How is Methemoglobin Created?

If hemoglobin is exposed to an agent or chemical that is able to extract an electron from 1 or more of the 4 ferrous ions in hemoglobin, the iron atom(s) adopt a +3 atomic valence (known as a ferric ion). The molecule of hemoglobin now has at least 1 iron atom in the ferric state. A molecule of hemoglobin with 1 or more of its iron atoms in the ferric ion status is referred to as methemoglobin . Inorganic chemistry teaches that the process whereby an iron atom’s valence is increased from +2 to +3 is referred to as oxidation. The agent or chemical causing the increased valence is called an oxidant.

As soon as even one of hemoglobin’s 4 iron atoms has been oxidized to the ferric state, the methemoglobin molecule then has an increased affinity for its bound oxygen and a decreased affinity for any unbound oxygen. Thus, less oxygen is transported by methemoglobin and the smaller amount of oxygen that is transported is not readily released in the peripheral tissues (ie, the oxyhemoglobin dissociation curve is shifted to the left). With less oxygen being transported to the periphery and less oxygen being released by methemoglobin in the periphery, the affinity of methemoglobin for carbon dioxide is decreased and less carbon dioxide is removed from the peripheral tissues. It is thought that the transition from hemoglobin to methemoglobin alters the molecule’s shape (ie, molecular conformation) and that this alteration of molecular shape is sustained by the presence of one or more ferric ions. The fraction of hemoglobin oxidized dictates the extent of compromise in oxygen delivery and carbon dioxide removal (ie, toxicity) and it is directly related to the efficacy of exposure to the oxidizing agent. If the exposure to an oxidant is great enough, cyanosis or color change in the blood and skin becomes apparent followed by progressively more serious signs and symptoms of methemoglobinemia ( Table 1 ).

Reducing Methemoglobin is a Physiologic Process

A blood level of methemoglobin between 0% and 2% is detectable in the human population at all times. This level is thought to exist because the body uses and is dependent on a prototypical oxidant, oxygen. Blood is continuously exposed to this oxidant because it must necessarily and continually transport oxygen. The human body has more than one compensatory physiologic mechanism to reduce ferric iron to ferrous iron. These systems continually reduce methemoglobin to hemoglobin and thereby maintain homeostasis of the oxygen delivery system in the body. The predominant enzyme system for the physiologic reduction of methemoglobin to hemoglobin is cytochrome b5 methemoglobin reductase. An alternate enzyme system that normally reduces only a small fraction of methemoglobin is referred to as nicotinamide adenine dinucleotide phosphate (NADPH ₃ ).

How Methemoglobin Levels Increase

When the body encounters an exogenous oxidant exposure of sufficient dosage and potency, the physiologic capacity for methemoglobin reduction is overwhelmed and increasing methemoglobin levels ensue. As methemoglobin levels increase, the reading on a conventional pulse oximeter falls to between 85% and 90%, and remains in that range. The pulse oximeter reading is unresponsive to the administration of supplemental oxygen. Methemoglobin concentrations approaching 10% to 15% may be associated with cyanosis in light-skinned individuals. Methemoglobin blood levels of 20% to 45% produce additional symptoms, which include nausea, lethargy, tachycardia, headache, and dizziness. Consciousness deteriorates as methemoglobin levels reach the range of 50% to 55%, and levels of 70% are usually fatal (see Table 1 ).

Measuring Methemoglobin Blood Levels

Before 2005, a laboratory test was required to identify the blood level of methemoglobin. This test was named oximetry analysis (commonly referred to as a co-oximetry test) and required that a blood specimen be drawn. The methemoglobin level was generally measured and reported as a percent of hemoglobin present in the blood. A noninvasive device that looks like a pulse oximeter was marketed in 2005 (Masimo, Inc, Irvine, CA, USA) that could reliably identify blood levels of methemoglobin and carboxyhemoglobin as well as the hemoglobin saturation of oxygen. The new monitor uses additional light transmission technology. It is of interest that this new device correctly reads elevated methemoglobin levels, whereas the pulse oximeter component may erroneously read, as previously described.

Potential Etiologies of Methemoglobinemia

Oxidation of hemoglobin to methemoglobin occurs continuously in the absence of any exogenous toxin or oxidizing medication and levels of 1% to 2% are the result of a physiologic process. As stated previously, this low methemoglobin level may be caused by the transport of oxygen and its inherent ability to act as an oxidant. In this discussion of etiologies of methemoglobinemia, only causes of methemoglobin levels that are more than those described as physiologic will be considered.

Congenital methemoglobinemia is a rare metabolic disorder of the newborn and is difficult to diagnose. The metabolic ability to reduce methemoglobin to hemoglobin is either absent or diminished. The diagnosis and treatment of this perinatal disease is important but it does not require the attention of the dental profession.

The most common etiology of methemoglobinemia is referred to as acquired methemoglobinemia. The first clinical descriptions of acquired or toxic methemoglobinemia date back to 1886. Many cases of acquired methemoglobinemia have as their etiology an oxidizing substance that may be one of a large number of medications or other exogenous toxins. Oxidizing medications that are used in dentistry include the topical anesthetic benzocaine (eg, Hurricaine) and the injected local anesthetic prilocaine (Citanest), or more accurately the two metabolites of prilocaine: o-toluidine and nitrosotoluidine. There are many other oxidants, including aniline (used in the manufacture of polyurethane), nitrites (used to treat angina, cyanide toxicity), nitrobenzene (a precursor of aniline), dapsone (Aczone, an antibiotic for acne), and phenazopyridine (Pyridium, a urologic antibiotic). The rate of increase and the peak levels of methemoglobin are a function of dose and route of absorption. Nitrous oxide has been implicated as an oxidant of hemoglobin by a few publications and is discussed later in detail.

In some cases of methemoglobinemia an etiology is never identified. In this situation, the diagnosis becomes idiopathic methemoglobinemia.

Interactions Between Oxidizing Agents and Diseases

Patients that are diagnosed with diseases that may compromise oxygen delivery to the peripheral tissues need to be assessed for the potential negative interaction with any oxidizing agents administered during dental or other treatments. This task is sometimes difficult because diseases vary as to their mechanism for decreasing oxygen delivery to peripheral tissues. Examples include patients with chronic kidney failure who commonly manifest a low hemoglobin value, patients diagnosed with sickle cell anemia and who are beginning a sickle cell crisis, and patients with pulmonary fibrosis who have hypoxemia caused by an oxygen-diffusion barrier in their lungs. Patients with any of these diagnoses may experience a life-threatening reduction in oxygen delivery to their peripheral tissues if they receive a modest dose of an agent or medication that oxidizes hemoglobin to methemoglobin.

Medications Used in Dentistry That Induce Methemoglobinemia

As previously mentioned, the dental profession in the United States commonly administers two medications that are well recognized as oxidants of hemoglobin. The two medications are discussed sequentially starting with prilocaine. Two other medications used in dentistry, lidocaine and nitrous oxide, have been held responsible for being oxidants of hemoglobin. However, after extensive review, they have not been clearly demonstrated to cause methemoglobinemia.

Prilocaine

The evidence supporting the oxidation of hemoglobin to methemoglobin subsequent to the clinical use of prilocaine has been clearly demonstrated for many decades. Investigations into the mechanism of oxidation clarified that prilocaine itself did not oxidize hemoglobin in vitro; however, oxidation did occur in vivo. Subsequently, it was discovered that two metabolites of prilocaine are responsible for the oxidation of hemoglobin. These metabolites have been identified as o-toluidine and nitrosotoluidine.

Parenteral local anesthetics are packaged in 1.8 mL cartridges for dental administration in the United States. The medications in cartridges include lidocaine, mepivacaine, prilocaine, articaine, and bupivacaine. These local anesthetics are packaged with and without vasoconstricting agents that enhance the duration and intensity of local anesthetic action and decrease the central nervous system toxicity. Prilocaine is packaged as a 4% solution without an agent for vasoconstriction and a 4% solution with an added agent for vasoconstriction (one 4% dental cartridge of 1.8 mL volume contains 72 mg of prilocaine). Of the listed local anesthetics packaged for parenteral use in the United States, only prilocaine is well documented to cause the oxidation of hemoglobin to methemoglobin (see later discussion).

Other injectable local anesthetics and methemoglobinemia

The only injectable local anesthetics cited in the literature as oxidizers of hemoglobin are prilocaine, lidocaine, tetracaine, and cocaine. Lidocaine has not been shown to be an oxidizer of hemoglobin after extensive review (see later discussion). Tetracaine is a local anesthetic with an ester structure that is used exclusively in medical anesthesiology for spinal anesthesia and is not available in dental cartridges in the United States. There is inadequate evidence to label tetracaine as an oxidizer of hemoglobin. Cocaine has not been used as an injectable local anesthetic in more than 100 years. There is no suggestion or evidence in the literature that mepivacaine, bupivacaine, or septocaine oxidizes hemoglobin and thereby causes methemoglobinemia.

Benzocaine

Benzocaine is commonly used by the dental profession as a topical anesthetic on oral mucosa before administering a local anesthetic injection and as a topical anesthetic on oral mucosa and gingiva before having the teeth cleaned. Less frequently, benzocaine is used to minimize pain from radiographic film when taking intraoral radiographs. Benzocaine spray is infrequently used by dental and medical anesthesiologists during laryngoscopy for endotracheal intubation under special circumstances. Benzocaine is marketed as an aerosol, gel, cream, liquid, and oral spray in concentrations ranging from 7.5% to 20.0%. It is marketed for all oral pain, including teething pain in infants. It is available in many over-the-counter products. Benzocaine is a well-documented but poorly understood cause of methemoglobinemia.