methemoglobinemia...........

1. METHEMOGLOBINEMIA
Palak Parikh
Morning Report
May 16, 2008

2. Methemoglobin
 Altered state of Hg in which the ferrous (Fe
2+) irons of heme are oxidized to the ferric
(Fe 3+) state.
 Ferric hemes of methemoglobin are unable
to bind oxygen.
 Oxygen dissociation curve is “left-shifted”,
and oxygen delivery to the tissues is
impaired.

3. Oxygen Dissociation Curve

4. Methemoglobinemia
 >1% of total Hg species is in the oxidized
form.
 Due to imbalance due to either increased
methemoglobin production or decreased
methemoglobin reduction.
 High levels can lead to severe and
irreversible tissue hypoxia and cell death.

5. Methemoglobin Reduction to
Hemoglobin
 NADH-dependent reaction catalyzed by
cytochrome b5 reductase (b5R) – only
physiologically important pathway
 Alternate pathway uses an enzyme utilizing
NADPH generated by G6PD in the hexose
monophosphate shunt as a source of
electrons.
 Note: This pathway needs an electron acceptor
or redox dye, such as methylene blue or flavin

6. Reduction of Methemoglobin

7. Causes of Methemoglobinemia
 Hereditary
 Cytochrome b5 reductase deficiency
 Hemoglobin M disease
 Cytochrome b5 deficiency
 Acquired

8. Agents that can cause
Methemoglobinemia
 Aniline dyes  Local Anesthetic
 Benzene derivatives Agents
 Benzocaine, Lidocaine,
 Chlorates Prilocaine
 Chloroquine  Metoclopramide
 Dapsone  Methylene Blue ***
 Nitrites  Paraquat
 NTG, Nitric oxide
 Primaquine
 Sulfonamides

9. Blood in Methemoglobinemia
 Dark-red, chocolate, or brownish to blue in
color
 Does not change in color w/ addition of
oxygen, unlike deoxyhemoglobin

10. Clinical Features of
Methemoglobinemia
 Cyanosis – detected when methemoglobin
concentration exceeds 1.5 g/dL, or 8-12% of total
hemoglobin.
 Early symptoms – headache, fatigue, dyspnea,
lethargy
 At higher methemoglobin levels – respiratory
depression, seizures, altered consciousness,
shock, death
 Erythrocytosis – rare

11. Diagnosis
 Standard – Co-oximeter
 Interprets all readings in 630 nm range as methemoglobin (peak
absorbance at 631 nm)
 False positives if sulfhemoglobin and methylene blue present
 Confirmatory – Evelyn-Malloy method
 Adds cyanide which binds to positively charged methemoglobin,
eliminating peak at 630-635 nm in direct proportion to
methemoglobin concentration
 Subsequently adds ferricyanide to convert entire specimen to
cyanomethemoglobin for measurement of total Hg concentration
 Methemoglobin expressed as percentage of total concentration
of Hg.

12. Treatment of Methemoglobinemia
 Cytochrome b5r deficiency
 indicated for cosmetic reasons only
 methylene blue or ascorbic acid
 Acquired Methemoglobinemia
 Discontinue offending agents – especially if dapsone or
xylocaine-related med
 Transfusion of pRBCs if anemic
 Activated charcoal if overdose
 Supplemental O2
 Methylene Blue – if severe

13. Methylene Blue
 Usually given only if methemoglobin level >
40-50% of total hemoglobin.
 Dose of 1 to 2 mg/kg IV over 5 minutes
 Dose may be repeated in 1 hr.
 Large (>7 mg/kg) cumulative doses can cause
dyspnea, chest pain, and hemolysis
 Should not be used in a pt. with G6PD deficiency
b/c it may further produce hemolysis.

14. G6PD Deficiency
 Populations w/ High Incidence
 African Americans
 People of Mediterranean descent
 Southeast Asians

15. Severe Methemoglobinemia in G6PD
Deficiency
 If Severe Methemoglonemia, can give:
 Ascorbic acid (300 – 1000 mg/day PO in divided
doses)
 Risk of hemolysis in very high doses
 Risk of kidney stone formation in high doses
 Hyperbaric Oxygen
 Exchange Transfusion

16. HIV Patients
 Have lower glutathione levels in plasma and T
lymphocytes, which may predispose them to
clinically significant methemoglobinemia.
 May take primaquine or dapsone for PJP
prophylaxis or treatment.
 If both drugs given within 1-2 days of each other,
may increase risk of methemoglobinemia as half
life of dapsone exceeds 30 hrs.

17. Take-Home Points
 Methemoglobinemia is a condition in which >1%
of total Hg species is in oxidized form (Fe 3+).
 Clinical Triad: Breathlessness, Cyanosis,
Chocolate-colored blood.
 Dapsone and primaquine can cause
methemoglobinemia, especially in HIV pts.
 Usually, if methemoglobin <40% of total Hg, can
treat with O2, possibly pRBCs, and
discontinuation of any offending agents.
 If methemoglobin >40% of total Hg, can give
methylene blue (unless G6PD deficient).

18. References
 Alexander, CM, et al. Principles of oximetry. Anesth Analg. 1989; 68:368.
 Curry, S. Methemoglobinemia. Annals of Emergency Medicine. 1982; 11:214-221.
 Darling, R., et al. The effect of methemoglobin on the equilibrium between oxygen
and hemoglobin. American Journal of Physiology. 1942; 137:56.
 Evelyn, K, Malloy, H. Microdetermination of oxyhemoglobin, methemoglobin, and
sulfhemoglobin in a single sample of blood. Journal of Biol Chem. 1938; 126:655.
 Goluboff, N. Methylene blue induced cyanosis and acute hemolytic anemia
complicating the treatment of methemoglobinemia. Journal of Pediatrics. 1961;
58:86.
 Mansouri, A., et al. Concise review; methemoglobinemia. American Journal of
Hematology. 1993; 42: 7-12.
 Prchal, Josef. Diagnosis and treatment of methemoglobinemia. UpToDate. 1/2008.
 Sin, Don, et al. Dapsone- and primaquine-induced methemoglobinemia in HIV-
infected individuals. Journal of Acquired Immune Deficiency. 1996; 12:477-481.