Symptoms include [6]:

•  Anxiety
•  Low or no urine output 
•  Profuse sweating
•  Dizziness
•  Confusion
•  Loss of consciousness
•  Chest pain
•  Tachycardia with weak pulse
•  Hypotension
•  Decreased urine output

Other signs may be:

•  Abdominal pain (in case of internal hemorrhage)
•  Melena and/or hematuria (in case of internal hemorrhage)
•  Progressive weakness leading to unconsciousness 
•  Peripheral and central cyanosis 

• Sepsis

  There was no signal of harm for hydroxyethyl starch in patients with severe sepsis / septic shock, in non-prespecified subset analyses. [pulmccm.org]

  DESIGN, SETTING, AND PARTICIPANTS: A multicenter, randomized clinical trial stratified by case mix (sepsis, trauma, or hypovolemic shock without sepsis or trauma). [ncbi.nlm.nih.gov]

  This may be one of the factors driving sepsis. [emedicine.medscape.com]

  Bench-to-bedside review: Endothelial cell dysfunction in severe sepsis: A role in organ dysfunction? Critical Care 2003;7:130-8. 15. Levi M, de Jonge E, van der Poll T. Sepsis and disseminated intravascular coagulation. [oadoi.org]

• Hypothermia

  Massively bleeding patients in hypovolemic shock should be treated with damage control resuscitation principles including limited crystalloid, whole blood or balance blood component transfusion to permissive hypotension, preventing hypothermia, and stopping [ncbi.nlm.nih.gov]

  A patient that is cool is losing body heat and is therefore at risk for hypothermia. (2) In cool weather, cover the casualty with a blanket, poncho, or other available materials to keep him warm and dry (figure 7-2). [brooksidepress.org]

  Warm all fluids: hypothermia increases mortality. In massive haemorrhage, give fresh frozen plasma and platelets early. Hypovolaemic shock is a clinical state in which loss of blood or plasma causes inadequate tissue perfusion. [bmj.com]

  In the meantime, follow these steps: Keep the person comfortable and warm (to avoid hypothermia ). Have the person lie flat with the feet lifted about 12 inches (30 centimeters) to increase circulation. [medlineplus.gov]

• Inflammation

  Activation of endothelial cells leads to release of vasoactive substances (nitric oxide, endothelin, platelet activating factor, prostacyclin, mitochondrial N-formyl peptide), mediators of inflammation (tumor necrosis factor α, interleukins, interferons [ncbi.nlm.nih.gov]

  الصفحة 185 - The intestinal disease form of anthrax may follow the consumption of contaminated food and is characterized by an acute inflammation of the intestinal tract. [books.google.com]

  The delayed and prolonged vascular leakage in inflammation. I. Topography of the leaking vessels after thermal injury. Am J Pathol 1964;45:261-81. 22. Ryan GB, Majno G. Acute inflammation. A review. Am J Pathol 1977;86:183-276. 23. Majno G. [oadoi.org]

  Molecular biology of inflammation and sepsis: a primer. [emedicine.medscape.com]

• Fever

  (known to contain salicylates), marketed as food and prescribed by his paediatrician to treat a mild cold accompanied by fever. Quali-quantitative analysis confirmed the presence of salicylates in the syrup. [ncbi.nlm.nih.gov]

  Initial signs of nausea, loss of appetite, vomiting, and fever are followed by abdominal pain, vomiting of blood, and severe diarrhea. ‏ الصفحة 378 - Children with Special Health Care Needs, and the American Academy of Pediatrics (AAP). [books.google.com]

  […] after a meal Venous pooling or postprandial hypotension Vomiting, diarrhea, bleeding, burns, diuretic use, clinical signs of dehydration Intravascular volume depletion Various symptoms of endocrine diseases Adrenal insufficiency, diabetes insipidus Fever [aafp.org]

  It's also possible from having a high fever or extreme sweating. [webmd.com]

• Unconsciousness

  Loss of consciousness Chest pain Tachycardia with weak pulse Hypotension Decreased urine output Other signs may be: Abdominal pain (in case of internal hemorrhage) Melena and/or hematuria (in case of internal hemorrhage) Progressive weakness leading to unconsciousness [symptoma.com]

  If severe it can lead to unconsciousness. It is usually diagnosed based on the clinical features and physical exam, blood tests and other diagnostic methods might be needed to determine the exact cause of shock if it is not clear. [burn-injury-resource-center.com]

  The signs and symptoms of hypovolemia include: • Cold skin • Agitation and anxiety • Decrease in the output of urine • Confusion • Feeling of weakness in general • Paleness in skin • Rapidness in breathing • Moist skin and increased sweating • Falling unconscious [healthguidance.org]

  Critical Essential Core Tested Community Questions (5) Sorry, this question is for PEAK Premium Subscribers only (M2.CV.201) A 46-year-old male was found unconscious in the field and brought to the emergency department by EMS. [medbullets.com]

  This helps the blood in the veins of his legs to return to his heart. (4) Place a small log, field pack, box, rolled field jacket, or other stable object under the casualty’s feet or ankles to maintain the elevation. (5) If the casualty is unconscious [brooksidepress.org]

• Tachypnea

  […] tachycardia with weak and faint pulse Extreme tachypnea Unconsciousness/coma Very little urine output It can be prevented by emergency medicine provided as early as possible. [symptoma.com]

  Increased breathing frequency (tachypnea) Capillary refill time (CRT) >2 seconds in infants, children and adults (CRT in healthy, especially in old people can be prolonged in cold ambient) >3 sec corresponds to ~10% drop of blood volume Body weight is [ehealthstar.com]

  […] in mental status (confusion, anxiety, agitation) Sweating with cool, pale skin Delayed capillary refill Urine output of approximately 20 milliliters/hour Stage 4 Loss greater than 40% (>2000 mL) Extreme tachycardia (>140) with weak pulse Pronounced tachypnea [boneandspine.com]

  Tachypnea and hyperventilation may be present. BP tends to be low ( 90 mm Hg systolic) or unobtainable; direct measurement by intra-arterial catheter, if done, often gives higher and more accurate values. Urine output is low. [merckmanuals.com]

  […] physical exam must include: 1) general appearance/alertness/eye contact/activity, 2) heart rate, 3) skin perfusion, a) capillary refill, b) color, c) skin temperature, 4) oliguria (if an observation period is permitted), 5) altered mental status, 6) tachypnea [hawaii.edu]

• Hematochezia

  UGI patients may present with blood in their vomit as well as melena or hematochezia. [artifactsjournal.missouri.edu]

• Hypotension

  […] to posttraumatic hypovolemia or other causes of hypotension. [ncbi.nlm.nih.gov]

  Shock is characterised by systemic hypotension due either to reduced cardiac output or to reduced effective circulating blood volume. [symptoma.com]

  Algorithm for the evaluation of orthostatic hypotension. Evaluation of Orthostatic Hypotension FIGURE 1. Algorithm for the evaluation of orthostatic hypotension. [aafp.org]

  Acute decreases in blood volume of this magnitude in other clinical situations have often been associated with shock or hypotension (16-21). [annals.org]

• Tachycardia

  Symptoms include: Anxiety Low or no urine output Profuse sweating Dizziness Confusion Loss of consciousness Chest pain Tachycardia with weak pulse Hypotension Decreased urine output Other signs may be: Abdominal pain (in case of internal hemorrhage) Melena [symptoma.com]

  There may be tachycardia and a fall in blood pressure (BP) or postural hypotension. Tachycardia and cold peripheries from vasoconstriction may occur before a fall in BP, especially in children and young adults. [patient.info]

  Tachycardia Hypotension Tachycardia, very weak pulse. Capillary refill is undetectable. The skin is pale and moist. Blood pressure very low or undetectable. 19. [slideshare.net]

  Tachycardia is sensitive but not specific indicator. Prolonged capillary refill (> 2 seconds), especially when combined with tachycardia, is more specific, although it may be difficult to measure. Cold skin and decreased urine output may be present. [openanesthesia.org]

  Subsequently, the patient had acute pulmonary edema, hypotension, and tachycardia developed. [omicsonline.org]

• Weak Pulse

  Weak pulse or absent pulses (they are more significant than weak pulses). Skin: pale, moist and cool. Tachycardia Hypotension Tachycardia, very weak pulse. Capillary refill is undetectable. The skin is pale and moist. [slideshare.net]

  Weak pulses, mottling, cyanosis, and impaired consciousness may all precede hypotension. In fact, hypotension is an ominous sign in pediatric patients Hypovolemia in Pediatrics: Signs Tachycardia : sensitive but not specific. [openanesthesia.org]

  Symptoms of shock include Confusion or lack of alertness Loss of consciousness Sudden and ongoing rapid heartbeat Sweating Pale skin A weak pulse Rapid breathing Decreased or no urine output Cool hands and feet Shock is a life-threatening medical emergency [icdlist.com]

  Symptoms include: Anxiety Low or no urine output Profuse sweating Dizziness Confusion Loss of consciousness Chest pain Tachycardia with weak pulse Hypotension Decreased urine output Other signs may be: Abdominal pain (in case of internal hemorrhage) Melena [symptoma.com]

  Symptoms include: anxiety blue lips and fingernails low or no urine output profuse (excessive) sweating shallow breathing dizziness confusion chest pain loss of consciousness low blood pressure rapid heart rate weak pulse External hemorrhaging (bleeding [healthline.com]

• Orthostatic Hypotension

  Algorithm for the evaluation of orthostatic hypotension. Evaluation of Orthostatic Hypotension FIGURE 1. Algorithm for the evaluation of orthostatic hypotension. [aafp.org]

  hypotension, which means there can be lowered blood pressure. [healthguidance.org]

  To be eligible, patients had to be in objective shock, and also to have evidence for hypovolemia with a low cardiac index, measured invasively or noninvasively (orthostatic hypotension, increased pulse pressure variation, or clinical signs). [pulmccm.org]

  2,7 Hemorrhagic pneumothorax Pulmonary embolism 27 Arteriovenous malformations 2 Vasodilation as a side effect of drugs, such as barbiturates, nitrates, opiates, antihypertensives (beta blockers, vasodilators) 7,25,26 Temporary autonomic dysfunction: Orthostatic [ehealthstar.com]

  Orthostatic hypotension is more common in diabetes patients ( 1, 2, 5, 10, 11 ), but diabetes patients with no detectable or only mild CAN also have an increased risk of hypotension during orthostatic stress and surgery, indicating the presence of other [care.diabetesjournals.org]

• Jugular Venous Distention

  Cardiac tamponade is suggested by jugular venous distention, muffled heart sounds, and a paradoxical pulse. [merckmanuals.com]

• Sweating

  Heavy sweating and intermittent loss of consciousness can occur at its most severe stage. There are four stages of hypovolemic shock based on how much blood volume has been lost. [medicalnewstoday.com]

  This can occur in cases of: excessive or prolonged diarrhea severe burns protracted and excessive vomiting excessive sweating Blood carries oxygen and other essential substances to your organs and tissues. [healthline.com]

  Vomiting, diarrhea, severe sweating, and burns can all trigger hypovolemic shock. Hypovolemic shock takes effect when circulation drops by approximately 20 percent or more. [sharecare.com]

  Symptoms of shock include Confusion or lack of alertness Loss of consciousness Sudden and ongoing rapid heartbeat Sweating Pale skin A weak pulse Rapid breathing Decreased or no urine output Cool hands and feet Shock is a life-threatening medical emergency [icdlist.com]

  As the rate of sweating rises, the concentration of sodium in the sweat rises, so that the total loss of sodium rises exponentially. Ability to remove sodium from sweat improves with acclimatisation. [patient.info]

• Urticaria

  The histamine also causes flushing of the skin, urticaria ( hives ), vomiting and diarrhea. A variety of mechanisms cause the heart muscle to pump weakly and blood vessels to leak fluid. [emedicinehealth.com]

  Some patients with anaphylactic shock have urticaria or wheezing. Numerous other symptoms (eg, chest pain, dyspnea, abdominal pain) may be due to the underlying disease or secondary organ failure. [merckmanuals.com]

• Cold, Clammy Skin

  clammy skin; (c) oliguria; (d) increased serum lactate. [annalsofintensivecare.springeropen.com]

• Increased Sweating

  The signs and symptoms of hypovolemia include: • Cold skin • Agitation and anxiety • Decrease in the output of urine • Confusion • Feeling of weakness in general • Paleness in skin • Rapidness in breathing • Moist skin and increased sweating • Falling [healthguidance.org]

• Anuria

  Severe oliguria or anuria 18. Heart • Cardiovascular signs are due to adrenergic response to blood loss. (Shock class I) (Shock class II) (Shock class III) (Shock class IIII) NONE Tachycardia due to catecholamine release. [slideshare.net]

• Polyuria

  Increased in fluid loss without red cell loss: Dehydration (diarrhea, vomiting, polyuria, excessive sweating) Plasma loss (burns) Sodium (Na): Normal in bleeding (initially) Decreased in hypovolemic hyponatremia Potassium (K) Chloride (Cl) Blood Urea [ehealthstar.com]

• Confusion

  A confused patient presented with hypovolemic shock and signs of arterial and venous obstruction of the left lower extremity; the correct diagnosis of urinary retention was made after phlebography. [ncbi.nlm.nih.gov]

  Anxiety, confusion. Confusion, drowsiness, and coma 21. [slideshare.net]

  Symptoms of shock include Confusion or lack of alertness Loss of consciousness Sudden and ongoing rapid heartbeat Sweating Pale skin A weak pulse Rapid breathing Decreased or no urine output Cool hands and feet Shock is a life-threatening medical emergency [icdlist.com]

• Dizziness

  Symptoms include: Anxiety Low or no urine output Profuse sweating Dizziness Confusion Loss of consciousness Chest pain Tachycardia with weak pulse Hypotension Decreased urine output Other signs may be: Abdominal pain (in case of internal hemorrhage) Melena [symptoma.com]

  The person feels dizzy and might even lose consciousness. Hypovolemia can hinder the amount of blood that the heart pumps to the organs. This indicates that there are many signs related to the heart caused by hypovolemia. [healthguidance.org]

  Headache, fatigue, nausea, profuse sweating, dizziness may occur as the condition develops. [en.wikipedia.org]

  Symptoms include: anxiety blue lips and fingernails low or no urine output profuse (excessive) sweating shallow breathing dizziness confusion chest pain loss of consciousness low blood pressure rapid heart rate weak pulse External hemorrhaging (bleeding [healthline.com]

  (Shock class I) (Shock class II) (Shock class III) (Shock class IIII) None or orthostatic dizziness. Restlessness, anxiety, agitation. Anxiety, confusion. Confusion, drowsiness, and coma 21. [slideshare.net]

• Agitation

  Restlessness, anxiety, agitation. Anxiety, confusion. Confusion, drowsiness, and coma 21. [slideshare.net]

  Signs and symptoms: Anxiety or agitation. Cold, pale skin. Confusion. General weakness. Low blood pressure. Rapid pulse. Decreased or no urine output. If severe it can lead to unconsciousness. [burn-injury-resource-center.com]

  The signs and symptoms of hypovolemia include: • Cold skin • Agitation and anxiety • Decrease in the output of urine • Confusion • Feeling of weakness in general • Paleness in skin • Rapidness in breathing • Moist skin and increased sweating • Falling [healthguidance.org]

  This can be due to: Burns Diarrhea Excessive perspiration Vomiting Symptoms Symptoms may include: Anxiety or agitation Cool, clammy skin Confusion Decreased or no urine output General weakness Pale skin color (pallor) Rapid breathing Sweating, moist skin [mountsinai.org]

• Lethargy

  Plasma loss Blood loss (external or internal bleeding or blood donation) Vasodilation Loss of electrolytes like sodium Pregnancy-associated conditions Severe diarrhea and vomiting Symptoms Symptoms and signs may include: Light headedness Dizziness and lethargy [symptoma.com]

  Late Symptoms Early symptoms plus the following: Dizziness Fainting Weakness Confusion Lethargy Late Signs Early signs plus the following: Mottled, cyanotic skin Increase of tachycardia, bradycardia or arrhythmia Increased breathing rate (tachypnea: > [ehealthstar.com]

  […] tachycardia (> 100 bpm) Tachycardia (> 120 bpm) Extreme tachycardia (> 140 bpm) with weak pulse Respiratory rate Normal Increased (> 20) Tachypneic (> 30) Extreme tachypnea Mental status Normal Slight anxiety, restless Altered, confused Decreased LOC, lethargy [en.wikipedia.org]

  […] milliliters/hour Stage 4 Loss greater than 40% (>2000 mL) Extreme tachycardia (>140) with weak pulse Pronounced tachypnea [increased respiratory rate] Significantly decreased systolic blood pressure of 70 mm Hg or less Decreased level of consciousness, lethargy [boneandspine.com]

  Also observe for restlessness, agitation, or lethargy. Compare your results with the baseline assessment to see if anything has changed. And check for laboratory results that indicate metabolic or electrolyte abnormalities. [163.178.103.176]

• Altered Mental Status

  […] diastolic blood pressure, systolic pressure maintained Tachypnea Mild anxiety Urine output of 20-30 millilitres/hour Stage III Blood loss up to 30-40% of total blood volume Hypotension Tachycardia Tachypnea Altered mental status Urine output 20 millilitres [symptoma.com]

  mental status (eg, lethargy, confusion, somnolence) is a common sign of shock. [merckmanuals.com]

  Altered mental status. .. .. c. Depressed anterior fontanelle. .. .. d. Hypotension. .. .. e. Absent distal pulses 5. An alert, 6 month old male has a history of vomiting and diarrhea. [hawaii.edu]

  mental status; (b) cold, clammy skin; (c) oliguria; (d) increased serum lactate. [annalsofintensivecare.springeropen.com]

Work up consists of a detailed history and physical examination.

Laboratory Tests

• Complete blood count
• Serum electrolytes 
• Kidney function tests
• Urinary catheterisation and urine output checking 
• Blood sugar levels 
• Arterial blood gases
• Prothrombin time and APTT

Imaging Studies

• Echocardiogram to assess heart function
• ECG
• Ultrasound
• X-ray
• CT scan of head, chest and abdomen to check for internal bleeding

Test Results

On the basis of history, physical assessment of the patient and test results, a diagnosis of hypovolemic shock can be made and intensive treatment should be immediately begun.

Control Bleeding

The cause of bleeding should be immediately identified and treated. Treatment could be surgical or via medications, depending upon the cause.

Treatment of burns

If the hypovolemia is due to severe burns, the primary goal of treatment should be to replace the lost volume.

Treating other underlying cause

If the cause of hypovolemia is due to a pregnancy-associated condition, or due to gastrointestinal disturbances or disease, or due to any other cause, that underlying cause should be identified and promptly treated.

Fluid resuscitation

Many fluids have been studied for use in resuscitation; these include isotonic sodium chloride solution, lactated Ringer solution [7], FFP, hypertonic saline, dextran 70, albumen, etc. The loss of blood volume should be recompensed with appropriate fluids to avoid systemic effects.

Oxygen

Emergency oxygen should be immediately employed to increase the efficiency of the patient's remaining blood supply. This intervention can be life saving [8].

Transfusions

Blood should be matched and transfusions should be performed to replace the lost blood volume.

Medications

Vasopressers and thrombogenic drugs may be administered if needed, to prevent further episodes of bleeding.

Prognosis depends upon how early treatment is begun. If patients are brought to the emergency and treated accordingly, prognosis is excellent. However, if the hypovolemia has extended to multiorgan failure, death may ensue.

Complications

Possible complications include the following:

•  Myocardial infarction
•  Cardiac arrest or fatal arrhythmias
•  Brain damage
•  Kidney damage
•  Multiorgan failure
•  Gangrene of extremities 
•  Coma
•  Death 

Hypovolemic shock results from low cardiac output due to the loss of blood or plasma volume, such as can occur with massive hemorrhage or fluid loss from severe burns [1]. Hemorrhage is the most common cause of hypovolemic shock.

Less common causes include plasma loss in severe burns, or into the abdominal cavity in acute pancreatitis, inappropriate vasodilatation in bacteraemic shock and anaphylactic shock, and excess urinary fluid loss as in diabetic ketoacidosis [3].

Excessive diarrhea and severe vomiting may also cause hypovolemic shock. Pregnancy associated conditions such as ectopic pregnancy rupture or placenta previa may cause hypovolemia, and so can arteriovenous malformations, gastrointestinal disturbances such as Mallory-Weiss tears, esophageal varices and peptic ulcers.

Incidence

More than 1 million patients present in shock or develop shock in the US hospitals each year, at an annual cost of more than $100 billion [2].

Sex

It has no known gender prevalence.

Age
Hypovolemic shock may occur at any age, depending upon the underlying etiology. It may occur in young children who have suffered severe burns or it may occur in adults who have had a serious accident leading to heavy blood loss. 

As discussed in the previous section, the commonest cause of hypovolemia is hemorrhage. Hemorrhage decreases the filling pressure of the circulation and, as a consequence, decreases venous return. As a result, the cardiac output falls below normal and shock may ensue [4]. Hypovolemia occurs so commonly due to hemorrhage that the term hypovolemic shock is sometimes used interchangeably with hemorrhagic shock.

The severity of hypovolemia can be staged. The stages include the following:

Stage I

• Blood loss up to 15% of total blood volume
• Normal or slightly low blood pressure 
• Normal mental status
• Normal respiratory rate 
• Normal urine output [5]

Stage II

• Blood loss up to 20-30% of total blood volume
• Increased diastolic blood pressure, systolic pressure maintained 
• Tachypnea 
• Mild anxiety
• Urine output of 20-30 millilitres/hour [5]

Stage III

• Blood loss up to 30-40% of total blood volume
• Hypotension
• Tachycardia
• Tachypnea 
• Altered mental status 
• Urine output 20 millilitres/hour

Stage IV

• Blood loss >40% of total blood volume
• Extreme tachycardia with weak and faint pulse 
• Extreme tachypnea
• Unconsciousness/coma
• Very little urine output

It can be prevented by emergency medicine provided as early as possible. First aid is critical in the prevention of hypovolemic shock.

Shock is characterised by systemic hypotension due either to reduced cardiac output or to reduced effective circulating blood volume [1]. Hypovolemic shock occurs due to a rapid fall in blood volume resulting in life threatening hypotension and may lead to multi organ failure, and ultimately, death.

Definition

Hypovolemic shock is a potentially life threatening condition that occurs when around 20% of the body's fluid volume is lost.

Cause

Common causes of hypovolemia are [9]:

• Plasma loss
• Blood loss (external or internal bleeding or blood donation [10])
• Vasodilation
• Loss of electrolytes like sodium
• Pregnancy-associated conditions
• Severe diarrhea and vomiting

Symptoms

Symptoms and signs may include:

• Light headedness
• Dizziness and lethargy
• Anxiety
• Increased heart rate with decreased pulse
• Hypotension
• Chest pain
• Unconsciousness

Diagnosis

Diagnosis is made by evaluating a combination of factors like history, physical examination and laboratory tests.

Treatment

Treatment includes fluid replacement, blood transfusions, oxygen and sometimes, surgical repair.

Prevention

Hypovolemic shock can be prevented by giving first aid on development of symptoms and admitting the patient to a hospital as soon as possible.

1. Robbins and Cotran. Pathologic Basis of Disease, 8th ed. Pa:Saunders Elsevier. Ch.4 p129
2. Rivers E. Approach to the patient with shock. In: Goldman L, Schafer L, eds. Cecil Medicine. 24th ed. Philadelphia, Pa: Saunders Elsevier; 2011:chap 106
3. Guyton and Hall. Textbook of Medical Physiology. 12th ed. Ch.24. Pa: Sanders Elsevier
4. Davidson's Principles and Practice of Medicine. Christopher RWE, Ian ADB, eds. 16th ed. Ch.8 p282 
5. Elizabeth D Agabegi; Agabegi, Steven S. (2008). Step Up To Medicine (Step-Up Series). Hagerstwon, MD: Lippincott Williams and Wilkins. ISBN 0-7817-7153-6
6. Rachel N, reviewed by Brenda B. Spriggs. Hypovolemic Shock. June 22, 2012. Retrieved on 17th Sept 2014. 
7. Ghafari MH, Moosavizadeh SA, Moharari RS, Khashayar P. Hypertonic saline 5% vs. lactated Ringer for resuscitating patients in hemorrhagic shock. Middle East J Anesthesiol. Oct 2008;19(6):1337-47 [Medline]
8. Takasu A, Prueckner S, Tisherman SA, Stezoski SW, Stezoski J, Safar P. (2000), Effects of increased oxygen breathing in a volume controlled hemorrhagic shock outcome model in rats. PMID 10959021. 
9. Sircar, S. Principles of Medical Physiology. Thieme Medical Pub. ISBN 9781588905727. 
10. Danic B, Gouezec H, Bigant E, Thomas T (June 2005). "[Incidents of Blood Donation]". Transfus Clinic Biol (in French) 12 (2):153-9. doi:10.1016/j.tracli.2005.04.003 PMID 15894504.