Acute on-take days can be very challenging ……….Yet, it is very rewarding to unravel a mysterious diagnosis.

It was another busy casualty day in the medical unit.

Menaka; a 20-year-old women is admitted with breathlessness of one day duration. She had tiredness and shortness of breath on exertion for about 5 days, and her symptoms has got worse during the past 24 hours. She has no previous history of asthma or valvular heart disease.

On examination she is dyspnoec and has central cyanosis. She is not pale and there is no clubbing or ankle oedema. Pulse rate is 100 bpm, blood pressure 120/70 mmHg, no cardiomegaly or murmurs. Respiratory system examination is normal.

Digital pulse oxymetry shows an O 2 saturation of 85% and she is commenced on high concentration O 2.

We request an urgent arterial blood gas which shows; Arterial PH 7.55, PCO2 17mmHg PO2 120 mmHg HCO3 17.9 HCO3 Std 21.3 O 2 saturation 98%

What is the most likely cause for her cyanosis?

Her history and clinical examination excludes common causes for cyanosis such as any severe lung disease interfering with oxygenation of blood (e.g. COPD, pulmonary embolism or pneumonia) or right to left shunt as a result of congenital heart disease.

There is oxygen ‘saturation gap’ observed between pulse oxymetry (SpO 2 ) and arterial blood gas analysis (SaO 2 ) (82% Vs 98%). This supports a diagnosis of methemoglobinaemia (see under discussion).

Confirmation of diagnosis is by serum methemoglobin test which is usually not available for immediate diagnosis.

Why this girl has methaemoglobinaemia?

Acute methemoglobinaemia is usually acquired; hence a predisposing condition should be sought. Going through her medical records we found that she has been seen in the Dermatology clinic for a rash on her face (Figure 1). Skin biopsy having confirmed multibacillary leprosy, she was commenced on combination therapy of dapsone, rifampicin and clofazimine one month ago.

Figure 1: Lepromatous skin lesion

Management

Methemoglobin fraction of 1% (0-3) is present in normal individuals. Symptoms are associated with higher levels and when associated with cyanosis and dyspnoea, methemoglobin level is likely to be in the range of 25-40%.

Methylene blue is the emergency treatment in symptomatic methemoglobinaemia. It is given intravenously in a dose of 1-2 mg/kg (up to a total of 50 mg) in normal saline infusion.

Methylene blue is contraindicated in G6PD deficiency as it can cause haemolyiss due to oxidative damage to red cells. Menaka’s G6PD assay carried out before commencement of dapsone has been within normal limits.

Menaka was treated with IV methylene blue. Her urine became green in colour! (Figure 2). The blue pigment in methylene blue combines with urochrome ( which gives the yellow colour to urine) to create a green colour urine.



Figure 2: Green colour urine

Other investigations revealed the following results.

WBC 9.8 N 71.0%, L 23.1% Haemoglobin 11.7 Normal red cell indices

Reticulocyte count 1%

Serum bilirubin, ALT, AST and LDH within normal limits

Renal function tests were normal

Chest X ray normal

2 D Echocardiography normal

Blood picture showed presence of bite cells (Figure 3).

Dapsone is a drug known to cause oxidant damage to haemoglobin causing precipitation of haemoglobin as Heinz bodies. They are not visible with Romanowsky dyes but needs supravital staining (e.g., with new methylene blue or bromocresol green).for visualization. Heinz bodies are removed by the spleen leading to characteristic ‘bite cells’.

This patient shows oxidant damage to red cells but there was no active haemolysis.



Figure 3: Bite cells http://wallpaper222.com/explore/bite-cells/

Discussion:

When is cyanosis seen?

Presence of 5g/dl or more of deoxygenated haemoglobin in capillary blood is clinically manifested as cyanosis.

Patients with normal hemoglobin manifest cyanosis at higher SaO 2 values than patients with anemia. Patients who are anaemic can become hypoxic without showing cyanosis.

When hypoxia is suspected measurement of PaO 2 or SaO 2 should be carried out because absence of cyanosis does not rule out hypoxia.

What is methemoglobinaemia?

The normal hemoglobins include oxyhemoglobin (O2Hb) and deoxyhemoglobin (HHb). The abnormal hemoglobins include carboxyhemoglobin (COHb), methemoglobin (MetHb), and sulfhemoglobin (SHb). Abnormal haemoglobins are not capable of binding to oxygen.

Normal haemoglobin has the iron in the reduced ferrous form (HbFe2+), As there are four heme sites, each haemoglobin molecule has four oxygen binding sites. Methemoglobin (MetHb) contains iron in the oxidized ferric state (Fe3+). Normally there is about 1% of methaemoglobin in the red cells. Methaemoglobinaemia occurs when the red blood cell MetHb rises more than 1%. MetHb is unable to bind with oxygen causing reduction in arterial oxygen saturation. MetHb also causes a shift of the oxygen-hemoglobin dissociation curve to the left, resulting in decreased release of oxygen to the tissues.

What is “ saturation gap”?

Presence of a “saturation gap” gives a clue to the diagnosis of methemoglobinemia. This is a situation where there is a difference between the oxygen saturation measured on pulse oximetry (SpO 2 ) and the oxygen saturation on the arterial blood gas results (SaO 2 ). This is because in methaemoglobinaemia, arterial blood gas analysis gives falsely elevated oxygen saturation.

Pulse oxymetry can measure only two wave lengths of light to differentiate between oxyhaemoglobin and deoxyhaemoglobin. It is unable to measure methemoglobin accurately. As a result, oxygen saturations by pulse oximetry in methemoglobinemia plateau at about 85%. Therefore, a patient with a methemoglobin level of 5% and a patient with a level of 40% will have the same oxygen saturation values (85%) on pulse oximetry. As a result a patient with severe cyanosis can have a falsely elevated SpO 2. (85%). The newer multi-wave length oxymeters can detect methemoglobinaemia accurately, therefore gives an accurate SpO 2 in a patient with methemoglobinaemia.

The partial pressure of oxygen (PO 2 ) in arterial blood gas measurement reflects dissolved oxygen content in plasma and does not correspond to the oxygen-carrying capacity of hemoglobin. Therefore, PO 2 should remain within the reference range in patients with methemoglobinemia.

What is the difference between O2 saturation (SaO2) and partial pressure of oxygen (PO 2 ) in ABG?

Oxygen is present in blood in two forms; bound to haemoglobin and dissolved in plasma.

SaO 2 is the amount of haemoglobin which is oxygenated (oxyhaemoglobin) in arterial blood. It is given as a percentage.

PaO 2 (partial pressure of O 2 ) is the amount of oxygen dissolved in arterial blood, measured in mmHg.

The relationship between the two is described in oxyhaemoglobin dissociation curve.

Relationship between SaO 2 & PaO 2

SaO2 50% = PaO2 26.6 mmHg

SaO2 70% = PaO2 40 mmHg

SaO2 90% = PaO2 60 mmHg

SaO2 99% = PaO2 100 mmHg

References