Cyanosis

Cyanosis is a bluish discolouration of the skin or mucous membranes caused by an increased concentration of deoxygenated haemoglobin (over 5 g/dL in capillary blood, or about 1.5 g/dL of methaemoglobin) or abnormal haemoglobin pigments. It is an unreliable sign of hypoxaemia: absent in anaemia, appears late, and is judged differently by different observers and in different light and skin tone.

Clinical relevance. New central cyanosis is an emergency: it signals significant arterial hypoxaemia (usually saturation under 85%) or an abnormal haemoglobin. Peripheral cyanosis with warm, well perfused central tissue may be benign (cold exposure), whereas peripheral cyanosis with poor perfusion signals shock or arterial or venous obstruction. Differentiating central from peripheral cyanosis points to the system at fault.

Classification.

• Central cyanosis (tongue, lips, buccal mucosa, conjunctivae; warm peripheries): arterial desaturation from lung disease, right to left shunt, high altitude, hypoventilation, or abnormal haemoglobin (methaemoglobinaemia, sulphaemoglobinaemia), polycythaemia.
• Peripheral cyanosis (hands, feet, nail beds, nose, ears; tongue pink): slow flow with high oxygen extraction in the tissue; cold exposure, low cardiac output, shock, arterial obstruction, venous obstruction, Raynaud phenomenon, acrocyanosis.
• Differential cyanosis: lower limbs cyanosed but not upper limbs (patent ductus arteriosus with pulmonary hypertension and reversed shunt); reversed differential (transposition with pulmonary hypertension): upper limbs more cyanosed.
• Mixed: heart failure with lung disease.
• Pseudocyanosis: amiodarone, silver (argyria), minocycline, dyes, bruising, venous staining, Mongolian blue spot, lighting.

Mechanism. Visible cyanosis needs deoxygenated haemoglobin over about 5 g/dL, so it depends on haemoglobin concentration: a polycythaemic patient (Hb 20 g/dL) appears cyanosed at saturation 75%, while an anaemic patient (Hb 7 g/dL) may not be visibly cyanosed until saturation is under 30%. Methaemoglobin (Fe3+) gives a slate grey or blue brown tinge from about 1.5 g/dL.

History.

• Onset (at birth, acute, gradual), distribution (central or peripheral), triggers (cold, exertion, crying, feeding, altitude, drugs, chemical exposure), associated breathlessness, chest pain, cough, fever, syncope, palpitations, headaches, squatting in childhood.
• Congenital heart disease, repair history, Down syndrome, rheumatic fever, lung disease, sleep apnoea, liver disease, spleen surgery, sickle cell disease, blood disorders.
• Drugs and chemicals: dapsone, nitrates, local anaesthetics (benzocaine, lidocaine, prilocaine), nitrites, phenazopyridine, aniline dyes, sulphonamides, primaquine, amyl nitrite, well water with nitrate (infants), amiodarone, minocycline.
• Smoking, carbon monoxide exposure, occupation.
• Cold sensitivity, Raynaud symptoms, rheumatological disease, vibration tools.
• Limb pain, swelling, trauma, thrombosis risk, cancer.
• Family history (hereditary methaemoglobinaemia, congenital heart disease, hereditary haemorrhagic telangiectasia).

Examination.

• Look in good natural light at tongue, inner lips and conjunctivae (central) and at fingers, toes, ears and nose (peripheral); compare with a healthy observer if unsure; check capillary refill and temperature.
• Vital signs: saturation (and check with arterial gas), respiratory rate, heart rate, blood pressure, temperature; four limb pressures and pulses; pre-ductal (right hand) and post-ductal (foot) saturations in infants.
• Clubbing (long standing hypoxaemia: cyanotic congenital heart disease, lung cancer, bronchiectasis, pulmonary arteriovenous malformation, cirrhosis), finger shape, polycythaemia (plethoric face), nail bed colour.
• Cardiac: murmurs, single second sound, loud P2, right ventricular heave, signs of heart failure, Eisenmenger syndrome, tricuspid regurgitation.
• Chest: hyperinflation, crackles, wheeze, bronchial breathing, stridor, effusion.
• Limbs: asymmetry, swelling, tenderness, absent pulses, cold limb (arterial or venous thrombosis).
• Skin: telangiectasia, spider naevi, rash, ulcers, livedo, purpura (vasculitis, cryoglobulinaemia).
• Neurological: alertness, focal deficits (paradoxical embolism, brain abscess).

Red flags.

• New central cyanosis at any age, particularly with distress, shock, reduced consciousness or failure of saturation to improve with oxygen.
• Neonate or infant with cyanosis (duct dependent congenital heart disease, persistent pulmonary hypertension, sepsis).
• Chocolate coloured blood, saturation about 85% with normal PaO2 (methaemoglobinaemia), after dapsone or local anaesthetic.
• Cyanosis with chest pain, haemoptysis, leg swelling (embolism).
• Cyanosis with stridor, drooling, wheeze or choking (airway obstruction).
• Acute limb cyanosis with pain, coldness and pulselessness (arterial occlusion), or swelling (phlegmasia cerulea dolens).
• Peripheral cyanosis with shock, cold clammy skin, oliguria.
• Digital cyanosis and necrosis in vasculitis, scleroderma, cryoglobulinaemia, antiphospholipid syndrome, heparin induced thrombocytopenia.
• Brain abscess, stroke or hyperviscosity in a patient with cyanotic heart disease.

Central cyanosis from lung and airway. Pneumonia, acute respiratory distress syndrome, pulmonary oedema, pulmonary embolism, severe asthma, chronic obstructive pulmonary disease, pneumothorax, large pleural effusion, airway obstruction and foreign body, aspiration, interstitial lung disease, pulmonary hypertension, neuromuscular respiratory failure, obesity hypoventilation, opioid overdose, high altitude pulmonary oedema.

Central cyanosis from cardiac shunt.

• Eisenmenger syndrome (atrial septal defect, ventricular septal defect or patent ductus arteriosus with reversed shunt).
• Tetralogy of Fallot, transposition of the great arteries, tricuspid atresia, total anomalous pulmonary venous return, truncus arteriosus, pulmonary atresia, Ebstein anomaly.
• Patent foramen ovale with raised right pressure, pulmonary arteriovenous malformation (hereditary haemorrhagic telangiectasia), hepatopulmonary syndrome.

Abnormal haemoglobin and blood. Methaemoglobinaemia (hereditary, drug or chemical), sulphaemoglobinaemia, polycythaemia vera, secondary polycythaemia, carboxyhaemoglobin (cherry pink not blue), rarely abnormal haemoglobin variants with low oxygen affinity.

Peripheral cyanosis.

• Cold exposure
• Raynaud phenomenon (primary and secondary: systemic sclerosis, lupus, cryoglobulinaemia, drugs)
• acrocyanosis
• low cardiac output and shock (cardiogenic, hypovolaemic, septic, obstructive)
• heart failure
• arterial occlusion (embolism, thrombosis, dissection)
• venous obstruction (deep vein thrombosis, superior vena cava obstruction, phlegmasia)
• vasculitis
• cold agglutinins, cryoglobulinaemia, hyperviscosity
• frostbite, chilblains, livedo reticularis
• medications (ergotamine, beta blockers, vasopressors)
• heparin induced thrombocytopenia

Pseudocyanosis and mimics. Amiodarone, minocycline, silver, dyes, methylene blue, bruises, venous pooling, poor lighting, tattoos.

1. Regard this as an emergency: airway, breathing, circulation; give oxygen and attach a monitor first.
2. Pulse oximetry (note unreliability in methaemoglobinaemia, carbon monoxide, poor perfusion), then arterial blood gas with co-oximetry: PaO2, PaCO2, pH, lactate, carboxyhaemoglobin, methaemoglobin, sulphaemoglobin.
3. Response to 100% oxygen: improvement points to lung disease or hypoventilation; no improvement (PaO2 under 20 kPa on 100% oxygen) indicates a fixed shunt (the hyperoxia test) or abnormal haemoglobin.
4. Central versus peripheral: tongue colour and warmth; if the tongue is blue, the cause is central.
5. Chest radiograph (cardiac silhouette, pulmonary vascularity, oedema, infiltrates, pneumothorax, effusion, hyperinflation), 12 lead ECG (right ventricular hypertrophy, right axis, Q waves, arrhythmia), and point of care ultrasound of heart and lung.
6. Echocardiography with agitated saline (bubble) contrast for intracardiac shunt (early left heart bubbles) and pulmonary arteriovenous malformation (late left heart bubbles); transoesophageal echocardiography and cardiac MRI or CT for complex congenital disease; cardiac catheterisation for pulmonary vascular resistance and shunt quantification.
7. Blood tests: full blood count (haemoglobin, haematocrit, white count, platelets), blood film (Heinz bodies, sickle cells), reticulocytes, ferritin, liver function, coagulation, urea, creatinine, lactate, toxicology.
8. Further blood tests: G6PD level before methylene blue when time permits, haemoglobin electrophoresis, methaemoglobin reductase level, JAK2 mutation, erythropoietin level.
9. Immunology: cold agglutinin and cryoglobulin tests, antiphospholipid antibodies, antinuclear antibody and extractable nuclear antigens, complement.
10. Peripheral causes: Doppler ultrasound of arteries and veins, ankle brachial pressure index, CT angiography, nailfold capillaroscopy, capillary refill; blood pressure in all four limbs.
11. Pulmonary investigations: CT pulmonary angiography, high resolution CT, spirometry, lung volumes, transfer factor, sleep study.
12. Hepatic and genetic tests as needed (hepatopulmonary syndrome contrast echocardiography, hereditary haemorrhagic telangiectasia gene testing, congenital heart disease genetics).

Limits. Clinical detection of cyanosis is imperfect: visible only when saturation is under about 85%; a lower threshold in anaemia, higher with polycythaemia; missed in dark skin. Pulse oximetry is unreliable for abnormal haemoglobins. Blood gas PaO2 is normal in methaemoglobinaemia and carbon monoxide poisoning. A pink tongue does not exclude central desaturation in severe anaemia.

Immediate priorities.

• Airway opening, high flow oxygen 15 L/min by reservoir mask (except neonate with suspected duct dependent lesion: titrate carefully with cardiology advice), sit upright, monitor saturation, ECG and blood pressure, intravenous access, blood gas, call for senior help.
• Treat the cause immediately; escalate respiratory support as needed (high flow nasal oxygen, continuous positive airway pressure, non invasive ventilation, intubation).
• Warm the limbs in peripheral cyanosis from cold; remove restrictive items; check perfusion.
• Remove the oxidising drug or chemical; decontaminate skin if chemical exposure.

Cause directed treatment.

• Lung and airway causes: treat the cause (pneumonia antibiotics, bronchodilators, steroids, drainage of pneumothorax, relief of obstruction, naloxone 400 micrograms intravenously repeated every 2 to 3 minutes for opioid overdose); intubation for exhaustion or refractory hypoxia.
• Pulmonary embolism: rivaroxaban 15 mg twice daily for 21 days then 20 mg daily, or apixaban 10 mg twice daily for 7 days then 5 mg twice daily, or enoxaparin 1 mg/kg twice daily; alteplase 100 mg over 2 hours if shocked.
• Methaemoglobinaemia (symptomatic or level over 20% to 30%, or over 10% with comorbidity): stop the oxidant; high flow oxygen.
• Methylene blue 1 to 2 mg/kg (1% solution) intravenously over 5 minutes, repeat once after 30 to 60 minutes if needed (maximum 7 mg/kg; avoid in G6PD deficiency, serotonin syndrome risk with serotonergic drugs).
• Ascorbic acid 1 g intravenously as an adjunct or alternative; exchange transfusion or hyperbaric oxygen in severe or refractory cases (G6PD deficiency).
• Hereditary methaemoglobinaemia: ascorbic acid 200 to 500 mg daily, riboflavin, avoid triggers.
• Sulphaemoglobinaemia: remove the offending drug; transfusion if severe (no antidote).
• Carbon monoxide: 100% oxygen until carboxyhaemoglobin is under 5%; hyperbaric oxygen in severe cases.
• Cyanide poisoning: hydroxocobalamin 5 g intravenously over 15 minutes (repeat once if needed).
• Congenital cyanotic heart disease in adults: avoid dehydration, iron deficiency and unnecessary venesection (venesect only for symptomatic hyperviscosity with haematocrit over 65% and after hydration, remove 250 to 500 mL with saline replacement); iron replacement for deficiency.
• Use air filters on intravenous lines to prevent paradoxical embolism; antibiotic prophylaxis for endocarditis in selected cases.
• Avoid pregnancy (maternal mortality 30% to 50% in Eisenmenger syndrome).
• Pulmonary vasodilators in Eisenmenger syndrome (bosentan 62.5 mg twice daily then 125 mg twice daily, sildenafil 20 mg three times daily); transplant assessment.
• Hypoxic spells in infants: knee to chest position, oxygen, morphine 0.1 mg/kg, intravenous fluids, phenylephrine or propranolol.
• Neonate with suspected duct dependent lesion: prostaglandin E1 (alprostadil) 0.01 to 0.05 micrograms/kg/minute infusion, urgent echocardiography and cardiology transfer; avoid high oxygen.
• Hepatopulmonary syndrome: oxygen, liver transplant assessment.
• Pulmonary arteriovenous malformation: embolisation (feeding artery 3 mm or over).
• Polycythaemia: venesection to haematocrit under 45% in polycythaemia vera, aspirin 75 mg daily, hydroxycarbamide for high risk; treat secondary causes (sleep apnoea, lung disease).
• Peripheral causes: warm the patient and treat shock (fluids, vasopressors: noradrenaline 0.05 to 0.5 micrograms/kg/minute, inotropes).
• Acute limb ischaemia: unfractionated heparin 5,000 units bolus then 18 units/kg/hour, urgent vascular surgery.
• Deep vein thrombosis with phlegmasia: anticoagulation, thrombolysis or thrombectomy.
• Raynaud phenomenon: keep warm, stop smoking, avoid triggers, nifedipine modified release 30 to 60 mg daily or amlodipine 5 to 10 mg daily, intravenous iloprost for critical ischaemia.
• Cryoglobulinaemia and vasculitis: immunosuppression (prednisolone 1 mg/kg daily, rituximab). Cold agglutinins: warm environment, rituximab.
• Pseudocyanosis from drugs: stop or review the agent (reassure; skin colour fades slowly).

Disposition.

• Resuscitation or critical care: any central cyanosis with distress, shock, hypoxaemia not correcting, methaemoglobin over 20%, neonates, acute limb ischaemia, suspected embolism.
• Admit: new central cyanosis, unexplained cyanosis, pulmonary vascular disease decompensation, methaemoglobinaemia needing treatment, peripheral cyanosis with systemic illness.
• Outpatient: long standing stable cyanosis in known congenital heart disease under specialist follow up; acrocyanosis and Raynaud phenomenon with advice.

Monitoring.

• Saturation, respiratory rate, perfusion, lactate.
• Methaemoglobin level 1 hour after methylene blue and then every 4 to 6 hours (rebound with long acting oxidants such as dapsone for 24 to 48 hours).
• Full blood count and ferritin in congenital heart disease every 6 to 12 months.
• Limb pulses and colour; renal function after contrast; oxygen need.

Referral and escalation. Critical care, cardiology (adult congenital heart disease centre), respiratory, haematology, toxicology, vascular surgery, rheumatology, hepatology, interventional radiology, paediatric cardiology for infants, pulmonary hypertension centre, transplant services.

Safety netting. Return urgently for new blue lips or tongue, breathlessness, chest pain, fainting, a cold painful blue limb, or confusion. Patients with cyanotic heart disease should carry an alert card, avoid dehydration and altitude, and seek review early for infection or bleeding.

Special groups. Neonates and infants: duct dependent congenital heart disease, persistent pulmonary hypertension of the newborn, respiratory distress syndrome, sepsis, methaemoglobinaemia from nitrate rich water (blue baby), choanal atresia, diaphragmatic hernia; hyperoxia test and pre and post ductal saturations. Children: tetralogy of Fallot spells, foreign body, croup, asthma.

Pregnancy: Eisenmenger syndrome (avoid pregnancy; termination advice), mitral stenosis, embolism. Older adults: peripheral cyanosis from shock and arterial disease. Dark skin: assess mucous membranes and nail beds; oximetry may overestimate saturation. Endemic regions: sickle cell disease, schistosomal pulmonary hypertension, rheumatic heart disease, high altitude disease and nitrate contaminated water.