Methemoglobinemia: Etiology, Pharmacology, and Clinical Management,☆☆

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Abstract

Methemoglobin (MHb) may arise from a variety of etiologies including genetic, dietary, idiopathic, and toxicologic sources. Symptoms vary from mild headache to coma/death and may not correlate with measured MHb concentrations. Toxin-induced MHb may be complicated by the drug’s effect on other organ systems such as the liver or lungs. The existence of underlying heart, lung, or blood disease may exacerbate the toxicity of MHb. The diagnosis may be complicated by the effect of MHb on arterial blood gas and pulse oximeter oxygen saturation results. In addition, other dyshemoglobins may be confused with MHb. Treatment with methylene blue can be complicated by the presence of underlying enzyme deficiencies, including glucose-6-phosphate dehydrogenase deficiency. Experimental antidotes for MHb may provide alternative treatments in the future, but require further study. [Wright RO, Lewander WJ, Woolf AD: Methemoglobinemia: Etiology, pharmacology, and clinical management. Ann Emerg Med November 1999;34:646-656.]

Section snippets

INTRODUCTION

Methemoglobinemia refers to the oxidation of ferrous iron (Fe++) to ferric iron (Fe+++) within the hemoglobin molecule.1 This reaction impairs the ability of hemoglobin to transport oxygen and carbon dioxide, leading to tissue hypoxemia and in severe cases, death. Methemoglobinemia most commonly results from exposure to an oxidizing chemical, but may also arise from genetic, dietary, or even idiopathic etiologies.2, 3 This review focuses on acquired forms of methemoglobinemia. Because of these

METHEMOGLOBINEMIA AND INTRACELLULAR OXIDATION

To understand oxidative toxicity and its potential complications, certain biochemical properties must first be reviewed. Oxidation involves the extraction of electrons from a substrate. Reduction involves the transfer of electrons to a substrate. A substance has been oxidized if it loses an electron, and if it gains an electron, it has been reduced.

Oxidation/reduction reactions are termed “redox” reactions because they always occur together, that is, for one substance to be reduced, another

PHYSICAL PROPERTIES OF METHEMOGLOBIN

Hemoglobin molecules contain iron within a porphyrin heme structure. The iron in hemoglobin is normally found in the Fe++ state. The iron moiety of hemoglobin can be oxidized to the Fe+++ state to form MHb.10 Once MHb is formed, the molecule loses its ability to carry molecular oxygen. Because RBCs are bathed in oxygen, a certain amount of physiologic MHb formation occurs continuously.10 Several endogenous reduction systems exist to maintain MHb in the reduced state, and in normal individuals

DIRECT ENDOGENOUS REDUCTION

Even in the absence of exogenous oxidative stress, endogenous oxidation from molecular oxygen would eventually convert enough hemoglobin to MHb to impair cellular respiration.10 To combat this process, there are several enzyme systems in the RBC that inhibit oxidation or reduce MHb back to hemoglobin. The cytochrome-b 5–MHb reductase system is the predominant system and accounts for approximately 99% of daily MHb reduction.10 Ascorbic acid and glutathione account for small amounts of reduction.

INDIRECT ENDOGENOUS PROTECTIVE MECHANISMS

Protective mechanisms against oxidative stress include sulfation enzymes, ascorbic acid, and glutathione. These enzymes and peptides serve to detoxify oxidative exogenous chemicals and thereby indirectly prevent methemoglobinemia. Reduced glutathione is quantitatively the most important cellular antioxidant, and is of key importance in all cells for the preservation of protein sulfhydryl groups and to prevent oxidative damage in general.15, 16 Glutathione is a minor pathway in the reduction of

Toxin-induced

The most common cause of MHb is ingestion or skin exposure to an oxidizing agent. MHb is most common in children older than 6 months. Common agents are aniline, benzocaine, dapsone, phenazopyridine (pyridium), nitrites, nitrates, and naphthalene (Table 1). Oxidizing agents can be divided into those that directly oxidize hemoglobin and those that indirectly oxidize hemoglobin. Direct oxidizers react directly with hemoglobin to form MHb. Indirect oxidizers are actually powerful reducing agents

DIFFERENTIAL DIAGNOSIS AND CLINICAL EFFECTS

The differential diagnosis for a small infant with cyanosis is much broader than that of a toddler, adolescent, or adult. Congenital causes of MHb are more likely to present in the first few hours or days of life. Idiopathic MHb associated with acidosis occurs in this age group, as well as MHb caused by well water nitrites. At 4 months and older, infants may be exposed to benzocaine in teething gels as a cause of MHb. Benzocaine is an analogue of aniline and can be metabolized to the same

CURRENT TREATMENT

Once recognized and confirmed, life-threatening methemoglobinemia must be treated rapidly. However, not all patients require antidotal therapy, and many do well with only supportive care. Furthermore, patients with chronic congenital methemoglobinemia, like the patient with cyanotic heart disease, may have adapted to the chronic cyanosis, such that very high levels of MHb are tolerated without any overt symptoms. Treatment of these patients and patients with acute MHb is summarized in the

ALTERNATIVE TREATMENTS

Several investigators have recently suggested alternatives to methylene blue therapy. Given that MHb can be caused and reversed by various agents, multiple potential antidotes exist and can be tailored to specific drugs. Two potential mechanisms of action exist: altering the metabolism of the toxin or directly reducing MHb.

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