Coma 1

Coma

Dylan B. Medley, MD

James E. Morris, MD, MPH

17 " a n a g e m e n t of L i fe-Threatening Problems

aragement i : Assessment

i : " " a c r a n i a l Pressure and He rn ia t i on ; . a t i o n of The Comatose pa t ien t

Emergency T r e a t m e n t of Specific Disorders Causing Coma Structura l Lesions Me tabo l i c Encepha lopa th ies Other Disorders Causing Coma

Criteria for Brain Dea th

ITE MANAGEMENT OF --.-THREATENING PROBLEMS

f*=fal Considerations i : ined as the total absence of arousal and aware-:i £ i : least 1 hour associated with injury or func-i i c r o n of the ascending reticular activating system

..-.item or bilateral cortical structures. Comatose onstrate no eye opening, speech, or sponta-

fments, and motor activity elicited by painful ::esent) is abnormal or reflexive rather than pur-ma must be differentiated from other pathologic

E ;onsciousness such as brain death, vegetative - : :ürium, although it may be difficult to do so in

jy department.

. MANAGEMENT i - igement of the comatose patient involves the : : r.eeded to manage any critically ill patient pre-

:he emergency department. Immediate assess-: support of airway, breathing, and circulation : performed before efforts to diagnose or address : rases of coma are undertaken, with the caveat

deration may be given to postponing intubation

until administration of empiric therapy for coma. Empiric therapy, often abbreviated by the acronym "D.O.N.T." con-sists of IV dextrose, supplemental oxygen, IV naloxone, and thiamine. Dextrose (50 mL of 50% solution in adults) reverses coma secondary to hypoglycemia and is indicated if rapid testing of blood glucose is unavailable. Oxygen therapy should be initiated to immediately correct pos-sible hypoxemic induced coma. Naloxone (0.4-2.0 mg IV) rapidly reverses coma and respiratory depression secondary to narcotic overdose but because of short half-life, multiple doses maybe required. Thiamine (100 mg IV) is commonly given along with dextrose to avoid precipitating Wernicke encephalopathy in predisposed patients. Flumazenil (0.2 mg/min IV) specifically antagonizes benzodiazepines but is not routinely given empirically as it may precipitate sei-zures that are then refractory to benzodiazepines. It may be indicated in iatrogenic coma secondary to excess benzodiaz-epine administration.

If coma persists following the administration of naloxone and dextrose, definitive management of airway and breath-ing should be considered. IV access with two large-bore IVs should be obtained and blood pressure (especially hypoten-sion) managed aggressively. A complete set of vital signs, including temperature and pulse oximetry, is essential to avoid missing coma complicated by severe hypo- or hyper-thermia and hypoxia. Cervical spine immobilization should be maintained if there is any suspicion of trauma. A focused

• 1 k' I»?«]L' tawSlK-EH

H

Secure ai establish ventilatior

rway and adequate

Pulses pres<

I

1. Obtain vital signs 2. Insert intravenous

cannula 3. Draw blood for tests 4. Give the following:

Glucose, 50 mL of 50% solution intravenously* Thiamine, 50-100 mg intravenously Naloxone, 0 .8-2 mg intravenously

Begin CPR (Chapter 9)

Treat for status epileptious (Chapter 19)

y

Generalized or focal seizures

No - Arterial blood gases: P C 0 2 > 60 mm Hg P 0 2 < 60 mm Hg

Yes

1

Body core temper-ature > 4 1 (105.8») or < 32 » C (89.6 ~F) !

Yes

No

Patient awakens quickly (2 -3 min.)

Yes

I

Treat for respiratory failure with supplemental oxygen and ventilatory support

Diagnosis: Hypoglycemia (blood glucose <30 mg/dL) or opiate overdose

'Hyperglycemia may increase brain damage from ischemia. If results of blood glucsoe measurements are available and in the normal range, withhold glucose.

A Figure 17 -1 . Approach to the unconscious patient.

K l Ov

Lumbar puncture needed immediately in suspected meningoencephalitis if not contraindicated (focal signs, papilledema); otherwise, obtain emergency CT scan.

Diagnosis: meningo-encephalitis versus subarachnoid hemorrhage

T Yes

Evidence of meningeal irritation

No

I Pinpoint pupils | - No

Yes

I

Reassess

1. History, trauma, drugs, seizures, symptoms

2. Physical examination

3. Neurologic examination: pupils, ocular movement, pain response, seizures

Repeat naloxone administration.

Diagnosis: Opiate overdose

Diagnosis: 1. Pontine or

cerebellar hemorrhage

2. Cholinesterase inhibitor poisoning

3. Miotic eye drops and coma of other cause

Supratentorial mass 1. Gradual onset of coma 2. Early hemiparesis and

hemihypesthesia 3. Rostral caudal progression

of symptoms.

Subtentorial mass 1. Abrupt onset of coma 2. Symmetric neurologic deficit 3. Pinpoint pupils or conjugate

deviation of gaze

Metabolic encephalopathy 1. Gradual onset of coma;

anteced-ent somnolence or delirium

2. Symmetric neurologic deficit 3. Reactive pupils despite loss of

extraocular movements and depreessed respiration

4. Often myoclonus with meningeal I signs or evidence of seizures (active or recent)

Psychogenic coma 1. Eyelid tone greater than

skeletal muscle tone 2. No roving eye movements 3. Normal response to caloric

testing 4. Normal electroencephalogram

> £71

o

TO £71

-o 73 O CO

Reflex Examination Technique Normal Response Brainstem Location

Response to light Direct and consensual restriction Midbrain

tralic Turn head from side to side Eyes move conjugately in direction opposite to head Pons

: - rcuiocephaiic Irrigate external auditory canal with cold water

Nystagmus with fast component away from stimulus

Pons

"eflex Stimulation of cornea Eyelid closure Pons

•flex Stimulation ol carina Cough Medulla

Stimulation of soft palate Symmetric elevation of soft palate Medulla

HHBHNSMHMMMMHMHMMMMi Glasgow Coma Scale.

Score Adult W i . Child <5 years Child >5 years

6 Follows commands Normal spontaneous movements Follows commands 5 Localizes pain Localizes to supraocular pain (>9 months) 4 Withdraws to pain Withdraws from nailbed pressure 3 Flexion Flexion to supraocular pain 2 Extension Extension to supraocular pain

1 None None

5 Oriented Age-appropriate speech/vocalizations Oriented 4 Confused speech Less than usual ability; irritable cry Confused 3 Inappropriate words Cries to pain Inappropriate words

2 Incomprehensible Moans to pain Incomprehensible 1 None No response to pain

Inane : amina t ion should be performed to evaluate for _ : recipitating factors (evidence of drug use, systemic

. Obtaining additional history from friends, rela-• ' inders, and EMS personnel is essential.

: LOGIC ASSESSMENT

f r assessment in comatose patients is of paramount and a structured evaluation should be con-

soon as possible once immediate threats to life addressed. Level of consciousness, cranial nerve

)n , and motor examination should be performed.

Lateralizing deficits and a rostrocaudal progression of brain-stem dysfunction are seen with structural lesions, while involuntary movements are suggestive of a metabolic cause of coma. Although originally developed for traumatic brain injury, the Glasgow Coma Scale (GCS) has been shown to have predictive value in many different types of coma. Both total and component (eye, verbal, motor) scores should be documented (see Table 17-1).

Cranial nerve examinat ion (especially pupillary response) is an essential part of the neurologic examina-tion and may assist in determining the level of brainstem dysfunction (see Table 17-2). Normal pupillary function

" " -2 . Brainstem Reflexes.

S E C T I O N II MANAGEMENT OF COMMON EMERGENCY PROBLEMS

Table 17-3 . Signs of Increased Intracranial Pressure and Herniation Syndromes.

Sign

Coma

Mechanism

Compression of midbrain tegmentum

Type of Herniation

Uncal, central

Pupillary dilation Compression of ipsilateral third nerve

Uncal

Miosis Compression of the midbrain

Central

Lateral gaze palsy Stretching of CN VI Central

Hemiparesis Compression of contralateral cerebral peduncle

Uncal

Decerebrate posturing

Compression of the midbrain

Central, uncal

Hypertension, bradycardia

Compression of the medulla

Central, uncal, cerebellar

Abnormal breathing Compression of the pons or medulla

Central, uncal, cerebellar

and eye movements may be seen in lesions rostral to the midbrain. Pupillary abnormalities (especially unilateral) may be an early indicator of herniation, and pupillary function should be assessed frequently when increased intracranial pressure (ICP) is a concern. Symmetrically reactive pupils that are unusually large or small are commonly secondary to drug ingestions.

Motor examination should focus on the presence of movements and whether they are involuntary, reflexive, or purposeful. Purposeful movements such as localization require some degree of cortical processing, while reflexes are stereotypical responses that occur in the absence of cortical input. Structural lesions may result in posturing. Decerebrate posturing, characterized by extension of both upper and lower extremities, is seen in lesions caudal to the midbrain. Decorticate posturing, characterized by flexion of the upper extremities and extension of the lower extremities, is seen in lesions rostral to the midbrain.

INCREASED INTRACRANIAL PRESSURE AND HERNIATION Herniation syndromes result f rom increased ICP and lead to brainstem compression, manifested by arterial hypertension, bradycardia, and respiratory irregularities (Cushing triad). Herniation may be classified as uncal, central, or cerebellar (see Table 17-3). Increased ICP commonly results f rom a space-occupying lesion such as a tumor or hematoma but may also result f rom cerebral edema secondary to trauma, infection, or severe metabolic derangements.

Treatment of increased ICP focuses on maintaining cerebral perfusion pressure, defined as mean arterial pre?-sure (MAP) minus ICP. The goal is to keep CPP > 70-S m m Hg. The Monro-Kellie principle states that the volume within the skull is fixed and contains three component; brain, blood, and CSF. Increase in the amount of the>: components (eg, cerebral edema, hematoma, hydrocepha-lus) or the addition of other components (eg, tumc: results in increased ICP. Using this principle, treatment a aimed at either reducing the volume of the components or expanding the volume available through surgical decom-pression.

Emergency department care of herniation consists in -tially of prompt recognition and maximizing resuscitat: on Hypoxia and hypotension must be avoided and other ] adverse systemic factors such as hyperglycemia and fe sr treated aggressively. The patient's head should be elevatec a 30° and adequate sedation and analgesia provided. Seiznn ; prophylaxis should be considered, particularly when pari lytics have been given. When available, further treatmefl should be guided by ICP monitoring. In the absence of I CJ monitoring, hyperventilation to a Paco2 of 30-35 m m rif should be initiated, followed by mannitol (0.25-1.0 c u IV) or hypertonic saline (2 mL/kg of 7.5% solution IN' 1 the ICP remains high and craniectomy is not indicatec ; not available, barbiturates may be used to decrease cerer~i. metabolism and thus cerebral blood flow. Induced hyp -thermia to 32-34°C has been shown to effectively low • otherwise refractory ICP.

ent inr -99—Wi

Jiang JY: Clinical study of mild hypothermia treatment severe traumatic brain injury. I Neurotrauma 2009;26:3' [PMID: 19260782],

FURTHER EVALUATION OF THE COMATOSE PATIENT

The differential diagnosis of coma is broad and i n d u J H primary cerebral disorders (bilateral/diffuse, unilatera. v r i l mass effect, and brain-stem disorders) as well as a n u m : & u I systemic derangements (see Table 17-4).

History History should be obtained f rom whatever sources are i able, including friends, bystanders, police, and EMS per- -<| nel. Crucial points include the following:

• Recent head trauma, even seemingly trivial

Drug use (including alcohol), recent or past

• Past medical history, including a history of seizures-betes, cirrhosis, or other neurologic disease

Medications, including narcotics and benzodiazepine-Precomatose activity and behavior (headache, conr_-vomiting)

^^^^BHlwnwt^-iesiMiM » e 17-4. Etiology of Coma and Altered Consciousness.

ill

cerebral disorders : or diffuse hemispheric disorders

lafic brain injury mic rrhagic (subarachnoid hemorrhage, intraventricular

emorrhage) . ic-ischernic encephalopathy al venous thrombosis

nancy -gitis/encephalitis 'î l ized or complex partial seizures; status epilepticus :ensive encephalopathy or reversible encephalopathy syndrome disseminated encephalomyelitis cephalus

•al Hemispheric disorders (with displacement of midline Tes) atic (contusions, subdural hematoma, epidural hematoma)

35 hemispheric ischemic stroke - ; . ry intracerebral hemorrhage

1 1 -: "•= r-ral abscess tumor

stem disorders (pons, midbrain) - j r rhage, infarction, tumor, trauma

al pontine myelinolysis :ression from cerebellar infarct, hematoma, abscess, tumor

- c derangements causing coma

¡ ^ c a t i o n overdose/adverse effects .gs of abuse

isures (carbon monoxide, heavy metals) lie

::emic inflammatory response syndrome/sepsis -»ipoxia - rercapnia -.pothermia - .poglycemia -•Derglycemic crises (DKA, NHHS) ¡-.po/hypernatremia -.percalcemia - ;pat ic failure Renal failure Wernicke encephalopathy

Bdocrine ^hypop i tu i ta r i sm - jrenal insufficiency -.po/hyperthyroidism

• Sudden versus gradual onset of coma

• Other individuals with similar symptoms

Physical Examination Tr.e physical examination (other than the neurologic exami--.ition) should focus on ruling out other threats to life such is hypovolemia and systemic trauma. Evidence of t rauma

COMA

elsewhere on the body is presumptive evidence of head trauma in the comatose patient.

Imaging Non-contrast head CT is an integral part of the workup for coma that is not obviously related to hypoglycemia, over-dose, or other metabolic cause, and should be strongly con-sidered in any patient who remains comatose after dextrose and naloxone. Contrast-enhanced head CT or MRI may be indicated in certain patient populations.

Laboratory Evaluation Electrolytes, LFTs, CBC, UA, glucose, urine/serum toxicol-ogy screens, thyroid function studies, BUN/Cr, and ABG should be obtained early in the evaluation of coma. Lumbar puncture and CSF analysis should be performed if not con-traindicated (eg, mass lesions or other evidence of increased ICP) in patients for whom the cause of coma is unclear or in whom an infectious cause or SAH is suspected. ECG should be obtained and cardiac monitoring instituted to eliminate cardiac arrhythmias as a contributing factor. An EEC should be obtained when possible, especially in intubated patients receiving paralytics and in those for whom nonconvulsive status epilepticus is a consideration.

Stevens RD, Bhardwaj A: Approach to the comatose patient. Crit Care Med 2006;34:31-41 [PMID: 16374153],

Wilber ST: Altered mental status ¡11 older emergency department patients. Emerg Med Clin North Am 2006; 24:299-316 [PMID: 16584959],

EMERGENCY TREATMENT OF SPECIFIC DISORDERS CAUSING COMA

STRUCTURAL LESIONS

1. Intracerebral Hemorrhage See also Chapter 37.

IALS OF D I A G N O S I S

• Headache, nausea, vomit ing • Hypertension • Focal neurologic deficit wi th signs of increased ICP

• General Considerations Intracerebral hemorrhage (ICH) can be classified as primary (unrelated to congenital or acquired lesions) or secondary

C H A P T E R 1 7

S E C T I O N II MANAGEMENT OF COMMON EMERGENCY PROBLEMS

Table 17-5 . Primary ICH Syndromes

Location Findings

Basal ganglia Contralateral motor deficits, gaze paresis, aphasia

Thalamus Contralateral sensory loss

Cerebellum Nausea, vomiting, ataxia, nystagmus, AMS, ipsilateral gaze/facial palsy

Pons Coma, pinpoint pupils, autonomic Instability, quadriplegia, altered respiratory patterns

(related to vascular malformations, tumors, or other lesions). The vast majority of primary ICH is related to hypertension and occurs in characteristic areas of the brain: cerebral lobes, basal ganglia, thalamus, pons, and cerebellum. Secondary ICH is more variable in location. Smoking, advanced age, and anticoagulant use are other risk factors for ICH. Early hematoma growth is more common than previously thought and is most likely responsible for sudden deterioration within the first 6 hours of initial presentation. Cytotoxic and vasogenic edema surrounding the hemorrhage may result in ischemia and are likely responsible for delayed deterioration.

Clinical Findings Presentation is related to the size and location of the hemorrhage (see Table 17-5). Patients with large areas of hemorrhage are often comatose on arrival. The major -ity of patients with brainstem or cerebellar hemorrhage present with a decreased level of consciousness necessitat-ing intubation. Headache is universally present in awake patients and may accompany other signs of increased ICP. Seizures occur in 10% of all ICH but in 50% of patients with lobar hemorrhage. Most patients are hyper-tensive on presentation, even if previously normotensive. Non-contras t CT scan is the diagnostic study of choice with CT angiography being useful in certain patient popu-lations.

Treatment and Disposition Care is primarily supportive and aimed at reducing ICP and controlling blood pressure. Aggressive blood pressure control using IV labetalol, esmolol, or nicardipine should be instituted with a target SBP < 180 m m Hg or MAP < 130 m m Hg. CPP should be maintained > 70. Patients on anticoagulants should receive reversal agents (FFP and vita-min K for warfarin, protamine for heparin) promptly. The use of prothrombin complex concentrate, factor IX complex concentrate, and rFVIIa have been shown to reverse the elevation of the INR very rapidly (often within 1-2 hours) and is faster to prepare than FFP. Corticosteroids are con-traindicated. Prompt neurosurgical consultation should be

obtained for all patients with declining neurological statu; or evidence of hydrocephalus on CT scan. Cerebellar hem-orrhages > 3 cm require surgery. Hemorrhages in typical locations may not need further diagnostic evaluation and are rarely amenable to surgery. All patients should be admitted for further care.

Broderick J et al: Guidelines for the management of spontaneou; intracerebral hemorrhage in adults: 2007 update: a guide-line from the American Heart Association/American Stroke Association Stroke Council, High Blood Pressure Research Council, and the Quality of Care and Outcomes in Research Interdisciplinary Working Group: The American Acadenr. of Neurology affirms the value of this guideline as an educa-tional tool for neurologists. Stroke 2007;38:2001-2023 [PMID: 17938297],

Hemphill JC. Treating warfarin-related intracerebral hemorrhage: is fresh frozen plasma enough? Stroke 2006;37:6-7 [PMID: 16306461],

Rincón F, Mayer SA: Clinical review: Critical care management c: spontaneous intracerebral hemorrhage. Crit Care 2008;12:23~ jl'MID 19108704],

2. Subdural Hematoma

E S S E N T I A L S OF D I A G N O S I S

• Headache • Confusion • Depressed level of consciousness • Hyperdense crescent-shaped (biconcave) extra-axial

collection of blood on CT scan

General Considerations The possibility of subdural hematoma must be considered in any comatose patient. Trauma is the most common cause but in about 25% of cases, there is no history or evidence of trauma. Elderly patients are particularly likely to presen: with absent or trivial trauma. Other risk factors include his-tory of alcoholism, seizures, and coagulopathies.

Clinical Findings Symptoms and signs are notoriously nonspecific, non-localizing, or absent and may be either stable or rapid/ progressive. The frequency of bilateral hematomas make ;

localization of the lesion even more difficult, as does the coexistence of associated cerebral contusion. Hemiparesis when present, is contralateral to the lesion in approximate!'. 60% of cases, and ipsilateral pupillary dilatation occurs ir. approximately 75% of cases. Seizures may occur. When

COMA

associated with trauma, a subdural hematoma is most :requently found contracoup to the side of injury. CT scan - the diagnostic study of choice, revealing a hyperdense

extra-axial crescent-shaped collection of blood, which rarely .rosses the falx or tentorium. Sub-acute lesions (2-3 weeks) may appear as isodense, and patients receiving anticoagula-tion may demonstrate layering of blood in acute-on-chronic 5 jbdural hematoma.

Treatment and Disposition immediate hospitalization and emergency neurosurgical : : r.sultation are indicated. Unstable patients with rapid »rrsening (minutes to hours) of their neurologic deficit

thought to be due to an expanding subdural hematoma : ~.ould be treated for increased ICP as discussed previously, ceroids have not been shown to be beneficial.

3. Epidural Hematoma

Treatment and Disposition Immediate neurosurgical consultation is required. In the event a neurosurgeon or CT confirmation of the diagnosis is unavailable and the patient is herniating, a burr hole per-formed ipsilateral to the area of t rauma (or to the dilated pupil if external t rauma is not apparent) may be life-saving. Care is otherwise supportive and aimed at decreasing ICP.

4. Cerebral Infarction

E S S E N T I A L S OF D I A G N O S I S

• Hemiparesis • Hemisensory losses • Aphasia (dominant hemisphere)

E S S E N T I A L S OF D I A G N O S I S

Headache History of trauma wi th overlying skull fracture Classic lucid interval: "talk and die"

• .ens-shaped (biconvex) extra-axial collection of blood on CT scan

General Considerations : : -ural hematoma is a collection of blood between the dura

: the inner table of the skull and occurs almost exclusively n :he setting of trauma. The majority of epidural hema-

per-as occur in the temporoparietal region secondary to ; ration of the middle meningeal artery. Occipital epidural - a t o m a s may progress rapidly and extend beneath the rcorium, resulting in apnea.

Clinical Findings - : : : ms are progressive. The classic presentation of head

i followed by a brief loss of consciousness, return _:7tness ("lucid interval"), then worsening headache

: smiting with subsequent coma is seen in only 1/5 of I Non-contrast CT scan is the diagnostic study of

: î . revealing a hyperdense lenticular (biconvex) collec-- : f blood that does not cross suture lines, differentiating r : m a subdural hematoma. Ipsilateral pupillary dilation i : mtralateral hemiparesis are ominous findings sugges-: : : impending herniation. When associated with trauma, - r . o m a is most frequently found on the coup side of the

General Considerations The brain swelling of cerebral edema following massive hemispheric infarction can produce contralateral hemi-spheric compression or transtentorial herniation that will result in coma. Such cerebral swelling becomes maximal 48-72 hours after the infarct.

Clinical Findings The principal findings are hemiparesis or hemisensory loss (and aphasia if the dominant hemisphere is involved). Evolving transtentorial herniation progresses slowly over many hours or several days to stupor and coma. Non-contrast CT scan is the initial diagnostic test of choice.

Treatment and Disposition Hemicraniectomy may be life-saving in younger patients. Patients who are comatose f rom massive cerebral infarc-tion have likely progressed to coma secondary to increased ICP rather than the infarction itself, and initial treatment is supportive and aimed at lowering ICP. Blood pressure management is controversial; in severe hypertension (SBP > 220 m m Hg, DBP > 120 m m Hg), IV labetalol or nicardipine are preferred with a goal of reducing the SBP by 15% in first 24 hours.

Adams Jr H et al: Guidelines for the early management of adults with ischemic stroke: a guideline from the American Heart Association/ American Stroke Association Stroke Council, Clinical Cardiology Council, Cardiovascular Radiology and Intervention Council, and the Atherosclerotic Peripheral Vascular Disease and Quality of Care Outcomes in Research Interdisciplinary Working Groups. Stroke 2007;38:1655-1711 [PMID: 17515473).

S E C T I O N II MANAGEMENT OF COMMON EMERGENCY PROBLEMS

5. Basilar Artery Occlusion

ESSENTI PUBS

situations where recanalization may be delayed, "bridg-ing therapy" with IV abciximab has shown to improve survival. Even with aggressive t reatment , mortali ty ranges up to 70%. Hospitalize the patient for t reatment and sup-portive care.

• Coma, altered mental status • Respiratory pattern Irregular • Pupillary abnormalities, absent or abnormal horizon-

tal eye movements • Hemiparesis, hyperreflexia, positive Babinski sign

Lindsberg PJ, Mattle HP: Therapy of basilar artery occlusion: a systematic analysis comparing intra-arterial and intravenous thrombolysis. Stroke 2006;37:922-928 [PMID: 16439705],

Nagel S et al: Therapy of acute basilar artery occlusion: intraarterial thrombolysis alone vs bridging therapy. Stroke 2009;40:140-146 [PMID: 18927446],

General Considerations Basilar artery thrombosis and embolic occlusion are rela-tively common vascular syndromes that cause coma because of direct involvement of the penetrating arteries supply-ing the central core of the brain stem. Patients are usually elderly and often have a history of hypertension or transient ischemic attacks or evidence of other atherosclerotic vascular disease.

Clinical Findings Basilar artery transient ischemic attacks are characterized by (in order of frequency of occurrence) dizziness, diplo-pia, weakness and ataxia, slurred speech, and nausea and vomiting. Basilar artery occlusion causes coma in half of affected patients, and almost all present with some altera-tion of consciousness. Focal subtentorial signs are present f rom the onset, and the respiratory pattern is irregular. Pupillary abnormalities vary with the site of the lesion. Skew deviation of the eyes is common. Horizontal eye movements are absent or asymmetric during the doll's eye maneuver or caloric testing. Conjugate eye deviation, if present, is directed away f rom the side of the lesion and toward the hemiparesis. Vertical eye movements in response to the doll's eye maneuver may be intact. Symmetric or asymmet-ric motor signs (hemiparesis, hyperreflexia, and Babinski sign) may be present. The classic "locked in syndrome" is characterized by complete quadriplegia, lower cranial nerve palsy, and mutism with retained consciousness and vertical gaze. CT scan of the head with CT angiography is the diagnostic study of choice, with MRA useful in special populations.

Treatment and Disposition Current therapy recommendat ion is recanalization with intravenous or intra-arterial thrombolyt ics in combi-nat ion with mechanical manipu la t ion , depending on the inst i tut ion. While specific guidelines are lacking, t ime to recanalization is of prognostic importance. In

6. Brain Tumor

E S S E N T I A L S OF D I A G N O S I S

• Headache • Focai weakness • Altered mental status • Seizures • Papilledema • CT scan, MRI findings

General Considerations Coma is seldom the presenting symptom in primary o: metastatic tumors of the CNS, although coma may resui: f rom seizures induced by the tumors. Acute bleeding into a tumor may also result in coma secondary to a sudder increase in ICP.

Clinical Findings The patient typically has a history of days to weeks of head-ache, focal weakness, and altered or depressed consciousneii Papilledema is present in 25% of cases. CT scan (noncontra;: followed by contrast-enhanced if needed) is the initial diag-nostic study of choice.

Treatment and Disposition Glucocorticoids (Dexamethasone 10 mg IV) are remark-ably effective at reducing surrounding edema and shou. : be initiated early in consul ta t ion with neurosurgery Hospitalization for supportive care and fur ther evaluatk r is indicated.

Roger HP, Butler I, Benzel HC: Neurosurgery in the elder, brain tumors and subdural hematomas. Clin Geriatr Nu-2006;22:623-44 [PMID: 16860250],

COMA

7. Brain Abscess METABOLIC ENCEPHALOPATHIES

• Fever (often low grade) • Leukocytosis • Contrast-enhanced CT scan or AARI findings of intrac-

ranial mass

General Considerations 3rain abscess accounts for only 2% of intracranial masses, r rain abscess should be considered in patients who are mmunocompromised who develop changes in mentat ion.

Sacterial brain abscesses most commonly are the result of contiguous spread of infection f rom the oropharynx, middle ear, and paranasal sinuses. Cranial t rauma and hematog-enous spread f rom distant infection are also causes.

Clinical Findings Progression to stupor and coma may be rapid, occurring

er days or, rarely, hours. Symptoms include headache 70%), mental status changes (70%), focal neurological

: -.its ( > 60%), and seizure (25—35%) at t ime of presenta-¡irn. The usual signs of infection are frequently absent. The Emperature is normal in half of patients, and the white i :od cell count is below 10,000/mL in over one-four th if patients. CT scan (non-contrast followed by contrast-inanced if needed) or MRI will reveal almost all abscesses, „mbar puncture is contra-indicated.

! Treatment and Disposition late antibiotic therapy early, prior to imaging if pos-

•¿e when the clinical suspicion for CNS infection is high. - rrbiotic choice should cover anaerobes as well as aerobes,

| rnc coverage for fungal or other organisms may be indicated ending on the patient 's history. Empiric therapy with a

i-cr emation of vancomycin 1.0-1.5 g IV plus metronida-• n e ".5 mg/kg IV plus a third- or fourth-generat ion cepha-"i r : rin is indicated. Carbapenems can be used in placed

ihe combinat ion of cephalosporins and metronidazole, •„rosurgical consultation should be obtained with opera-

intervention necessary of abscesses > 2.5cm. The use of nds remains controversial and is generally deferred for indication. Seizure prophylaxis should be initiated early

Jiir.-g hospitalization.

i i I, Warren OK. Central nervous system infections: nicnin • and brain abscess. Infect Dis Clin N Am 2009;23:609-623

MID: 19665086;.

• Progressive somnolence • Intoxication, toxic delirium • Agitation, stupor, coma • Headache • Symmetric neurologic findings • Reactive pupils • Hypoventilation, abnormal respiratory pattern • Loss of extraocular movements

Clinical Findings Metabolic encephalopathies are characterized by a period of progressive somnolence, intoxication, toxic delirium, or agitation, after which the patient gradually sinks into a s tuporous and finally comatose state. Headache is not an initial symptom of metabolic encephalopathy except in the case of meningitis or poisoning due to organophosphate compounds or carbon monoxide.

Neurologic examination fails to reveal focal hemispheric lesions (hemiparesis, hemisensory loss, aphasia) before loss of consciousness. Neurologic findings are symmetric except in some patients with hepatic encephalopathy and hypoglycemic coma, which may be accompanied by focal signs (especially hemiparesis) that may alternate sides. Asterixis may be present.

The hal lmark of metabolic encephalopathy is reactive pupils (a midbra in func t ion) in the presence of impaired func t ion of the lower brain stem (eg, hypoventi lat ion, loss of extraocular movements) , an anatomically inconsistent set of abnormalit ies. Respiratory pat terns in metabolic coma vary widely and may help establish the cause of coma.

Treatment and Disposition Treatment depends entirely on the cause of coma. All patients require hospitalization for supportive care and specific therapy.

1. Hypoglycemia See also Chapter 43.

! General Considerations Unlike other organs, the brain relies mainly on glucose to supply its energy requirements. Abrupt hypoglycemia rap-idly interferes with brain metabolism and quickly produces

2 SECTION II MANAGEMENT OF COMMON EMERGENCY PROBLEMS

symptoms. Insulin and oral hypoglycemic drug overdose are the most common causes of hypoglycemia.

Clinical Findings Signs of sympathetic nervous system activity (tachycardia, sweating, and anxiety) may warn patients of impending hypoglycemia, although these signs may be masked by yS-blockers and may be absent in patients with diabetic autonomic neuropathy. Common neurologic abnormalities are delirium, seizures, focal signs that often alternate sides, stupor, and coma. Hypoglycemic coma may be tolerated for 60-90 minutes, but once the stage of flaccidity with hypore-flexia has been reached, glucose administration within 15 minutes is mandatory to avoid irreversible damage.

Treatment and Disposition Give glucose, 50 mL of 50% solution intravenously (adult dose). Once the diagnosis of hypoglycemia is confirmed by analysis of blood drawn before treatment, give an additional 50 mL as needed or begin an infusion of dextrose 5% in water. Subcutaneous or intramuscular glucagon should be considered in patients in which IV access cannot be obtained. Although case reports of octreotide use in hypoglycemia have been shown to be effective, the indications and dosage have not clearly been defined. Patients should be observed for 1-2 hours after glucose supplementation has been dis-continued to ensure that hypoglycemia does not recur before they are discharged from the hospital. In some cases, hospi-talization may be necessary, especially if hypoglycemia recurs despite treatment or in the event of long-acting insulin or oral hypoglycemic agent overdose (eg sulfonylureas).

Rowden AK, Fasano CJ: Emergency management of oral hypogly-cemic drag toxicity. Emerg Med Clin N Am 2007;25:347-356 {PMID: 17482024],

2. Hypoxemia Clinical Findings

Hypoxemia produces brain damage only as a result of con-comitant cerebral ischemia. Cerebral blood flow diminishes and brain ischemia occurs when the arterial Po2 falls to 20-45 mm Hg. In cerebral anoxia due to cardiac arrest, where the duration can be timed precisely, 4-6 minutes of asystole begins to result in permanent CNS damage. Following asystole, the pupils dilate rapidly and become fixed, and tonic posturing is observed. A few seizure-like tonic-clonic movements are common.

Treatment and Disposition Treatment of hypoxemia depends on the cause. Support cardiac output and maintain arterial Po, above 60 m m Hg by supplemental oxygen or mechanical ventilation. Induction

of mild hypothermia (~33°C) after cardiac arrest has been shown to improve survival and neurological outcome. Hospitalize all patients for diagnosis and treatment.

Arrich J, Holzer M, Herkner H, Mûllneï M: Hypothermia for neuroprotection in adults after cardiopulmonary resuscita-tion. Cochrane Database Syst Rev 2009;7:CD004128 [PMID: 19821320],

3. Drug Overdose See also Chapter 47.

Drug overdose is one of the most common causes of coma in patients presenting to the emergency department. Many drugs may be implicated, including sedative-hypnotics, opi-ates, tricyclic antidepressants, and antiepileptics. Details o: management can be found in Chapter 47.

Ethanol Intoxication Alcohol intoxication produces a metabolic encephalopa-thy similar to that produced by sedative-hypnotic drugs-although nystagmus during wakefulness and early impair-ment of lateral eye movements are not as common. Periphery vasodilatation is a prominent manifestation and produce; tachycardia, hypotension, and hypothermia.

In individuals who are not chronic alcoholics, stupo: occurs when blood alcohol levels reach 250-300 mg/dL, anc coma occurs when levels reach 300-400 mg/dL. Becaus: alcohol has significant osmotic pressure (100 mg/dL = 22.4 mOsm), alcohol intoxication is one cause of hyperosmolalm

Management is discussed in Chapter 47. Patients shoulc be observed until improvement has occurred with norm^ orientation and judgment, and satisfactory coordination Hospitalize patients who have abnormalities that woulc usually require hospitalization (eg, metabolic abnormalities Wernicke encephalopathy).

Narcotic Overdose In narcotic overdose, hypoventilation is almost always pres-ent, along with pinpoint pupillary constriction and absen: extraocular movements in response to the doll's eye maneu-ver. Pinpoint pupils are also associated with other disorder-that must be ruled out: use of miotic eye drops, pontic; hemorrhage, Argyll-Robertson pupils from syphilis, anc organophosphate insecticide poisoning.

Narcotic intoxication is confirmed by rapid pupillar> dilation and awakening after administration of a narcoti: antagonist such as naloxone, 2 mg, by rapid IV injection o : intranasally. Note: Patients who have overdosed on certair narcotics (eg, propoxyphene) may not respond to 2 m : and may require 4 mg or more. The duration of action : naloxone varies with the dose and route of administrador (20-90 minutes). Repeat doses are frequently necessan especially following intoxication with long-acting narcotic: (eg, methadone).

COMA

Treatment of drug overdose and poisoning is out-lined above and discussed in more detail in Chapter 47. Hospitalization should be considered for patients who do not recover completely in the emergency department or who have taken long-acting narcotics.

Merlin MA, Saybolt M, Kapitanyan R, Alter SM, Jeges J, Liu J, Calabrese S, Rynn KO, Perritt R, Pryor PW: Intranasal nalox-one delivery is an alternative to intravenous naloxone for opioid overdoses. Am I Emerg Med 2010;28:296-303 [PMID: 20223386],

/ -Hydroxybutyrate ;/-Hydroxybutyrate is a CNS depressant and can induce coma. The drug has become popular at rave parties and has also been called the "date rape drug." Detection of the drug is difficult, because most of it is eliminated through the lungs. Treatment is primarily supportive and may involve endotra-cheal intubation. Some patients require hospitalization for prolonged supportive care.

4. Hepatic Encephalopathy Clinical Findings

Hepatic encephalopathy can occur in patients with severe lai te or chronic liver disease. Jaundice need not be present. In n e patient with preexisting liver disease, encephalopathy may :evelop rapidly following an acute insult such as gastrointesti-nal hemorrhage or infection. Patients with surgical portacaval aunts are especially predisposed to encephalopathy.

Mental status is altered and ranges f rom somnolence to ;elirium or coma. There is increased muscle tone; hyper-reflexia is common. Prominent asterixis occurs in the som-nolent patient. Seizures, either generalized or focal, occur ^frequently. Ammonia levels correlate poorly with disease •¿verity. Hyperventilation with respiratory alkalosis is nearly _niversal and may be demonstrated by measuring arterial : ,ood pH. CSF is normal but may appear xanthochromic in ratients with serum bilirubin levels higher than 4 -6 mg/dL.

Treatment and Disposition inergency department care is supportive. Treatment aimed at : rcreasing intestinal ammonia absorption (lactulose, neomycin) maybe initiated but should not take the place of hospitalization

: definitive treatment. Studies on induced hypothermia in . rate liver failure are inconclusive to this point.

•.nil/ RT, Larsen FS: Therapeutic hypothermia for acute liver failure. Crit Care Med 2009;37:S258-264 [PMID: 19535956].

5. Hyponatremia "•elirium and seizures are common presenting features : hyponatremia. Hyponatremia may cause neurologic

symptoms when serum sodium levels are below 120 mEq/L, and symptoms are common with levels below 110 mEq/L. When the serum sodium level falls rapidly, symptoms occur at higher serum sodium levels.

Treatment and Disposition The diagnosis and treatment of these entities are discussed in Chapter 44. Hospitalization is mandatory in symptomatic patients.

6. Hypothermia/Hyperthermia Clinical Findings

Hypothermia and hyperthermia are associated with sym-metric neurologic dysfunction that may progress to coma. All comatose patients must have rectal temperature taken with an extended-range thermometer if the standard ther-mometer fails to register.

A. Hypothermia Internal body temperatures below 26°C (78.8°F) uniformly cause coma; hypothermia with core temperatures above 32°C (89.6°F) does not cause coma. Body temperatures of 26-32°C (78.8-89.6°F) are associated with varying degrees of obtundation. Pupillary reaction will be sluggish below 32°C (89.6°F) and lost below 26.5°C (80°F).

B. Hyperthermia Internal body temperatures above 41-42°C (105.8-107.6°F) are associated with coma and may also rapidly cause per-manent brain damage. Seizures are common, especially in children.

Treatment and Disposition Diagnostic and treatment measures for both hypothermia and hyperthermia are discussed in detail in Chapter 46. Hospitalization is mandatory.

7. Meningoencephalitis See also Chapter 42

Clinical Findings The classic triad of fever, neck stiffness, and altered mental status is poorly sensitive for bacterial meningitis (40%). Any patient with altered mental status, seizure, focal neurologic deficit, or evidence of increased ICP should undergo neu-roimaging prior to lumbar puncture to minimize the risk of herniation. CSF pleocytosis is common although depending on the stage of the disease, the differential may be variable. CSF glucose < 40 mg/dL is more consistent with bacterial meningitis.

MANAGEMENT OF COMMON EMERGENCY PROBLEMS

P " • • : e s s e pos tk t

3 Psychogen

¿/gm » - î î i en t is unre • j fma l physic

• r-=ccid symme » ' • " m a l and syi

V>rmal Babinst *• • • stagmus wit l • o rma l electrof

• Clinical Findi

Treatment and Disposition Start antibiotic therapy immediately based on clinical find-ings, prior to obtaining imaging. Current recommendations are for vancomycin with a third-generation cephalosporin, and dexamethasone (0.6 mg/kg) should be given with or before antibiotic administration. Hospitalization is indicated for all patients with meningitis who present in coma or in whom bacterial meningitis cannot be excluded.

Van de Beck D, de Gans ], Mclntyre P, Prasad K: Corticosteroids for acute bacterial meningitis. Cochrane Database Svst Rev 2007;]: CD004405 [PMID: 17253505],

OTHER DISORDERS CAUSING COMA

1. Subarachnoid Hemorrhage See also Chapter 37.

Treatment and Disposition Emergency department care is supportive. After stabilization, the patient should be admitted or transferred for definitive therapy by neurosurgery for craniotomy and clipping or interventional radiology for coiling. Blood pressure should be treated aggressively to be kept within normal limits untn the aneurysm has been secured. Nimodipine (60 mg), an oraf calcium channel antagonist, is commonly used to preven: delayed vasospasm and can be initiated in the emergenc. department.

Bederson JB, Connolly ES Jr, Batjer HH, Dacey RG, Dior JE, Diringer UN, DuiJner JE Jr, Harbaugh RE, Patel AB. Rosenwasser RH; American Heart Association: Guidelines for the management of aneurysmal subarachnoid hemorrhage: -statement for healthcare professionals from a: special writing group of the Stroke Council, American Heart Association. Stroke 2009;40:994-1025 [PMID: 19164800],

2. Seizure See also Chapter 19.

• Patient is unresponsive to pain • Nonfocal neurologic examination • Babinski sign (transient) • Todd paralysis • Signs of recent seizure: tongue trauma, inconti-

nence, rapidly clearing anion gap lactic acidosis

General Considerations Coma resulting from seizure disorders is usually not a dif-ficult diagnostic problem, because recovery of consciousnes is rapid following the end of the seizure. Prolonged postictal coma (several hours) followed by several days of confusior may occur after status epilepticus, in patients with brain dam-age (eg, multiple cerebral infarctions, head trauma, encephe litis, mental retardation) and in patients with metabo..-encephalopathy that alters consciousness and induces seizure (eg, hyponatremia, hyperglycemia). Nonconvulsive status ep: lepticus is more common than previously thought and shoul: be considered in any patient with no other apparent cause : coma, especially in those with a history of seizure disorder.

Clinical Findings Patients may initially be unresponsive to deep pain anc exhibit sonorous respirations. The neurologic examination usually nonfocal, although Babinski sign may be transien: i

: genic coma i; mide only after s:cal examination

examination j; eased muscle to i e normal dotv

The pup i ; tonally larger an ements elicited w not be present, 1

reflex.

• Sudden onset of severe headache • Nausea and vomit ing • Photophobia, visual changes

General Considerations Aneurysmal subarachnoid hemorrhage (SAH) accounts for 80% of all cases of nontraumatic SAH. Risk factors include cigarette smoking, hypertension, cocaine and alcohol use, first-degree relatives with a history of SAH, female sex, African-American race, and connective tissue disorders.

Clinical Findings Typical presentation of SAH involves nausea or vomiting (77%), sudden onset of severe headache (74%), meningis-mus (35%), photophobia, and may include decreased level of consciousness. A "thunderclap" headache may signify a sentinel leak, and the headache may resolve relatively quickly. The patient may lose consciousness at onset (53%) or may experience a seizure (20%). Retinal hemorrhages may be present on fundoscopic examination and blood pressure is usually markedly elevated. Noncontrast enhanced CT scan of the head is the initial diagnostic study of choice. Because the diagnostic sensitivity of CT scanners is only 98-100% for SAH within the first 12 hours, current recommendations are to follow a negative CT with CSF analysis. If CSF is normal (no xanthochromia, no elevated RBCs), SAH is effectively excluded. Positive or indeterminate CSF findings require CT angiography or traditional angiography to rule out the pres-ence of an aneurysm.

Treatmen

CHAPTER 17 ^ 275 COMA

:. Uncommonly, there may be focal abnormalities paralysis) referable anatomically to the focus of sel-

ectivity in the brain, er evidence of a recent seizure maybe present, such as to the tongue from biting, incontinence, or a rapidly

5 anion gap (lactic) acidosis. The rapid resolution of :n a patient with a witnessed seizure or known seizure t should suggest the diagnosis of the postictal state cause of coma. Coma that is at first thought to be

"al but fails to improve should prompt an investiga-tor underlying processes contributing to mental status rision, including metabolic encephalopathy, underlying

brain damage, encephalitis, and structural lesion. : ?riate investigations could include measurements of

•n electrolytes, calcium, and magnesium; CT scan; and ar puncture.

Treatment and Disposition rment depends on the underlying cause of the seizure,

ilert for metabolic causes and treat them appropriately. Ir.apter 19 for details of management. Immediate hos-^ation is required for all cases of status epilepticus and

j: r.ged postictal coma and for seizures due to metabolic ses that are not quickly correctable.

Psychogenic Coma

E S S E N T I A L S OF D I A G N O S I S

- rt ient is unresponsive Normal physical examination

»• 1 accid symmetric decreased muscle tone Normal and symmetric reflexes

• Normal Babinski - Nystagmus wi th ice water calorics

Normal electroencephalogram findings

• Clinical Findings rhogenic coma is a diagnosis of exclusion that should made only after careful documentat ion. The general

pttTsical examination should elicit no abnormalities; neu-•g : gic examination generally reveals flaccid, symmetrically :: creased muscle tone, normal and symmetric reflexes, ec r the normal downward response to Babinski plantar emulation. The pupils are normal in size (2-3 mm) or crasionally larger and respond briskly to light. Lateral eye - : vements elicited with the doll's eye maneuver may or - r v not be present, because visual fixation can suppress a is reflex.

Differentiating Psychogenic Coma from Organic Coma

A. Eye Movements The slow, conjugate roving eye movements of patients in metabolic coma cannot be imitated and, if present, are incom-patible with a diagnosis of psychogenic unconsciousness.

B. Eyelid Tone The slow, often asymmetric and incomplete eyelid closure commonly seen in organic forms of coma following passive opening of the lids cannot be mimicked. In addition, the patient with psychogenic coma usually shows some volun-tary muscle tone of the eyelids during passive opening by the examiner.

C. Ice Water Caloric Response A helpful objective test in diagnosing psychogenic uncon-sciousness is the caloric test: there is no response at all or tonic deviation to the side of the irrigation in organic coma, but nystagmus occurs in psychogenic coma. Because the quick (return ) phase of nystagmus requires an intact cortex, its presence is incompatible with a diagnosis of true coma.

0. Electroencephalogram The electroencephalogram in psychogenic coma is that of a normal, awake person. In coma due to other causes, it is invariably abnormal.

f - Treatment and Disposition Obtain psychiatric consultation. Hospitalization may be required.

Bazakis AM, Kunzler C: Altered mental status due to metabolic or endocrine disorders. Emerg Med Clin North Am 2005;23: 901-908 [PMID: 15982551],

Chen JW, Wasterlain CG: Status epilepticus: pathophysiology and management in adults. Lancet Neurol 2006;5:246-256 {PMID: 16488380]. f:

Marmo EM, Atkinson II, Fulgham JR, Wijdicks EI:: Emerging medical and surgical management strategies in the evaluation and treatment of intracerebral hemorrhage. Mayo Clin Proc 2005;80:420-433 (PMID: 15757025],

Mas A: Hepatic encephalopathy: from pathophysiology to treat-ment. Digestion 2006;73:86-93 [PMID: 16498256],

Mayer SA, Brun NC, Broderick J, Davis S, Diringer MN, Skolnick BE, Steiner T; Europe/AustralAsia NovoSeven ICH Trial Investigators: Safety and feasibility of recombinant factor Vila for acute intracerebral hemorrhage. Stroke 2005;36:74-79 [PMID: 1556987)].

Mayer SA, Rincon F: Treatment of intracerebral haemorrhage. Lancet Neurol 2005;4:662-672 |PM1D: 16168935],

Rathlev NK, Medzon R, Lowery D, Pollack C, Bracken M, Barest G, Wolfson AB, Hoffman IR, Mower WR: Intracranial

SECTION II MANAGEMENT OF COMMON EMERGENCY PROBLEMS

Brain death is defined as the irreversible loss of function of the brain, including the brain stem. Before a patient may be evaluated for the diagnosis of brain death, the patient must meet certain criteria:

• Clinical or neuroimaging evidence of catastrophic CNS event compatible with the clinical diagnosis of brain death

• Exclusion or correction of medical conditions that may confound clinical assessment:

- Acid-base disorders

- Severe electrolyte disorder

- Endocrinopathies

- Absence of drug intoxication/poisoning

- Patient core temperature > 32°C (90°F)

Once these criteria have been met, the patient can be tested for the diagnosis of brain death. If the patient meets the following criteria, the patient is observed for at least 6 hours and clinical testing is repeated. If patient testing remains unchanged, a diagnosis of brain death can be made.

• Coma (unresponsiveness): no cerebral motor response to pain

• Absence of brain-stem reflexes (all of the below):

- No pupillary response to light

- No oculocephalic reflex (doll's eyes maneuver)

- No response to cold water calorics

- No corneal reflexes

- No jaw reflex

- No grimacing to painful stimulus

- No gag reflex

- No cough response to tracheal/bronchial stimulation

- Apnea over 8 minutes with Pco2 > 60 m m Hg

Confirmatory testing may be used when complicating factors are present such as severe facial trauma, preexisting pupillary abnormalities, or toxic drug levels. Confirmatory tests result in findings that are consistent with brain death and are not diagnostic. The standard confirmatory test; include cerebral angiography," transcranial Doppler ultra-sonography, technetium-99m-hexamethylpropyleneamin-. brain scan, and somatosensory-evoked potentials. In some cases these tests may aid in the diagnosis and in others the", may confuse the picture. Documentat ion of the diagnosis o: brain death should include the cause and irreversibility of the condition, the absence of brain-stem reflexes, the absence o: any motor response to pain, the formal apnea test result and the justification for and results of any confirmatory test; The initial and repeat examinations should be includec Currently most authorities feel that the same criteria above can be used for full-term infants more than 7 days old Criteria for premature and newborns are still unclear.

Manno EM, Wijdicks EF: The declaration of death and the withdrawal of care in the neurologic patient. Neurol Clir. 2006;24:159-169 [PMID: 16443137],

Wijdicks EF, Rabinstein AA, Manno EM, Atkinson JD: Pronouncir r brain death: contemporary practice and safety of the apnea tes* Neurology 2008;71:1240-1244 [PMID: 18852438],