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METHEMOGLOBIN


A. Definition

1. Methemoglobin (MetHb) forms when haemoglobin (Hb) becomes oxidized.
  • An iron atom in Hb loses one electron to an oxidant and is oxidized from the ferrous (Fe2+) state to the ferric (Fe3+) state.

C. Methemoglobin Physiology

1. Red cells are constantly exposed to oxidant stresses.

2. Healthy people have a normal MetHb concentration of 0-3%.

3. Biologic reductive systems are responsible for maintaining a normal level of methemoglobinaemia
  • The NADH MetHb reductase enzyme system is the body’s primary means of reducing MetHb.
    • The Embden Meyerhof glycolytic pathway generates NADH.
    • The NADH-dependent enzyme MetHb reductase, reduces MetHb (ferric state) to Hb (ferrous state).
    • This enzyme system lacks full activity until about 4 months of age. As a result, infants are more susceptible to oxidant stresses.
  • The NADPH MetHb reductase enzyme system reduces only a small percentage of MetHb under normal circumstances.

4. Ascorbic acid and reduced glutathione can be used as electron donors to reduce oxidized iron.
  • These methods are much slower and quantitatively less important under normal circumstances.

D. Pathophysiology

1. Elevated MetHb levels occur when oxidation overwhelms the body’s reductive capacity.

2. Methemoglobinaemia results in cellular hypoxia due to impaired oxygen delivery to the tissue.
  • MetHb cannot bind oxygen.
    • Iron must be in the ferrous (Fe2+) state in order to bind oxygen.
  • MetHb impairs oxygen release from normal Hb.
    • Leftward shift of the oxyhaemoglobin dissociation curve.

E. Etiologies

1. Hereditary
  • NADH MetHb reductase deficiency
  • Haemoglobin M
    • Changes in the amino acid sequence of Hb allow for easier iron oxidation.

2. Acquired
  • Medications: amyl nitrite, benzocaine, dapsone, lidocaine, nitroglycerin, nitroprusside, phenacetin, phenazopyridine, prilocaine, quinines, sulfonamides. (bolded are most common)
  • Chemical agents: aniline dye derivatives, butyl nitrite, chlorobenzene, food containing nitrites, isobutyl nitrite, naphthalene, nitrophenol, nitrous gases, silver nitrate, trinitrotoluene, well water contaminated with nitrates.
  • Fires
    • Heat induced haemoglobin denaturation.
    • Inhalation of nitrogen oxide in smoke.

3. Paediatric
  • Reduced NADH MetHb reductase activity in infants less than 4 months of age.
  • Bottle-fed infants exposed to nitrites/nitrates from well water.
  • In infants, the most common cause may be endogenous formation of MetHb associated with low birth weight, prematurity, dehydration, acidosis, diarrhoea, and hyperchloraemia.

4. Some oxidants that cause methemoglobinaemia, may also cause haemolysis.

F. Clinical Presentation

1. Cyanosis
  • Develops when 1.5 g/dL of MetHb is present.
    • This corresponds to MetHb level of 10% in a normal person with a Hb of 15 g/dL . Other than cyanosis, these patients are often asymptomatic.
    • This corresponds to a MetHb level of 20% in an anaemic patient with a Hb of 7.5 g/dL. In addition to cyanosis, this patient will manifest signs and symptoms of MetHb poisoning.
  • Cyanosis due to hypoxaemia requires 5 g/dL of deoxyhaemoglobin (deoxyHb).
    • This represents a 33% reduction in oxygen carrying capacity in patients with a Hb of 15 g/dL. In addition to cyanosis, these patients are always symptomatic.

2. Signs and symptoms
  • Related to impaired oxygen delivery to the tissue.
  • Severity corresponds to an increasing percentage of MetHb.
  • Severity also corresponds to the rate of formation and elimination.
    • Previously healthy patients lack the compensatory mechanisms that develop over a lifetime in individuals with hereditary compromise.
  • Primarily affect the cardiovascular system and CNS.
||
Methemoglobin Level
Signs and Symptoms*
0 to 3%
Normal levels. No symptoms.
10 - 20%
Mild symptoms. Cyanosis. Chocolate-brown colored blood.
20% to 50%
Dyspnea, exercise intolerance, fatigue, headache, dizziness, confusion, tachycardia, syncope
Above 50%
CNS hypoxia: CNS depression, seizures, coma Cardiac hypoxia: dysrhythmias, ischemia Systemic hypoxia: tachypnea, metabolic acidosis
Above 70%
Severe hypoxic symptoms, death

G. Diagnosis Of Methemoglobinaemia

1. Exposure history is critical, but not always present or available.

2. Cyanosis
  • Is out of proportion to clinical signs and symptoms.
  • Does not improve with supplemental oxygen.
  • Is not associated with a right-left cardiac shunt.
  • Is associated with a normal pO2 and oxygen saturation on arterial blood gas (see below).

3. Blood that is chocolate brown in colour and remains so with exposure to oxygen.

4. A “saturation gap” is present; this is the difference between the O2 saturations measured by blood gas and cooximeter, blood gas and the pulse oximeter, or cooximeter and pulse oximeter.
  • Arterial blood gas often demonstrates a normal oxygen saturation.
    • Measures the pO2 (dissolved oxygen content of the blood) which is usually normal.
    • The O2 saturation is calculated from the pO2, temperature, and pH.
    • It assumes that only normal haemoglobin is present.
  • Pulse oximetry readings frequently over around 85%; may be lower depending on oximeter
    • The pulse oximeter reads absorbance of light at wavelengths of 660 nm and 940 nm, which are chosen to efficiently separate oxyhemoglobin (oxyHb) and deoxyHb.
    • The oximeter assumes that blood is only either oxy-Hb or deoxy-Hb.
    • The oximeter calculates the different concentrations of these two Hb species by using experimentally derived tables that correlate light absorbance and Hb concentration.
    • MetHb interferes with pulse oximetry because its absorbance of light at these wavelengths is greater than either oxy- or deoxyhaemoglobin.
    • The oximeter assumes that blood is only either oxy-Hb or deoxy-Hb. Tables used to calculate concentration of oxy- and deoxyhaemoglobin do not account for the presence of MetHb and attribute absorbance of light to oxy- and deoxyhaemoblin, instead.
  • Co-oximeter
    • Measures light absorbance at multiple wavelengths.
    • Uses multiple equations to calculate an accurate percentage of oxyHb, deoxyHb, MetHb, and carboxyhaemoglobin. Some newer machines have an expanded spectrum and are also able to read fetal haemoglobin and sulfhemoglobin.

see Simple Quantative Bedside testing for MetHb



H. Treatment

1. Supportive care.

2. Administer 100% oxygen to maximize oxygenation of normal Hb.

3. Methylene blue

  • Dosing: 1 - 2 mg/kg (0.1 - 0.2 mL/kg of 1% methylene blue) IV over 5 minutes.
    • If cyanosis has not resolved within 1 hour, a second dose should be given.
  • Mechanism
    • Acts as electron carrier to increase the activity of NADPH MetHb reductase.
    • Methylene blue is reduced to leucomethylene blue (LMB) by NADPH MetHb reductase.
    • LMB reduces MetHb to Hb as it is oxidized back to methylene blue.
    • NADPH MetHB reductase requires a supply of NADPH.
    • Glucose 6-phosphate dehydrogenase (G6PD) is enzyme responsible for maintaining adequate stores of NADPH.
      • Methylene blue should not be used in patients with severe G6PD deficiency because methylene blue itself is a mild oxidant and may worsen methemoglobinaemia if it cannot be converted to LMB.
  • Indications for methylene blue
    • Significant tissue hypoxia
    • Tachycardia or tachypnea
    • Metabolic acidosis
    • End-organ dysfunction.
      • Altered mental status, seizures
      • Dysrhythmias, myocardial ischaemia
    • Levels > 20%, even in asymptomatic patients.
***Can be given at lower levels in patients with baseline anaemia or hypoxaemia.
  • Relative contraindications for methylene blue:
    • Severe G6PD deficiency.
      • Avoid repeat doses in cases of suspected G-6-PD deficiency if patient does not respond. Due to oxidant effects of methylene blue.
  • Cautions:
    • Patients may complain of dysuria.
    • Urine will turn blue-green.
    • Pulse oximetry will transiently drop to a very low percentage due to the presence of a coloured agent (i.e. methylene blue) in the blood.

4. Other Treatment Options:
  • Supportive care
    • The half-life of MetHb is 1 to 3 hours assuming formation has stopped.
  • Exchange transfusions
    • Useful in small children when methylene blue is not effective.
  • Hyperbaric oxygen.
    • Significantly increases the level of dissolved oxygen in the blood, thereby allowing for adequate oxygen delivery despite the absence of Hb.

I. Treatment Failure

1. Inadequate methylene blue dose.

2. Ongoing methemoglobin production (inadequate decontamination).

3. Severe G-6-PD deficiency (rare).

4. Sulfhemoglobin (sulfHb)
  • Produces cyanosis when only 0.5 g/dL of blood is affected
  • Shifts the oxyHb dissociation curve to the right, thereby reducing the clinical effect of sulfHb at the tissue level.
  • Haemoglobin M.
  • NADPH MetHb reductase deficiency.

J. Suggested readings

Barker SJ, Tremper KK, Hyatt J: Effects of methemoglobinaemia on pulse oximetry and mixed venous oximetry. Anesthesiology 1989;70:112-117.
Curry S: Methemoglobinaemia. Ann Emerg Med 1982;11:214-221.
Dawson AH, Whyte IM: Management of dapsone poisoning complicated by methaemoglobinaemia. Med Toxicol Adverse Drug Exp 1989;4:387-392.
Hall AH, Kulig KW, Rumack BH: Drug-and chemical-induced methaemoglobinaemia. Clinical features and management. Med Toxicol 1986;1:253-260.
Lebby T, Roco JJ, Arcinue EL: Infantile methemoglobinaemia associated with acute diarrhoeal illness. Am J Emerg Med 1993;11:471
Lukens JN: Landmark perspective: The legacy of well-water methemoglobinaemia. JAMA 1987;257:2793-2795.
Prchal JT, Borgese N, Moore MR, et al: Congenital methemoglobinaemia due to methemoglobin reductase deficiency in two unrelated American black families. Am J Med 1990;89:516-522.
Rodriguez LF, Smolik LM, Zbehlik AJ: Benzocaine-induced methemoglobinaemia: report of a severe reaction and review of the literature. Ann Pharmacother 1994;28:643-649.
Wright RO, Lewander WJ, Woolf AD. Methemoglobinaemia: Etiology, Pharmacology, and Clinical Management. Annals of Emergency Medicine 1999; 34