Cyanosis - Complete Details

Definition

• Cyanosis becomes clinically visible when the concentration of reduced hemoglobin in capillary blood exceeds 4-5 g/dL (some sources cite 40 g/L)
• Sensitive observers in ideal lighting may detect central cyanosis at as low as 1.5 g/dL of deoxyhemoglobin
• Harrison's 22E, p. 321

Key Pathophysiologic Principle: Absolute, Not Relative

• Severe anemia: even with marked arterial desaturation, the absolute reduced Hb may remain below 4-5 g/dL, so cyanosis does NOT appear - the patient may look pale instead
• Polycythemia: high total hemoglobin means cyanosis appears at a higher SaO2 than normal, because there is enough total Hb for a large absolute amount to be reduced
• Implication: cyanosis is an insensitive indicator of tissue oxygenation - a severely anemic, hypoxic patient may not be visibly cyanotic
• Harrison's 22E, p. 321; Fishman's Pulmonary Diseases, p. 447; Rosen's EM

Classification: Central vs. Peripheral

• Tintinalli's EM, p. 62; Harrison's 22E, p. 322

Causes of Central Cyanosis

1. Decreased Arterial Oxygen Saturation (Decreased SaO2)

• High altitude (cyanosis typically at >4,000 m / 13,000 ft)
• Enclosed spaces, CO2 build-up

• Neuromuscular disease (myasthenia gravis, GBS, ALS)
• Obesity hypoventilation syndrome
• Opiate/sedative overdose
• CNS lesions affecting respiratory drive

• Perfusion of unventilated or poorly ventilated alveoli
• Chronic bronchitis and emphysema (COPD)
• Acute pneumonia, pulmonary edema
• Diffuse interstitial fibrosis (may be normal at rest, cyanotic on exertion)
• Pulmonary embolism

• Pulmonary fibrosis
• Alveolar-capillary block syndromes

• Congenital heart disease (the most common cause of cyanosis from birth):
  • Tetralogy of Fallot
  • Transposition of the great arteries
  • Tricuspid atresia
  • Truncus arteriosus
  • Total anomalous pulmonary venous return (TAPVR)
  • Pulmonary atresia
  • Hypoplastic left heart syndrome (HLHS)
  • Large VSD with Eisenmenger syndrome
• Pulmonary arteriovenous fistulae (congenital or acquired; seen in hereditary hemorrhagic telangiectasia)
• Multiple small intrapulmonary shunts
• Hepatopulmonary syndrome (in cirrhosis - portal vein to pulmonary vein anastomoses)

• Rare hemoglobin variants that release O2 even at normal PaO2

2. Abnormal Hemoglobin Derivatives

• Ferrous (Fe2+) iron is oxidized to ferric (Fe3+) iron, making hemoglobin unable to carry O2 or CO2
• Blood appears chocolate brown; does NOT respond to supplemental O2
• Normal PaO2 on ABG but low SaO2 (pulse ox reads falsely normal ~85%)
• Normally <2% methemoglobin in erythrocytes (kept low by methemoglobin reductase)
• Hereditary: Hb M variants, methemoglobin reductase deficiency
• Acquired (drugs/chemicals):
  • Dapsone, nitrates/nitrites, nitroglycerin
  • Aniline dyes, chlorates, phenacetin, primaquine
  • Benzocaine (topical anesthetics)
• 10-25% methemoglobin: usually asymptomatic cyanosis

• 25%: dizziness, fatigue, headache

• 50%: seizures, cardiac arrhythmias, death

• Acquired only (sulfonamides, phenacetin, metoclopramide)
• Cannot be reduced back to normal hemoglobin; persists for the life of the RBC
• Very low concentrations (0.5 g/dL) cause visible cyanosis

• Fishman's Pulmonary Diseases; Harrison's 22E; Tintinalli's EM

Causes of Peripheral Cyanosis

1. Reduced cardiac output - heart failure, cardiogenic shock (blood diverted from skin to vital organs)
2. Cold exposure - most common cause of peripheral cyanosis
3. Vasoconstriction/redistribution - distributive shock states (septic, anaphylactic)
4. Arterial obstruction - embolism, thrombosis, Raynaud's phenomenon
5. Venous obstruction - DVT, thrombophlebitis (dilates subpapillary venous plexus)
6. Raynaud's disease/phenomenon - arteriolar spasm causes cyanosis of nail beds

Differential Diagnosis Summary Table (Harrison's Table 42-1)

• Decreased atmospheric O2 (high altitude)
• Alveolar hypoventilation
• V/Q inhomogeneity (perfusion of hypoventilated alveoli)
• Impaired O2 diffusion
• Anatomic shunts: congenital heart disease, pulmonary AV fistulas, multiple small intrapulmonary shunts
• Hemoglobin low O2 affinity
• Methemoglobinemia (hereditary or acquired)
• Sulfhemoglobinemia (acquired)

• Reduced cardiac output
• Cold exposure
• Redistribution of blood flow from extremities
• Arterial obstruction
• Venous obstruction

Neonatal Cyanosis (Special Considerations)

• Airway obstruction: Choanal atresia, laryngeal web/cyst, tracheal stenosis, Pierre Robin sequence
• Cardiac: TGA, tricuspid atresia, truncus arteriosus, TAPVR, pulmonary atresia, coarctation of aorta, HLHS, persistent pulmonary hypertension of the newborn (PPHN)
• Pulmonary: RDS, meconium aspiration, pneumonia, congenital diaphragmatic hernia, pulmonary hypoplasia
• CNS/metabolic: intracranial hemorrhage, hypoglycemia, sepsis, polycythemia, methemoglobinemia

• Tintinalli's EM, p. 718; Rosen's EM

Factors That Affect Clinical Detection

• Harrison's 22E, p. 321; Tintinalli's EM

Approach to the Patient with Cyanosis (Harrison's Protocol)

1. Time of onset: Cyanosis since birth or infancy - think congenital heart disease
2. Differentiate central vs. peripheral: Massage/warm the extremity - peripheral cyanosis will resolve, central will not
3. Clubbing: Chronic central cyanosis (congenital heart disease, lung abscess, pulmonary AV fistulae) - associated with clubbing. Peripheral cyanosis and acute central cyanosis - no clubbing
4. Measure PaO2 and SaO2: ABG is essential. If mechanism is obscure, do spectroscopic examination of blood to identify abnormal hemoglobin types (methemoglobin, sulfhemoglobin)
5. O2 trial: Significant improvement with 100% O2 = pulmonary cause; minimal improvement = right-to-left shunt or abnormal Hb

Pseudocyanosis

• Drugs: chlorpromazine, minocycline, amiodarone, nicorandil
• Heavy metals: gold (chrysiasis), silver (argyria)

• Lips and mucous membranes are normal color
• Discoloration does NOT blanch with pressure
• More intense in sun-exposed areas
• O2 saturation is normal

Cyanosis + Clubbing

• Selective bulbous enlargement of distal digit due to soft tissue proliferation
• Nails become curved in longitudinal and coronal planes
• Hyponychial angle becomes blunted; nail base is spongy
• Seen in: cyanotic congenital heart disease, lung abscess, pulmonary AV fistulae, bronchiectasis, cystic fibrosis, lung cancer, hepatic cirrhosis
• NOT seen in: peripheral cyanosis or acute central cyanosis

Investigation Summary

Key Clinical Pearls

• CO poisoning does NOT cause cyanosis - it causes cherry-red flush (COHb)
• Methemoglobinemia: blood is chocolate brown, SaO2 artificially reads ~85% on pulse oximetry, PaO2 is normal on ABG - only co-oximetry gives the true diagnosis
• Cyanotic congenital heart disease worsens with crying; pulmonary cyanosis improves with crying
• In patent ductus arteriosus with reversal (Eisenmenger): lower extremities are cyanotic, upper extremities are normal - "differential cyanosis"
• Venous obstruction (DVT) causes peripheral cyanosis by dilating the subpapillary venous plexus
• Severe anemia + hypoxia = NO cyanosis; polycythemia + mild hypoxia = visible cyanosis