brainstem. However, failure of both eyes to move to one side, can indicate damage or destruction of the affected side. In special cases, where only one eye deviates and the other does not, this often indicates a lesion (or damage) of the medial longitudinal fasciculus (MLF), which is a brainstem nerve tract. Caloric reflex test also evaluates both cortical and brainstem function; cold water is injected into one ear and the patient is observed for eye movement; if the patient's eyes slowly deviate toward the ear where the water was injected, then the brainstem is intact, however failure to deviate toward the injected ear indicates damage of the brainstem on that side. Cortex is responsible for a rapid nystagmus away from this deviated position and is often seen in patients who are conscious or merely lethargic.

An important part of the physical exam is also assessment of the cranial nerves. Due to the unconscious status of the patient, only a limited number of the nerves can be assessed. These include the cranial nerves number 2 (CN II), number 3 (CN III), number 5 (CN V), number 7 (CN VII), and cranial nerves 9 and 10 (CN IX, CN X). Gag reflex helps assess cranial nerves 9 and 10. Pupil reaction to light is important because it shows an intact retina, and cranial nerve number 2 (CN II); if pupils are reactive to light, then that also indicates that the cranial nerve number 3 (CN III) (or at least its parasympathetic fibers) are intact. Corneal reflex assess the integrity of cranial nerve number 7 (CN VII), and cranial nerve number 5 (CN V). Cranial nerve number 5 (CN V), and its ophthalmic branch (V1) are responsible for the afferent arm of the reflex, and the cranial nerve number 7 (CN VII) also known a facial nerve, is responsible for the efferent arm, causing contraction of the muscle orbicularis oculi resulting in closing of the eyes.

Pupil assessment is often a critical portion of a comatose examination, as it can give information as to the cause of the coma; the following table is a technical, medical guideline for common pupil findings and their possible interpretations:[3]

Pupil sizes (Left eye vs. Right eye) Possible interpretation
ʖ Normal eye with two pupils equal in size and reactive to light. This means that the patient is probably not in a coma and is probably lethargic, under influence of a drug, or sleeping.
ʖ "Pinpoint" pupils indicate heroin or opiate overdose, and can be responsible for a patient's coma. The pinpoint pupils are still reactive to light, bilaterally (in both eyes, not just one). Another possibility is the damage of the pons.[3]
ʖ One pupil is dilated and unreactive, while the other is normal (in this case the R eye is dilated but the L eye is normal in size). This could mean a damage to the oculomotor nerve (cranial nerve number 3, CN III) on the right side, or possibility of vascular involvement.
ʖ Both pupils are dilated and unreactive to light. This could be due to overdose of certain medications, hypothermia or severe anoxia (lack of oxygen).

Imaging and special tests findings[edit]

Imaging basically encompasses computed tomography (CAT or CT) scan of the brain, or MRI for example, and is performed to identify specific causes of the coma, such as hemorrhage in the brain or herniation of the brain structures. Special tests such as an EEG can also show a lot about the activity level of the cortex such as semantic processing,[12] presence of seizures, and are important available tools not only for the assessment of the cortical activity but also for predicting the likelihood of the patient's awakening.[13] The autonomous responses such as the Skin Conductance Response may also provide further insight on the patient's emotional processing.[14]

History[edit]

When diagnosing any neurological condition, history and examination are fundamental. History is obtained by family, friends or EMS. The Glasgow Coma Scale is a helpful system used to examine and determine the depth of coma, track patients progress and predict outcome as best as possible. In general a correct diagnosis can be achieved by combining findings from physical exam, imaging, and history components and directs the appropriate therapy.

Severity and classification[edit]

Plum and Posner classify coma[3] as either (1) supratentoral (above Tentorium cerebelli), (2) infratentoral (below Tentorium cerebelli), or (3) metabolic or (4) diffused. This classification is merely dependent on the position of the original damage that caused the coma, and does not correlate with severity or the prognosis. The severity of coma impairment however is categorized into several levels. Patients may or may not progress through these levels. In the first level, the brain responsiveness lessens, normal reflexes are lost, the patient no longer responds to pain and cannot hear.

The Rancho Los Amigos Scale is a complex scale that has eight separate levels, and is often used in the first few weeks or months of coma while the patient is under closer observation, and when shifts between levels are more frequent.

Treatment[edit]

Medical treatment[edit]

The treatment hospitals use on comatose patients depends on both the severity and cause of the comatose state. Although the best treatment for comatose patients remains unknown, hospitals usually place comatose patients in an Intensive Care Unit (ICU) immediately.[5] In the ICU, the hospital monitors a patient’s breathing and brain activity through CT scans. Attention must first be directed to maintaining the patient's respiration and circulation, using intubation and ventilation, administration of intravenous fluids or blood and other supportive care as needed. Once a patient is stable and no longer in immediate danger, the medical staff may concentrate on maintaining the health of patient’s physical state. The concentration is directed to preventing infections such as pneumonias, bedsores (decubitus ulcers), and providing balanced nutrition.[15] These infections may appear from the patient not being able to move around, and being confined to the bed. The nursing staff moves the patient every 2–3 hours from side to side and depending on the state of consciousness sometimes to a chair. The goal is to move the patient as much as possible to try to avoid bedsores, atelectasis and pneumonia. Pneumonia can occur from the person’s inability to swallow leading to aspiration, lack of gag reflex or from feeding tube, (aspiration pneumonia). Physical therapy may also be used to prevent contractures and orthopedic deformities that would limit recovery for those patients who emerge from coma.

A person in a coma may become restless, or seize and need special care to prevent them from hurting themselves. Medicine may be given to calm such individuals. Patients who are restless may also try to pull on tubes or dressings so soft cloth wrist restraints may be put on. Side rails on the bed should be kept up to prevent the patient from falling.[15]

In attempt to wake comatose patients, some hospitals treat their patients by either reversing the cause of comatose (i.e., glucose shock if low sugar), giving medication to stop brain swelling, or inducing hypothermia. Inducing hypothermia on comatose patients provides one of the main treatments for patients after suffering from cardiac arrest. In this treatment, medical personnel expose patients to “external or intravascular cooling” at 32-34 °C for 24 h.; this treatment cools patients down about 2-3 °C less than normal body temperature.[16] In 2002, Baldursdottir and her coworkers[16] found that in the hospital, more comatose patients survived after induced hypothermia than patients that remained at normal body temperature. For this reason, the hospital chose to continue the induced hypothermia technique for all of its comatose patients that suffered from cardiac arrest.[16]

Emotional challenges[edit]

Coma has a wide variety of emotional reactions from the family members of the affected patients, as well as the primary care givers taking care of the patients. Common reactions, such as desperation, anger, frustration, and denial are possible. The focus of the patient care should be on creating an amicable relationship with the family members or dependents of a comatose patient as well as creating a rapport with the medical staff.[17]

Prognosis[edit]

Comas can last from several days to several weeks. In more severe cases a coma may last for over five weeks, while some have lasted as long as several years. After this time, some patients gradually come out of the coma, some progress to a vegetative state, and others die. Some patients who have entered a vegetative state go on to regain a degree of awareness. Others remain in a vegetative state for years or even decades (the longest recorded period being 42 years).[18]

The outcome for coma and vegetative state depends on the cause, location, severity and extent of neurological damage. A deeper coma alone does not necessarily mean a slimmer chance of recovery, because some people in deep coma recover well while others in a so-called milder coma sometimes fail to improve.

People may emerge from a coma with a combination of physical, intellectual and psychological difficulties that need special attention. Recovery usually occurs gradually—patients acquire more and more ability to respond. Some patients never progress beyond very basic responses, but many recover full awareness.[19] Regaining consciousness is not instant: in the first days, patients are only awake for a few minutes, and duration of time awake gradually increases. This is unlike the situation in many movies where people who awake from comas are instantly able to continue their normal lives. In reality, the coma patient awakes sometimes in a profound state of confusion, not knowing how they got there and sometimes suffering from dysarthria, the inability to articulate any speech, and with many other disabilities.

Predicted chances of recovery are variable owing to different techniques used to measure the extent of neurological damage. All the predictions are based on statistical rates with some level of chance for recovery present: a person with a low chance of recovery may still awaken. Time is the best general predictor of a chance of recovery: after four months of coma caused by brain damage, the chance of partial recovery is less than 15%, and the chance of full recovery is very low.[20]

The most common cause of death for a person in a vegetative state is secondary infection such as pneumonia, which can occur in patients who lie still for extended periods.

Occasionally people come out of coma after long periods of time. After 19 years in a minimally conscious state, Terry Wallis spontaneously began speaking and regained awareness of his surroundings.[21] Similarly, Polish railroad worker Jan Grzebski woke up from a 19-year coma in 2007.

A brain-damaged man, trapped in a coma-like state for six years, was brought back to consciousness in 2003 by doctors who planted electrodes deep inside his brain. The method, called deep brain stimulation (DBS) successfully roused communication, complex movement and eating ability in the 38-year-old American man who suffered a traumatic brain injury. His injuries left him in a minimally conscious state (MCS), a condition akin to a coma but characterized by occasional, but brief, evidence of environmental and self-awareness that coma patients lack.[22]

Comas lasting seconds to minutes results in post-traumatic amnesia (PTA) that lasts hours to days; recovery plateau occurs over days to weeks. Comas that lasts hours to days results in PTA lasting days to weeks; recovery plateau occurs over months. Comas lasting weeks results in PTA that lasts months; recovery plateau occurs over months to years.[23]

Society and culture[edit]

Research by Dr. Eelco Wijdicks on the depiction of comas in movies was published in Neurology in May 2006. Dr. Wijdicks studied 30 films (made between 1970 and 2004) that portrayed actors in prolonged comas, and he concluded that only two films accurately depicted the state of a coma victim and the agony of waiting for a patient to awaken: Reversal of Fortune (1990) and The Dreamlife of Angels (1998). The remaining 28 were criticized for portraying miraculous awakenings with no lasting side effects, unrealistic depictions of treatments and equipment required, and comatose patients remaining muscular and tanned.[24]

For decades, medical personnel and others have argued, and continue to argue, to define the circumstances under which a patient is considered dead.[25] Society places a lot of importance on the idea of “brain death” because most “industrialized countries have equated this with death of the individual”.[5] However, according to Rady and coworkers,[26] “human death is a singular phenomenon characterized by irreversible cessation of all vital functions (circulation, respiration, and consciousness)”. This means that death may be consisted of much more than just the brain’s inability to function. For example, although a patient may be “brain dead”, they may still be considered alive because they can still grow and even reproduce.[26]

See also[edit]

  • Brain death, lack of activity in both cortex, and lack of brainstem function
  • Coma scale, a system to assess the severity of coma
  • Induced coma, a deliberately caused coma to protect a patient's brain or during treatment
  • Locked-in syndrome, Paralysis of most muscles, except ocular muscles of the eyes, while patient is conscious
  • Persistent vegetative state (vegetative coma), deep coma without detectable awareness. Damage to the cortex, with an intact brainstem.
  • Process Oriented Coma Work, for an approach to working with residual consciousness in comatose patients.

References[edit]

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  2. ^ Bordini, A.L.; Luiz, T.F.; Fernandes, M.; Arruda, W. O.; Teive, H. A. (2010). "Coma scales: a historical review". Arquivos de neuro-psiquiatria 68 (6): 930–937. doi:10.1590/S0004-282X2010000600019. PMID 21243255. 
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  4. ^ "Persistent vegetative state: A medical minefield". New Scientist: 40–3. July 7, 2007.  See diagram.
  5. ^ a b c d e f Young, G.B. (2009). "Coma". Ann N Y Acad Sci 1157 (1157): 32–47. Bibcode:2009NYASA1157...32Y. doi:10.1111/j.1749-6632.2009.04471.x. 
  6. ^ "Video of man at beginning of documented 3 month coma.". 
  7. ^ "Video of man still nonresponsive to stimuli while in coma.". 
  8. ^ Russ Rowlett. "Glasgow Coma Scale". University of North Carolina at Chapel Hill. 
  9. ^ Benjamin Werdro. "Induced Coma". 
  10. ^ a b c Liversedge, Timothy; Hirsch (2010). "Coma". Anaesthesia & Intensive Care Medicine 11 (9): 337–339. doi:10.1016/j.mpaic.2010.05.008. 
  11. ^ Busl, K. M.; Greer, D. M. (2010). "Hypoxic-ischemic brain injury: Pathophysiology, neuropathology and mechanisms". NeuroRehabilitation: 5–13. 
  12. ^ Daltrozzo, J., Wioland, N., Mutschler, V., Lutun, P., Jaeger, A., Calon, B., Meyer, A., Pottecher, T., Lang, S., Kotchoubey, B. (2009c). Cortical Information Processing in Coma, Cognitive & Behavioral Neurology, 22(1), 53-62.[1]
  13. ^ Daltrozzo, J., Wioland, N., Mutschler, V., Kotchoubey, B. (2007). Predicting Coma and other Low Responsive Patients Outcome using Event-Related Brain Potentials: A Meta-analysis. Clinical Neurophysiology, 118, 606-614.[2]
  14. ^ Daltrozzo, J., Wioland, N., Mutschler, V., Lutun, P., Calon, B., Meyer, A., Jaeger, A., Pottecher, T., Kotchoubey, B. (2010a). Electrodermal Response in Coma and Other Low Responsive Patients. Neuroscience Letters, 475(1), 44-47.[3]
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  16. ^ a b c Baldursdottir, S.; Sigvaldason, K.; Karason, S.; Valsson, F.; Sigurdsson, G. H. (2010). "Induced hypothermia in comatose survivors of asphyxia: a case series of 14 consecutive cases". Acta Anaesthesiol. Scand. 54 (7): 821–826. doi:10.1111/j.1399-6576.2010.02248.x. PMID 20497127. 
  17. ^ Coma Care (2010-03-30). "Caring for Care Giver and Family". Retrieved 2010-12-08. 
  18. ^ Edwarda O’Bara, who spent 4 decades in a coma, dies at 59 Read more here: http://www.miamiherald.com/2012/11/22/3109800/edwarda-obara-who-spent-4-decades.html#storylink=cpy
  19. ^ NINDS (October 29, 2010). "Coma Information Page: National Institute of Neurological Disorders and Stroke (NINDS)". Retrieved 2010-12-08. 
  20. ^ Formisano R, Carlesimo GA, Sabbadini M et al. (May 2004). "Clinical predictors and neuropleropsychological outcome in severe traumatic brain injury patients". Acta Neurochir (Wien) 146 (5): 457–62. doi:10.1007/s00701-004-0225-4. PMID 15118882. 
  21. ^ "Mother stunned by coma victim's unexpected words". The Sydney Morning Herald. 2003-07-12. 
  22. ^ "Electrodes stir man from six-year coma-like state". Cosmos Magazine. 2 August 2007. 
  23. ^ "Post-traumatic amnesia". 
  24. ^ Eelco F.M. Wijdicks, MD and Coen A. Wijdicks, BS (2006). "The portrayal of coma in contemporary motion pictures". Neurology 66 (9): 1300–1303. doi:10.1212/01.wnl.0000210497.62202.e9. PMID 16682658. Retrieved 2009-11-25. 
  25. ^ Wijdicks, E. F. (2002). "Brain death worldwide: accepted fact but no global consensus in diagnostic criteria". Neurology 58 (1): 20–25. doi:10.1212/WNL.58.1.20. PMID 11781400. 
  26. ^ a b Rady, M. Y.; Verheijde, J. L.; McGregor, J. L. (2010). "Scientific, legal, and ethical challenges of end-of-life organ procurement in emergency medicine". Resuscitation 81 (9): 1069–1078. doi:10.1016/j.resuscitation.2010.05.007. PMID 20678461.