INTRODUCTION

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Background

Subarachnoid hemorrhage (SAH) implies the presence of blood within the subarachnoid space from some pathologic process. The common medical use of the term SAH refers to the nontraumatic types of hemorrhages, usually from rupture of a berry aneurysm or arteriovenous malformation (AVM). The scope of this article is limited to these nontraumatic hemorrhages.

Frequency

United States

Annual incidence of nontraumatic aneurysmal SAH is 6-25 per 100,000. More than 27,000 Americans suffer ruptured intracranial aneurysms each year. Annual incidence increases with age and probably is underestimated, because death is attributed to other reasons that are not confirmed by autopsies.

International

Varying incidences have been reported in other areas of the world (2-49 per 100,000).

Mortality/Morbidity

• An estimated 10-15% of patients die before reaching the hospital. Mortality rate reaches as high as 40% within the first week. About half die in the first 6 months.
• Mortality and morbidity rates increase with age and poorer overall health of the patient.
• Advances in the management of SAH have resulted in a relative reduction in mortality rate that exceeds 25%. However, more than one third of survivors have major neurologic deficits.

Race

Blacks have a higher risk for SAH than whites (2.1:1) (Broderick, 1992).

Sex

Incidence of aneurysmal SAH is higher in women than in men.

Age

Mean age of SAH is 50 years.

CLINICAL

Section 3 of 11  

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History

• Headaches
• • Patient experiences sudden onset of a severe headache.
  • Prodromal (warning) headache(s) from minor blood leakage (referred to as sentinel headache) is reported in 30-50% of aneurysmal SAHs.
    • Sentinel headaches may occur a few hours to a few months before the rupture, with a reported median of 2 weeks prior to diagnosis of SAH.
    • Minor leaks commonly do not demonstrate signs of elevated intracranial pressure (ICP) or meningeal irritation.
    • Minor leaks are not a feature of AVM.
    • More than 25% of patients experience seizures close to the acute onset; the location of a seizure focus has no relationship to the location of the aneurysm.
• Nausea and/or vomiting
• Symptoms of meningeal irritation (eg, neck stiffness, low back pain, bilateral leg pain): These are seen in over 75% of SAH, but many take several hours to develop.
• Photophobia and visual changes
• Loss of consciousness: About half of patients experience this at the time of bleeding onset.

Physical

Physical examination findings may be normal, or the clinician may find some of the following:

• Global or focal neurologic abnormalities in more than 25% of patients
• Syndromes of cranial nerve compression
• • Oculomotor nerve palsy (posterior communicating artery aneurysms) with or without ipsilateral mydriasis
  • Abducens nerve palsy
  • Monocular vision loss (ophthalmic artery aneurysm compressing the ipsilateral optic nerve)
• Motor deficits from middle cerebral artery aneurysms in 15% of patients
• No localizing signs in 40% of patients
• Seizures
• Ophthalmologic signs
• • Subhyaloid retinal hemorrhage (small round hemorrhage, perhaps with visible meniscus, near the optic nerve head); other retinal hemorrhage
  • Papilledema
• Vital signs
• • About half of patients have mild-to-moderate blood pressure (BP) elevation.
  • BP may become labile as ICP increases.
  • Fever is unusual at presentation but becomes common after the fourth day from blood breakdown in the subarachnoid space.
  • Tachycardia may be present for several days after the occurrence of a hemorrhage.
• Grade SAH according to the following scheme:
• • Grade I - Mild headache with or without meningeal irritation
  • Grade II - Severe headache and a nonfocal examination, with or without mydriasis
  • Grade III - Mild alteration in neurologic examination, including mental status
  • Grade IV - Obviously depressed level of consciousness or focal deficit
  • Grade V - Patient either posturing or comatose

Causes

• Primary SAH may result from rupture of the following types of pathologic entities (the first 2 are most common):
• • Saccular aneurysm
  • AVM
  • Mycotic aneurysmal rupture
  • Angioma
  • Neoplasm
  • Cortical thrombosis
• SAH may reflect a secondary dissection of blood from an intraparenchymal hematoma (eg, bleeding from hypertension or neoplasm).
• Two thirds of nontraumatic SAH are caused by rupture of saccular aneurysms.
• Congenital causes also may be responsible for SAH.
• • Occasional familiar occurrence
  • Frequency of multiple aneurysms
  • Association of aneurysms with specific systemic diseases, including Ehlers-Danlos syndrome, Marfan syndrome, coarctation of the aorta, and polycystic kidney disease
• Environmental factors associated with acquired vessel wall defects include age, hypertension, smoking, and arthrosclerosis.

DIFFERENTIALS

Section 4 of 11  

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WORKUP

Section 5 of 11  

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Lab Studies

• Complete blood count
• Prothrombin time, activated partial thromboplastin time
• Blood typing and screening
• • Blood bank typing is indicated when SAH is identified or a severe bleed is suspected.
  • Intraoperative transfusions may be required.
• Troponin I (cTnI): cTnI measurement is a powerful predictor for the occurrence of pulmonary and cardiac complications, but it does not carry additional prognostic value for clinical outcome in patients with aneurysmal SAH (Schuiling, 2005).

Imaging Studies

• The initial study of choice is an urgent CT scan without contrast (see Picture 1).
• • Sensitivity decreases with time from onset and with older resolution scanners.
  • In one recent study published by New England Journal of Medicine, good quality CT scanning revealed subarachnoid hemorrhage in 100% of cases within 12 hours of onset and 93% within 24 hours of onset (Suarez, 2006). Other studies traditionally report 90-95% sensitivity within 24 hours of onset of bleeding, 80% at 3 days, and 50% at 1 week.
  • CT also can detect intracerebral hemorrhage, mass effect, and hydrocephalus.
  • A falsely negative CT scan can result from severe anemia or small-volume SAH.
• Distribution of SAH can provide information about the location of an aneurysm and prognosis.
• • Intraparenchymal hemorrhage may occur with middle communicating artery and posterior communicating artery aneurysms. Interhemispheric and intraventricular hemorrhages may occur with anterior communicating artery aneurysms.
  • Outcome is worse for patients with extensive clots in basal cisterns than for those with a thin, diffuse hemorrhage.
• Cerebral angiography is performed once the SAH diagnosis is made.
• • This study assesses the following:
    • Vascular anatomy
    • Current bleeding site
    • Presence of other aneurysms
  • This study helps plan operative options.
  • Angiography findings are negative in 10-20% of patients with SAHs.
  • If negative, some advocate repeating angiography a few weeks later.
• Magnetic resonance imaging (MRI) is performed if no lesion is found on angiography.
• • Its sensitivity in detecting blood is considered equal or inferior to that of CT scan.
  • The higher cost, lower availability, and longer study time make it less optimal for detecting SAH.
  • MRI mostly is used to identify possible AVMs that are not visible on angiography.
  • MRI may miss small symptomatic lesions that have not yet ruptured.
• Magnetic resonance angiography (MRA) is less sensitive than angiography in detecting vascular lesions; however, many believe CT angiography and/or MRA one day will play a more central role.
• Multidetector computed tomography angiography (MD-CTA) of the intracranial vessels is now a routine examination, and it is becoming fully integrated into the imaging and treatment algorithm of patients presenting with acute subarachnoid hemorrhage in many centers in the United Kingdom and Europe (Goddard, 2005). Digital-subtraction cerebral angiography has been the criterion standard for the detection of cerebral aneurysm, but CT angiography has gained more popularity and is frequently used owing to its noninvasiveness and a sensitivity and specificity comparable to that of cerebral angiography (Jayaraman, 2004).

Other Tests

• Electrocardiogram
• • About 20% of SAH cases have myocardial ischemia from the increased circulation of catecholamines.
  • Typical results are nonspecific ST-and T-wave changes, prolonged QRS segments, U waves, and increased QT intervals.
  • ECG changes reflect myocardial ischemia or infarction and should be treated in the usual manner. Suspicion of SAH is a contraindication to thrombolytic and anticoagulant therapy.

Procedures

• Lumbar puncture
• • Lumbar puncture (LP) is indicated if the patient has possible SAH and negative CT scan findings.
  • Perform CT scan prior to LP to exclude any significant intracranial mass effect or obvious intracranial bleed.
  • LP may be negative less than 2 hours after the bleed; LP is most sensitive at 12 hours after symptom onset.
  • Red blood cells (RBCs) in the cerebrospinal fluid (CSF) remain consistently elevated in 2 sequential tubes or punctures in SAH, whereas the number of RBCs in technically traumatic punctures decrease over time.
  • Xanthochromia (yellow-to-pink CSF supernatant) usually is seen by 12 hours after the onset of bleeding; ideally this is measured spectrographically, although many laboratories rely on visual inspection.
  • LP findings were thought to be positive in 5-15% of all SAH presentations that are not evident on the CT scan. This number may be no longer valid with the advent of newer generations of CT scans. A recent small retrospective chart review about patients presenting to the emergency department undergoing fifth generation CT scans and LP showed no patients with positive LP and negative CT scan (Boesiger, 2005).

TREATMENT

Section 6 of 11  

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Prehospital Care

• Address the ABCs.
• Triage and transport patients with altered level of consciousness or an abnormal neurologic examination to the closest medical center with a CT scan and neurosurgical backup.
• Ideally, avoid sedating these patients en route.

Emergency Department Care

• In patients with a suspected grade I or II SAH, ED care essentially is limited to diagnosis and supportive therapy.
  • Early identification of sentinel headaches is key to reduced mortality and morbidity rates.
  • Use sedation judiciously.
  • Secure intravenous (IV) access during ED stay and closely monitor the patient's neurologic status.
• In patients with a grade III, IV, or V SAH (ie, altered neurologic examination), ED care is more extensive.
• • Address the ABCs.
  • Endotracheal intubation of obtunded patients protects from aspiration caused by depressed airway protective reflexes.
  • Intubate to hyperventilate patients with signs of herniation.
    • Thiopental and etomidate are the optimal induction agents in SAH during an intubation. Thiopental is short-acting and has a barbiturate cytoprotective effect. It should be used only in hypertensive patients because of its propensity to drop systolic blood pressure (SBP), which is the leading cause of secondary brain injury. In hypotensive and normotensive patients, use etomidate.
    • Use rapid sequence intubation if possible. In the process, to blunt ICP increase, ideally use sedation, defasciculation, short-acting neuromuscular blockade, and other agents with ICP-blunting properties (such as IV lidocaine).
    • Avoid excessive or inadequate hyperventilation. Target the pCO₂ at 30-35 mm Hg to reduce elevated ICP. Excessive hyperventilation may be harmful to areas of vasospasm.
  • Avoid excessive sedation. It makes serial neurologic exams more difficult and has been reported to increase ICP directly.
• Reliable neurologic examinations before and after initial treatment are critically important to optimizing management and to deciding on the appropriate neurosurgical intervention.
• Use the following interventions early and judiciously to decrease elevated ICP when herniation is suspected:
  • Use osmotic agents, such as mannitol, which reduces ICP 50% in 30 minutes, peaks after 90 minutes, and lasts 4 hours.
  • Loop diuretics, such as furosemide, also decrease ICP without increasing serum osmolality.
  • IV steroid therapy to control brain edema is controversial and debated.
• Monitoring
• • Monitor cardiac activity, oximetry, automated BP, and end-tidal carbon dioxide, when applicable.
  • End-tidal carbon dioxide monitoring of intubated patients enables the clinician to avoid excessive or inadequate hyperventilation. Target the pCO₂ at about 30-35 mm Hg to reduce elevated ICP.
  • Invasive arterial line monitoring is indicated when dealing with labile BP (common in high-grade SAH).
• Antihypertensive agents
• • Antihypertensive agents previously were advocated for an SBP greater than 160 mm Hg or diastolic BP (DBP) greater than 90 mm Hg.
  • Keep systolic blood pressure 90-140 mm Hg before aneurysm treatment, then allow hypertension to keep systolic blood pressure less than 200 mm Hg (Suarez, 2006).
  • Consult critical care providers who will be involved in ongoing care of the patient, as individual practices vary.
  • Use medications that can be titrated rapidly.
  • Vasopressors may be indicated to keep SBP over 120 mm Hg; this avoids CNS damage in the ischemic penumbra from the reactive vasospasm seen in SAH.
• Adjunctive therapies and measures
• • Provide supplemental oxygen for all patients with CNS impairment.
  • Elevate the head of the bed 30° to facilitate intracranial venous drainage.
  • Fluids and hydration
    • Maintain euvolemia (CVP, 5-8 mm Hg); if cerebral vasospasm is present, maintain hypervolemia (CVP 8-12 mm Hg, or PCWP, 12-16 mm Hg) (Suarez, 2006).
    • Do not overhydrate patients because of risks of hydrocephalus.
    • Patients with SAH also may have hyponatremia from cerebral salt wasting.
  • Serum glucose: Maintain level at 80-120 mg/dL; use sliding or continuous infusion of insulin if necessary (Suarez, 2006).
  • Core body temperature: Keep at 37.2°C; administer acetaminophen (325-650 mg PO q4-6h) and use cooling devices if necessary (Suarez, 2006).
  • Consider antiemetics for nausea or vomiting.
  • Sedate cautiously to avoid masking the neurologic examination, which may jeopardize the reliability of the findings. However, avoid any increase in ICP due to excessive agitation from pain and discomfort.
• Seizures
  • Prophylactic use of anticonvulsants does not acutely prevent seizures after SAH, but use anticonvulsants in patients who have had a seizure or if local practice dictates routine use.
  • Begin with anticonvulsants that do not change the level of consciousness (ie, phenytoin first; barbiturates or benzodiazepines only to stop active seizures).
• Calcium channel blockers decrease the incidence and severity of cerebral vasospasm.
  • Judicious use is essential because of the risk of detrimental primary or secondary hypotension.
  • Short-acting medication is recommended; discuss this intervention with the neurosurgeon.
• Statins
  • Statins may improve cerebral vasomotor reactivity through cholesterol-dependent and cholesterol-independent mechanisms.
  • Their use is still controversial, but 2 small studies have shown promise. Acute treatment with statins ameliorated cerebral vasospasm and reduced vasospasm-related delayed ischemic deficits (Tseng, 2005; Lynch, 2005).
• Use of antifibrinolytics, such as epsilon aminocaproic acid, is controversial.
  • They competitively inhibit plasminogen activation and have been reported to reduce the incidence of rebleeding.
  • Other reports warn of their detrimental vasospastic effect and increased occurrence of hydrocephalus. Consult a neurosurgeon concerning their use.
• Emergent ventricular drainage by the neurosurgeon may be necessary.

Consultations

• Obtain emergent neurosurgical consultation for definitive treatment.
• Interventional radiology may be needed when surgical intervention is deemed necessary by the neurosurgical consultant (eg, a large clot causing a mass effect is present and needs to be evacuated emergently).
• Many centers opt for early angiography in all patients.

MEDICATION

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The goals of therapy are to reduce pain, edema, and severity of cerebral vasospasm, relieve nausea and vomiting, and prevent convulsions.

Drug Category: Analgesics

Pain control is essential to quality patient care. It ensures patient comfort and promotes pulmonary toilet. Most analgesics have sedating properties that benefit patients who have sustained trauma.

Drug Category: Antiemetics

These agents are used for the treatment of nausea or vomiting.

Drug Category: Anticonvulsants

These agents are used to prevent posttraumatic seizures. Use in patients with SAH who have not had seizures is controversial and dependent on individual neurosurgical preference; they usually are used only in patients who have had seizures. Conventional loading doses may be employed.

Drug Category: Osmotic agents

These agents are used in an attempt to lower ICP and cerebral edema by creating an osmotic gradient across an intact blood-brain barrier; as water diffuses from the brain into the intravascular compartment, ICP decreases.

Drug Category: Diuretics

These agents are used to decrease plasma volume and edema by causing diuresis.

Drug Category: Calcium channel blockers

These agents may attenuate deleterious effects of calcium influx in patients with acute neurotrauma. Unfortunately, experimental studies using conventional calcium channel blockers in head injury models have been disappointing overall; however, some studies have suggested that calcium channel blockers may be effective in attenuating cerebral edema and postinjury cognitive dysfunction compared to placebo.

Drug Category: Hemostatic agents

These agents are potent inhibitors of fibrinolysis and can reverse states that are associated with excessive fibrinolysis. Use is controversial; consultation with admitting physicians is urged prior to use.

Drug Category: Antihypertensive agents

These agents are used to attempt to reduce ICP by reducing peripheral PB.

Drug Category: General anesthetics

These agents provide sedation when neuromuscular blocking agents are used for intubation.

FOLLOW-UP

Section 8 of 11  

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Further Inpatient Care

• Admit to ICU for serial neurologic examinations and for hemodynamic monitoring.
• • Arrange for a darkened, quiet, private room to minimize stimuli that may lead to an elevation of ICP.
  • Closely monitor BP and treat appropriately.
  • Some centers favor volume expansion to treat vasospasm that develops days after the initial bleeding episode.
  • Neurosurgical team should institute a workup and treatment plan.
  • Although the timing of surgery has been debated, most neurovascular surgeons recommend early operation. Evidence from clinical trials suggests that patients undergoing early surgery (within 72 h) have a lower rate of rebleeding and tend to fair better than those treated later (Whitfield, 2001).
  • Emergent imaging and intervention may be necessary if mass effect or rebleeding develops.

Transfer

• Patients with possible ruptured or leaking SAH should be transferred emergently to the closest center with CT scan and neurosurgical staff.
• Stabilize patients promptly for transfer in an advanced cardiac life support (ACLS)–monitored unit. Address airway and the possible need for intubation or other emergent interventions, such as mannitol and hyperventilation, prior to transfer.

Complications

• Hydrocephalus may develop within the first 24 hours because of obstruction of CSF outflow in the ventricular system by clotted blood.
• Rebleeding of SAH occurs in 20% of patients in the first 2 weeks. Peak incidence of rebleeding occurs the day after SAH. This may be from lysis of the aneurysmal clot.
• Vasospasm from arterial smooth muscle contraction is symptomatic in 36% of patients.
• Neurologic deficits from cerebral ischemia peak at days 4-12.
• Hypothalamic dysfunction causes excessive sympathetic stimulation, which may lead to myocardial ischemia or labile detrimental BP.
• Hyponatremia may result from cerebral salt wasting.
• Aspiration pneumonia and other complications of critical care may occur.
• Left ventricular systolic dysfunction: LV systolic dysfunction in humans with SAH is associated with normal myocardial perfusion and abnormal sympathetic innervation. These findings may be explained by excessive release of norepinephrine from myocardial sympathetic nerves, which could damage both myocytes and nerve terminals (Nader, 2005).

Prognosis

• Cognitive deficits are present, even in many patients considered to have a good outcome.
• More than one third of survivors have major neurologic deficits.
• Factors that affect morbidity and mortality rates are as follows:
• • Severity of hemorrhage
  • Degree of cerebral vasospasm
  • Occurrence of rebleeding
  • Location of bleeding
  • Age and overall health of the patient
  • Presence of comorbid conditions and the hospital course (eg, infections, myocardial infarction)
• Survival correlates with the grade of SAH upon presentation. Reported figures include a 70% survival rate for grade I, 60% for grade II, 50% for grade III, 40% for grade IV, and 10% for grade V.

MISCELLANEOUS

Section 9 of 11  

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Medical/Legal Pitfalls

• Failure to detect a sentinel bleed or an actual low-grade SAH
• Failure to address severe hypertension or hypotension
• Failure to monitor or stabilize patient with SAH
• Delay in detecting herniation or a worsening neurologic picture
• Delay in mobilizing adequate neurosurgical backup

MULTIMEDIA

Section 10 of 11  

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Media file 1:  Brain CT scan showing subtle finding of blood at the area of the circle of Willis consistent with acute subarachnoid hemorrhage. Image courtesy of Dana Stearns, MD, Massachusetts General Hospital.
	View Full Size Image
Media type:  CT

REFERENCES

Section 11 of 11

• Authors and Editors
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• Banki NM, Kopelnik A, Dae MW. Acute neurocardiogenic injury after subarachnoid hemorrhage. Circulation. Nov 22 2005;112(21):3314-9. [Medline].
• Boesiger BM, Shiber JR. Subarachnoid hemorrhage diagnosis by computed tomography and lumbar puncture: are fifth generation CT scanners better at identifying subarachnoid hemorrhage?. J Emerg Med. Jul 2005;29(1):23-7. [Medline].
• Broderick JP, Brott T, Tomsick T. The risk of subarachnoid and intracerebral hemorrhages in blacks as compared with whites. N Engl J Med. Mar 12 1992;326(11):733-6. [Medline].
• Chyatte D, Tindall G, Cooper P. Diagnosis and management of aneurysmal SAH. In: The Practice of Neurosurgery. Williams and Wilkins;1996.
• Goddard AJ, Tan G, Becker J. Computed tomography angiography for the detection and characterization of intra-cranial aneurysms: current status. Clin Radiol. Dec 2005;60(12):1221-36. [Medline].
• Inagawa T. What are the actual incidence and mortality rates of subarachnoid hemorrhage?. Surg Neurol. Jan 1997;47(1):47-52; discussion 52-3. [Medline].
• Jayaraman MV, Mayo-Smith WW, Tung GA. Detection of intracranial aneurysms: multi-detector row CT angiography compared with DSA. Radiology. Feb 2004;230(2):510-8. [Medline].
• Juvela S. Minor leak before rupture of an intracranial aneurysm and subarachnoid hemorrhage of unknown etiology. Neurosurgery. Jan 1992;30(1):7-11. [Medline].
• Lynch JR, Wang H, McGirt MJ. Simvastatin reduces vasospasm after aneurysmal subarachnoid hemorrhage: results of a pilot randomized clinical trial. Stroke. Sep 2005;36(9):2024-6. [Medline].
• Sawin PD, Loftus CM. Diagnosis of spontaneous subarachnoid hemorrhage. Am Fam Physician. Jan 1997;55(1):145-56. [Medline].
• Schievink W, Shaffrey C, Lanzino G. Nonoperative treatment of aneurysmal subarachnoid hemorrhage. In: Neurological Surgery. WB Saunders;1996.
• Schuiling WJ, Dennesen PJ, Tans JT. Troponin I in predicting cardiac or pulmonary complications and outcome in subarachnoid haemorrhage. J Neurol Neurosurg Psychiatry. Nov 2005;76(11):1565-9. [Medline].
• Suarez JI, Tarr RW, Selman WR. Aneurysmal subarachnoid hemorrhage. N Engl J Med. Jan 26 2006;354(4):387-96. [Medline].
• Tseng MY, Czosnyka M, Richards H. Effects of acute treatment with pravastatin on cerebral vasospasm, autoregulation, and delayed ischemic deficits after aneurysmal subarachnoid hemorrhage: a phase II randomized placebo-controlled trial. Stroke. Aug 2005;36(8):1627-32. [Medline].
• Weaver JP, Fisher M. Subarachnoid hemorrhage: an update of pathogenesis, diagnosis and management. J Neurol Sci. Sep 1994;125(2):119-31. [Medline].
• Whitfield PC, Kirkpatrick PJ. Timing of surgery for aneurysmal subarachnoid haemorrhage. Cochrane Database Syst Rev. 2001;CD001697. [Medline].
• Zweifler RM. Management of acute stroke. South Med J. Apr 2003;96(4):380-5. [Medline].

Article Last Updated: Oct 3, 2006