Methemoglobinemia: Quick Diagnosis Key

Methemoglobinemia is a medical emergency that requires prompt recognition and treatment. It is characterized by a high level (>1%) of methemoglobin (MetHb) in the blood.

MetHb is produced when the iron moiety in the hemoglobin (Hgb) molecule is oxidized from Fe²⁺ to Fe³⁺ and results in impaired oxygen affinity.^1,2 As the Hgb molecule has 4 subunit proteins (tetramer), different states of oxidized and reduced iron can exist in methemoglobinemia and an increased affinity for oxygen occurs in the remaining heme sites in the Fe²⁺ state but release of oxygen to tissues is impaired. Red blood cells, carrying Hgb and oxygen, are frequently exposed to oxidative stress which produces approximately 2.5% MetHb daily.¹ This physiologic amount is reduced back to Hgb through enzymatic pathways and MetHb levels rarely exceed 1% in the blood.² The primary enzyme responsible is cytochrome-b₅-MetHb reductase, using nicotinamide adenine dinucleotide (NADH) as a cofactor, reduces 95-99% of MetHb back to Hgb. A secondary glucose-6 phosphate hydrogenase (G6PD) dependent pathway uses nicotinamide adenine dinucleotide phosphate (NADPH) as a cofactor and accounts for the remaining MetHb reduction.

Causes

Congenital methemoglobinemia is a genetic disorder caused by enzymatic deficiencies of the cytochrome-b₅-MetHb reductase pathway and is diagnosed by cyanosis in the infant within the first few weeks of life.³ Deficiencies are classified as type I-IV and are dependent on the expression and distribution of the enzyme deficiency within cells, protein variations, and whether the deficiency is homozygous or heterozygous. The clinical presentation can vary largely, from asymptomatic chronic methemoglobinemia to reduced or lack of cytochrome-b₅-MetHb reductase enzyme leading to severe neurologic dysfunction and pre-mature death.^3,4

Acquired methemoglobinemia, caused by a drug or toxin, is the most common presentation. The Table lists agents associated with methemoglobinemia. This occurs through direct oxidation of Fe²⁺ to form MetHb by the agent or its metabolites or, more commonly, indirectly by reducing free oxygen to the free radical O₂^- which oxidizes Hgb to MetHb; cytochrome-b₅-MetHb reductase enzyme remains normal.²

Nitrates and environmental causes of methemoglobinemia date back to 1868.^2,5 They are still implicated in rural communities where well water may contain high nitrate levels due to pesticide runoff. Nitrates are then converted to nitrites by bacteria in the gastrointestinal tract following ingestion.⁶ Additionally, increased nitric oxide production secondary to sepsis may lead to increased nitrate and MetHb production which has been investigated as an early marker of sepsis.^7,8

Agents Associated with Methemoglobinemia^1,2

Drugs

Toxins

Benzocaine

Acetanilid

Chloroquine

Aniline (dyes, ink)

Dapsone*

Antipyrine

Flutamide

Arsine

Lidocaine

Benzene derivatives

Metoclopramide

Chlorates

Methylene blue

Chlorobenzene

Nitroglycerin

Copper Sulfate

Nitroprusside

Dinitrophenol

Phenacetin

Dinitrotoluene

Phenazopyridine

Hydroxylamine

Phenytoin

Menadione

Prilocaine

Naphthalene

Primaquine

Nitrates/Nitrites

Rifampin

Paraquat/Diquat

Sodium valproate

Phenol

Sulfonamides

Phenylhydrazine

Zopiclone

Smoke Inhalation

Trinitrotoluene

*Incidence of methemoglobinemia can be as high as 20% with normal treatment that can occur months after initiating therapy.⁹

Signs and Symptoms

Elevated MetHb levels decrease effective oxygen delivery and aerobic metabolism. Methemoglobinemia may be acute or chronic and development of symptoms depend on the rapidity of formation or exposure to a causative agent. Levels of 10-20% may be tolerated well or associated with headache, nausea, lightheadedness, or mild cyanosis.^1,2 Levels of 30% or more are associated with dyspnea, nausea, confusion, and tachycardia and levels approaching 50% or more with acidosis, lethargy, stupor, seizures, metabolic acidosis, and coma.^1,2 Even higher levels are associated with cardiac arrhythmias, circulatory failure, and death. Since MetHb level is reported as a percent of the total body Hgb, symptoms at different MetHb levels are largely variable and patients with anemia, for example, may require treatment at lower MetHb levels. Presentation is further complicated since MetHb shifts the oxygen-Hgb dissociation curve to the left, increasing Hgb binding affinity for oxygen and decreasing the ability for oxygen to diffuse into tissues.¹⁰ Consequently a concentration of 10% MetHb would theoretically have 90% oxygen delivery, but in reality, this is lower due to dissociation curve shift.

Diagnosis

Diagnosis of methemoglobinemia is often delayed due to its relatively low occurrence and lack of clinician familiarity.² Cyanosis is often the first sign and other early symptoms may include headache, dyspnea, lightheadedness, and chest pain. Blood sample examination when obtaining a blood gas can be helpful as arterial blood with a higher MetHb level will appear chocolate brown since it is saturated with oxygen as opposed to bright red in normal blood.

Blood gas interpretation can be tricky as analyzers evaluate dissolved gasses in solution with the assumption of normal Hgb. The PaO₂ may look falsely elevated as the machine cannot detect what structure oxygen is bound to. Pulse oxygen saturation can be used to compare as this will decrease, but rarely drops below 85% because the two wavelengths of light can absorb oxy- and deoxy-Hgb and MetHb. A co-oximeter may be a more appropriate device as it is able to differentiate MetHb, but its limited availability clinically hinders its use. The saturation gap between the blood gas and pulse oximeter may help to identify MetHb production.

Treatment

Removal of the offending agent(s) is the first step in treatment for acquired methemoglobinemia. Methylene blue oxidizes NADPH through the G6PD-mediated pathway forming the reduced product leukomethylene blue, which in turn reduces MetHb to Hgb and restores oxygen carrying capacity and delivery.^1,2,11 Treatment is indicated in symptomatic patients with a MetHb level >20% or asymptomatic patients >30%. For levels below 20%, its use is less clear, as methemoglobinemia may resolve on its own. The usual dose is 1-2 mg/kg intravenously over five minutes which causes rapid reversal appreciable within minutes and maximal effect in 30-60 minutes. Persistent cyanosis or sustained elevated MetHb level may warrant an additional dose at 30-60 minutes. Further doses may be necessary every 4-6 hours if there is continued absorption or slow elimination of the offending agent(s).

Higher doses of methylene blue (4 mg/kg) can worsen methemoglobinemia and cause hemolysis. An increased amount of methylene blue present over leukomethylene blue may cause methylene blue to oxidize Hgb instead of NADPH. This is a greater concern in patients with G6PD deficiency since G6PD is primarily responsible for NADPH production in red blood cells.^2,12 It is also concerning that methylene blue may be less effective in some patients with G6PD deficiency. Given the lack of immediately available G6PD testing and varying degrees of enzyme activity in G6PD deficiency and NADPH available, methylene blue is still recommended in most patients with symptoms and G6PD deficiency. A lower dose could be administered initially. Ascorbic acid, a reducing agent, or exchange transfusion may be treatment options in a patient with G6PD deficiency and methemoglobinemia.

Conclusion

Methemoglobinemia is a medical emergency requiring prompt recognition and treatment. Its diagnosis can be difficult, but recognition of common symptoms, especially cyanosis, and quick bedside tests can be performed. Rapid treatment with methylene blue is indicated in symptomatic patients or those with MetHb levels >30% to quickly reverse the disease process and restore tissue oxygenation.

About the authors:Faisal Syed Minhaj, PharmD, is a PGY-2 Emergency Medicine Pharmacy Resident at UR Medicine | Strong Memorial Hospital, Department of Pharmacy Services, in Rochester, NY, and Nicole M. Acquisto, PharmD, FCCP, BCCCP is an Emergency Medicine Clinical Pharmacy Specialist, Department of Pharmacy at the University of Rochester Medical Center

References

1. Skold A, Cosco DL, Klein R. Methemoglobinemia: pathogenesis, diagnosis, and management. South Med J. 2011;104(11):757-761.

2. Wright RO, Lewander WJ, Woolf AD. Methemoglobinemia: etiology, pharmacology, and clinical management. Ann Emerg Med. 1999;34(5):646-656.

3. Jaffe E. Enzymopenic hereditary methemoglobinemia: a clinical/biochemical classification. Blood Cells. 1986;12(1):81-90.

4. Rehman HU. Methemoglobinemia. West J Med. 2001;175(3):193-196.

5. Gamgee A. XXIV. Researches on the blood.—On the action of nitrites on blood. Philos Trans R Soc Lond B Biol Sci. 1868(158):589-625.

6. Walton G. Survey of literature relating to infant methemoglobinemia due to nitrate-contaminated water. In: American Public Health Association; 1951.

7. Ohashi K, Yukioka H, Hayashi M, Asada A. Elevated methemoglobin in patients with sepsis. Acta Anaesthesiol Scand. 1998;42(6):713-716.

8. Schuerholz T, Irmer J, Simon TP, Reinhart K, Marx G. Methemoglobin level as an indicator for disease severity in sepsis. Crit Care. 2008;12(Suppl 2):P448-P448.

9. Esbenshade AJ, Ho RH, Shintani A, Zhao Z, Smith LA, Friedman DL. Dapsone-induced methemoglobinemia: a dose-related occurrence? Cancer. 2011;117(15):3485-3492.

10. Darling RC, Roughton F. The effect of methemoglobin on the equilibrium between oxygen and hemoglobin. Am J Physio. 1942;137(1):56-68.

11. Wendel WB. The control of methemoglobinemia with methylene blue. J Clin Invest. 1939;18(2):179-185.

12. Cappellini MD, Fiorelli G. Glucose-6-phosphate dehydrogenase deficiency. Lancet. 2008;371(9606):64-74.