Cyanosis

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Cyanosis is a discoloration of the skin and mucous membranes that ranges from pale gray to blue and is caused by elevated concentrations of desaturated hemoglobin (typically > 3–5 g/dL). Cyanosis is not a sensitive indicator for hypoxia and/or hypoxemia because it is affected by skin pigmentation, venous congestion, and lighting. Central cyanosis results from reduced arterial oxygen content and is most evident in the oral mucosa, tongue, and conjunctivae. Common causes include pulmonary disease, intracardiac or intrapulmonary shunting, and abnormal hemoglobin. Peripheral cyanosis results from reduced peripheral blood flow with normal arterial oxygenation, leading to increased deoxygenated hemoglobin, and it is typically seen in the extremities, nail beds, and circumoral skin. Causes include low cardiac output, arterial obstruction, and peripheral vasoconstriction. The response of cyanosis and SpO₂ to supplemental oxygen helps guide diagnosis and distinguish between central and peripheral causes. Management is directed at the underlying cause. In newborns, peripheral cyanosis may be normal, but central cyanosis that persists despite supplemental oxygen requires urgent evaluation to exclude congenital heart disease.

• Cyanosis: a discoloration of the skin and mucous membranes that ranges from pale gray to blue depending on skin tone and is caused by elevated concentrations of desaturated hemoglobin (typically > 3–5 g/dL) ^[2][3][4]
• Central cyanosis
  • A form of cyanosis that affects the mucous membranes (tongue, oral mucosa), perioral skin, and conjunctivae and results from reduced arterial oxygen saturation
  • Causes include reduced pulmonary oxygenation, right-to-left cardiac shunts, and rare hemoglobinopathies (methemoglobinemia, sulfhemoglobinemia).
• Peripheral cyanosis
  • A discoloration of the distal extremities that ranges from blue to gray depending on skin tone and results from reduced peripheral blood flow despite normal arterial oxygen saturation
  • Causes include vasoconstriction (e.g., cold exposure), low cardiac output (e.g., shock, heart failure), and arterial obstruction or venous stasis.
  • Mucous membranes are typically spared.

Cyanosis reflects the level of deoxygenated hemoglobin; it appears at a lower PaO₂ in patients with anemia and a higher PaO₂ in patients with polycythemia. ^[2][5]

Cyanosis is not a sensitive or specific indicator of arterial hypoxemia and thus should not be used as a surrogate indicator of hypoxemia. ^[4]

See “Cyanosis in newborns” for etiologies specific to that population.

Central cyanosis

• Respiratory impairment
  • Hypoventilation
  • V/Q mismatch
  • Oxygen diffusion impairment
• Anatomical shunts
  • Intrapulmonary shunt
  • Pulmonary arteriovenous fistula
  • Cyanotic congenital heart disease
  • Primary persistent pulmonary hypertension with right-to-left shunt at the ductus arteriosus, atria, or ventricles
• Hemoglobin abnormality
  • Methemoglobinemia
  • Sulfhemoglobinemia
  • Hemoglobinopathy
• Environmental
  • High altitude (low alveolar partial pressure of oxygen)
  • Hypoxic gas mixture

Peripheral cyanosis

All causes of central cyanosis may manifest with cyanosis in the extremities, complicating the differential diagnosis of peripheral cyanosis.

• Low cardiac output
  • Left heart failure
  • Hypovolemia
  • Septic shock
• Reduced arterial circulation
  • Peripheral arterial disease
  • Acute arterial occlusion (e.g., acute limb ischemia)
  • Vasospasm (e.g., Raynaud phenomenon)
  • Redistributed blood flow from extremities (e.g., during shock)
• Venous stasis
  • Pregnancy
  • Obesity
  • Deep vein thrombosis
• Increased blood viscosity
  • Polycythemia vera
  • Cryoglobulinemia
  • Gammopathy
• Environmental: cold exposure (including cold water immersion)

Focused history

• Duration
• Additional symptoms (e.g., dyspnea, fever, cough, reduced exercise tolerance, fatigue, chest pain, weight gain, swelling and/or pain of lower extremities)
• Comorbidities (e.g., lung disease, atherosclerotic cardiovascular disease, hypercoagulable syndrome, connective tissue diseases)
• Precipitating features (physiological triggers, e.g., cold exposure, high altitude, exercise)
• Exposures (e.g., dyes, new prescription medications, over-the-counter medications)

Focused physical examination

• Distribution of cyanosis
  • Cyanosis of the buccal mucosa, underside of the tongue, lips, and/or conjunctivae suggests central cyanosis.
  • Cyanosis of the extremities and/or nail beds suggests peripheral cyanosis, but may also be a manifestation in central cyanosis.
  • Differential cyanosis and reverse differential cyanosis suggest congenital heart disease.
• Signs of respiratory distress or signs of respiratory failure
• Signs of heart failure
• Clinical features of peripheral arterial disease (including examination of peripheral and central pulses)
• Signs of thrombosis or nonthrombotic embolism (e.g., splinter hemorrhage)
• Digital clubbing

Skin pigmentation, venous congestion, and ambient lighting affect the visibility of cyanosis; assessment is most reliable on the lips and tongue under natural light or low-intensity illumination. ^[4]

Approach

• Perform a focused history and focused physical examination.
• Obtain routine testing.
• Consider a hyperoxia test in neonates and infants.
• Choose advanced testing based on the results of routine testing and clinical suspicion.

Routine testing

Routine testing is used to screen for hypoxemia, heart failure, infection, and end-organ damage.

• Laboratory studies
  • ABG
  • CBC
  • CMP
• Bedside studies
  • Pulse oximetry in upper and lower extremities
  • ECG
  • CO-oximetry
• Imaging studies
  • Chest x-ray (CXR)
  • Echocardiography

Hyperoxia test ^[3]

• Indication: to differentiate between pulmonary and cardiac causes of cyanosis (especially in infants)
• Technique
  • Measure PaO₂ on room air.
  • Have the patient breathe 100% oxygen for 10 minutes.
  • Remeasure PaO₂.
• Interpretation
  • PaO₂ < 100 mm Hg: suggests congenital cardiac disease and/or pulmonary hypertension
  • PaO₂ 100–250 mm Hg: indeterminate; further testing is necessary.
  • PaO₂ > 250 mm Hg: Congenital heart disease is unlikely.

Advanced testing

Advanced testing is based on the suspected cause of the cyanosis after focused examination and initial testing.

• Respiratory impairment
  • Hypoventilation: airway endoscopy , electromyography and/or nerve conduction studies , sleep study, pulmonary function tests
  • V/Q mismatch: CT chest , bronchoscopy, sputum samples , V/Q scan or pulmonary angiography
  • Diffusion abnormality: diffusion capacity of the lung for carbon monoxide
• Anatomical shunts
  • Congenital heart disease: cardiac CT, cardiac MRI, cardiac catheterization
  • Intrapulmonary shunt: angiography
• Hemoglobin abnormality: CO-oximetry, whole blood spectrophotometry

• Infants: See "Cyanosis in the newborn."
• Perform an ABCDE assessment, including peripheral pulses.
• Administer supplemental oxygen and monitor response.
• Obtain initial diagnostics as indicated.
• Determine whether cyanosis is central (lips, tongue, conjunctivae) or peripheral (fingers, nail beds).
• Administer provocative testing with oxygen and/or warmth.
  • Central cyanosis
    • Improves with oxygen: Consider pneumonia, heart failure, hypoventilation, or pulmonary embolism.
    • No improvement with oxygen: Consider cyanotic congenital heart disease, large right-to-left shunt, or abnormal hemoglobin.
  • Peripheral cyanosis
    • Improves with oxygen: Consider hypovolemia, sepsis, or heart failure.
    • No improvement with oxygen: Warm the affected extremity.
    • Improves with warming: Consider environmental exposure or vasospasm.
    • Persists despite warming: Consider arterial embolism or venous thrombosis.
• Initiate cause-specific treatment and determine disposition.
  • Central cyanosis: Hospitalization is recommended (especially for the initial episode). ^[6]
  • Peripheral cyanosis: The need for hospitalization depends on the underlying cause.

Cyanosis in a peripheral location may also be caused by decreased arterial oxygen saturation; causes of central cyanosis should always be considered when evaluating distal cyanosis.

• Transferred dyes or pigments (e.g., blue clothing dye in jeans)
• Consumption of blue-dyed food (e.g., candy, popsicles)
• Hemosiderin deposits
• Drug metabolite deposits (e.g., amiodarone, chlorpromazine) ^[4]
• Ingested silver and/or gold
• Tattoos
• Birth marks

Cyanosis in newborns ^[3][5][11]

Etiology

• Peripheral cyanosis
  • Peripheral vasoconstriction (common in the first 24 hours of life)
  • Less common causes: sepsis, hypovolemia, low cardiac output, polycythemia
• Central cyanosis
  • Most common causes
    • Congenital cyanotic heart disease
    • Persistent pulmonary hypertension of the newborn (PPHN)
    • Neonatal respiratory distress syndrome
    • Meconium aspiration
  • Other causes
    • Hypoventilation (e.g., secondary to meningitis, hypoglycemia, opioids, and/or congenital airway abnormality)
    • Congenital pulmonary parenchymal disease, congenital diaphragmatic hernia
    • Hemoglobinopathy

Clinical evaluation

• Focused history (prenatal and delivery): rapidly screens for common congenital and perinatal complications that may cause cyanosis
  • Gestational diabetes
  • Oligohydramnios
  • Polyhydramnios
  • Prolonged rupture of membranes
  • Maternal ingestion of NSAIDs
  • Difficult delivery
  • Meconium-stained amniotic fluid
• Focused physical examination
  • Signs of respiratory distress and/or signs of respiratory failure
  • Respiratory rate, heart rate, and peripheral pulses
  • Preductal SpO₂ ^[5]
  • Distribution of cyanosis
    • Peripheral cyanosis: Extremities and circumoral areas are cyanotic, but mucous membranes remain pink.
    • Central cyanosis: Underside of the tongue, mucus membranes, and/or conjunctivae are cyanotic.
    • Differential cyanosis: Cyanosis only affects the lower extremities.
    • Reverse differential cyanosis: Cyanosis only affects the upper half of the body.
  • Neurological examination (e.g., crying, muscle tone)

Examine the underside of the newborn's tongue to distinguish between peripheral and central cyanosis. ^[3]

Diagnostics

• Bedside
  • Pulse oximetry
    • Measure and compare preductal saturation (earlobe and/or right upper extremity) and postductal saturation (lower extremity).
    • SpO₂ should be ≥ 95% ≥ 24 hours after birth, with no gradient between preductal and postductal SpO₂ levels. ^[12]
  • Hyperoxia test
  • CO-oximetry (if methemoglobin is suspected)
• Laboratory
  • Glucose
  • CBC
  • ABG
• Imaging
  • CXR: to evaluate for pulmonary pathology and/or congenital heart disease
  • Echocardiography
    • Goal: to evaluate for congenital cyanotic heart disease or PPHN
    • Indications: persistent cyanosis, SpO₂ < 95%, and/or there is a gradient between preductal and postductal SpO₂

The American Academy of Pediatrics recommends routine preductal and postductal SpO₂ screening at ≥ 24 hours of life to detect congenital heart disease, even in patients without cyanosis. ^[12]

Initial management

• Place the newborn in a radiant warmer or other thermoneutral environment.
• Assess for signs of respiratory distress; provide neonatal respiratory support if indicated.
• Initiate oxygen therapy at FiO₂ 0.4–0.6 to minimize oxygen toxicity.
• Obtain initial laboratory studies and CXR.
• Consider a hyperoxia test in consultation with a neonatologist or pediatric cardiologist.
• Obtain an echocardiogram if cyanosis persists, preductal-postductal gradient in SpO₂ is present, and/or the hyperoxia test is positive.

Disposition

Consult neonatology or pediatric cardiology for central cyanosis or persistent peripheral cyanosis in newborns.