Methemoglobin (MetHb) was first described by Felix Hoppe-Seyler in 1864.
MetHb is a potentially lethal accumulation of oxidized hemoglobin. Although it is usually acquired, it can also be congenital.
Epidemiology
Incidence
Dapsone (used to treat leprosy, or Pneumocystis pneumonia) accounts for 42% of acquired cases (1).
Benzocaine spray accounts for the most severe cases (1).
Prevalence
50% of cases involve infants and the elderly, with infants <4 months being particularly susceptible (2).
Mortality
Death occurs when methemoglobin fractions approach 70%.
Etiology/Risk Factors
Exposure to an oxidizing agent is the most common cause of MetHb (3).
Examples of oxidizing agents: Benzocaine, lidocaine, prilocaine, acetaminophen, methylene blue (high dose), metoclopramide, and nitrates; also aniline, dapsone, celecoxib, chloroquine, cyclophosphamide, ifosfamide, methanol, phenazopyridine, phenytoin, primaquine, riluzole, trimethoprim–sulfamethoxazole.
Other exogenous oxidizing agents are found in teething gels, automobile exhaust, inhalants, industrial chemicals, smoke, and pesticides.
Well water and foods containing nitrates can be converted to nitrites (powerful oxidizers) by intestinal flora (4).
States of high oxidative stress including systemic infection and cancer (3).
Anemia (including mild degrees): MetHb is more likely to progress to symptoms when there is a lower hemoglobin reserve.
Acidosis: Endogenous reducing enzymes are less efficient at a low pH (4).
Idiopathic MetHb is commonly seen among infants <4 months old (4).
Genetic mutation is a rare cause of MetHb. Although usually benign, these patients are at increased risk of developing acute toxicity when exposed to oxidizers or oxidative states (4).
Other than the risk factors described herein, it is unknown why some people develop MetHb while others do not.
Physiology/Pathophysiology
Oxidative toxicity involves the "redox" reaction, or loss of electrons from a substrate; whereas reduction involves the transfer (gain) of electrons to a substrate.
Hemoglobin is composed of four heme groups, each with one atom of iron. The iron atom binds oxygen only in the reduced ferrous (Fe2+) state. Thus, when oxidation occurs (Fe2+ to Fe3+), a ferric heme state is created, known as methemoglobin, that does not bind and transport oxygen to tissues.
RBC's are uniquely susceptible to oxidation and as such, MetHb typically presents before oxidative injury in other tissues. RBCs:
Carry O2, and hence are constantly exposed to oxygen free radicals.
Lack a nucleus and cannot synthesize new proteins; thus "older" cells are more prone to oxidative injury.
Lack mitochondria. They are less efficient at generating the cofactors and energy needed for reducing enzymes.
Normally, methemoglobin is quickly reduced (gains electrons) back to hemoglobin by cytochrome-b5 reductase (b5R); it is responsible for 99% of daily methemoglobin reduction. This keeps methemoglobin levels at around 1% in healthy individuals.
Methemoglobin is incapable of binding O2, and additionally, the Fe3+ heme creates an allosteric change that decreases the O2 unloading from any remaining Fe2+ heme groups. Thus, it produces a combined:
Decrease in O2 carrying capacity; oxyhemoglobin becomes non-oxygen carrying methemoglobin.
Decrease in peripheral O2 delivery (impaired unloading); seen as a left-shift of the oxygen-dissociation curve.
These abnormalities result in functional anemia and tissue hypoxia.
MetHb occurs when there is:
Increased methemoglobin production.
Decreased reduction capacity.
Thus, toxicity and symptoms depend on the methemoglobin level and any concomitant conditions that impair the ability to deliver O2 to the tissues.
Methemoglobin can also covalently bind sulfur to form sulfhemoglobin. Endogenous glutathione can serve as the sulfur donor and many drugs capable of producing MetHb can also produce sulfhemoglobinemia, which will affect treatment (4).
Prevantative Measures
Re-exposure, high concentrations (>20%), and liberal use of benzocaine should be avoided.
Identify those individuals at high risk and make methylene blue (MB) and blood available for the procedure.
Diagnosis⬆⬇
Cyanosis is the first sign.
Develops with 1.5 g/dL of methemoglobin (~15% total hemoglobin) due to its spectrographic properties as compared to deoxyhemoglobin that requires 5 g/dL
Difficult to detect in dark skinned patients
Maintain a high index of suspicion when cyanosis is refractory to O2 supplementation, and especially if it develops 20–60 minutes (up to 2 hours) after benzocaine, prilocaine, or lidocaine administration
Severity of symptoms is dependent on the level of methemoglobin. MetHb as a % of total hemoglobin:
Concomitant conditions: Anemia, acidosis, respiratory compromise, and cardiac disease may make patients more symptomatic for a given methemoglobin level.
Oxidant-induced hemolysis can accompany MetHb.
Pulse oximeters measure two wavelengths of light: 660 nm (red, oxyhemoglobin) and 940 nm (infrared, deoxyhemoglobin). Methemoglobin absorbs equal amounts of these wavelengths; a ratio of pulsatile and nonpulsatile absorbances equal to 1 corresponds to a hemoglobin saturation of 85%. Thus, regardless of the actual oxygen saturation, MetHb will read at 85% oxygen saturation on pulse oximeter.
Co-oximeters detect multiple wavelengths of light, and can measure the concentration of different forms of hemoglobin including reduced hemoglobin, oxyhemoglobin, carboxyhemoglobin, and methemoglobin. Measurements are accurate and available in <2 minutes.
Methemoglobin levels rise with storage time
Both sulfhemoglobin and MB have similar absorbencies and will be reported as methemoglobin
Arterial line: Placement allows for frequent arterial blood gas (ABG) measurements (lactic acidosis), beat-to-beat pressure regulation, and direct measurement of methemoglobin levels. Because PaO2 refers to dissolved gas, it will reflect true partial pressure values; however, the SpO2% calculation assumes normal hemoglobin oxygen binding characteristics and will yield a false value. Thus, the SaO2% should be directly measured by the lab.
Arterial blood appearance
High concentrations of methemoglobin appear chocolate brown.
Deoxyhemoglobin appears dark red and upon exposure to atmospheric O2 will turn bright red. In contrast, methemoglobin will not change color over time, as it is unable to bind to oxygen.
Sulfhemoglobin also appears chocolate brown.
EKG: Presence of myocardial ischemia indicates decreased O2 delivery to other tissues.
Potassium cyanide (Drabkin's reagent) test.
Distinguishes between sulfhemoglobin and methemoglobin.
Methemoglobin will react to the addition of potassium cyanide and turns bright red.
Sulfhemoglobin is inert and will remain chocolate brown.
MetHb toxicity can be rapidly lethal but with prompt recognition and early initiation of treatment, outcomes are good.
Any oxidizing agents should be sought and discontinued.
Supportive care
Administer 100% oxygen
Maintain airway
Hemodynamic support
Methylene blue (MB): NADPH-methemoglobin reductase is a generalized reductase found in the body and has a high affinity for MB dye. If NADPH is available, it will reduce MB, which in turn reduces methemoglobin back to hemoglobin.
Treatment is indicated at approximately 20% MetHb in symptomatic patients, 30% MetHb in asymptomatic patients, and 10–30% MetHb in patients with concurrent problems that compromise O2 delivery.
The dose of 1% solution is 1–2 mg/kg or 0.1–0.2 mL/kg over 3–5 minutes intravenously, followed by 15–30 mL normal saline flush. If symptoms persist after 20 minutes, another dose of 1 mg/kg can be given 30–60 minutes after the initial dose. Do not exceed a total of 7 mg/kg because at these doses, MB can cause MetHb.
Ineffective in the following scenarios:
G6PD deficiency: NADPH is largely generated by glucose-6-phosphate dehydrogenase (G6PD). MB may also induce oxidant injury or hemolysis
NADPH-methemoglobin reductase deficiency
Sulfhemoglobin emia
Secondary options if failure to respond to standard treatment or methemoglobin levels exceed 50%:
Hyperbaric oxygen administration
Exchange transfusion
Dextrose solutions catabolize glucose via glycolysis and replenish NADH and NADPH, which are both necessary cofactors for the reduction of methemoglobin.
Follow-Up⬆⬇
An ABG should be obtained to confirm the absence of acidosis and no increase in methemoglobin.
Therapeutic MB can cause a false elevation in methemoglobin levels due to the similar absorbance spectrum. Confirmation should be performed by using the specific Evelyn–Malloy method which involves adding cyanide and ferricyanide reagents.
Some drugs like dapsone and aniline have been reported to produce a rebound MetHb 4–12 hours after successful MB therapy because their metabolites are oxidizers.
Oxidative hemolysis can follow MetHb 12–24 hours after first exposure to the etiologic agent.
The future use of oxidizing agents should be avoided in these patients.
References⬆⬇
HamiltonRJ.Acquired methemoglobinemia: A retrospective series of 138 cases at 2 teaching hospitals. Ann Emerg Med. 2005;46(5):477–478.
SoT, et al.Topical benzocaine-induced methemoglobinemia in the pediatric population. J Pediatr Health Care. 2008;22(6):335–339.
KaneGC, et al.Benzocaine-induced methemoglobinemia based on the Mayo Clinic Experience from 28,478 transesophageal echocardiograms. Arch Intern Med. 2007;167(18): 1977–1982.
WrightRO, et al.Methemoglobinemia: Etiology, pharmacology, and clinical management. Ann Emerg Med. 1999;34(5):646–656.
Additional Reading⬆⬇
See Also (Topic, Algorithm, Electronic Media Element)
Measures light absorbance at the wavelengths 660 and 940 nm which is the absorbance of oxy- and deoxygenated blood, respectively. SpO2 is calculated from this ratio
Methemoglobin is absorbed at both of these wavelengths and will give a false value
Significant methemoglobin will only be detected as mild to moderate O2 desaturation