Sickle cell crisis: Difference between revisions

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==Background==
==Background==
[[File:Sickle cell 01.jpg|thumb|(A) normal red blood cells flowing freely through a blood vessel. (B) abnormal, sickled red blood cells sticking at the branching point in a blood vessel. Cross-section shows long polymerized sickle haemoglobin (HbS) strands stretching and distorting the cell.]]


===Precipitating Factors===
*For [[vaso-occlusive crisis]]:
**Stress
**Cold weather
**[[Dehydration]]
**[[Hypoxia]]
**[[Infection]]
**[[Acidosis]]
**[[Alcohol intoxication]]
**[[Pregnancy]]
**Exertional stress
*For [[aplastic crisis]]:
**[[Parvovirus B19]] infection
**[[Folate deficiency]]


* Sickle cell disease is the most common monogenetic disorder worldwisde affecting 30 million people
==Clinical Features==
* disease can manifest with vaso-occlusion (pain), acute-chest syndrome, stroke, aplastic anemia, priapism, etc
===Vaso-Occlusive Crisis<ref>Lovett P. et al. Sickle cell disease in the emergency department. Emerg Med Clin North Am. 2014 Aug;32(3):629-47</ref>===
''See [[Vaso-occlusive pain crisis]]


==Precipitating Factors==
===[[Avascular necrosis|Bony infarction]]===
*More debilitating and refractory pain than past episodes
*Localized bone tenderness, [[leukocytosis|elevated WBC]]
**[[Fat embolism]] can be complication


===[[Dactylitis]]===
*Tender, swollen hands/feet
*May have low-grade [[fever]]
*Occurs in <2yr old, extremely rare >5yr old
*Radiographs will show soft tissue swelling in the acute phase. Recurrent episodes can lead to a mottled appearance of hand and feet small bones on radiography. <ref>George, A., DeBaun, M., & DeBaun, M. (2021, April 28). Acute and chronic bone complications of sickle cell disease. Retrieved April 20, 2022, from https://www.uptodate.com/contents/acute-and-chronic-bone-complications-of-sickle-cell-disease?search=sickle%20cell%20disease%20children&topicRef=110699&source=see_link</ref>


* For vaso-occlusion:
===[[Avascular necrosis]] of femoral head===
* cold weather
<ref>George, A., DeBaun, M., & DeBaun, M. (2021, April 28). Acute and chronic bone complications of sickle cell disease. Retrieved April 20, 2022, from https://www.uptodate.com/contents/acute-and-chronic-bone-complications-of-sickle-cell-disease?search=sickle%20cell%20disease%20children&topicRef=110699&source=see_link</ref>
* hypoxia
*Due to occlusion of blood vessel lumens, which causes microfractures, leading to collapse of cancellous bone and the articular surface
* infection
*Occurs in 30% of patients by age 30yr, prevalence increases with age
* dehydration
*Patients present with afebrile, inguinal pain with weight-bearing but can be asymptomatic
* acidosis
**Decreased ROM and pain with ambulation or passive ROM
* alcohol intoxication
*Other common sites of involvement are the humeral head and the area above the knee
* emotional stress
* pregnancy
* exertional stress
* Foraplastic crisis:
* parvovirus B19 infection
* folic acid deficiency
* For acute chest syndrome:
* fat embolus
* infection
* pain crisis
* asthma


==Diagnosis==
===[[Respiratory distress]] and [[chest pain]]===
*[[Acute Chest Syndrome]]
*[[Pneumonia]]
**Caused by [[chlamydia]], [[mycoplasma]], [[viruses|viral]], [[strep pneumo]], [[staph]], [[H. flu]]
**Only need blood culture in patients ill enough to require ventilator
*[[Asthma]]
**Common in patients with SCD
**Increases likelihood of acute chest syndrome by 4-6x
*[[Pulmonary Hypertension]]
**Develops in 15-35% of children with SCD
***[[Chest pain]], [[dyspnea|DOE]], [[hypoxia]], right-sided [[heart failure]], [[syncope]]
*[[Pulmonary embolism]]
**Increased risk in SCD
**Consider especially if signs of [[DVT]]


===[[Abdominal pain]]===
*[[vaso-occlusive crisis|Pain crisis]]
**3rd most common site of pain crisis
**Sudden onset of poorly localized abdominal pain
***May have tenderness, guarding; should not have rigidity/rebound
*[[Gallbladder disease]] (stones) is common; may occur as early as 2-4yr old
**[[RUQ pain]], [[jaundice]]/bilirubin higher than baseline, anorexia, tender hepatomegaly, fever
*Acute hepatic or [[splenic sequestration]]
**Labs are variable
**[[ultrasound: Abdomen|US]] or CT shows diffuse hepatomegaly or splenomegaly
*Bacterial [[gastroenteritis]]
**Increased risk for [[salmonella]]
**Consider treatment with [[ciprofloxacin]] and [[Bactrim]] in ill-appearing


Insert
===[[Infection]]===
*Across all ages, infection is leading cause of death
**Increased prevalence of [[meningitis]], [[pneumonia]], [[septic arthritis]], [[osteomyelitis]]
**[[Asplenic|No spleen]] means more susceptible to encapsulated organisms
*Children aged 6mo to 3yr at greatest risk for sepsis
*[[Parvovirus B19]]
**Can cause several different syndromes:
***Erythema infectiosum ("slapped cheeks" rash)
***Gloves and socks syndrome
****Well-demarcated, painful, erythema of hands and feet
*****Evolves into petechiae, purpura, vesicles, skin sloughing
***[[arthralgia|Arthropathy]] - symmetric or asymmetric, knees and ankles
***[[Aplastic crisis]]
****Reticulocyte count drops 5d post-exposure, followed by hemoglobin drop
****Can cause serious anemia which lasts for 2wk


===Musculoskeletal infection===
*Patients with SCD have increased rates of [[osteomyelitis|bone]] and [[septic arthritis|joint infection]]
**Difficult to distinguish from bony infarcts
***High [[fever]] is more typical of infection
***Limited range of motion is much more typical of infection
***Left shift is unique to infection
***ESR is unreliable
***May require bone scan or MRI to definitely distinguish infection from infarct


==Work-Up==
===[[Splenic sequestration]]===
*Major cause of mortality in <5yr old
*Labs: hemoglobin drop, no change in bili, normal to increased retic count
**2 types: major and minor
***Major
****Rapid drop of hb (>3pt)
****Pallor, [[LUQ pain]], splenomegaly
****Can progress within hours to [[altered mental status]], [[hypotension]], [[pediatric shock|cardiovascular collapse]]
***Minor
****More insidious, smaller drop in hemoglobin


===Neurologic disease===
*[[CVA]] is 250x more common in children with SCD
**10% of children suffer clinically overt stroke
**20% found to have silent CVA on imaging
*Increased rate of cerebral aneurysm and [[ICH]]


* CBC/STAT Hemaglobin-assess change in anemia
===GU===
* Chem7/LFT/lipase-if abd pain, may develop cholecystitis, mesenteric ischemia, or perforation
*[[Priapism]]
* Retic-if aplastic crisis considered-rare in adults
**Occurs in 25% by age 20
* pCXR-if cough, sob, or febrile
*Papillary necrosis
* O2-if pain crisis, hypoxic , otherwise may inhibit erythopoesis
**[[Hematuria]] without casts or pyuria
* ECG
* T&S/T&C
* BCx2
* ABG
* UA
* ICON
* Head CT/MRI if symptoms of stroke


==DDx==
==Differential Diagnosis==
{{Sickle cell DDX}}


==Evaluation==
[[File:Sickle Cell.png|thumb|Algorithm for the Evaluation and Management of Sickle Cell Crises]]
===Work-up===
''Based on clinical presentation, but may include:''
*CBC (assess for significant anemia)
*Reticulocyte count (<0.5% suggests aplastic crisis - rare in adults), calculating reticulocyte index
**Laboratory value is a percentage, and absolute count corrects for level of anemia
**Absolute retic count = % retics x (pt Hct / normal Hct)
**Retic index = absolute retic count / maturation factor<ref>Poorana PP and Subhashree AR. Role of Absolute Reticulocyte Count in Evaluation of Pancytopenia-A Hospital Based Study. J Clin Diagn Res. 2014 Aug; 8(8): FC01–FC03.</ref>
***≥35%, maturation factor 1.0
***25 to <35%, maturation factor 1.5
***20 to <25%, maturation factor 2.0
***<20%, maturation factor 2.5
**Reticulocyte index ≥2 means adequate response
**Reticulocyte index <2 suggests hypoproliferation
*Metabolic panel, lipase (if abdominal pain)
*[[CXR]] (if cough, shortness of breath, or fever)
*[[ECG]]
*[[VBG]]
*[[Urinalysis]]
*Pregnancy test
*[[CT brain]] (if symptoms of CVA)
**Note that if patient is anemic, CT non-contrast is unreliable in ruling out hemorrhagic stroke, [[subarachnoid hemorrhage]]<ref>Lyon M et al. Approach to the diagnosis and treatment of acute subarachnoid hemorrhage in a patient with sickle cell disease. Am J Emerg Med. 2015 Mar;33(3):481.e3-4.</ref>
**Will need CTA, MRI, and/or MRA


* ACS
===Evaluation===
* anemia (acute, chronic)
*Generally a clinical diagnosis
* appendicitis
*Certain syndromes require imaging/labs for confirmation (see below)
* cholecystitis
* cout
* hepatitis
* meningitis
* osteomyelitis
* pancreatitis
* PID
* pneumonia
* priapism
* pulmonary embolism/infarction
* rheumatic fever
* sepsis
* stroke (ischemic or hemorrhagic)
* UTI
* URI


==Treatment==
==Management==
*Only use supplemental [[oxygen]] for patients who are hypoxic (<92%)
*Reserve [[IVF]] bolus for patients who are hypovolemic
**Over hydration may cause atelectasis which may precipitate [[Acute Chest Syndrome]] and hyperCl acidosis which could lead to further sickling \
**Make sure to use hypotonic fluids: 1/2NS, D5-1/2NS


===[[Anemia]]===
*[[Packed red blood cells]] (transfuse 10 mL/kg over 2hr period)
**Indications:
***[[Aplastic crisis]]
***[[splenic sequestration|Sequestration crisis]]
***Hemoglobin <6 with inappropriately low retic count
***Hemoglobin <10 with acute crisis (e.g. symptomatic dizziness, [[SOB]], [[chest pain]])


* Abd Pain-Surgery if abdominla injury
===[[Vaso-occlusive pain crisis]]===
* Aplastic Anemia-Exculde reverible causes and tranfuse for severe anemia (Hb <6-7)
*[[Analgesia]]
* Pain crisis-IVF, pain meds, O2 if hypoxic
**IV [[opioids]] ([[morphine]] or [[hydromorphone]])
* Priapism-pain meds, exchange tranfusion before surgery, urology consult
***Redose in 30min if inadequate
* Acute chest syndrome-admit if infiltrate, treat pain and give IV Abx
**Non-opioid analgesia
* Sepsis-admit
***[[NSAIDs]] (e.g. [[ketorolac]] 15mg q6h)
* Sickle cell stroke-Head CT +/- LP, IVF, keep HbS <30% total blood vol
***[[Acetaminophen]]
***IV/IM [[haloperidol]] or [[droperidol]] 5-10mg<ref>*Lyness, D., & Motov, S. (2016, July 7). CERTA Opioid Alternatives and Analgesics. Retrieved July 25, 2016, from http://www.propofology.com/infographs/certa-opioid-alternatives-as-analgesics</ref>
***[[Ketamine]] (IN 1mg/kg 1ml per nostril or IV 0.3mg/kg)<ref>*Lyness, D., & Motov, S. (2016, July 7). CERTA Opioid Alternatives and Analgesics. Retrieved July 25, 2016, from http://www.propofology.com/infographs/certa-opioid-alternatives-as-analgesics</ref>
**Nonpharmacologic measures (e.g. heating packs, distraction)
*Hydration
**Controversial
***Dehydration promotes sickling
***[[IVF]] bolus may lead to atelectasis, pulmonary edema, and acute chest syndrome. Hyperchloremic metabolic acidosis due to normal saline may further precipitate sickling. <ref> Glassberg, J., Evidence-based management of sickle cell disease in the emergency department.Emerg Med Pract, 2011. 13(8): p. 1-20</ref> <ref> Carden, M.A., et al., Variations in pediatric emergency medicine physician practices for intravenous fluid management in children with sickle cell disease and vaso-occlusive pain: A single institution experience.Pediatr Blood Cancer, 2018. 65(1) </ref> <ref> Carden, M.A., et al., Normal Saline Bolus Use in Pediatric Emergency Departments is Associated with Worse Pain Control in Children with Sickle Cell Anemia and Vaso-occlusive Pain.Am J Hematol, 2019. </ref>
***There are no randomized controlled trials that have assessed the safety and efficacy of different routes, types or quantities of fluid.<ref>Okomo U, Meremikwu MM. Fluid replacement therapy for acute episodes of pain in people with sickle cell disease. Cochrane Database of Systematic Reviews 2015, Issue 3. Art. No.: CD005406. DOI: 10.1002/14651858.CD005406.pub4</ref>
*O2 if [[hypoxia]]; otherwise may inhibit erythropoiesis


==Disposition==
===[[Acute Chest Syndrome]]===
*[[O2]]; titrate to pulse oximetry >92%
*Incentive Spirometer
*Hydration: [[oral rehydration therapy|Oral hydration]] preferred, [[IV hydration]] with hypotonic fluid if patient unable to tolerate PO
*[[Analgesia]]: pulmonary toilet is important but avoid excessive sedation
*[[Bronchodilators]]
*[[Antibiotics]]: 3rd generation [[cephalosporin]] + [[macrolide]]
*[[Transfusion]] (leucocyte depleted); consider [[pRBCs|transfusion]] to goal of hemoglobin 11 / hematocrit 30 for:
**O2 Sat <92% on room air
**hematocrit 10-20% below patient's usual hematocrit or dropping hematocrit
*[[Exchange transfusion]]; consider for:
**Progression of acute chest syndrome despite simple transfusion
**Severe [[hypoxemia]]
**Multi-lobar disease
**Previous history of severe acute chest syndrome or cardiopulmonary disease


===[[Priapism]]===
*[[IVF|Hydration]]
*[[pRBCs|Transfusion]] and/or [[exchange transfusion]]
*Urology consult
*If persists for >4-6hr:
**Aspiration of corpora
**Irrigate and infuse 1:1,000,000 epinephrine solution


* Admission if:
===Neurologic disease===
* Acute Chest Syndrome-pain/pulmonary infiltrates from infection or pulm infarct
*[[tPA]] is ''not'' recommended
* Stroke, priapism, serious bacterial infection, aplastic crisis, hypoxia, acidosis
*[[Exchange transfusion]] urgently (within 8 hours) to decrease hemoglobinS below 30%
* Unable to take fluids orally or inadequate pain control, abnormal vital signs
*[[IVF|Hydration]]
* Consider if pregnant (in crisis),  or uncertain dx of SCD


==See Also==
===[[Splenic sequestration]]===
*[[Volume resuscitation]]
*Simple [[pRBCs|transfusion]] vs [[exchange transfusion]]


===[[Fever]]===
*Any fever of ≥38.5C requires empiric [[antibiotics]] (regardless of well appearance or any localized infection found)
*[[Ceftriaxone]] 50mg/kg (maximum single dose 2g)


Acute Chest Syndrome
==Disposition==
 
===Consider admission to the hospital===
*[[Fever]]
 
*[[Acute chest syndrome]] is suspected
==Source==
*[[Sepsis]], [[osteomyelitis]], or other serious infection is suspected
 
*[[Priapism]], [[aplastic crisis]], [[hypoxia]]
 
*[[leukocytosis|WBC >30K]]
DONALDSON 6/07
*[[thrombocytopenia|Platelet <100K]]
 
*Pain is not under control after 2-3 rounds of analgesics in ED
SOTELO 10/09
*<1yr old
 
TUNG 7/10


===Consider discharge===
*Pain is under control and patient can take oral fluids and medications
*Ensure appropriate oral analgesics are available
*Provide home care instructions
*Ensure resource for follow-up


==See Also==
*[[Acute Chest Syndrome]]
*[[Aplastic crisis]]


==References==
<references/>


[[Category:Heme/Onc]]
[[Category:Heme/Onc]]

Latest revision as of 19:12, 5 August 2025

Background

(A) normal red blood cells flowing freely through a blood vessel. (B) abnormal, sickled red blood cells sticking at the branching point in a blood vessel. Cross-section shows long polymerized sickle haemoglobin (HbS) strands stretching and distorting the cell.

Precipitating Factors

Clinical Features

Vaso-Occlusive Crisis[1]

See Vaso-occlusive pain crisis

Bony infarction

  • More debilitating and refractory pain than past episodes
  • Localized bone tenderness, elevated WBC

Dactylitis

  • Tender, swollen hands/feet
  • May have low-grade fever
  • Occurs in <2yr old, extremely rare >5yr old
  • Radiographs will show soft tissue swelling in the acute phase. Recurrent episodes can lead to a mottled appearance of hand and feet small bones on radiography. [2]

Avascular necrosis of femoral head

[3]

  • Due to occlusion of blood vessel lumens, which causes microfractures, leading to collapse of cancellous bone and the articular surface
  • Occurs in 30% of patients by age 30yr, prevalence increases with age
  • Patients present with afebrile, inguinal pain with weight-bearing but can be asymptomatic
    • Decreased ROM and pain with ambulation or passive ROM
  • Other common sites of involvement are the humeral head and the area above the knee

Respiratory distress and chest pain

Abdominal pain

Infection

  • Across all ages, infection is leading cause of death
  • Children aged 6mo to 3yr at greatest risk for sepsis
  • Parvovirus B19
    • Can cause several different syndromes:
      • Erythema infectiosum ("slapped cheeks" rash)
      • Gloves and socks syndrome
        • Well-demarcated, painful, erythema of hands and feet
          • Evolves into petechiae, purpura, vesicles, skin sloughing
      • Arthropathy - symmetric or asymmetric, knees and ankles
      • Aplastic crisis
        • Reticulocyte count drops 5d post-exposure, followed by hemoglobin drop
        • Can cause serious anemia which lasts for 2wk

Musculoskeletal infection

  • Patients with SCD have increased rates of bone and joint infection
    • Difficult to distinguish from bony infarcts
      • High fever is more typical of infection
      • Limited range of motion is much more typical of infection
      • Left shift is unique to infection
      • ESR is unreliable
      • May require bone scan or MRI to definitely distinguish infection from infarct

Splenic sequestration

  • Major cause of mortality in <5yr old
  • Labs: hemoglobin drop, no change in bili, normal to increased retic count

Neurologic disease

  • CVA is 250x more common in children with SCD
    • 10% of children suffer clinically overt stroke
    • 20% found to have silent CVA on imaging
  • Increased rate of cerebral aneurysm and ICH

GU

  • Priapism
    • Occurs in 25% by age 20
  • Papillary necrosis

Differential Diagnosis

Sickle cell crisis

Evaluation

Algorithm for the Evaluation and Management of Sickle Cell Crises

Work-up

Based on clinical presentation, but may include:

  • CBC (assess for significant anemia)
  • Reticulocyte count (<0.5% suggests aplastic crisis - rare in adults), calculating reticulocyte index
    • Laboratory value is a percentage, and absolute count corrects for level of anemia
    • Absolute retic count = % retics x (pt Hct / normal Hct)
    • Retic index = absolute retic count / maturation factor[4]
      • ≥35%, maturation factor 1.0
      • 25 to <35%, maturation factor 1.5
      • 20 to <25%, maturation factor 2.0
      • <20%, maturation factor 2.5
    • Reticulocyte index ≥2 means adequate response
    • Reticulocyte index <2 suggests hypoproliferation
  • Metabolic panel, lipase (if abdominal pain)
  • CXR (if cough, shortness of breath, or fever)
  • ECG
  • VBG
  • Urinalysis
  • Pregnancy test
  • CT brain (if symptoms of CVA)
    • Note that if patient is anemic, CT non-contrast is unreliable in ruling out hemorrhagic stroke, subarachnoid hemorrhage[5]
    • Will need CTA, MRI, and/or MRA

Evaluation

  • Generally a clinical diagnosis
  • Certain syndromes require imaging/labs for confirmation (see below)

Management

  • Only use supplemental oxygen for patients who are hypoxic (<92%)
  • Reserve IVF bolus for patients who are hypovolemic
    • Over hydration may cause atelectasis which may precipitate Acute Chest Syndrome and hyperCl acidosis which could lead to further sickling \
    • Make sure to use hypotonic fluids: 1/2NS, D5-1/2NS

Anemia

Vaso-occlusive pain crisis

  • Analgesia
  • Hydration
    • Controversial
      • Dehydration promotes sickling
      • IVF bolus may lead to atelectasis, pulmonary edema, and acute chest syndrome. Hyperchloremic metabolic acidosis due to normal saline may further precipitate sickling. [8] [9] [10]
      • There are no randomized controlled trials that have assessed the safety and efficacy of different routes, types or quantities of fluid.[11]
  • O2 if hypoxia; otherwise may inhibit erythropoiesis

Acute Chest Syndrome

  • O2; titrate to pulse oximetry >92%
  • Incentive Spirometer
  • Hydration: Oral hydration preferred, IV hydration with hypotonic fluid if patient unable to tolerate PO
  • Analgesia: pulmonary toilet is important but avoid excessive sedation
  • Bronchodilators
  • Antibiotics: 3rd generation cephalosporin + macrolide
  • Transfusion (leucocyte depleted); consider transfusion to goal of hemoglobin 11 / hematocrit 30 for:
    • O2 Sat <92% on room air
    • hematocrit 10-20% below patient's usual hematocrit or dropping hematocrit
  • Exchange transfusion; consider for:
    • Progression of acute chest syndrome despite simple transfusion
    • Severe hypoxemia
    • Multi-lobar disease
    • Previous history of severe acute chest syndrome or cardiopulmonary disease

Priapism

Neurologic disease

Splenic sequestration

Fever

  • Any fever of ≥38.5C requires empiric antibiotics (regardless of well appearance or any localized infection found)
  • Ceftriaxone 50mg/kg (maximum single dose 2g)

Disposition

Consider admission to the hospital

Consider discharge

  • Pain is under control and patient can take oral fluids and medications
  • Ensure appropriate oral analgesics are available
  • Provide home care instructions
  • Ensure resource for follow-up

See Also

References

  1. ↑ Lovett P. et al. Sickle cell disease in the emergency department. Emerg Med Clin North Am. 2014 Aug;32(3):629-47
  2. ↑ George, A., DeBaun, M., & DeBaun, M. (2021, April 28). Acute and chronic bone complications of sickle cell disease. Retrieved April 20, 2022, from https://www.uptodate.com/contents/acute-and-chronic-bone-complications-of-sickle-cell-disease?search=sickle%20cell%20disease%20children&topicRef=110699&source=see_link
  3. ↑ George, A., DeBaun, M., & DeBaun, M. (2021, April 28). Acute and chronic bone complications of sickle cell disease. Retrieved April 20, 2022, from https://www.uptodate.com/contents/acute-and-chronic-bone-complications-of-sickle-cell-disease?search=sickle%20cell%20disease%20children&topicRef=110699&source=see_link
  4. ↑ Poorana PP and Subhashree AR. Role of Absolute Reticulocyte Count in Evaluation of Pancytopenia-A Hospital Based Study. J Clin Diagn Res. 2014 Aug; 8(8): FC01–FC03.
  5. ↑ Lyon M et al. Approach to the diagnosis and treatment of acute subarachnoid hemorrhage in a patient with sickle cell disease. Am J Emerg Med. 2015 Mar;33(3):481.e3-4.
  6. ↑ *Lyness, D., & Motov, S. (2016, July 7). CERTA Opioid Alternatives and Analgesics. Retrieved July 25, 2016, from http://www.propofology.com/infographs/certa-opioid-alternatives-as-analgesics
  7. ↑ *Lyness, D., & Motov, S. (2016, July 7). CERTA Opioid Alternatives and Analgesics. Retrieved July 25, 2016, from http://www.propofology.com/infographs/certa-opioid-alternatives-as-analgesics
  8. ↑ Glassberg, J., Evidence-based management of sickle cell disease in the emergency department.Emerg Med Pract, 2011. 13(8): p. 1-20
  9. ↑ Carden, M.A., et al., Variations in pediatric emergency medicine physician practices for intravenous fluid management in children with sickle cell disease and vaso-occlusive pain: A single institution experience.Pediatr Blood Cancer, 2018. 65(1)
  10. ↑ Carden, M.A., et al., Normal Saline Bolus Use in Pediatric Emergency Departments is Associated with Worse Pain Control in Children with Sickle Cell Anemia and Vaso-occlusive Pain.Am J Hematol, 2019.
  11. ↑ Okomo U, Meremikwu MM. Fluid replacement therapy for acute episodes of pain in people with sickle cell disease. Cochrane Database of Systematic Reviews 2015, Issue 3. Art. No.: CD005406. DOI: 10.1002/14651858.CD005406.pub4
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