Cyanosis

Cyanosis is a bluish discolouration of skin and mucous membranes from increased concentration of deoxygenated haemoglobin (above 3-5 g/dL in capillary blood, or about 5 g/dL absolute), or abnormal haemoglobin derivatives. It is a clinical sign, not a diagnosis, and its detection depends on total haemoglobin (patients with anaemia may be hypoxic without cyanosis; polycythaemic patients appear cyanotic at higher saturations).

Types

• Central cyanosis: reduced arterial oxygen saturation (generally below 85%, visible at 80-85% if haemoglobin is normal). Affects tongue, lips, buccal mucosa and warm peripheries.
  • Pulmonary: severe pneumonia, COPD, pulmonary oedema, pulmonary embolism, ARDS, interstitial lung disease, pneumothorax, pleural effusion, airway obstruction, hypoventilation (neuromuscular, opioid, obstructive sleep apnoea), high altitude.
  • Cardiac (right-to-left shunt): cyanotic congenital heart disease (tetralogy of Fallot, transposition of great arteries, tricuspid atresia, total anomalous pulmonary venous return, truncus arteriosus, Ebstein anomaly, pulmonary atresia), Eisenmenger syndrome, pulmonary arteriovenous malformations (hereditary haemorrhagic telangiectasia), hepatopulmonary syndrome, and persistent pulmonary hypertension of the newborn.
  • Haemoglobin abnormalities: methaemoglobinaemia, sulfhaemoglobinaemia, carboxyhaemoglobin (cherry-red, not truly cyanotic), low affinity haemoglobin variants (Hb M, Hb Kansas).
  • Polycythaemia (secondary or vera): high absolute deoxygenated haemoglobin.
• Peripheral cyanosis (acrocyanosis): normal arterial saturation, with increased oxygen extraction due to slow capillary flow. Affects fingers, toes, nose, ears, and cool extremities, tongue pink.
  • Cold exposure, low cardiac output (heart failure, shock), vasoconstriction (Raynaud phenomenon, vasculitis), arterial obstruction (embolism, thrombosis, peripheral arterial disease), venous obstruction (deep vein thrombosis), hyperviscosity, cryoglobulinaemia, cold agglutinin disease, acrocyanosis and normal in neonates (first 24-48 hours).
• Differential cyanosis: lower body cyanosis with pink upper body (patent ductus arteriosus with pulmonary hypertension, coarctation or interrupted aortic arch with reversed shunting), and reverse differential cyanosis (transposition with pulmonary hypertension).
• Mixed cyanosis: in cardiac failure with pulmonary oedema.

Epidemiology of cyanotic heart disease: about 20-25% of congenital heart disease is cyanotic, with tetralogy of Fallot the commonest beyond infancy and transposition the commonest in the neonate.

Pathophysiology of long-standing cyanosis: compensatory erythrocytosis (hyperviscosity), clubbing, hypertrophic osteoarthropathy, iron deficiency, bleeding diathesis (thrombocytopenia, platelet dysfunction, coagulation abnormalities), gout, gallstones, renal dysfunction, paradoxical emboli, brain abscess, stroke, and endocarditis.

• Blue-purple discolouration, best seen on lips, tongue, nail beds, earlobes, conjunctivae; may be missed in dark skin (check mucous membranes, tongue, palms and soles, conjunctiva, gums). Poor lighting and anaemia mask it.
• Features pointing to cause:
  • History: onset (acute versus chronic), exertional or at rest, cough, sputum, wheeze, chest pain, orthopnoea, drug or chemical exposure (nitrites, dapsone, local anaesthetics: benzocaine, lidocaine, prilocaine, aniline dyes, nitrates), family history, high altitude, prematurity, and congenital heart disease.
  • Examination: respiratory rate and effort, accessory muscles, auscultation (crackles, wheeze, decreased breath sounds), heart murmurs, single second sound, cardiac thrill, signs of heart failure (raised JVP, hepatomegaly, oedema), clubbing (after 3-6 months of cyanosis), peripheral temperature, pulses (bounding in AV malformation), blood pressure in all limbs, spider naevi/liver disease, telangiectasia (HHT), neurological signs.
• Neonates: central cyanosis with or without distress. Cyanosis with respiratory distress suggests lung disease, cyanosis without distress points to cyanotic heart disease or methaemoglobinaemia.
• Methaemoglobinaemia: chocolate-brown blood, cyanosis unresponsive to oxygen, saturation fixed at 85% by pulse oximetry, with headache, dyspnoea, dizziness, confusion, seizures at high levels (above 50%).
• Hypoxic (tet) spells in tetralogy of Fallot: sudden increased cyanosis and irritability during crying or feeding, squatting in older children.
• Eisenmenger syndrome: cyanosis, clubbing, dyspnoea, haemoptysis, syncope, in an adult with previous left to right shunt.
• Acute causes (airway obstruction, pneumothorax, massive PE, anaphylaxis) present with distress.

Red flags: cyanosis with respiratory distress, depressed consciousness, hypotension, stridor, neonatal cyanosis, and cyanosis not responding to oxygen.

Initial assessment

• Airway, breathing, circulation. Pulse oximetry (note limitations: unreliable in methaemoglobinaemia, carboxyhaemoglobinaemia, shock, nail polish, motion; fixed ~85% in methaemoglobinaemia), arterial blood gas with co-oximetry (PaO2, saturation, methaemoglobin, carboxyhaemoglobin), lactate.
• Hyperoxia test (neonates): arterial PaO2 in 100% oxygen for 10-15 minutes: PaO2 above 150 mmHg suggests lung disease, below 100-150 mmHg suggests cyanotic congenital heart disease (below 100 strongly). Preductal (right hand) and postductal (foot) saturation difference over 10% suggests duct-dependent right to left shunting.

Investigations

• CBC (haemoglobin, haematocrit, platelets), blood film, reticulocytes, iron studies, coagulation, glucose, electrolytes, liver and renal function, and G6PD (before methylene blue).
• Chest radiograph: lung disease, cardiac silhouette (boot-shaped heart in tetralogy, egg on a string in transposition, snowman in total anomalous pulmonary venous return), pulmonary vascularity (oligaemia vs plethora).
• ECG: right ventricular hypertrophy, axis deviation (left axis deviation in tricuspid atresia).
• Echocardiography with bubble study: structural defects, shunt, pulmonary pressures. Intrapulmonary shunt (late bubbles after 3-5 cardiac cycles) in hepatopulmonary syndrome or AVM.
• CT pulmonary angiography, high-resolution CT chest, cardiac MRI/CT, catheter angiography, and bronchoscopy as indicated.
• Methaemoglobin level by co-oximetry. Spectrophotometry of blood (does not turn red in air), and haemoglobin electrophoresis/hemoglobin M testing.
• Pulmonary function tests, polysomnography, shunt study (100% oxygen test: shunt fraction), and ventilation-perfusion scan.
• Neonatal screening: pulse oximetry screening for critical congenital heart disease at 24 hours (saturation below 90% or difference over 3% in right hand and foot, or between 90-94% persistently).
• Complications screening in chronic cyanosis: iron deficiency (ferritin), uric acid, renal function, urinalysis, coagulation, echocardiography, hearing/neurological assessment, and dental review.

Immediate management

Secure airway and give high-flow oxygen (15 L/min via non-rebreather mask) with monitoring. Treat life-threatening causes: relieve airway obstruction, needle decompression of tension pneumothorax, ventilatory support for respiratory failure, adrenaline for anaphylaxis, thrombolysis for massive pulmonary embolism, diuretic and noninvasive ventilation for pulmonary oedema. Peripheral cyanosis: warm the patient, restore perfusion, treat shock.

Specific causes

• Neonatal cyanotic heart disease (duct-dependent): start prostaglandin E1 (alprostadil) 0.01-0.05 micrograms/kg/min IV infusion (titrate to the lowest effective dose), watch for apnoea (intubate if above 0.03 micrograms/kg/min or on transport), fever, hypotension, seizures. Avoid excess oxygen in some lesions. Urgent cardiology referral, echocardiography, balloon atrial septostomy (transposition), then surgical correction (arterial switch operation within 1-2 weeks for transposition, Blalock-Thomas-Taussig shunt or complete repair for tetralogy at 3-6 months).
• Tetralogy of Fallot hypercyanotic spell: knee-chest position (older children), oxygen, calm the infant, morphine 0.1-0.2 mg/kg SC or IM, fluid bolus 10-20 mL/kg, phenylephrine 5-20 micrograms/kg IV (increase systemic resistance), propranolol 0.1 mg/kg slow IV (relieves infundibular spasm), sodium bicarbonate 1 mEq/kg for acidosis, ketamine 1-2 mg/kg, and emergency surgery or shunt for refractory spells. Prophylaxis: propranolol 1-2 mg/kg every 6 hours orally, iron to correct deficiency.
• Persistent pulmonary hypertension of the newborn: oxygen, gentle ventilation, inhaled nitric oxide 20 ppm, sildenafil 1 mg/kg every 6-8 hours, milrinone, surfactant, and ECMO.
• Eisenmenger syndrome: avoid dehydration, pregnancy (maternal mortality 30-50%), high altitude, and routine venesection. Treat with pulmonary vasodilators (bosentan 62.5 mg twice daily then 125 mg twice daily, sildenafil 20 mg three times daily or tadalafil 40 mg daily, macitentan 10 mg daily), long-term oxygen if it relieves symptoms, iron replacement for deficiency (avoid iron overload), and avoid air filters in IV lines (use air filters to prevent paradoxical embolism). Heart-lung or lung transplantation in end-stage. Endocarditis prophylaxis and meticulous dental care.
• Methaemoglobinaemia: stop the offending agent. Oxygen. Methylene blue 1-2 mg/kg (0.1-0.2 mL/kg of 1% solution) IV over 5 minutes, repeated after 30-60 minutes if needed (maximum 7 mg/kg), for symptomatic patients or levels above 20-30% (above 10% with comorbid cardiopulmonary disease). Contraindicated in G6PD deficiency (haemolysis, ineffective), and serotonin syndrome risk with SSRIs. Alternatives: ascorbic acid 1-2 g IV/orally, exchange transfusion, hyperbaric oxygen. Congenital forms (cytochrome b5 reductase deficiency): ascorbic acid 200-500 mg daily or riboflavin 20 mg daily.
• Carbon monoxide poisoning: 100% oxygen, hyperbaric oxygen for severe cases.
• Hepatopulmonary syndrome: oxygen, liver transplantation (the only definitive therapy).
• Pulmonary arteriovenous malformations (HHT): embolisation (coils, plugs) for lesions with feeding artery diameter 3 mm or more, antibiotic prophylaxis for dental procedures, IV air filters, and avoidance of scuba diving.
• Polycythaemia: therapeutic phlebotomy only for symptomatic hyperviscosity (headache, visual disturbance, fatigue) with haematocrit above 65%, isovolumic (replace with saline), avoiding excessive venesection (iron deficiency worsens). Treat iron deficiency, correct dehydration.
• Chronic lung disease and hypoventilation: long-term oxygen therapy for PaO2 at or below 55 mmHg (or 60 with cor pulmonale), noninvasive ventilation, CPAP for sleep apnoea.
• Peripheral cyanosis: treat shock, rewarm, vasodilators, anticoagulation for thrombosis, avoid cold exposure for Raynaud, treat cold agglutinin disease (warming, rituximab, sutimlimab 6.5-7.5 g IV).

Long-term complications of chronic cyanosis

• Annual surveillance with CBC, ferritin, uric acid, creatinine, urinalysis, echocardiography, and consider anticoagulation cautiously. Treat gout, gallstones, and bleeding diathesis (avoid aspirin/NSAIDs, vitamin K, platelet or plasma before surgery). Avoid dehydration and long-haul travel without hydration.
• Adult congenital heart disease clinic follow-up, contraception advice (avoid oestrogen: use progestin-only or IUD), and counsel on pregnancy.

Follow-up

Monitor saturations at baseline, symptom progression, and complications. Prognosis depends on cause: excellent after surgical repair of correctable lesions, guarded in Eisenmenger syndrome (survival to the fourth to fifth decade with modern therapy).