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CHAPTER 207: Dyshemoglobinemias 1329 intervals, QT prolongation and torsades de pointes, hypotension, syn cope, and sudden death.51 Quinine also has significant ocular toxicity in acute overdose, and blindness may result from serum levels >10 to 15 micrograms/mL (31 to 46 micromol/L).52,53 Quinine-induced ototoxicity can produce symptoms that range from tinnitus to deafness.54 Hypoglycemia may also result from hyperinsulinemia. Sodium bicarbonate to maintain a serum pH of 7.55 is the mainstay of treatment for quinine-induced cardiac toxicity while avoiding class IA, IC, and III antidysrhythmic agents. Quinine overdose is one of the few drugs for which multiple-dose activated charcoal is truly indicated. ANTIPARASITICS Most antiparasitics, such as albendazole, mebendazole, and thiabenda zole, have minimal toxicity following an acute overdose, usually only producing abdominal pain, nausea, and vomiting. Levamisole, an anti helminthic that was discontinued in the United States in 1999 due to agranulocytosis, has been a common adulterant in illicit cocaine. Com plications found among cocaine users stemming from the levamisole contaminant include leukocytoclastic vasculitis, cutaneous necrotizing vasculitis, and thrombotic vasculopathy without vasculitis. ANTITUBERCULOUS MEDICATIONS  ISONIAZID First-line medications used to treat both latent and active tuberculosis include isoniazid, rifampin, ethambutol, and pyrazinamide. Of these, isoniazid is associated with high morbidity and mortality in over dose. 56,57 At therapeutic doses, adverse effects from isoniazid include neuropathy and hepatic injury. The clinical symptoms of acute isoniazid overdose typically begin with nausea, mental status changes, and ataxia, which may be seen as early as 30 minutes after ingestion. These symptoms may progress to the three classic features of acute isoniazid overdose: seizures, metabolic acidosis, and protracted coma. 58,59 Seizures typically fol low acute isoniazid ingestions of greater than 20 to 30 milligrams/kg. Isoniazid-induced seizures are generalized tonic-clonic in nature and are often refractory to standard anticonvulsive therapy with benzodiaz epines and barbiturates. The mechanism for isoniazid-induced seizures is a functional deficiency of pyridoxine (vitamin B 6) and inhibition of the synthesis of γ-aminobutyric acid, the primary CNS inhibitory neu rotransmitter. Seizures with therapeutic doses of isoniazid have been reported, 60 presumably due to very low vitamin B6 levels.61 Although the metabolic acidosis that accompanies isoniazid-induced seizures is likely due to motor activity, the lactic acidemia may not resolve as rapidly as with other more typical epileptic seizures. Consider isoniazid overdose in patients with refractory seizures . Isoniazid-induced seizures are treated with a combination of benzodi azepines and pyridoxine. The dose of pyridoxine is a gram-for-gram equivalent to the amount of isoniazid ingested.62 For patients who ingest an unknown quantity of isoniazid, the recommended dose of pyridox ine is 5 grams IV in adults and 70 milligrams/kg (maximum 5 grams) in pediatric patients. Pyridoxine should be administered at a rate of approximately 1 gram IV every 2 to 3 minutes until the seizures stop or the maximum dose has been given. After the seizures have ceased, the remainder of the pyridoxine dose should be given over the following 4 to 6 hours to limit recurrent seizures.

in pediatric patients. Pyridoxine should be administered at a rate of approximately 1 gram IV every 2 to 3 minutes until the seizures stop or the maximum dose has been given. After the seizures have ceased, the remainder of the pyridoxine dose should be given over the following 4 to 6 hours to limit recurrent seizures. If seizures persist after the full dose has been given, it may be repeated. Adequate single-dose therapy of pyridoxine should be effective to stop most seizures, but patients who do not receive adequate pyridoxine dosing may have repeat seizures. Pyridoxine may also assist in revers ing isoniazid-induced coma. Hospitals where tuberculosis is endemic should ensure that an adequate supply of IV pyridoxine is maintained to treat overdoses. 63 If only pyridoxine tablets are available, they may be crushed and administered by nasogastric tube. Phenytoin has no role in treating seizures originating from isoniazid overdose, and there is little role for sodium bicarbonate treatment of the metabolic acidosis resulting from isoniazid toxicity. Because most isoniazid-induced toxicity occurs within 2 hours of ingestion, patients who remain asymptomatic for 6 hours after ED presentation are safe for medical clearance.  OTHER ANTITUBERCULOSIS AGENTS Other antituberculous medications are associated with a variety of adverse reactions of a milder nature. Ethambutol toxicity is also primarily GI in nature but additionally may cause unilateral or bilateral ocular toxicity including blurred vision, disruption of color perception, and loss of peripheral vision. 64 Rifampin infrequently causes severe toxicity and is most often associated with GI symptoms. Acute toxicity has been associated with flushing, angioedema, and neurologic effects including numbness, extremity pain, ataxia, and weakness. Rifampin has been presumptively implicated in producing acute kidney injury with proteinuria. 65 Pyrazinamide is not associated with any toxic effects following an acute overdose. ANTIVIRAL/RETROVIRAL MEDICATIONS Common side effects from oseltamivir, used for the treatment of influ enza, are nausea, vomiting, diarrhea, dizziness, and headache. Oselta mivir is associated with QT prolongation,66 but there is no evidence the drug causes torsades de pointes or should be avoided in patients with congenital long QT syndrome. 67 Oseltamivir can cause acute neuro psychiatric effects including depression, agitation, and hallucinations within 24 hours of the first dose. 66,68 In the treatment of human immunodeficiency virus, protease inhibi tors as a class can cause QT prolongation 69 and nephrolithiasis, 70 whereas reverse transcriptase inhibitors can cause lipodystrophy 71 and lactic acidosis.72 For patients being induced to or taking buprenorphine, the University of California, San Francisco (http://hivinsite.ucsf.edu/) maintains a list of antiretrovirals that affect buprenorphine levels. Methadone also has important interactions with antiretrovirals, mostly requiring methadone dose increases. Check available databases or infectious disease specialists for specific information. REFERENCES The complete reference list is available online at www.TintinalliEM.com. Dyshemoglobinemias Brenna M. Farmer Lewis S. Nelson INTRODUCTION Dyshemoglobinemias are disorders in which the hemoglobin molecule is functionally altered and prevented from carrying oxygen. The most clinically relevant dyshemoglobinemias are carboxyhemoglobin, methemoglobin, and sulfhemoglobin. 1 Carboxyhemoglobin is created follow ing carbon monoxide exposure and, because of its unique importance and prevalence, is discussed separately (see Chapter 222, “Carbon Monoxide”). METHEMOGLOBINEMIA  PATHOPHYSIOLOGY The iron moiety within deoxyhemoglobin normally exists in the ferrous (bivalent or Fe 2+) state.

bin. 1 Carboxyhemoglobin is created follow ing carbon monoxide exposure and, because of its unique importance and prevalence, is discussed separately (see Chapter 222, “Carbon Monoxide”). METHEMOGLOBINEMIA  PATHOPHYSIOLOGY The iron moiety within deoxyhemoglobin normally exists in the ferrous (bivalent or Fe 2+) state. Ferrous iron avidly interacts with compounds seeking electrons, such as oxygen or other oxidizing agent, and in the process is oxidized to the ferric (trivalent or Fe 3+) state. Hemoglobin CHAPTER Tintinalli_Sec15_p1187-1332.indd 1329 8/2/19 8:40 PM

bin. 1 Carboxyhemoglobin is created follow ing carbon monoxide exposure and, because of its unique importance and prevalence, is discussed separately (see Chapter 222, “Carbon Monoxide”). METHEMOGLOBINEMIA  PATHOPHYSIOLOGY The iron moiety within deoxyhemoglobin normally exists in the ferrous (bivalent or Fe 2+) state. Ferrous iron avidly interacts with compounds seeking electrons, such as oxygen or other oxidizing agent, and in the process is oxidized to the ferric (trivalent or Fe 3+) state. Hemoglobin CHAPTER Tintinalli_Sec15_p1187-1332.indd 1329 8/2/19 8:40 PM 1330 SECTION 15: Toxicology FIGURE 207-1. Methemoglobin formation and mechanism of action of methylene blue. G6PD = glucose-6-phosphate dehydrogenase; Hb(Fe2+) = hemoglobin; Hb(Fe3+) = methemoglobin; NAD+ = oxidized nicotinamide adenine dinucleotide; NADH = reduced form of nicotinamide adenine dinucleotide; NADP + = nicotinamide adenine dinucleotide phosphate; NADPH = reduced form of nicotinamide adenine dinucleotide phosphate; PO 4 = phosphate. TABLE 207-1 Drugs Causing Methemoglobinemia Oxidant Comments Analgesics Phenazopyridine Commonly reported Phenacetin Rarely used Antimicrobials Antimalarials Common Dapsone Hydroxylamine metabolite formation is inhibited by cimetidine Sulfamethoxazole Uncommon Local Anesthetics Benzocaine Most commonly reported of the local anesthetics Lidocaine Rare Prilocaine Common in topical anesthetics Dibucaine Rare Nitrates/Nitrites Amyl nitrite Cyanide antidote kit and used to enhance sexual encounters Isobutyl nitrite Used to enhance sexual encounters Sodium nitrite Cyanide antidote kit Ammonium nitrate Cold packs Silver nitrate Excessive topical use Well water Problem in infants, due to nitrate fertilizer runoff Nitroglycerin Rare Other Rasburicase Treatment for hyperuricemia in tumor lysis syndrome Glucose Glucose 6–PO4 Glucose Hexokinase Oxidant stress Glucose 6–PO4 NAD+ To electron transport chain Glutathione formation Hexose monophosphate shunt NADH NADP+ NADPH 6-Phosphogluconate Glyceraldehyde 3–PO4 Cytochrome b5 reductase NADPH MetHb reductase Reduced Cytochorome b5 Oxidized Cytochorome b5 Leuco methylene blue Methylene blue Hb(Fe3+) Hb(Fe2+) Hb(Fe2+) 1,3 Diphosphoglycerate Glycolysis in the ferric form is unable to bind oxygen for transport and is termed methemoglobin. Normally, <1% to 2% of circulating hemoglobin exists as methemoglobin; higher concentrations define the condition of methemoglobinemia. Methemoglobin accumulation is enzymatically prevented by the rapid reduction of the ferric iron back to the ferrous form. Cytochrome 5 reductase is primarily responsible for this reduction, in which reduced nicotinamide adenine dinucleotide donates its electrons to cytochrome b 5, which subsequently reduces methemoglobin to hemoglobin (Figure 207-1). This pathway is responsible for reducing nearly 95% of methemoglobin produced under typical circumstances. Methemoglobinemia occurs when this enzymatic reduction is over whelmed by an exogenous oxidant stress, such as a drug or chemical agent (Table 207-1). Methemoglobin can also be reduced by a second enzymatic pathway using the reduced form of nicotinamide adenine dinucleotide phosphate (or NADPH) and NADPH-methemoglobin reductase. 2 This pathway is normally of minimal importance and is responsible for <5% of total reduction under typical circumstances. However, this enzyme and pathway are crucial for the antidotal effect of methylene blue (Figure 207-1). The limited role for NADPH partially explains why patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency with a resultant deficit of NADPH are not at increased risk of developing methemoglo binemia, although they are at risk of developing hemolysis following exposure to an oxidant stress. To a very limited extent, nonenzymatic reduction systems, such as vitamin C and glutathione, may participate in the reduction of methemoglobin to hemoglobin. The primary adverse clinical effect of methemoglobin is the reduction in the oxygen content of the blood.

oping hemolysis following exposure to an oxidant stress. To a very limited extent, nonenzymatic reduction systems, such as vitamin C and glutathione, may participate in the reduction of methemoglobin to hemoglobin. The primary adverse clinical effect of methemoglobin is the reduction in the oxygen content of the blood. Because hemoglobin-bound oxygen accounts for the vast majority of an individual’s oxygen-carrying capacity, as the methemoglobin concentration rises, oxygen-carrying capacity falls. Patients with methemoglobinemia are often more symptomatic than patients with a simple anemia that produces an equivalent reduc tion in oxygen-carrying capacity. This is caused by a leftward shift in the oxyhemoglobin dissociation curve, the consequence of which is a reduced release of oxygen from the erythrocyte to the tissue at a given partial pressure of oxygen (Figure 207-2). The oxyhemoglobin dissociation curve of blood with a 50% reduc tion in erythrocytes (i.e., anemia) follows a curve similar to that of nonanemic blood; although the oxygen content is lower, unbinding of half of the oxygen (50% oxygen saturation) occurs at the same partial pressure of oxygen. With 50% methemoglobin, the leftward shift of the oxyhemoglobin dissociation curve means that hemoglobin is less willing to give up its oxygen, so that tissue hypoxia is more severe than in those with a 50% anemia. Acquired Methemoglobinemia Drugs in conventional doses rarely produce clinically significant methemoglobinemia ( Table 207-1). Benzocaine is the local anesthetic most commonly associated with met hemoglobinemia.3-6 Methemoglobin induction with sodium nitrite is a therapeutic goal in the management of patients suffering from Tintinalli_Sec15_p1187-1332.indd 1330 8/2/19 8:40 PM

ely produce clinically significant methemoglobinemia ( Table 207-1). Benzocaine is the local anesthetic most commonly associated with met hemoglobinemia.3-6 Methemoglobin induction with sodium nitrite is a therapeutic goal in the management of patients suffering from Tintinalli_Sec15_p1187-1332.indd 1330 8/2/19 8:40 PM CHAPTER 207: Dyshemoglobinemias 1331 cyanide poisoning (see Chapter 204, “Industrial Toxins”). With certain compounds, particularly dapsone, metabolism to the “active” oxidant is required before induction of methemoglobinemia, so there may be substantial delay until toxicity is evident. 7 Occupational methemoglobinemia usually involves exposure to aromatic compounds, primarily amino- and nitro-substituted benzenes. 8 Routes of absorption are typi cally dermal or inhalational due to the high lipophilicity and volatility of these compounds, respectively. Neonates and infants are more susceptible to methemoglobin accu mulation because of undeveloped methemoglobin reduction mech anisms. This accounts for the relatively common development of methemoglobinemia in infants given certain nitrogenous vegetables (e.g., spinach), who consume well water that contains high nitrate levels (generally from fertilizer use), or who experience gastroenteritis where GI flora can convert nitrate to the nitrite form. 9,10 Hereditary Methemoglobinemia Hereditary methemoglobinemia results from either an enzymatic deficiency (i.e., cytochrome b 5 reductase) or from the presence of an amino acid substitution within the hemoglobin molecule itself, termed hemoglobin M. 1 Patients with cytochrome b5 reductase deficiency develop methemoglobin levels of 20% to 40%. Cyanosis in these individuals begins at birth, but they remain asymptomatic and develop normally. Hemoglobin M, an abnormal form of hemoglobin, has altered tertiary structure so that the heme iron exists in an environment favoring the ferric form. This disorder only occurs in the heterozygous form, because the homozygous form is incompatible with life. As with cytochrome b 5 reductase deficiency, patients develop profound cyanosis but tolerate the elevated methemoglobin concentrations well due to compensatory mechanisms.  CLINICAL FEATURES Healthy patients who have normal hemoglobin concentrations do not usually develop clinical effects until the methemoglobin level rises above 20% of the total hemoglobin. 11,12 At methemoglobin levels between 20% and 30%, anxiety, headache, weakness, and lightheadedness develop, and patients may exhibit tachypnea and sinus tachycardia. Methemoglobin levels of 50% to 60% impair oxygen delivery to vital tissues, resulting in myocardial ischemia, dysrhythmias, depressed mental status (including coma), seizures, and lactate-associated metabolic acidosis. Levels above 70% are largely incompatible with life. Cyanosis associated with methemoglobin is often described as a gray discoloration of skin, with a detection threshold for methemoglobin of 1.5 grams/dL, corresponding to methemoglobin levels between 10% and 15% in a nonanemic individual. Anemic patients may not exhibit cyanosis until the methemoglobin level rises well above 10% because cyanosis detection is dependent on the concentration of methemo globin, not the percentage. Anemic patients may likewise develop clinical features at lower methemoglobin concentrations because the relative percentage of hemoglobin in the oxidized form is greater. Patients with preexisting cardiopulmonary diseases that impair oxy gen delivery will also manifest abnormalities with lesser elevations in their methemoglobin levels. Conversely, compensatory mechanisms that shift the oxyhemoglobin dissociation curve to the right, such as acidosis or elevated 2,3-diphosphoglycerate, may result in somewhat better tolerance of methemoglobin.

impair oxy gen delivery will also manifest abnormalities with lesser elevations in their methemoglobin levels. Conversely, compensatory mechanisms that shift the oxyhemoglobin dissociation curve to the right, such as acidosis or elevated 2,3-diphosphoglycerate, may result in somewhat better tolerance of methemoglobin.  DIAGNOSIS Consider methemoglobinemia in patients with cyanosis, particularly if cyanosis does not improve with supplemental oxygen (Figure 207-3). 4,5,7,11,12 A useful clue is that patients with methemoglobin-associated cyanosis generally are less symptomatic than equivalently appearing patients with hypoxemia-induced cyanosis. This is due to the more deeply pig mented color of methemoglobin compared with deoxyhemoglobin; it takes about 5 grams/dL of deoxyhemoglobin to cause cyanosis, which equates to an oxygen-carrying capacity of approximately 67% of normal (in someone with a total hemoglobin of 15 grams/dL), compared with the cyanosis visible with a methemoglobin concentration of 1.5 grams/ dL, which equates to an oxygen-carrying capacity of 90% of normal. Blood containing more than 20% methemoglobin has a characteristic “chocolate brown” color when phlebotomized. A color reference chart has been developed to estimate methemoglobin levels from drops of blood on white absorbent paper. 13,14 Pulse oximetry results are not accurate in patients with methemoglobinemia.15 The standard pulse oximeter uses two wavelengths of light, 660 nm and 940 nm, to calculate the percentage of oxyhemoglobin. Methemoglobin is also detected by these wavelengths, so light absorption by methemoglobin confounds the calculation for the oxyhemoglobin 40 60 PO2 (mm Hg) Arterial blood Venous blood 100% Oxyhemoglobin 50% Methemoglobin 50% Anemia (oxyhemoglobin) Oxygen content (volume percent) FIGURE 207-2. Oxyhemoglobin dissociation curve. Supportive care, ABG, airway management Decontamination Response Response No response No response aMetHb: Methemoglobin bAsx: Asymptomatic Cardiovascular or pulmonary etiology Cyanosis Observe repeat methylene blue PRN Consider: Inadequate dose of methylene blue Chlorates Inadequate decontamination NADPH-dependent MetHb r eductase deficiency Hemoglobin M Sulfhemoglobinemia Observe Methylene blue 1 mg/kg Asx b Symptomatic <25% >25% High flow O2 Draw MetHba concentration FIGURE 207-3. Toxicologic approach to the cyanotic patient. ABG = arterial blood gas; NADPH = reduced form of nicotinamide adenine dinucleotide phosphate. [Reproduced with permission from Nelson LS, Howland MA, Lewin NA, Smith SW, Goldfrank LR, Hoffman RS, (eds): Goldfrank’s Toxicologic Emergencies, 11th ed. New York: McGraw-Hill, Inc., 2019; Figure 124-7.] Tintinalli_Sec15_p1187-1332.indd 1331 8/2/19 8:40 PM

= reduced form of nicotinamide adenine dinucleotide phosphate. [Reproduced with permission from Nelson LS, Howland MA, Lewin NA, Smith SW, Goldfrank LR, Hoffman RS, (eds): Goldfrank’s Toxicologic Emergencies, 11th ed. New York: McGraw-Hill, Inc., 2019; Figure 124-7.] Tintinalli_Sec15_p1187-1332.indd 1331 8/2/19 8:40 PM 1332 SECTION 15: Toxicology percentage. In patients with methemoglobinemia, the pulse oximeter will report a falsely elevated value for arterial oxygen saturation percentage. The specific values vary by oximeter, but typically report approximately 85%. Commercially available pulse co-oximeters and pulse spectroscopy use additional wavelengths of light to measure the total hemoglobin concentration and percentages of carboxyhemoglobin and methe moglobin. 16-18 Their accuracy for detecting methemoglobinemia has improved with additional wavelengths, improved probes, and more robust software. Definitive identification of dyshemoglobinemias requires cooximetry, a spectrophotometric method capable of differentiating oxyhemoglobin, deoxyhemoglobin, carboxyhemoglobin, and methe moglobin species. 11,12 This widely available test can be performed on a venous or arterial specimen. Arterial blood gas results may be initially deceptive because the partial pressure of oxygen, a measure of dissolved, not bound, oxy gen, is normal. Thus, calculation of oxygen saturation from measured partial pressure by the blood gas analyzer will produce a falsely elevated result.  TREATMENT Patients with methemoglobinemia require supportive measures to ensure oxygen delivery and administration of appropriate antidotal therapy, if indicated ( Table 207-2). 11,12 Gastric decontamination is of limited value, because there often is a substantial time interval between exposure to the toxic agent and the development of methemoglobin. If a source of continuing GI exposure is suspected, decontamination is indicated, and in most stable patients, a single dose of activated charcoal is likely sufficient. Dermal decontamination should be used as indicated. Antidotal therapy with methylene blue is reserved for symptomatic patients or for those asymptomatic patients with methemoglobin levels >25%. Methylene blue indirectly accelerates the enzymatic reduction of methemoglobin by NADPH-methemoglobin reductase. NADPHmethemoglobin reductase reduces methylene blue to leucomethylene blue, which is then capable of directly reducing the oxidized iron (Fe 3+) back to the ferrous state (Fe2+) (Figure 207-1). The initial dose of methylene blue is 1 milligram/kg (0.1 mL/kg of the 1% solution or approxi mately 7 mL in an adult) IV slowly over 5 minutes. The infusion should be slow because rapidly administered doses of methylene blue are painful. Clinical improvement should be seen within 20 minutes, and as the methemoglobin level falls, the most severe signs and symptoms will resolve first. Resolution of the cyanosis occurs later only after the methemoglobin concentration falls below 1.5 grams/dL. Repeat dosing of methylene blue is acceptable if cyanosis has not cleared in 1 hour. Serotonin syndrome is a rare risk when methylene blue is administered to patients on serotonergic drugs such as antidepressants. 19,20 Treatment failures may result if the patient has G6PD deficiency, because this enzyme is critical for the production of NADPH by the hexose monophosphate shunt (Figure 207-1). Hemolysis may impede a response to methylene blue, which requires an intact erythrocyte to be effective. Oxidant drugs with long serum half-lives, such as dapsone, with a half-life of approximately 50 hours, produce prolonged oxidant stress to the red blood cell. Therefore, dapsone-exposed patients may require repetitive dosing of methylene blue.

nse to methylene blue, which requires an intact erythrocyte to be effective. Oxidant drugs with long serum half-lives, such as dapsone, with a half-life of approximately 50 hours, produce prolonged oxidant stress to the red blood cell. Therefore, dapsone-exposed patients may require repetitive dosing of methylene blue. 21 Because the hydrox ylamine metabolite of dapsone is responsible for the production of methemoglobin, inhibition of its formation by cytochrome P450 with cimetidine, in standard doses, is generally recommended. In rare instances, patients may be deficient in NADPH-methemoglobin reductase, the required enzyme for methylene blue activation. Treat ment failure may occur in patients with sulfhemoglobinemia, which is clinically indistinguishable from methemoglobinemia but which is not responsive to methylene blue. Methemoglobinemia due to chlorate poisoning is responsive to methylene blue when used early in mild cases, but less responsive in severe poisonings when hemolysis is present. Patients who do not respond to methylene blue should be treated sup portively. If clinically unstable, the use of packed red cell transfusions or exchange transfusions may be indicated. SULFHEMOGLOBINEMIA  PATHOPHYSIOLOGY Sulfhemoglobinemia is a rare condition that occurs when a sulfur atom irreversibly binds to the porphyrin ring of the heme moiety and induces the permanent oxidation of iron to the ferric (Fe 3+) state.1 Many of the agents responsible for sulfhemoglobinemia are identical to those associated with methemoglobin. Because many of these drugs or chemicals do not contain sulfur, the origin of sulfur is speculative; hypotheses include alteration of intestinal flora with production of hydrogen sulfide and/ or glutathione from bacteria such as Morganella morganii. 22,23 Historically, sulfhemoglobinemia was most often associated with acetanilide, phenacetin, sulfonamide, and a proprietary mixture that contained sodium bromide. Because these drugs are rarely used and the sodium bromide component in the proprietary mixture was removed in 1975, contemporary cases of drug-induced sulfhemoglobinemia are now most often reported with phenazopyridine, dapsone, metoclopramide, and sumatriptan. 24,25 Sulfhemoglobinemia has been associated with indus trial chemicals, such as trinitrotoluene, hydroxylamine sulfate, dimethyl sulfoxide, and hydrogen sulfide.  CLINICAL FEATURES Patients with sulfhemoglobinemia can have a clinical presentation similar to those with methemoglobinemia. 27 However, the disease process itself is substantially less concerning because, although the reduction in the patient’s oxygen-carrying capacity is quantitatively similar, the sulfhemoglobin oxygen dissociation curve is shifted rightward, not leftward as in methemoglobinemia, favoring the release of hemoglobinbound oxygen to the tissue with sulfhemoglobinemia. Because of the milder symptoms, it is likely that cases of sulfhemoglobinemia are often missed.  DIAGNOSIS The pigmentation of the blood by sulfhemoglobin is substantially more intense than other colored hemoglobin species; only 0.5 gram/dL of sulfhemoglobin is needed to produce a cyanosis equivalent to that produced by 1.5 grams/dL of methemoglobin or 5 grams/dL of deoxyhemoglobin. The color of blood drawn from a patient with sulfhemoglobinemia has been described as dark green-black. In sulfhemoglobinemia, standard pulse oximetry tends to report a falsely low value for arterial oxygen saturation percentage. 29 The diagnosis of sulfhemoglobinemia may be difficult to confirm as special settings for laboratory co-oximetry are required to reliably measure sulfhemoglobin concentration.  TREATMENT Sulfhemoglobin persists for the life of the red cell and the level is not reduced by treatment with methylene blue.

ion percentage. 29 The diagnosis of sulfhemoglobinemia may be difficult to confirm as special settings for laboratory co-oximetry are required to reliably measure sulfhemoglobin concentration.  TREATMENT Sulfhemoglobin persists for the life of the red cell and the level is not reduced by treatment with methylene blue. Most patients require only supportive care, although exchange transfusion or packed red cell transfusion is occasionally recommended for patients with severe toxicity. REFERENCES The complete reference list is available online at www.TintinalliEM.com. TABLE 207-2 Management of Methemoglobinemia •   Assess airway, breathing, and circulation; exclude other causes of cyanosis. •   Insert an IV line. •   Administer oxygen. •   Attach the patient to a cardiac monitor and pulse oximeter or co-oximeter. •   Obtain an ECG as indicated. •   Decontaminate the patient as needed. •   Administer methylene blue if symptomatic or methemoglobin >25%. •   Consider cimetidine for patients taking dapsone. Tintinalli_Sec15_p1187-1332.indd 1332 8/2/19 8:40 PM