Carboxyhaemoglobin and Methaemoglobin

Carboxyhaemoglobin (COHb) and methaemoglobin (MetHb) are dyshaemoglobins measured by multiwavelength co-oximetry on arterial or venous whole blood, usually on the blood gas analyser, in 1 to 2 minutes. Co-oximetry measures absorbance at four or more wavelengths and reports oxyhaemoglobin, deoxyhaemoglobin, COHb and MetHb as a percentage of total haemoglobin.

Pulse co-oximeters estimate COHb (SpCO) and MetHb (SpMet) non-invasively but are less accurate (error of plus or minus 3 to 5 percentage points). Conventional two wavelength pulse oximeters cannot distinguish these species: they read COHb as oxyhaemoglobin (falsely normal saturation) and MetHb as a fixed reading near 85%.

Carbon monoxide binds haemoglobin with about 240 times the affinity of oxygen, shifts the dissociation curve to the left and inhibits cytochrome oxidase, causing tissue hypoxia despite normal oxygen tension.

It is the commonest cause of fatal poisoning worldwide (fires, faulty heaters, charcoal braziers, generators, car exhaust, indoor cooking with biomass fuel), with about 1 to 2 deaths in each 100 000 people in many countries, and delayed neurological sequelae in up to 40% of survivors of serious poisoning.

Methaemoglobinaemia results from oxidation of iron to the ferric state, either congenital (cytochrome b5 reductase deficiency, haemoglobin M) or acquired (drugs and chemicals: dapsone, local anaesthetics such as benzocaine and prilocaine, nitrites, nitrates in well water and food, aniline dyes, primaquine, rasburicase, sulphonamides, nitric oxide), and causes cyanosis that does not improve with oxygen.

Indications. Carbon monoxide: exposure to fire, smoke or enclosed space combustion; headache, dizziness, nausea, confusion, syncope, chest pain, or several household members unwell together; coma of unknown cause; pregnancy with exposure.

Methaemoglobin: cyanosis with normal oxygen tension, chocolate brown blood, oxygen saturation of 85% that does not respond to oxygen, after exposure to drugs or chemicals, infants with diarrhoea or exposure to nitrate rich water, G6PD deficiency with haemolysis. Haemoglobin variants as the cause of low pulse oximeter readings.

Not for chronic low level exposure screening, which uses breath carbon monoxide.

Specimen. Arterial or venous heparinised whole blood 0.5 to 1 mL in a syringe, air excluded, analysed immediately (COHb is stable for hours at 4 °C in a sealed tube, but MetHb rises on storage and should be measured within 30 minutes).

Record the time of exposure, the time of sampling and any oxygen therapy, because high flow oxygen shortens the half life of COHb from 4 to 6 hours in room air to about 60 to 90 minutes. A sample after prolonged oxygen therapy underestimates the exposure.

Reference values. COHb: non-smokers under 2% (up to 3% in urban settings), smokers 3 to 8% (heavy smokers up to 10 to 15%). MetHb: under 1.5% of total haemoglobin (0.5 to 1.5%). Congenital cytochrome b5 reductase deficiency causes 10 to 40%.

Interpretation.

• COHb 10 to 20%: headache, nausea, dyspnoea on exertion. 20 to 30%: severe headache, dizziness, impaired judgement, visual disturbance. 30 to 40%: confusion, vomiting, syncope, tachycardia. 40 to 60%: coma, seizures, myocardial ischaemia. Over 60%: usually fatal. Symptoms correlate poorly with levels, and young, healthy people may tolerate higher levels than patients with heart or lung disease.
• Normal COHb does not exclude exposure when the sample is delayed or oxygen has been given; symptoms and history decide.
• Lactate over 10 mmol/L in smoke inhalation suggests combined cyanide poisoning (hydrogen cyanide in house fires), which needs separate treatment.
• MetHb 10 to 20%: cyanosis, usually asymptomatic. 20 to 30%: headache, dizziness, fatigue, tachycardia. 30 to 50%: dyspnoea, confusion, acidosis. 50 to 70%: coma, arrhythmias, seizures. Over 70%: usually fatal.
• Anaemia, heart or lung disease and G6PD deficiency lower the tolerated level, and symptoms appear at lower MetHb in those patients.
• Pulse oximeter reading of 85% with normal pO2 on blood gas (oxygen saturation gap) strongly suggests methaemoglobinaemia.
• Persistent cyanosis from birth with normal MetHb: cyanotic congenital heart disease or lung disease. Congenital methaemoglobinaemia is confirmed by enzyme assay or genetic analysis.
• Sulphaemoglobin (from sulphonamides and hydrogen sulphide) is not reversed by methylene blue and also causes cyanosis with a normal pO2.

Critical values and findings needing immediate action.

• COHb over 25%, or any level with coma, seizures, syncope, chest pain, ECG ischaemia, pregnancy or neurological signs: 100% oxygen by tight fitting mask or ventilator until COHb is under 5% (and symptoms resolve), and consideration of hyperbaric oxygen in severe poisoning, pregnancy with high levels, or persistent neurological signs, in line with local access.
• Smoke inhalation with high lactate or shock: empirical cyanide antidote (hydroxocobalamin) and airway assessment for burns.
• MetHb over 20%, or over 10% with symptoms, hypoxia, heart disease or anaemia: methylene blue 1 to 2 mg/kg intravenously over 5 minutes, repeated once if needed, with oxygen.
• Methylene blue is ineffective or harmful in G6PD deficiency (haemolysis), cytochrome b5 reductase independent methaemoglobinaemia, and sulphaemoglobinaemia; use exchange transfusion, ascorbic acid, or hyperbaric oxygen as the situation requires. It also interacts with serotonergic drugs (serotonin syndrome).
• Removal from the exposure source, ventilation of the premises, and notification of public health for carbon monoxide incidents (other occupants may be affected).
• Any pregnant woman with COHb over 15 to 20%: foetal haemoglobin binds carbon monoxide strongly, so treatment is prolonged and obstetric assessment follows.

Interferences and pitfalls.

• Conventional pulse oximetry and calculated oxygen saturation on older blood gas analysers are falsely normal in carbon monoxide poisoning. Only co-oximetry gives true fractional saturation.
• Methylene blue itself, and dyes such as indocyanine green and isosulphan blue, cause falsely low pulse oximeter readings and interfere with co-oximetry; high bilirubin, foetal haemoglobin and lipaemia may affect some analysers.
• Delay in sampling, prior oxygen and transfer by ambulance reduce COHb, so the first level is a minimum estimate of exposure.
• Sample handling: exposure to air, clotted blood and old samples change values; MetHb rises with storage.
• Delayed neurological syndrome (confusion, memory loss, parkinsonism, mood changes) occurs 2 to 40 days after apparent recovery, and cannot be predicted by COHb alone.
• Myocardial injury is common (troponin rise in 35%) and increases long term mortality, so ECG and troponin are routine in significant poisoning.
• Cherry red skin is a rare and late sign, and pulse oximetry, skin colour and symptoms are unreliable.
• Methaemoglobinaemia can recur after methylene blue (with long acting oxidants such as dapsone), so monitoring for 12 to 24 hours or more is required.
• Cyanosis in a neonate from nitrate contaminated water ("blue baby syndrome") is a public health issue.

Special groups.

• Children and infants: higher susceptibility to both conditions; infants have lower cytochrome b5 reductase activity and foetal haemoglobin is more readily oxidised.
• Pregnancy: carbon monoxide crosses the placenta, foetal COHb is higher and clears slowly, and miscarriage, stillbirth and brain injury may occur even with mild maternal symptoms.
• Smokers and urban workers: raised baseline COHb.
• Patients with G6PD deficiency: haemolysis with oxidant drugs; avoid methylene blue.
• Firefighters, miners, garage workers and users of indoor braziers: occupational and domestic exposures.
• Regions: indoor biomass cooking and charcoal heating in cold climates drive carbon monoxide poisoning in low income and displaced populations, and nitrate in well water drives methaemoglobinaemia in rural infants.

Follow up tests. Repeat co-oximetry every 2 to 4 hours during treatment, arterial blood gas with lactate, ECG and troponin, full blood count, G6PD assay before methylene blue where feasible, bilirubin and lactate dehydrogenase for haemolysis, urea and creatinine (rhabdomyolysis, creatine kinase), chest radiograph and bronchoscopy in smoke inhalation, cyanide level where available,

CT or MRI brain for neurological signs, neuropsychological assessment at follow up, cytochrome b5 reductase assay and haemoglobin electrophoresis or gene analysis in congenital forms, and pregnancy test.