Methemoglobinemia

Introduction

• It is oxidized hemoglobin in which iron is in ferric state (Fe+++)
• It is incapable of reversibly combining with oxygen due to its very high affinity to oxygen.
• Methemoglobin has brownish blue color that does not revert back to red on exposure to oxygen
• Pulse oxymeter gives false low readings, but arterial blood gas analysis shows that pO2 is normal. Some ABG analyzers give amount of methemoglobin present in the sample.
• Normally 2% of total Hb is converted to methemoglobin everyday
• Normal reducing mechanisms which prevent formation of methemoglobin include:
  • NADH methemoglobinreductase 1
  • Cytochrome B5 reductase
  • Ascorbic acid
  • GSH NADH Methemoglobinreductase 2
  • NADPH Methemogobinreductase

Causes of methemoglobinemia

• Exposure to oxidizing chemicals/ drugs- sulfonamides, lidocaine, nitrites/nitrates, pyridium, dapsone, aniline, paraquat,primaquine, benzocaine
• Congenital defects in reducing systems- Ex: cytochrome b5 reductase
• Hemoglobin M
  • Mutations that stabilize heme iron in ferric state
  • Abnormal hemoglobins, that are resistant to enzymatic reduction
  • Several types with different amino acid substitutions exist.

Clinical features

• Dyspnea
• Cyanosis when methemoglobin is >10% (Arterial PaO2 is normal)
• Chronic cases- Asymptomatic
• Hemoglobin M- Some present with neonatal hemolytic anemia. Some present with cyanosis at 6-9 months of age.
• Acute toxic methemoglobinemia
  • Seen in acquired cases
  • They suffer from hypoxia
  • It is a serious medical emergency
  • Present with shortness of breath, palpitations, malaise, giddiness, vascular collapse, later leading to coma and death.

Investigations

• Evelyn- Malloy method- Maximum absorbance band at a wavelength of 630nm at pH 7-7.4. If cyanide is added to hemolysate the band disappears.
• 8 wavelength pulse oxymeter (Masimorad 57)
• NADH methemoglobinreductase levels- Measures levels of cytochrome B5 reductase.
• Hemoglobin electrophoresis for measurement of hemoglobin M (All hemoglobins must be converted to methemoglobin prior to running the sample)

Treatment:

• Acquired cases
  • Mild cases- Do not need any treatment
  • Severe cases: 
    • Removal of offending agent
    • High flow oxygen
    • Reducing agents- Methylene blue- 1-2mg/kg over 5 min as 1% solution in saline
    • Continue observation even after improvement, as there is continuous absorption from GIT
    • Repeat dose after 60 min if required.
    • Cumulative dose of>4-7mg/kg may cause cyanosis, dyspnea and acute hemolysis
    • It is not useful in congenital causes
    • Methylene blue is rapidly reduced by NADPH formed in HMP shunt pathway (this reaction is catalysed by NADPH diaphorase) to form leucomethylene blue. Leucomethylene blue in turn non-enzymatically reduces methemoglobin to hemoglobin.
    • Methylene blue is not useful if there is G6PD defiency, in fact it causes hemolysis in these patients.
    • If there is G6PD deficiency/ if methylene blue is not available- Do exchange transfusion
  • Cimetidine (which inhibits N-hydroxylation) is useful in dapsone induced methemoglobinemia
• For patients with deficiency in reductase system
  • No treatment is required
  • Cyanosis can be improved by oral methylene blue- 100-300mg/day
  • Ascorbic acid- 200mg-PO-TDS
  • Riboflavin- 20mg/day
• For Hemoglobin M cases- No treatment is required

Sulfhemoglobinemia

• Stable compound, which is formed when sulfur combines with heme
• Green colored compound
• Cannot carry oxygen
• Normal levels- <2.2%
• Cyanosis is seen when levels are >3%
• Mild hemolysis is often present
• Causative agents- Sulfonamides, Phenacetin, clostradiumwelchii infection
• Absorption band is seen at 620nm. Unlike methemoglobin, this is not abolished by addition of cyanide.
• Benign disorder
• No treatment is required.

Carboxyhemoglobinemia

• Carboxyhemoglobin is formed when hemoglobin is exposed to carbon monoxide
• Carboxyhemoglobin has very high affinity for oxygen
• It imparts cherry red color to blood and skin
• Normal levels can be as high as 10%, especially in city dwellers and smokers
• Estimation is done by Tietz and Fiereck method using sodium hydrosulphide and measuring absorbance at 541nm
• Acute poisoning can lead to cerebral edema and pulmonary edema 
• Chronic intoxication leads to irritability, nausea, lethargy, headache, eventually leading to polycythemia
• Treatment- Remove from carbon monoxide containing environment and oxygen therapy