METHAEMOGLOBINAEMIA

    DEFINITION

    Clinical condition arising from the excessive conversion of
    haemoglobin to methaemoglobin, which is incapable of binding and
    carrying oxygen.  Methaemoglobin is formed when iron in the haem
    molecule is oxidized from the ferrous (Fe2+) to the ferric state
    (Fe3+).

    TOXIC CAUSES

    Methaemoglobin occurs when haemoglobin is oxidized at a rate exceeding
    the normal enzymatic capacity for haemoglobin reduction. Certain
    individuals with impaired enzymatic capacity for haemoglobin reduction
    may be susceptible to milder oxidative stresses. Numerous agents may
    be responsible for this oxidation.  The most frequently encountered
    are:

         Aniline
         Benzocaine
         Chlorates
         Chloroquine
         Dapsone
         Ground or surface water contaminated with nitrates
         Nitrates
         Nitrites
         Nitrophenol
         Phenazopyridine
         Primaquine
         Sodium nitroprusside
         4-dimethylaminophenol

    NON-TOXIC CAUSES

    Congenital enzyme deficiencies

    CLINICAL FEATURES

    Methaemoglobinaemia is characterized by cyanosis in the absence of
    cardiac or pulmonary disease, and refractory to oxygen administration. 
    A typically greyish cyanosis is observed when levels of methaemoglobin
    exceed 1.5 g/dL, about 10% of the total haemoglobin in a normal
    individual.  At this level, the patient may be otherwise asymptomatic.

    Symptoms related to impaired oxygen delivery including headache,
    weakness, tachycardia and breathlessness develop progressively as
    concentrations of methaemoglobin exceed 20%.  Concentrations > 50%
    result in severe hypoxaemia and CNS depression. Concentrations > 70%
    may be incompatible with life. Presence of anaemia, cardiac failure or
    pulmonary disease may produce symptoms of hypoxia at lower percentage
    levels of methaemoglobin. A blood sample of a patient with more than

    15% methaemoglobinaemia has a chocolate brown colour which does not
    change when exposed to air.

    DIFFERENTIAL DIAGNOSIS 

    Sulphaemoglobinaemia.
    Cyanosis due to other causes (e.g. hypoxia).

    RELEVANT INVESTIGATIONS

    Arterial blood gases.  The p02 is normal while the measured oxygen
    saturation is decreased. 
    Blood methaemoglobin concentration

    Pulse oximeters are not accurate in the presence of
    methaemoglobinaemia.

    TREATMENT

     Oxygen. High flow oxygen should be administered

    Identification of offending agent and prevention of further exposure. 
    This measure alone is usually adequate for mild cases.
    Gastrointestinal or skin decontamination may be necessary. 

     Methylene blue. This specific antidote is indicated in any patient
    with symptoms and/or signs of hypoxia (mental changes, tachycardia,
    dyspnoea, chest pain).

    Initial dose of  methylene blue: 1 to 2 mg/kg not exceeding 4 mg/kg
    (maximum 7 mg/kg) as a 1% solution intravenously over 5 minutes.

    In cases not responding to  methylene blue or where  methylene blue 
    is contraindicated (G6PD deficiency), the following measures may be
    considered: 

         Exchange transfusion
         Hyperbaric oxygenation

    CLINICAL COURSE AND MONITORING

    Clinical improvement as a result of methylene blue therapy should be
    observed within one hour.  Methaemoglobin levels should be
    subsequently monitored to document adequacy of response and/or
    recurrent methaemoglobinaemia. In these cases, further doses of
    methylene blue are indicated.

    POTENTIAL SEQUELAE

    Hypoxic organ injury if treatment is delayed or inadequate.

    AUTHOR(S)/REVIEWERS

    Author:             Prof. Ad N.P. van Heijst, Bosch en Duin,
                        Netherlands.
    Peer Review:        Cardiff 3/95, Berlin 10/95: V. Danel, T. Meredith,
                        L. Murray, J. Pronczuk.