Methemoglobin: Its Causes and Effects on Pulmonary Function and SpO2 Readings

Rachel Callister

April 17, 2003


Methemoglobin: Its Causes and Effects on Pulmonary Function and SpO2  Readings


Hemoglobin is a substance within red blood cells. It is responsible for transporting oxygen and carbon dioxide between tissues and the lungs. Without hemoglobin, or functional hemoglobin, the body would have no way of adequately oxygenating itself. For this reason, it is important to understand the causes and effects of dysfunctional hemoglobin, specifically methemoglobin, in order that one might stay clear of its precursors and have the knowledge to quickly recognize its clinical manifestations.


Methemoglobin is an abnormal hemoglobin where the iron molecule is in the ferric state (Fe ) rather than the ferrous state (Fe ). Erythrocytes have four hemoglobin chains, which carry oxygen to the tissues.  Each chain contains a heme moiety. Methemoglobin occurs as a result of oxidation of the iron moiety (ie/ loss of an electron) changing the normal ferrous state of hemoglobin to the ferric (Fe ) state. In this ferric state, an alteration of the molecule has occurred which inhibits its oxygen-binding properties.  Under normal circumstances, the body is subjected to continual production of methemoglobin. The red blood cells have two mechanisms for maintaining the methemoglobin below 1%.


The first mechanism works by reducing the amount of oxidizing agent within the body before it transforms hemoglobin into methemoglobin. Red blood cells rely on nicotinamide adenine dinucleotide phosphate (NADPH), which is formed by the hexose monophospate shunt pathway. This NADPH reduces oxidized glutathione to glutathione (GSH). When in the presence of glutathione peroxidase, GSH can prevent the formation of methemoglobin by combining with oxidizing agents. Substances such as ascorbic acid and sulfhydryl compounds are also capable of reducing oxidizing compounds within the bloodstream. This first mechanism has quite an insignificant effect at reducing methemoglobin when compared to the second.


The body’s other mechanism of lowering dysfunctional hemoglobin levels operates by converting methemoglobin into hemoglobin as soon as it is formed. There are two enzyme systems working towards the goal. Diaphorase I (NADH- dependent reductase) is responsible for 95% of the RBCs reducing capacity. The other 5% is reduced by diaphorase II (NADPH-dependent methemoglobin reductase). Each of these enzymes must be present with their cofactors in order to combine with methemoglobin and reduce it back to its normal ferrous state. Diaphorase I can use methylene blue as a cofactor. Homozygous NADH-dependent reductase patients are those who have little to no enzyme activity and must rely on non-enzymatic reduction. Methemoglobin levels can be anywhere up to 50% in these patients. Fortunately, these high levels are tolerated quite well so any treatment is primarily for cosmetic purposes. They are given methylene blue or ascorbic acid for daily ingestion in order to increase non-enzymatic reduction of methemoglobin.  Children, particularly those less than four months, are more susceptible to methemoglobinemia. The erythrocyte protective mechanism that fights against oxidative stress, the NADH system, is not fully developed. This means that the NADH methemoglobin reductase activity and concentrations are low.


High levels of methemoglobin can be acquired or caused by an inherited trait. The inherited form of methemoglobin is generally due to a deficiency of NADH methemoglobin reductase activity or to an abnormal hemoglobin known as hemoglobin M. The problem with abnormal hemoglobin M is that it holds the iron molecule in the methemoglobin form. This form, of abnormal hemoglobin, is apparently incompatible with life. It cannot be reduced by the mechanisms present in the erythrocyte and it will remain unchanged with the administration of methylene blue or ascorbic acid.


There are other causes of methemoglobinemia other than the inherited form. Acquired levels of methemoglobin occurs when the rate at which methemoglobin is formed is greater than the rate at which it is cleared. This is caused by the exposure to certain chemicals. Methemoglobin inducers can be classes into two categories:

1.   Chemicals for which methemoglobin formation is the principal cause of toxicity.

2.   Chemicals for which methemoglobin formation is not the principal cause of toxicity.

Some examples of industrial chemicals, which cause the principal effect of toxicity, are, aliphatic nitrates (ie. Prophylene glycol dinitrate), aliphatic nitros (ie. n-Propyl nitrate), aromatic amines (ie. Dimethylaniline), fluorides (ie. Nitrogen trifluoride), irritant gases (ie. Nitric oxide), and nitrosobenzens (p-Dinitrosobenzene) (,


The secondary causes of methemoglobinemia are those chemicals which generally do not cause a clinically significant increase in blood level toxicity. The detection of increased levels, however, can be a helpful indicator of an unhealthy exposure to chemicals at a workplace or within the home. Some examples of those chemicals, which do not have a principal effect on methemoglobin toxicity, are, toxic gases (ie. Methylhydrazine), herbicides (ie. Propanil), and aromatic amines (ie. Benzidine).


Nitrites and aniline derivatives are two of the most common causes of methemoglobin toxicity. Sodium nitrite is used as a meat preservative and looks very similar to table salt. Because of these two reasons, it is frequently responsible for causing methemoglobinemia. Nitrites are also used as medicinal ingredients.  Silver nitrate, used for burn patients, causes increased levels of methemoglobin because infecting bacteria converts nitrate to nitrite. One of the most common causes of nitrate-induced toxicity is an infant who is fed contaminated well water. The nitrate salts are converted to nitrites by the enteric bacteria, which is then rapidly absorbed by the gastrointestinal tract. Certain household products such as inks and shoe polish contain aniline. It is also found in red and orange crayons. Phenacetin, sulfonamides, and pyridium are drugs associated with methemoglobinemia. Hurricane spray, a topical anesthetic commonly used for intubations, contains benzocaine, which is also a known cause. Maternal exposure to these agents can cause fetal methemoglobin.


Common inducers of methemoglobinemia are listed below:

Contaminated well water (inorganic nitrates/nitrites)

Meat Preservatives (inorganic nitrates/nitrites)

Vegetables-carrot juice, spinach (inorganic nitrates/nitrites)

Silver nitrate burn therapy (inorganic nitrates/nitrites)

Industrial salts (inorganic nitrates/nitrites)

Contaminants of nitrous oxide canisters for anesthesia (inorganic nitrates/nitrites)

Room deodorizer propellants (Butyl/isobutyl nitrite)

Inhalant in cyanide antidote kit (Amyl nitrite)

Pharmaceuticals for treatment of angina (Nitroglycerin)

Laundry ink (Aniline/aminophenols)

Industrial solvents; gun-cleaning products (Nitrobenzene)

Antibacterial drugs (Sulfonamides)

Pyridium (Phenazopyridine)

Chloroquine; Primaquine (Antimalarials)

Dapsone (Sulfones)

Bactericide [tuberculostatic] (p-Aminosalicylic acid)

Mothballs (Naphthalene)

Fungicide for plants, seed treatment (Copper sulfate)

Antiseborrheic, antipruritic, antiseptic (Resorcinol)

Matches, explosives, pyrotechnics (Chlorates)

Fires (Combustion products)

Benzocaine; Lidocaine; Propitocaine; Prilocaine (Local anesthetics)



There are many different effects of methemoglobinemia, all varying, depending on severity of the case.  Headaches, cyanosis, fatigue, coma, and death are all possible effects. Patients, who present with cyanosis and have no apparent cause of hypoxia, should be considered for increased levels of methemoglobinemia. While oxygenated blood is red and deoxygenated blood is blue, blood containing too much methemoglobin is reddish-brown, or a characteristic chocolate-brown. At high levels, the hallmark ‘chocolate cyanosis’ remains in the mucous membranes even after the rest of the skin has turned blue or purple. Blood remains the reddish-brown colour after exposure to oxygen, and urine may be a black or brown colour. Drawing an arterial sample in order to analyze its colour is a quick test for methemoglobinemia. This dark colour causes clinical cyanosis at levels of 1.5 g/dL (approx. 10-15% methemoglobin level). Deoxygenated blood requires a higher level of 5.0 g/dL in order to cause the same hue or cyanosis. This means that methemoglobin can be detected at lower levels before there are any cardiopulmonary symptoms. Methemoglobinemia is made worse in anemic patients because the oxy-hemoglobin curve is already shifted to the left further reducing their oxygen unloading capacity.


Headache, fatigue, tachycardia, weakness, and dizziness are clinical symptoms, which appear at levels of 30-40% methemoglobin. Dyspnea, acidosis, arrhythmias, coma, and convulsions occur at 50-60%.  These are true signs that oxygenation of tissues is inadequate. At concentrations of 70% or greater death is impending. Organs that require more oxygen, such as the central nervous system, or cardiovascular system, are the first to show signs of methemoglobinemia. This, however, does not occur until levels of approximately 30-40% are reached.  Pulmonary function of the patient becomes progressively compromised as levels of methemoglobin rise. As was noted previously, when in the ferric state, hemoglobin has lost its oxygen carrying capacities. This explains the clinical symptom of dyspnea. After several minutes or hours of experiencing this difficulty in breathing, the patient’s accessory muscles for inspiration will tire. As a result, a decrease in pH will appear, as the patient becomes unable to clear carbon dioxide from their lungs. The change in pH, which occurs at this point, is only a measurement of the remaining functional hemoglobin.  The patient would have already been in an acidotic state because methemoglobin has no capacity for carrying either carbon dioxide or oxygen.


Methemoglobinemia also has an interesting effect on equipment used by healthcare professionals. A pulse oximeter must be used with caution as it can produce an incorrect reading. It measures hemoglobin saturation by sending out two different wavelengths and interpreting their light absorption.  This separates out the oxy-hemoglobin and deoxy-hemoglobin. Unfortunately, it cannot differentiate methemoglobin from oxy-hemoglobin and reports them both as oxy-hemoglobin. This, as a result, gives a false reading of functional oxy-hemoglobin and can be quite misleading. The pulse oximeter, oddly, measures a hallmark SpO2  reading of 85% in many cases of methemoglobinemia. This must also be considered when assessing a patient for its potential toxicity. Cooximetry must be used on these patients because it uses four or more wavelengths so it can decipher between different types of hemoglobin, including carboxyhemoglobin and methemoglobin.


Methemoglobin can be treated with the administration of methylene blue. It is commonly given in doses of 1-2 mg/kg of 1% IV over a five minute period and not given until blood levels reach at least 30% methemoglobin. The subsequent doses are given as persisting cyanosis and hypoxia dictate. However, the doses should never exceed 7mg/kg ( hemeonc/metheme.htm). Along with the administration of methylene blue, the patient may also need their skin and clothing washed in order to remove all offending chemicals. Hemodialysis may be necessary depending on the severity of the case. Methylene blue is used because it acts as a cofactor to NADPH methemoglobin reductase, thus permitting the formation of functional hemoglobin. There are some side effects of the drug, which require careful monitoring of the patient including, dyspnea, dysuria, and mild hemolysis.


Increased levels of methemoglobin present due to several causes.  These could include: an impairment of the body’s mechanisms to clear methemoglobin, an inherited trait, or exposure to certain chemicals.  When methemoglobin levels greatly surpass common levels, the normal, functional hemoglobin is impeded.  Without enough functional hemoglobin, the body would have no way of adequately oxygenating itself.  There are many signs and symptoms associated with methemoglobinemia.  It is important for the health professional to be diligent at knowing and recognizing these signs in order that the most appropriate, effective care is given to the patient.

Case Study

A three-year-old patient presents to the emergency department complaining of shortness of breath. There is no pertinent history involved with this patient other than that he/she currently resides outside the city.

Vital signs are:

Blood Pressure 150/90, Pulse 150, RR 30, Temperature: afebrile

Upon examination, the patient had clinical cyanosis to the extremities. The pulse oximeter reads 85% and arterial blood gases drawn have a chocolate brown appearance. By this point, the patient was on 50% oxygen by simple mask.

Arterial blood gas results are as follows:

pH 7.35, pCO2  30, pO2  250, O2  saturation 100%

After blood gases were drawn and run on a cooximeter, methemoglobin was found to be 40%. It was determined that the patient was suffering from high levels of methemoglobin and was treated accordingly with administration of methylene blue. After a 1mg/kg dosage over a five minute period, the patient eventually recovered from their cyanosis, and respirations began to decrease closer to a normal rate.  It was later established that these high levels of methemoglobin were caused by the ingestion of contaminated well water.



Hemoglobin Derivatives. Retrieved, December 20, 2002,

Malley, William. Clinical Blood Gases. Philadelphia: W.B. Saunders Co., 1990.

Methemoglobinemia. Retrieved, December 20, 2002, methemoglobinemia.htm.

Methemoglobinemia. Retrieved, December 20, 2002, metheme.htm.

Methemoglobinemia: Primary Industrial Chemicals and Non-Occupational Exposures.  Retrieved,  December 20, 2002,

Soda at a Funeral Home. Retrieved, December 20, 2002,

VanDerslice, Jim. Dose-response of Nitrate and Other Methemoglobin Inducers on Methemoglobin Levels of Infants. Retrieved, December 20, 2002, cfm/fuseaction/display.abstractDetail/abstract/5379/report/0.

Wilkins, Robert, Susan Krider and Richard Sheldon. Clinical Assessment in Respiratory Care, fourth edition. St. Louis: Mosby, 2000.