Contact Us    Contact Us     |     Feedback
MOBILE VIEW  | 

SULFHEMOGLOBINEMIA

Export To Excel

Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Sulfhemoglobin is a green pigmented molecule with a sulfur atom incorporated into the porphyrin ring of hemoglobin by oxidant stress which results in the inability to transport oxygen (Park & Nagel, 1984; Haddad et al, 1998).
    B) The term is often misused to describe an abnormal hemoglobin generated either in vivo or in vitro in the absence of exogenous sulfur, often associated with either: ingestion of oxidant agents (e.g. phenacetin, chlorate, naphthalene), presence of an abnormal hemoglobin such as M or H, and/or exposure of G-6-PD deficient individuals to sulfonamides or methylene blue (Amdur et al, 1991).
    C) Agents capable of producing sulfhemoglobin are reviewed in this management:
    1) Specific managements are available for some agents and should be used to treat specific cases. Several managements are listed below:
    1) Refer to DAPSONE management for further information.
    2) Refer to ANILINE management for further information.

Specific Substances

    A) AGENTS THAT HAVE PRODUCED SULFHEMOGLOBINEMIA
    1) Acetanilid derivatives
    2) Aminophenol
    3) p-Aminopropiophenone
    4) Ammonium nitrite
    5) Amyl nitrite
    6) Aniline derivatives
    7) Anilinoethanol
    8) Benzocaine (topical)
    9) Bismuth subnitrite
    10) Dapsone
    11) Dimethylamine
    12) Dimethyl sulfoxide (DMSO)
    13) Dinitrobenzene
    14) Ethyl nitrite
    15) Flutamide (aniline derivative)
    16) Hydroxylacetylanilide
    17) Hydroxylamine
    18) Methylacetylanilide
    19) Metoclopramide (high dose)
    20) Naphthylamine
    21) Nitrites
    22) p-Nitroaniline
    23) Nitrobenzene
    24) Nitroglycerin
    25) Paint
    26) Phenacetin (withdrawn from US market)
    27) Phenazopyridine
    28) Phenylenediamine
    29) Phenylhydroxylamine
    30) Sulfanilamide
    31) Sulfapyridine
    32) Sulfathiazole
    33) Sulfur Compounds
    34) Toluenediamine
    35) Tolylhydroxylamine
    36) Trinitrotoluene
    37) Zinc ethylene bisdithiocarbamate

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) TOXICOLOGY: Sulfhemoglobin is a darkly colored hemoglobin with a sulfur atom incorporated into the heme molecule, that produces a relatively benign overall clinical course. Relatively low (mean capillary concentration of 0.5 g/dL, corresponding to a concentration of 3.3% in a normal subject with a Hb of 15 g/dL) concentrations of sulfhemoglobin (SHb) can produce cyanosis (compared with 1.5 g/dL of methemoglobinemia). Various drugs and chemicals can induce sulfhemoglobinemia, many of these substances can also produce methemoglobinemia. Some cases may occur as a result of chronic constipation or a diarrheal illness.
    B) EPIDEMIOLOGY: Sulfhemoglobinemia is rare, much less common than methemoglobinemia.
    C) MILD TO MODERATE POISONING: Cyanosis, described as slate-grey in color, appears at relatively low sulfhemoglobin concentrations. Headache, constipation, diarrhea, tachycardia, and mild dyspnea on exertion are fairly common manifestations. Onset of cyanosis may occur days after exposure, and may persist for days to weeks. Sulfhemoglobin is an extremely stable compound and is thus irreversible, remaining in the circulation for the life of the erythrocyte.
    D) SEVERE POISONING: Because sulfhemoglobinemia shifts the hemoglobin oxygen dissociation curve to the right, facilitating oxygen unloading by normal hemoglobin, clinical manifestations of severe tissue hypoxia are very unlikely. In patients with severe manifestations (severe dyspnea, dysrhythmias, mental status changes, seizures), concurrent severe methemoglobinemia should be suspected.
    0.2.5) CARDIOVASCULAR
    A) Cardiac insufficiency is rare in patients with sulfhemoglobinemia. It may produce exercise intolerance and chest pain.
    0.2.6) RESPIRATORY
    A) Respiratory insufficiency is unlikely to occur unless the level of sulfhemoglobin is very high. There have been infrequent reports of respiratory insufficiency following exposure.
    0.2.7) NEUROLOGIC
    A) WITH POISONING/EXPOSURE
    1) Headache is commonly associated with sulfhemoglobinemia.
    0.2.8) GASTROINTESTINAL
    A) WITH POISONING/EXPOSURE
    1) Constipation is a common complaint with sulfhemoglobinemia, but whether this is causative or a resultant effect is controversial.
    0.2.13) HEMATOLOGIC
    A) Cyanosis, described as slate grey color in the absence of cardiopulmonary symptoms, is the most common sign of sulfhemoglobinemia.
    0.2.20) REPRODUCTIVE
    A) Sulfhemoglobinemia and Heinz body formation have been reported in a 36-week pregnant woman after ingesting codeine compound tablets.

Laboratory Monitoring

    A) GENERAL APPROACH: If patient is cyanotic, administer oxygen and manage airway as needed. Obtain an arterial blood gas and measure methemoglobin and sulfhemoglobin concentrations (note: many co-oximeters can not distinguish sulfhemoglobin from methemoglobin). Pulse oximetry is NOT reliable in patients with sulfhemoglobinemia. Obtain a CBC (total hemoglobin). Obtain a chest x-ray and ECG.
    B) CO-OXIMETRY: Sulfhemoglobin may be inappropriately identified as methemoglobin depending on which co-oximeter is used. Instruments that use more wavelengths can discriminate a greater number of hemoglobin compounds. There are 3 instruments reported to reliably measure sulfhemoglobin: AVL 912 (AVL Medical Instruments, Schaffhausen, Switzerland); Ciba Corning 270 (Ciba Corning Diagnostics, Medfield, MA); and Radiometer OSM3 (Radiometer, Copenhagen, Denmark). Of these the AVL 912 gives a numerical result of the concentration measured. Some newer co-oximeters can also distinguish between several species of hemoglobin at once. The IL 482 (Instrumentation Laboratory, Lexington, MA) may erroneously report sulfhemoglobin as methemoglobin.
    C) CLINICAL DIAGNOSIS: If the proper assay is not available it may be a diagnosis of exclusion based on history and physical exam. Subjects with presumed methemoglobinemia who do not respond to methylene blue therapy are likely to suffer from occult sulfhemoglobinemia.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) DECONTAMINATION
    1) Sulfhemoglobinemia usually develops after chronic exposure or many hours to days after acute exposure to oxidizing substances. Gastrointestinal decontamination is usually not necessary.
    B) MILD TO MODERATE TOXICITY
    1) Treatment is symptomatic and supportive. Withdraw the causative agent. Oxygen therapy should be administered to all cyanotic patients.
    C) SEVERE TOXICITY
    1) Exchange transfusion and hyperbaric oxygen may be useful in severe cases, but are rarely necessary.
    D) ANTIDOTE
    1) There is no antidote. Methylene blue has NO effect on sulfhemoglobin. It should only be used if there is significant coexisting methemoglobinemia.
    E) EXCHANGE TRANSFUSION
    1) Exchange transfusion should be considered in rare cases where an elevated sulfhemoglobin concentration is present and the patient is severely symptomatic. Total hemoglobin concentration will increase with a decrease in the sulfhemoglobin fraction/concentration.
    F) PITFALLS
    1) In patients with severe symptoms, another diagnosis should be sought (eg, methemoglobinemia, hypoxia of another etiology).
    2) Many co-oximeters cannot distinguish methemoglobin from sulfhemoglobin.
    3) Aggressive treatment is rarely necessary; most patients recover with administration of oxygen and identification and discontinuation of the precipitating agent.
    G) DIFFERENTIAL DIAGNOSIS
    1) Methemoglobinemia, hypoxia of any etiology, agyria (silver-grey discoloration of skin).
    H) PATIENT DISPOSITION
    1) OBSERVATION CRITERIA: Cyanotic patients should be evaluated in a healthcare facility. Patients who are asymptomatic or have only mild dyspnea in whom the diagnosis of sulfhemoglobinemia is certain may be discharged after 4 to 6 hours of observation, provided the precipitating agent has been identified and discontinued.
    2) ADMISSION CRITERIA: Patients who have more than mild dyspnea should be admitted.
    3) CONSULT CRITERIA: Consult a poison center or medical toxicologist for patients with severe symptoms or in whom the diagnosis or precipitating agent is unclear.
    I) PREDISPOSING CONDITIONS
    1) Sulfhemoglobinemia is a relatively mild syndrome in persons with hemoglobin A, but could be potentially toxic in patients with hemoglobin S, in whom it could potentiate sickling.
    J) TOXICOKINETICS
    1) Sulfhemoglobin persists for the life of the erythrocyte, it may take days to weeks for cyanosis to resolve.
    0.4.5) DERMAL EXPOSURE
    A) OVERVIEW
    1) Sulfhemoglobinemia has been reported following dermal exposure. Refer to the ORAL TREATMENT section.

Range Of Toxicity

    A) A sulfhemoglobin concentration of 0.5 g/dL (3.3% in a patient with a hemoglobin of 15 g/dL) produces an observable cyanosis in which the skin appears slate grey.
    B) Background sulfhemoglobin concentrations in adults were less than 0.4%.
    C) Sulfhemoglobin concentrations as high as 16% have been reported, with cyanosis and dyspnea as the predominant clinical manifestations. Sulfhemoglobin concentrations above 10% of total hemoglobin are unusual.

Clinical Effects

Summary Of Exposure

    A) TOXICOLOGY: Sulfhemoglobin is a darkly colored hemoglobin with a sulfur atom incorporated into the heme molecule, that produces a relatively benign overall clinical course. Relatively low (mean capillary concentration of 0.5 g/dL, corresponding to a concentration of 3.3% in a normal subject with a Hb of 15 g/dL) concentrations of sulfhemoglobin (SHb) can produce cyanosis (compared with 1.5 g/dL of methemoglobinemia). Various drugs and chemicals can induce sulfhemoglobinemia, many of these substances can also produce methemoglobinemia. Some cases may occur as a result of chronic constipation or a diarrheal illness.
    B) EPIDEMIOLOGY: Sulfhemoglobinemia is rare, much less common than methemoglobinemia.
    C) MILD TO MODERATE POISONING: Cyanosis, described as slate-grey in color, appears at relatively low sulfhemoglobin concentrations. Headache, constipation, diarrhea, tachycardia, and mild dyspnea on exertion are fairly common manifestations. Onset of cyanosis may occur days after exposure, and may persist for days to weeks. Sulfhemoglobin is an extremely stable compound and is thus irreversible, remaining in the circulation for the life of the erythrocyte.
    D) SEVERE POISONING: Because sulfhemoglobinemia shifts the hemoglobin oxygen dissociation curve to the right, facilitating oxygen unloading by normal hemoglobin, clinical manifestations of severe tissue hypoxia are very unlikely. In patients with severe manifestations (severe dyspnea, dysrhythmias, mental status changes, seizures), concurrent severe methemoglobinemia should be suspected.

Cardiovascular

    3.5.1) SUMMARY
    A) Cardiac insufficiency is rare in patients with sulfhemoglobinemia. It may produce exercise intolerance and chest pain.
    3.5.2) CLINICAL EFFECTS
    A) CARDIOVASCULAR FINDING
    1) LACK OF EFFECT
    a) Sulfhemoglobinemia only rarely results in cardiovascular symptoms (e.g. tachycardia, chest pain, dyspnea) (Noor & Beutler, 1998a) due to an impaired oxygen exchange (Barrueto et al, 2002; Haddad et al, 1998).

Respiratory

    3.6.1) SUMMARY
    A) Respiratory insufficiency is unlikely to occur unless the level of sulfhemoglobin is very high. There have been infrequent reports of respiratory insufficiency following exposure.
    3.6.2) CLINICAL EFFECTS
    A) DYSPNEA
    1) WITH THERAPEUTIC USE
    a) Dyspnea and tachypnea are unlikely physiologic responses seen with sulfhemoglobinemia, unless the concentration of sulfhemoglobin is very high (Noor & Beutler, 1998; Haddad et al, 1998). Exertional dyspnea may occur in the presence of methemoglobinemia and sulfhemoglobinemia (Lambert et al, 1982; Burgess et al, 1998).
    b) Physiologically, sulfhemoglobin results in a rightward shift of the hemoglobin oxygen dissociation curve due to a molecular shift in the unliganded conformation and a reduction in the oxygen affinity of their unmodified subunits (Park & Nagel, 1984a). This results increased oxygen delivery by functional hemes (unlike methemoglobinemia) and fortunately fewer respiratory complications (Langford & Sheikh, 1999). Overall, oxygen-carrying capacity is reduced, but oxygen-delivery to the tissues remains for the most part intact.
    c) CASE REPORT- A 57-year-old woman developed cyanosis and dyspnea following the use of phenazopyridine for several years. Vital signs were: blood pressure 135/65 mmHg, pulse 105 bpm, respiratory rate 22/minute; pulse oximetry 86% on room air. The ECG revealed only sinus tachycardia. A sulfhemoglobin concentration of 13.9% was reported. Following supportive therapy for seven days, she was discharged without any sequelae (Barrueto et al, 2002).
    B) CASE REPORT
    1) Mild exertional dyspnea, fatigue and cyanosis developed within 24 hours of topical application of dimethyl sulfoxide (DMSO) (total 1.8 g/kg) to the lower abdomen of an adult in the treatment of interstitial cystitis (Burgess et al, 1998). An initial diagnosis of methemoglobinemia was unresponsive to methylene blue, and a sulfhemoglobin concentration of 6.2% was reported; methemoglobin concentration level was <0.1%.
    a) Treatment consisted of oxygen therapy and a transfusion with 2 units of packed red blood cells. The patient was discharged to home on day 3 in stable condition.
    2) Increasing dyspnea along with progressive cyanosis of the lips and peripheral extremities was described in a 70-year-old man receiving flutamide (Kouides et al, 1996). An initial methemoglobinemia concentration of 32% was unaffected by methylene blue administration. The patient received two units of red cells with improvement of symptoms. Further laboratory analysis revealed a sulfhemoglobin concentration of 15%, which gradually declined over several weeks.

Neurologic

    3.7.1) SUMMARY
    A) WITH POISONING/EXPOSURE
    1) Headache is commonly associated with sulfhemoglobinemia.
    3.7.2) CLINICAL EFFECTS
    A) NEUROLOGICAL FINDING
    1) LACK OF EFFECT
    a) Sulfhemoglobinemia only rarely results in impairment of oxygen delivery resulting in alteration of central nervous system function (Haddad et al, 1998).
    B) HEADACHE
    1) WITH THERAPEUTIC USE
    a) Headache may develop with sulfhemoglobinemia.
    b) Based on a review of patient data collected over 10 years, 62 patients with drug-induced sulfhemoglobinemia were identified. Of those patients, 40 developed headache, most of which were described as tension or migraine headaches (Brandenburg, 1951).

Gastrointestinal

    3.8.1) SUMMARY
    A) WITH POISONING/EXPOSURE
    1) Constipation is a common complaint with sulfhemoglobinemia, but whether this is causative or a resultant effect is controversial.
    3.8.2) CLINICAL EFFECTS
    A) DRUG-INDUCED GASTROINTESTINAL DISTURBANCE
    1) Although the literature appears inconsistent, sulfhemoglobinemia may occur as a result of chronic constipation, persistent diarrhea in newborns, and in individuals who purge (Price, 2006; Pandey et al, 1996).
    B) DIARRHEA
    1) CASE REPORT - A 4-week-old breast-fed infant developed cyanosis following diarrheal illness which was treated with an unidentified drug by a private practitioner (Pandey et al, 1996). An initial methemoglobin of 32.9% was reported along with a normal G-6-PD concentration.
    a) Despite an improving methemoglobin concentration, cyanosis was still present after 2 weeks. A sulfhemoglobin concentration of 2.7 g/dL was found Cyanosis gradually improved over several months. The authors concluded that the diarrheal illness was a source of sulfhemoglobin, which in part may have been due to the release of hydrogen sulfide by the intestinal tract.
    C) CONSTIPATION
    1) Constipation has been reported to be associated with sulfhemoglobinemia, but whether this is a cause or clinical effect remains controversial (Brandenburg, 1951).

Hematologic

    3.13.1) SUMMARY
    A) Cyanosis, described as slate grey color in the absence of cardiopulmonary symptoms, is the most common sign of sulfhemoglobinemia.
    3.13.2) CLINICAL EFFECTS
    A) CYANOSIS
    1) WITH THERAPEUTIC USE
    a) SUMMARY
    1) Central cyanosis, described as a slate grey color, has been reported with sulfhemoglobinemia (Wu & Kenny, 1997a), along with reports of peripheral and circumoral (lips and tongue) cyanosis (Barrueto et al, 2002; Lambert et al, 1982; Haddad et al, 1998; Noor & Beutler, 1998).
    2) Cyanosis may be delayed in onset following exposure (up to several days) and persist for days to several months (the approximate lifecycle of an erythrocyte) (Kneezel & Kitchens, 1976; Lambert et al, 1982; Haddad et al, 1998). In most patients, treatment is limited to clinical observation (Noor & Beutler, 1998).
    3) The concentration of sulfhemoglobin in blood necessary to produce cyanosis is 0.5 g/dL, which is less than that necessary for methemoglobin (1.5 g/dL) or deoxyhemoglobin (5 g/dL). This correlates with a sulfhemoglobin concentration of 3.3% in a normal person with a Hb of 15 g/dL.
    b) CASE REPORT - Cyanosis with fatigue and mild exertional dyspnea began 24 hours after dermal application of DMSO in an adult (Burgess et al, 1998). Approximately, 10 days after exposure (when patient sought treatment) a sulfhemoglobin concentration of 6.2% was reported with a methemoglobin concentration of <0.1%. The patient recovered following oxygen therapy and a blood transfusion (2 units of packed red blood cells).
    c) CASE REPORT - A 15-year-old girl developed cyanosis after 12 doses of metoclopramide was given following an acetaminophen overdose which was treated with oral N-acetylcysteine (Langford & Sheikh, 1999). A sulfhemoglobin concentration of 16% (representing the sulfhemoglobin fraction of whole blood) was reported. The patient was treated with supplemental oxygen and supportive care, with noticeable improvement at 48 hours, and complete resolution of cyanosis by hospital day 3.
    d) CASE REPORT- A 57-year-old woman developed cyanosis and dyspnea following the use of phenazopyridine for several years. Vital signs were: blood pressure 135/65 mmHg, pulse 105 bpm, respiratory rate 22/minute; pulse oximetry 86% on room air. The ECG revealed only sinus tachycardia. A sulfhemoglobin concentration of 13.9% was reported. Following supportive therapy for seven days, she was discharged without any sequelae (Barrueto et al, 2002).
    2) WITH POISONING/EXPOSURE
    a) CASE REPORT - A greyish-blue cyanosis of the skin, tongue and lips was observed approximately 10 hours after ingestion of 3 grams of dapsone in a 22-year-old man (Lambert et al, 1982). Symptoms of headache, dizziness, nausea, and exertional dyspnea were also present. Initial methemoglobinemia (41.5% of total hemoglobin) was treated with methylene blue which temporarily improved cyanosis within the first 24-hours post exposure. By day 4 the sulfhemoglobin concentration had risen to 9%, and dropped below 5% on the tenth day which corresponded with the absence of cyanosis; no treatment was required.
    B) HEMOLYTIC ANEMIA
    1) Hemolytic anemia may occur in patients with sulfhemoglobinemia (Langford & Sheikh, 1999; Gopalachar et al, 2005). Hemolytic anemia in patients with sulfhemoglobinemia has been associated with Heinz body formation (Pinkhas et al, 1963).
    C) HB SS DISEASE
    1) Sulfhemoglobinemia is a relatively mild syndrome in persons with hemoglobin A, but could be potentially toxic in patients with hemoglobin S, in whom it could potentiate sickling (Park & Nagel, 1984).

Reproductive

    3.20.1) SUMMARY
    A) Sulfhemoglobinemia and Heinz body formation have been reported in a 36-week pregnant woman after ingesting codeine compound tablets.
    3.20.3) EFFECTS IN PREGNANCY
    A) SULFHEMOGLOBINEMIA
    1) CASE REPORT - Sulfhemoglobinemia and Heinz body formation were reported in a 36-week pregnant woman with history of ingesting up to 20 codeine-compound tablets daily (each containing 250 mg phenacetin) for several months (Cumming & Pollock, 1967). The patient delivered a 4.5 pound male infant who also had Heinz body anemia; sulfhemoglobin was not found.

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) GENERAL APPROACH: If patient is cyanotic, administer oxygen and manage airway as needed. Obtain an arterial blood gas and measure methemoglobin and sulfhemoglobin concentrations (note: many co-oximeters can not distinguish sulfhemoglobin from methemoglobin). Pulse oximetry is NOT reliable in patients with sulfhemoglobinemia. Obtain a CBC (total hemoglobin). Obtain a chest x-ray and ECG.
    B) CO-OXIMETRY: Sulfhemoglobin may be inappropriately identified as methemoglobin depending on which co-oximeter is used. Instruments that use more wavelengths can discriminate a greater number of hemoglobin compounds. There are 3 instruments reported to reliably measure sulfhemoglobin: AVL 912 (AVL Medical Instruments, Schaffhausen, Switzerland); Ciba Corning 270 (Ciba Corning Diagnostics, Medfield, MA); and Radiometer OSM3 (Radiometer, Copenhagen, Denmark). Of these the AVL 912 gives a numerical result of the concentration measured. Some newer co-oximeters can also distinguish between several species of hemoglobin at once. The IL 482 (Instrumentation Laboratory, Lexington, MA) may erroneously report sulfhemoglobin as methemoglobin.
    C) CLINICAL DIAGNOSIS: If the proper assay is not available it may be a diagnosis of exclusion based on history and physical exam. Subjects with presumed methemoglobinemia who do not respond to methylene blue therapy are likely to suffer from occult sulfhemoglobinemia.
    4.1.2) SERUM/BLOOD
    A) ACID/BASE
    1) Obtain arterial blood gases with measured oxygen saturation and co-oximetry in the presence of cyanosis; as in the case of methemoglobinemia pulse oximetry and calculated oxygen saturation are not reliable indicators of true oxygen saturation.
    2) Most co-oximeters measure oxyhemoglobin, deoxyhemoglobin, carboxyhemoglobin, and methemoglobin. The absorption characteristics of sulfhemoglobin and methemoglobin are similar, and sulfhemoglobin is usually misinterpreted as methemoglobin using commonly available co-oximeters. Adding potassium cyanide allows differentiation of sulfhemoglobin from methemoglobin by converting methemoglobin to cyanmethemoglobin and changing its peak absorption spectrum. This method does not distinguish sulfhemoglobin from hemoglobin M.
    B) OTHER
    1) Chronic sulfhemoglobinemia or methemoglobinemia should prompt a search for an abnormal hemoglobin or enzyme deficiency. Hemoglobin electrophoresis, methemoglobin reductase activity, and G-6-PD activity may be diagnostic.
    C) HEMATOLOGIC
    1) Hemoglobin should be obtained because anemia may further decrease oxygen carrying capacity.
    2) Hemolysis has been associated with Heinz body formation (Cumming & Pollock, 1967a).
    4.1.4) OTHER
    A) OTHER
    1) ECG
    a) Cardiac monitoring is generally NOT indicated, unless underlying disease or clinical symptoms are present. Sinus tachycardia rarely occurs in the presence of sulfhemoglobin alone.

Radiographic Studies

    A) If patient is cyanotic, obtain chest x-ray to rule out underlying cardiopulmonary disease.

Methods

    A) Pulse oximetry and calculated oxygen saturation are NOT reliable methods to determine true oxygen saturation if sulfhemoglobin is present (Langford & Sheikh, 1991).
    B) MULTIPLE WAVELENGTH CO-OXIMETERY - is generally the initial laboratory test used to evaluate the blood (by fractionation of hemoglobin derivatives) of a cyanotic patient with possible sulfhemoglobinemia. Although this method can measure the presence of oxyhemoglobin, deoxyhemoglobin, carboxyhemoglobin, and methemoglobin, it is not able to directly measure sulfhemoglobin (Haddad et al, 1998; Noor & Beutler, 1998) Langford & Sheikh, 1999).
    1) CO-OXIMETERS: There are 3 instruments reported to reliably measure sulfhemoglobin - AVL 912 (AVL Medical Instruments, Schaffhausen, Switzerland), Ciba Corning 270 (Ciba Corning Diagnostics, Medfield MA), and Radiometer OSM3 (Radiometer, Copenhagen, Denmark). Of these the AVL 912 gives a numerical result of the concentration measured (Green & Swanson, 1996). Although not indicated by the manufacturer, the OSM3 - CO-oximeter (Radiometer, Copenhagen, Denmark) was able to quantify sulfhemoglobin in a patient (Wu & Kenny, 1997).
    2) Some newer co-oximeters can also distinguish between several species of hemoglobin at once. The IL 482 (Instrumentation Laboratory, Lexington, MA) may erroneously report sulfhemoglobin as methemoglobin (VanVeldhuizen & Wyatt, 1995)
    3) MALLOY METHOD - is an assay method which uses either potassium or sodium cyanide (cyanide-ferricyanide procedure) to determine the presence of methemoglobin. If present, the blood sample will turn bright red or pink forming cyanomethemoglobin (Haddad et al, 1998) Langford & Sheikh, 1999). An unchanged sample is most likely a result of sulfhemoglobin, and rarely hemoglobin M disease (Haddad et al, 1998).
    4) BACKGROUND - The addition of cyanide to methemoglobin will result in the formation of cyanomethemoglobin, and loss of its peak absorbance at 626 nm. If sulfhemoglobin is present there will be continued absorbance in the range of 620 nm (Curry & Gerkin, 1987). Other hemoglobin species (hemoglobin M, mixtures of partially denatured and partially oxidized hemoglobin) also absorb light at 620 nm, thus this test does not definitively identify sulfhemoglobin (Amadur et al, 1991).
    C) OTHER - Van Veldhuizen & Wyatt (1995) described a follow-up method to the co-oximeter that further differentiates between methemoglobin and sulfhemoglobin (VanVeldhuizen & Wyatt, 1995). The Beckman DU7 spectrophotometer, Beckman Instruments, Fullerton, CA (samples sent to Mayo Medical Laboratories, Rochester, MN) method measures a maximum spectral absorbance of 630 for methemoglobin and 620 sulfhemoglobin (Langford & Sheikh, 1991).
    D) ISOELECTRIC FOCUSING - was first described by Park & Nagel (1984) as a hemoglobin electrophoresis method to distinguish between methemoglobin, sulfhemoglobin, and M hemoglobin (Park & Nagel, 1984a). Gel isoelectric focusing and optical spectrophotometry have also been used (Park et al, 1986). This is considered to be one of the most reliable tests to determine and quantify the presence of sulfhemoglobin (Haddad et al, 1998).

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.1) DISPOSITION/ORAL EXPOSURE
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) Patients may be asymptomatic shortly after exposure. The development of sulfhemoglobinemia can be delayed up to several days. Many agents that produce sulfhemoglobin can also produce methemoglobin.
    B) Observation of asymptomatic or mildly symptomatic individuals may be advisable with exposure to chemicals (e.g., aniline, nitrates) which produce both sulfhemoglobin and methemoglobin.

Monitoring

    A) GENERAL APPROACH: If patient is cyanotic, administer oxygen and manage airway as needed. Obtain an arterial blood gas and measure methemoglobin and sulfhemoglobin concentrations (note: many co-oximeters can not distinguish sulfhemoglobin from methemoglobin). Pulse oximetry is NOT reliable in patients with sulfhemoglobinemia. Obtain a CBC (total hemoglobin). Obtain a chest x-ray and ECG.
    B) CO-OXIMETRY: Sulfhemoglobin may be inappropriately identified as methemoglobin depending on which co-oximeter is used. Instruments that use more wavelengths can discriminate a greater number of hemoglobin compounds. There are 3 instruments reported to reliably measure sulfhemoglobin: AVL 912 (AVL Medical Instruments, Schaffhausen, Switzerland); Ciba Corning 270 (Ciba Corning Diagnostics, Medfield, MA); and Radiometer OSM3 (Radiometer, Copenhagen, Denmark). Of these the AVL 912 gives a numerical result of the concentration measured. Some newer co-oximeters can also distinguish between several species of hemoglobin at once. The IL 482 (Instrumentation Laboratory, Lexington, MA) may erroneously report sulfhemoglobin as methemoglobin.
    C) CLINICAL DIAGNOSIS: If the proper assay is not available it may be a diagnosis of exclusion based on history and physical exam. Subjects with presumed methemoglobinemia who do not respond to methylene blue therapy are likely to suffer from occult sulfhemoglobinemia.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) SUMMARY
    1) Sulfhemoglobinemia is generally acquired from the ingestion of oxidant agents such as nitrate and aniline derivatives. It usually develops after chronic exposure or many hours to several days following an acute exposure. Gastrointestinal decontamination is usually not necessary.
    6.5.2) PREVENTION OF ABSORPTION
    A) SUMMARY
    1) Sulfhemoglobinemia is generally acquired from the ingestion of oxidant agents such as nitrate and aniline derivatives. It usually develops after chronic exposure or many hours to several days following an acute exposure. Gastrointestinal decontamination is usually not necessary.
    6.5.3) TREATMENT
    A) SUPPORT
    1) Therapy consists of supportive measures and withdrawal of the causative agent. Correction of possible coexisting methemoglobinemia or severe anemia may be indicated to ensure adequate tissue oxygenation. See METHEMOGLOBINEMIA management as indicated.
    2) There is NO antidote for sulfhemoglobinemia; methylene blue is ineffective (Lambert, 1982) (Park & Nagel, 1984).
    3) Rarely, exchange or blood transfusion may be indicated in the presence of sulfhemoglobin.
    B) OXYGEN
    1) Although symptoms are generally benign, oxygen therapy is indicated in severe cases. It is also indicated in patients where methemoglobin and sulfhemoglobin coexist.
    2) Hyperbaric oxygen may be useful in severely symptomatic patients as a temporary measure, but this has not been adequately studied (Burgess et al, 1998).
    C) EXCHANGE TRANSFUSION
    1) INDICATIONS
    a) Should be considered in rare cases where an elevated sulfhemoglobin concentration is present and the patient is severely symptomatic. Total hemoglobin concentration will increase with a decrease in the sulfhemoglobin fraction/concentration (Haddad et al, 1998).

Range Of Toxicity

Summary

    A) A sulfhemoglobin concentration of 0.5 g/dL (3.3% in a patient with a hemoglobin of 15 g/dL) produces an observable cyanosis in which the skin appears slate grey.
    B) Background sulfhemoglobin concentrations in adults were less than 0.4%.
    C) Sulfhemoglobin concentrations as high as 16% have been reported, with cyanosis and dyspnea as the predominant clinical manifestations. Sulfhemoglobin concentrations above 10% of total hemoglobin are unusual.

Minimum Lethal Exposure

    A) SUMMARY
    1) Exposure is usually self-limited. One fatality has been reported in a patient with a toxic paint ingestion.

Maximum Tolerated Exposure

    A) SUMMARY
    1) A sulfhemoglobin concentration as low as 0.5 g/dL (correlates with a concentration of 3.3% in a normal subject with a Hb of 15 g/dL) produces an observable cyanosis in which the skin appears slate grey (Haddad et al, 1998). In contrast, a concentration of 1.5 g/dL (correlates with a concentration of 10% in a normal subject with a Hb of 15 g/dL) of methemoglobin (Langford & Sheikh, 1991) and 5 g/dL (5%) of deoxyhemoglobin are required to produce clinically detectable cyanosis (Haddad et al, 1998; Noor & Beutler, 1998).
    2) Background sulfhemoglobin concentrations in a large group of adult patients undergoing surgery was less than 0.4% (Burgess et al, 1998). Sulfhemoglobin concentrations generally do NOT exceed 10% of total hemoglobin (Wu & Kenny, 1997).
    3) In the literature, tolerance concentrations have been reportedly quite variable (20% to 60%) with only minor symptoms reported (Wu & Kenny, 1997). However, the authors suggested that further research is needed to draw any conclusions from this data.
    B) CASE REPORTS
    1) A 57-year-old woman developed cyanosis and dyspnea following the use of phenazopyridine for several years. Vital signs were: blood pressure 135/65 mmHg, pulse 105 bpm, respiratory rate 22/minute; pulse oximetry 86% on room air. The ECG revealed only sinus tachycardia. A sulfhemoglobin concentration of 13.9% was reported. Following supportive therapy for seven days, she was discharged without any sequelae (Barrueto et al, 2002).
    2) A greyish-blue cyanosis of the skin, tongue and lips was observed approximately 10 hours after ingestion of 3 grams of dapsone in a 22-year-old man (Lambert et al, 1982). Symptoms of headache, dizziness, nausea, and exertional dyspnea were also present. Initial methemoglobinemia (41.5% of total hemoglobin) was treated with methylene blue which temporarily improved cyanosis within the first 24-hours post exposure. By day 4, the sulfhemoglobin concentration had risen to 9%, and dropped below 5% on the tenth day which corresponded with the absence of cyanosis; no treatment was required.
    3) A 15-year-old girl developed cyanosis after 12 doses of metoclopramide was given following an acetaminophen overdose which was treated with oral N-acetylcysteine (Langford & Sheikh, 1999). A sulfhemoglobin concentration of 16% (representing the sulfhemoglobin fraction of whole blood) was reported. The patient was treated with supplemental oxygen and supportive care, with noticeable improvement at 48 hours, and complete resolution of cyanosis by hospital day 3.

Pharmacology Toxicology

Pharmacologic Mechanism

    A) SUMMARY
    1) Sulfhemoglobin is a green pigmented molecule with a sulfur atom which is incorporated into the porphyrin ring which severely limits oxygen affinity and thus makes oxygen transport ineffective. Once present it cannot be converted to hemoglobin (Schmitter, 1975), it exists for the lifespan of the red blood cell; therefore, cyanosis can be prolonged for 120 days corresponding to the typical circulation lifetime of erythrocytes (Schmitter, 1975; Van Veldhuizen & Wyatt, 1995; Haddad et al, 1998). A sulfhemoglobin concentration above 10% of total hemoglobin is rare (Wu & Kenny, 1997).
    B) OXYGEN SATURATION
    1) Sulfhemoglobin results in reduced oxygen-carrying capacity, but oxygen delivery is generally within normal limits. Unlike methemoglobinemia, sulfhemoglobinemia results in the shifting of the affected molecules toward the nonliganded conformation, which reduces oxygen affinity of their unmodified subunits (Price, 2006; Haddad et al, 1998). This results in the right shift of the partial pressure of oxygen at 50% hemoglobin saturation (p50) and improves oxygen delivery to tissues despite the reduced oxygen-binding capacity (Van Veldhuizen & Wyatt, 1995; Haddad et al, 1998).
    a) Symptoms, such as dyspnea, are frequently absent, unless the sulfhemoglobin concentrations are very high.
    C) CLINICAL COURSE
    1) In addition, sulfhemoglobinemia has a protracted course, as compared to methemoglobinemia, which allows the individual to compensate for the reduced oxygen-carrying capacity. As a result, clinical symptoms are frequently absent, including pulmonary insufficieny, unless high levels of sulfhemoglobin are present (Haddad et al, 1998).
    D) IMPLICATED AGENTS
    1) Similar to methemoglobin, sulfhemoglobin is often produced by various oxidant drugs, which are most often linked to nitrate and aniline derivatives. At present, it is not clear why certain oxidant agents are capable of producing methemoglobin in most individuals and sulfhemoglobin in others (Haddad et al, 1998).
    2) Sulfhemoglobin has also been produced in vitro by hydrogen sulfide (Price, 2006).

References

General Bibliography

    1) Amdur MO, Doull J, & Klaassen CD: Casarett and Doull's Toxicology: The Basic Science of Poisons, 4th Ed, Pergamon Press, New York, NY, 1991, pp 274-275.
    2) Barrueto F Jr, Ryon D, Howland MA, et al: Phenazopyridine-induced sulfhemoglobinemia. J Toxicol Clin Toxicol 2002; 40(3):470.
    3) Brandenburg RO: Sulfhemoglobinemia; a study of 62 clinical cases. Am Heart J 1951; 42(4):582-588.
    4) Burgess JL, Hamner AP, & Robertson WO: Sulfhemoglobinemia after dermal application of DMSO. Vet Human Toxicol 1998; 40:87-89.
    5) Cumming RL & Pollock A: Drug induced sulphaemoglobinaemia and heinz body anaemia in pregnancy with involvement of the foetus. Scott Med J 1967a; 12(9):320-322.
    6) Cumming RLC & Pollock A: Drug induced sulphaemoglobinaemia and heinz body anaemia in pregnancy with involvement of the foetus. Scot Med J 1967; 12:320-322.
    7) Curry SC & Gerkin RD: A patient with sulfhemoglobin? (Letter). Annal Emerg Med 1987; 16:828-829.
    8) Gopalachar AS, Bowie VL, & Bharadwaj P: Phenazopyridine-induced sulfhemoglobinemia. Ann Pharmacother 2005; 39:1028-1030.
    9) Haddad LM, Shannon MW, & Winchester JF: Clinical Management of Poisoning and Drug Overdose, 3rd Ed., W.B, Saunders Co, Philadelphia, PA, 1998.
    10) Kneezel LD & Kitchens CS: Phenacetin-induced sulfhemoglobinemia: report of a case and review of the literature. Johns Hopkins Med J 1976; 139:175-177.
    11) Kouides PA, Abboud CN, & Fairbanks VF: Flutamide-induced cyanosis refractory to methylene blue therapy. Br J Haematol 1996; 94:73-75.
    12) Lambert M, Sonnet J, & Mahieu P: Delayed sulfhemoglobinemia after acute dapsone intoxication. J Toxicol - Clin Toxicol 1982; 19:45-50.
    13) Langford JS & Sheikh S: An adolescent case of sulfhemoglobinemia associated with high-dose metoclopramide and N-acetylcysteine. (Part 1). Ann Emerg Med 1991; 34:538-541.
    14) Langford JS & Sheikh S: An adolescent case of sulfhemoglobinemia associated with high-dose metoclopramide and N-acetylcysteine. Ann Emerg Med 1999; 34:538-541.
    15) Noor M & Beutler E: Acquired Sulfhemoglobinemia. An underreported diagnosis?. West J Med 1998; 169:386-389.
    16) Noor M & Beutler E: Acquired sulfhemoglobinemia. An underreported diagnosis?. West J Med 1998a; 169(6):386-389.
    17) Pandey J, Chellani H, & Garg M: Case reports: Congenital sulfhemoglobin and transient methemoglobinemia secondary to diarrhoea. Indian J Pathol Microbiol 1996; 39:217-220.
    18) Park CM & Nagel RL: Sulfhemoglobinemia. Clinical and molecular aspects. N Engl J Med 1984a; 310(24):1579-1584.
    19) Park CM & Nagel RL: Sulfhemoglobinemia: clinical and molecular aspects. N Engl J Med 1984; 310:1579-1584.
    20) Park CM, Nagel RL, Blumberg WE, et al: Sulfhemoglobin. Properties of partially sulfurated tetramers. J Biol Chem 1986; 261(19):8805-8810.
    21) Pinkhas J, Djaldetti M, DeVries A, et al: [Complications of leukemia and their treatments]. Harefuah 1963; 65:353-356.
    22) Price D: Methemoglin Inducers. In: Goldfrank LR, Flomenbaum N, Hoffman RS, et al, eds. Goldfrank's Toxicologic Emergencies. 8th ed., 8th ed. McGraw Hill, New York, NY, 2006, pp -.
    23) Schmitter CR: Sulfhemoglobinemia and methemoglobinemia - Uncommon causes of cyanosis. Anesthesiol 1975; 43:586-587.
    24) Van Veldhuizen PJ & Wyatt A: Metoclopramide-induced sulfhemoglobinemia. Am J Gastroenterol 1995; 90:1010-1011.
    25) VanVeldhuizen PJ & Wyatt A: Metoclopramide-induced sulfhemoglobinemia. Am J Gastroenterol 1995; 90(6):1010-1011.
    26) Wu C & Kenny MA: A case of sulfhemoglobinemia and emergency measurement of sulfhemoglobin with an OSM3 CO-oximeter. Clin Chem 1997; 43(1):162-166.
    27) Wu C & Kenny MA: A case of sulfhemoglobinemia and emergency measurement of sulfhemoglobin with an OSM3 CO-oximeter. Clin Chem 1997a; 43(1):162-166.