METHEMOGLOBINEMIA
Left panel, “April Love”, oil on canvas, Arthur Hughes 1856, Tate Gallery, London.
Middle panel, Original Bottle of William Perkin’s “Mauve”, 1856, Science Museum, London
Right panel, Paco Rabanne catwalk model, (Chris Moore Agency) 2000.
In the mid Nineteenth century decade of 1855 to 1865, the fashion conscious elite of Western Europe, Britain and France in particular, developed a passion for the color purple, or more precisely “mauve”. This color became very much all the rage and was reflected not only in the fabrics of the ballgowns, but also in many of the paintings of the time. This may be seen in the glorious swathe of mauve that dominates the pre-Raphaelite painter Arthur Hughes’s “April Love”. This is Hughes’s best-known work. It was exhibited in 1856, accompanied by a quotation from Tennyson’s poem “The Millers’ Daughter”, whose theme is the frailty of young love. The teary eyed girl in mauve is not a direct illustration of the poem, but she does echo its theme of disappointed love. The fallen rose petals further symbolize love’s transience. The ivy, however, as a symbol of eternal life, may indicate the possibilities of salvation in the next world whatever the trials and tribulations of earthly existence.
Before 1856 all painted and material color pigments had to be painstakingly and expensively extracted from animals, minerals or plants. It has been estimated that one royal procession of the time required 10 million dead insects. The pigments thus extracted also had a habit of fading or changing their color with time and exposure to sunlight. In 1853 the dyer James Napier commented, “could this color be obtained of a permanent character and fixed upon cotton, its value would be inestimable”
In 1856 a young eighteen-year-old chemist called William Perkin made just such a discovery to his own inestimable benefit. In a small garden shed at his home in Shadwell, East London Perkin was attempting to make synthetic quinine, which normally had to be extracted from the bark of the cinchona tree. He figured that by combining two molecules of allyltoluidine to every one of oxygen he could produce one molecule of quinine and one of water. In other words, he hoped that oxidation of allyltoluidine might be a means of producing synthetic quinine. It wasn’t. All he managed to produce was a reddish brown sludge, aniline. His youthful exuberance not to be deterred however, he began experimenting with this material. In his own words, “ On experimenting with the coloring matter thus obtained I found it to be a very stable compound dying silk a beautiful purple which resisted the light for a long time”. Indeed the color is still glorious even today. Young William had stumbled upon a means of mass producing the most fashionable color of the age by means of a synthetic chemical reaction. Before his discovery the field of chemistry had been largely a theoretical science, now however chemistry seemed to matter very much in a practical sense. Born at just the right time during the height of the industrial revolution, he went on to develop the process on the proverbial industrial scale and became extremely wealthy. His discovery has since come to be recognized as the beginning of the practical impact of science on industry, which has transformed the world.
Today we can see the benefits of William Perkin’s discovery all around us. Almost every conceivable hue can be chemically manufactured and is available “off the shelf”. Whilst mauve is no longer quite the rage it once was, William would be pleased to see his invention today. His “mauve” has certainly advanced a long way from the Nineteenth century teary- eyed innocence of Hughes’s “April Love” to the not so innocent, aggressively confident and sophisticated catwalk models of Paris in the 21st century.
All great advances in “civilization” however come at a price, no better example than the toxic wastes now produced as a consequence of modern industrial chemistry. In the case of William’s invention this comes in the form of aniline poisoning. With large exposures workers may experience their own shade of mauve in the form of cyanosis as a consequence of the methemoblobinemia it can induce. Our hopes in the benefits of progress often prove transient, like the rose petals of “April Love”. However should any of our patients present with the “mauve” affliction due to methemoglobinemia there is, like the ivy in the background of “April Love” still hope for their future. This hope comes to us in the form of methylene blue.
METHEMOGLOBINEMIA
Introduction
Methemaglobinemia refers to hemoglobin, which contains its iron in the Fe+++ (ferric) form, as opposed to the normal Fe++ (ferrous) form. Unlike the Fe++ form the Fe+++ form cannot carry oxygen. Normal adults have levels of methemaglobin of up to 1%.
Levels that are greater than 1% are referred to as methemaglobinemia
Normal Methemaglobin Metabolism
Fe+++ Hb
NADPH dependent NADH dependent Met Hb reductase Met Hb reductase (5%) (95%)
Fe++ Hb
Methylene Blue (acts as a co-factor for the minor pathway and therefore greatly enhances the activity of this pathway)
Causes of Methemaglobinemia
Congenital:
● Hb M disease.
● NADH dependent Met Hb reductase deficiency
Acquired:
Causes are drugs and toxins, which can act as oxidizing agents
● Nitrites
● Nitrates (much less so than the nitrites)
● Aniline dyes (inks, paints, varnish, shoe polish)
● Some local anesthetic agents, prilocaine, procaine.
● Some antibiotics, sulfonamides, dapsone.
● Phenytoin
● Quinones, chloroquine, primaquine.
Clinical Features
Cyanosis not responding to oxygen therapy.
The signs and symptoms are those of hypoxia.
Level metHb Clinical features
<15% Generally no signs or symptoms.
15% Cyanosis (at about 1.5gms/ 100mls compared with 5gms/100mls needed for deoxy Hb to show cyanosis)
30% Symptoms appear, tachycardia, dyspnea.
>60% Increasing signs of hypoxia, seizures, confusion, arrhythmias hypotension.
>70% Can be lethal in otherwise healthy individuals.
Look closely: profound cyanosis in a woman who had overdosed on dapsone and who had developed life threatening methemaglobinemia, (photograph courtesy Dr. Christopher Groombridge)
Investigations
1. CXR, to rule out other causes of hypoxia.
2. Pulse oximeter reading will not be reliable.
● Methemaglobinemia interferes with normal oximetry.
● With increasing levels of methemaglobin, oximeter readings fall to about 85%, but then will stay around this level with further increases. Methemaglobin has a maximal light absorption at a wavelength similar to oxyhemaglobin (660 nm) and is therefore not readily differentiated from oxyhemoglobin.
3. ABGs:
● The PaO2 will not be affected.
● Co-oximetry will give a direct met Hb level, the definitive diagnosis.
● A metabolic acidosis, reflecting tissue hypoxia.
4. A crude bedside test is to drop some blood from the patient onto some filter paper, its color will appear typically chocolate brown.
Management
1. Immediate attention to the usual ABC issues of supportive care.
● IV access, take bloods.
● Establish ECG monitoring and pulse oximetry.
2. Consider charcoal if recent ingestion of causative agent and if airway is not (nor likely to be) compromised.
3. Methylene blue:
The specific antidote is methylene blue, (see below)
● Give 1mg/kg IV over 5 minutes.
● This dose can be repeated after 30 minutes to 1 hour.
● Improvement should be seen within 30-60 minutes.
Possible alternatives to methylene blue therapy include:
4. Hyperbaric oxygen therapy:
● An alternative is hyperbaric oxygen treatment.
● The partial pressure of oxygen in plasma can be increased to such a degree as to ensure adequate oxygen transport in the absence of any functioning Hb.
5. Exchange transfusions:
● Exchange transfusions is an alternative for patients with G-6-P deficiency (methylene blue can cause massive hemolysis in these patients) or in patients who fail to respond to methylene blue therapy.
METHYLENE BLUE
Introduction
Methylene blue is tetramethylthionine.
It is the specific treatment for symptomatic drug induced methemaglobinemia.
Preparation
50 mg in 5 mls ampoules (ie a 1% solution)
Mechanism of action
Methylene blue acts to promote the minor metabolic pathway of met Hb metabolism.
Indications
● Consider in all cases above 20% met Hb 1
● All symptomatic patients with elevated met Hb levels.
Cyanosed patients who do not have any symptoms do not require methylene blue. Symptoms usually will occur at around 15-30%.
Adverse reactions
1. Excessive doses (>7 mg/Kg) have oxidizing properties of its own and can therefore paradoxically induce metHb in its own right!
2. May induce mild hemolysis in normal individuals, but in those with G-6-P deficiency can induce massive hemolysis. It is therefore contra-indicated in these patients.
3. Rarely patients may have a congenital deficiency of NADPH met Hb reductase.
4. May be irritating to the vein (follow doses with saline flushes)
Failure of Methylene Blue Treatment
The following will need to be considered.
1. Wrong diagnosis. eg In sulfhemoglobinemia or CO poisoning methylene blue is not effective.
2. The patient has NADPH met Hb reductase deficiency (very rare)
3. The dose of methylene blue given has been excessive.
4. The dose of methylene blue given has not been adequate.
5. There is ongoing formation of methemaglobinemia, such as continual GIT absorption of a toxic agent.
Dose
1 mg / Kg (= 0.1 ml / kg of the 1% solution) IV slowly over 5 minutes.
Up to 2mg/kg (= 0.2 ml/ Kg of the 1% solution) IV slowly over 5 minutes may be given. 1
This dose can be repeated in 30 minutes to one hour if necessary.
End points:
● Resolution of symptoms
● Falling methemoglobin levels.
References:
1. Methylene blue in L Murray et al. Toxicology Handbook 1st ed 2007
2. Zalstein S Methaemoglobinaemia case report in Emergency Medicine: 1993:5 p 71
Dr J Hayes Reviewed June 2011