Haemoglobin consists of four polypeptide chains, each with its own haem molecule. Each haem molecule contains a central iron atom which binds oxygen. In normal haemoglobin, the iron is thought to exist in its divalent form, Fe
2+. Methaemoglobin is an oxidised form of haemoglobin in which the iron is oxidised from Fe 2+ to Fe 3+ (Fig. 3). Methaemoglobin cannot transport oxygen and is dark brown in colour (1, 2).
Figure 3 a. In normal haemoglobin, iron is thought to be in its divalent form (Fe2+). The oxidised form of haemoglobin is called methaemoglobin and cannot transport either O₂ or CO₂. Nitrites are powerful oxidising agents and are one of the most frequent causes of methaemoglobinaemia ( 1, 2). b. Enzyme systems inside cells reduce methaemoglobin as soon as it forms. Methylene blue can act as a cofactor ( 1, 2)
Methaemoglobinaemia involves a reduction in the ability of erythrocytes to transport oxygen, giving rise to tissue hypoxia and cyanosis that is refractory to oxygen therapy. The normal level of methaemoglobin in human blood is less than 1 %, and a clinically significant reduction in oxygen transport occurs at levels of 10 % or above. Symptoms of methaemoglobinaemia are cyanosis, drowsiness, lethargy, muscular weakness, ataxia, dyspnoea, tachycardia, nausea and vomiting. The blood turns brownish-blue, giving rise to so-called chocolate cyanosis. The urine may become brownish-black and proteinuria is common. If levels increase to over 30 – 40 %, more serious phenomena such as CNS depression, unconsciousness and cardiac arrhythmias occur. Methaemoglobin levels above about 70 % are assumed to be fatal
In methaemoglobinaemia there is often a discrepancy between pO₂ and SaO₂. Arterial blood gas analysis shows approximately normal pO₂, whereas peripheral capillary oxygen saturation (SaO₂) falls. The pO₂ value reveals the amount of oxygen dissolved in the plasma component of the blood, i.e. the partial pressure of oxygen in the plasma. It is influenced by several factors: the oxygen content of inhaled air, the diffusion of oxygen from the alveoli to the capillary blood, and the shunt fraction, i.e. the proportion of the cardiac output that is not oxygenated upon passage through the lungs. SaO₂, or oxygen saturation, is expressed as a percentage and is the proportion of haemoglobin available for oxygen transport that actually binds oxygen. Measurement of SaO₂ with pulse oximetry is spectrophotometric and is based on the ratio of oxyhaemoglobin to deoxyhaemoglobin in the blood. The extent to which methaemoglobin influences this measurement varies between different models of pulse oximeter, but in general SaO₂ falls as the methaemoglobin level rises
Methaemoglobinaemia may be congenital, as a consequence of enzyme defects, or caused by ingestion of toxic agents, such as nitrates, nitrites, methanol, aniline, dapsone and some local anaesthetics
Nitrites are powerful oxidising agents and are among the most common causes of methaemoglobin formation. Exposure to nitrite occurs mainly via endogenous conversion of nitrate. Nitrate itself is relatively non-toxic, but concerns have been raised over the nitrate metabolites nitrite, nitrogen monoxide (NO) and N-nitroso compounds. Human exposure to nitrate is mainly through ingestion via vegetables or contaminated well water, and a certain amount is also produced by the body itself
(2). The few human studies of nitrate exposure that exist have not shown methaemoglobinaemia after ingestion of nitrate alone (4). The nitrate concentrations normally found in food and water are considered unlikely to induce methaemoglobinaemia (5, 6).
A number of volatile nitrites are used as intoxicants and aphrodisiacs, often under the name «poppers». There have been several reported cases of severe methaemoglobinaemia following ingestion of volatile nitrites
Most methaemoglobinaemias are mild and do not require specific treatment once the triggering agent has been removed. Supplemental oxygen is recommended, even though the ability of erythrocytes to make use of this is reduced. Methylene blue is used as an antidote and is recommended with methaemoglobin levels above 25 – 30 % or severe symptoms. The recommended dosage is 1 – 2 mg/kg
(1, 2). Methylene blue has a rapid onset of action, but a short half-life, and repeated dosing may be necessary. Methylene blue works by acting as a cofactor that increases the rate of reaction of enzyme systems responsible for reducing the methaemoglobin formed inside cells (1, 2). In our patient the maximum methaemoglobin level detected was 22 %. She recovered well with no treatment other than supplemental oxygen.
The reagent in the Strep test kit contained sodium nitrite. The label states that the reagent is toxic if swallowed, highly corrosive and should be kept locked away and out of reach of children. This case report shows that the Strep test reagent contains enough sodium nitrite to cause significant methaemoglobinaemia. In the wake of this incident, the casualty clinic in question has reviewed its procedures for storing the Strep test kit.
When the patient first arrived at the Acute Admissions section of the local hospital, the receiving doctor had no information about what kind of substance the patient had ingested in the casualty clinic. The paramedics received an admission note from the casualty clinic, but this somehow disappeared during the patient transfer. The paramedics reported verbally that the patient had ingested a reagent in the casualty clinic which meant that she required observation in hospital. The doctor in the casualty clinic did inform the duty medical officer about the nature of the poison, but this information did not reach the receiving doctor straight away because of a busy Acute Admissions. Since the patient was stable, the casualty clinic was contacted and asked to send the admission note again, and it was eventually received by fax. There is always a risk that important information can disappear or become distorted when passed along many links in a chain, and our case report is an example of this. There were no consequences for the patient, but the situation could have been dangerous had the poisoning been more severe.