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Methemoglobinemia: Etiology, Pharmacology, and Clinical Management

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Methemoglobinemia: Etiology, Pharmacology, and Clinical Management REVIEW Methemoglobinemia: Etiology, Pharmacology, and Clinical Management From the Department of Pediatrics, Robert O Wright, MD* Methemoglobin (MHb) may arise from a variety of etiologies Division of Emergency Medicine, William J Lewander, MD* including genetic, dietary, idiopathic, and toxicologic sources. Hasbro Children’s Hospital, Brown Alan D Woolf, MD, MPH‡ Medical School, Rhode Island Poison Symptoms vary from mild headache to coma/death and may Control Center, Providence, RI*; and not correlate with measured MHb concentrations. Toxin- Department of Medicine, Program in induced MHb may be complicated by the drug’s effect on other Clinical Toxicology, Boston Children’s Hospital; Harvard Medical School, organ systems such as the liver or lungs. The existence of Massachusetts Poison Control System, underlying heart, lung, or blood disease may exacerbate the ‡ Boston, MA. toxicity of MHb. The diagnosis may be complicated by the Received for publication effect of MHb on arterial blood gas and pulse oximeter oxygen July 24, 1998. Revisions received February 8, 1999, and saturation results. In addition, other dyshemoglobins may be June 28, 1999. Accepted for confused with MHb. Treatment with methylene blue can be publication August 23, 1999. complicated by the presence of underlying enzyme deficiencies, Address for correspondence: including glucose-6-phosphate dehydrogenase deficiency. Robert O Wright, MD, Rhode Island Hospital, Davol Building, Experimental antidotes for MHb may provide alternative 593 Eddy Street, Providence, RI treatments in the future, but require further study. 02903; 401-444-6680, fax 401-444-4307; [Wright RO, Lewander WJ, Woolf AD: Methemoglobinemia: E-mail [email protected]. Etiology, pharmacology, and clinical management. Ann Emerg Copyright © 1999 by the American Med November 1999;34:646-656.] College of Emergency Physicians. 0196-0644/99/$8.00 + 0 47/1/102246 INTRODUCTION Methemoglobinemia refers to the oxidation of ferrous iron (Fe++) to ferric iron (Fe+++) within the hemoglo- bin 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 expo- sure to an oxidizing chemical, but may also arise from genetic, dietary, or even idiopathic etiologies.2,3 This review focuses on acquired forms of methemoglobine- mia. Because of these disparate causes, confusion may arise in the recognition and management of methe- moglobinemia. Physicians may be aware of one etiology, such as dietary nitrites in well water, but may be unfa- miliar with others, such as the ingestion of teething gels. Furthermore, laboratory data, which clinicians may 646 ANNALS OF EMERGENCY MEDICINE 34:5 NOVEMBER 1999 METHEMOGLOBINEMIA Wright, Lewander & Woolf believe to be diagnostic, may instead be falsely normal in variety of enzymatic systems exist that protect the RBC methemoglobinemia, leading to misdiagnosis and under- from oxidation reactions. However, unlike other cells, recognition of the condition. Therefore, the purposes of RBCs lack a nucleus and cannot synthesize new protein.9 this review are fourfold: (1) to summarize the biochemi- Enzymes that normally detoxify oxidant agents degrade cal properties by which methemoglobin (MHb) is with time. Therefore, older cells are more susceptible to formed, (2) to bring together its disparate etiologies into oxidation, as they cannot detoxify drugs as well as their common endpoints, (3) to illustrate diagnostic tests younger cells.9 Furthermore, RBCs also lack mitochon- that yield falsely normal results in methemoglobinemia dria and are less efficient than other cells in generating and those that provide reliable results, and (4) to high- energy and cofactors necessary for chemical detoxifica- light issues surrounding treatment and its potential com- tion. These properties explain why blood toxicity, mani- plications. festing as hemolysis and methemoglobinemia, occurs more frequently than oxidative toxicity in other tissues. METHEMOGLOBINEMIA AND INTRACELLULAR OXIDATION PHYSICAL PROPERTIES OF METHEMOGLOBIN To understand oxidative toxicity and its potential compli- Hemoglobin molecules contain iron within a porphyrin cations, certain biochemical properties must first be heme structure. The iron in hemoglobin is normally reviewed. Oxidation involves the extraction of electrons found in the Fe++ state. The iron moiety of hemoglobin from a substrate. Reduction involves the transfer of elec- can be oxidized to the Fe+++ state to form MHb.10 Once trons to a substrate. A substance has been oxidized if it MHb is formed, the molecule loses its ability to carry loses an electron, and if it gains an electron, it has been molecular oxygen. Because RBCs are bathed in oxygen, a reduced. certain amount of physiologic MHb formation occurs Oxidation/reduction reactions are termed “redox” continuously.10 Several endogenous reduction systems reactions because they always occur together, that is, for exist to maintain MHb in the reduced state, and in nor- one substance to be reduced, another must be oxidized.1 mal individuals only about 1% of total hemoglobin is Highly reactive, unstable molecules with redox potential MHb at any given time.10 Because oxidized hemoglobin are often termed “free radicals.” These free radicals can is incapable of carrying oxygen (or carbon dioxide), oxidize cellular enzymes inhibiting their function. These excess MHb leads to cyanosis, impaired aerobic respira- reactions may in turn lead to the formation of more free tion, metabolic acidosis, and in severe cases, death. radicals. Some reactions cause the formation of covalent Hemoglobin is a tetrameric molecule, and the com- bonds between the arylating oxidant agent and cellular/ plete oxidation to MHb would represent a 4-electron membrane proteins.4 This covalent bond may cause dis- loss. However, under conditions of oxidative stress, ruption of cellular membrane integrity and enzymatic partial oxidation of the individual subunits predomi- function. Unchecked, the process ultimately leads to cell nates, and as such 8 different dimers may exist (there 5,6 α β lysis and death. When oxidation occurs within the are 4 subunits to hemoglobin ( 2 2) and 2 iron heme moiety of hemoglobin, MHb is formed. Inevitably, valences (Fe++ and Fe+++); thus, 8 different states can oxidation is also occurring elsewhere in the cell and may exist.1,10 The nonoxidized portions of these hybrid cause damage to other cellular enzymes and organelles. valence forms have a high affinity for oxygen and shift Whereas some agents may be specific in reacting with the oxygen dissociation curve to the left.10 In other hemoglobin, most are not and methemoglobinemia is words, any oxygen that is carried by the nonoxidized usually accompanied by some degree of hemolysis. In hemoglobin subunits is held on to more tightly and addition, if these oxidative reactions occur outside poorly released to tissues. This property is important the vascular space, cell damage may also occur in other clinically. For example, a patient with 35% MHb has a organs, such as the lungs or liver. theoretical oxygen-carrying capacity of 65% of his or RBCs are uniquely susceptible to oxidant stress. RBCs her hemoglobin. Functionally, however, this is not the carry oxygen in high concentration and are therefore con- case, because allosteric changes to the hemoglobin tinuously exposed to oxygen free radicals.7,8 Blood serves molecule cause oxygen to bind more tightly in the par- as the transport medium for oxidant xenobiotic agents tially oxidized hemoglobin molecules. This increased after absorption from the gut, exposing RBCs to further affinity causes a left shift in the hemoglobin-oxygen sat- potential oxidation. To combat these processes, a wide uration curve. NOVEMBER 1999 34:5 ANNALS OF EMERGENCY MEDICINE 647 METHEMOGLOBINEMIA Wright, Lewander & Woolf Oxidation also results in a net positive charge to the confusing because the 2-enzyme system is referred to as MHb molecule compared with normal hemoglobin. a single enzyme, NADH-MHb reductase. MHb has high affinity for negative anions such as cyanide, fluoride, or chloride (CN–, F–, and Cl–) as Reduced nicotinamide adenine dinucleotide phosphate–MHb reductase opposed to the uncharged binding ligands (CO2, CO, 1,10 and O2) of normal hemoglobin. Another enzyme that reduces MHb is reduced nicotinamide adenine dinucleotide phosphate DIRECT ENDOGENOUS REDUCTION (NADPH)–MHb reductase. Also known as NADPH- flavin reductase and NADPH-MHb–diaphorase, under Even in the absence of exogenous oxidative stress, normal conditions this enzyme plays a negligible role endogenous oxidation from molecular oxygen would in reducing MHb. It is actually a generalized reductase eventually convert enough hemoglobin to MHb to with an affinity for dyes, such as methylene blue, Nile impair cellular respiration.10 To combat this process, blue, and divicine.12-14 In the presence of the cofactor there are several enzyme systems in the RBC that inhibit NADPH, this enzyme will reduce these dyes, which in oxidation or reduce MHb back to hemoglobin. The turn reduce MHb (Figure 1). The primary function of cytochrome-b5–MHb reductase system is the predomi- this reductase is probably to metabolize oxidant xeno- nant system and accounts for approximately 99% of daily biotics and not MHb. It is somewhat fortuitous that the MHb reduction.10 Ascorbic acid and glutathione reduced form of methylene blue has a high affinity for account
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