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Methaemoglobinaemia
Complications of poisoning
Methaemoglobinaemia
Amino- and nitro-derivatives of benzene are particularly potent methaemoglobin-formers because once absorbed they are activated to a metabolite that enters a cyclical process of methaemo globin production such that even small exposures can result in clinically significant methaemoglobinaemia.1–3
Sally Bradberry
Features Methaemoglobinaemia is characterized by grey-blue central ‘cyanosis’, which is usually asymptomatic at methaemoglobin concentrations less than 20% of total haemoglobin. This discoloration is caused predominantly by the slate-grey colour imparted by the methaemoglobin pigment rather than the presence of deoxygenated haemoglobin. At increasing methaemoglobin concentrations, features reflect impaired oxygen transport to, and liberation at, body tissues. Headache, weakness and fatigue predominate at methaemoglobin concentrations below 30%,6 while nausea,7,8 dizziness,7 anxiety, chest pain and dyspnoea7 may be observed at concentrations of 30–50%.6 Impaired consciousness6,9 and seizures10 are likely at methaemoglobin concentrations exceeding 60% and concentrations approaching 80% are life-threatening.
Abstract Methaemoglobin is formed when ferrous haemoglobin iron (II) is oxidized to ferric iron (III), which cannot participate in oxygen transport. Methaemoglobin-forming chemical groups of particular importance in poisoning are organic nitrites (e.g. amyl and isobutyl nitrite) and aminoor nitro-derivatives of benzene (e.g. aniline, dapsone and lidocaine). An asymptomatic, apparent ‘cyanosis’ is the earliest clinical feature, occurring when approximately 15% of total haemoglobin is replaced by methaemoglobin. Progressive manifestations of tissue hypoxia ensue at increasing methaemoglobin concentrations and concentrations approaching 80% may be fatal.
Diagnosis Two clinical observations may help. First, the victim is often less unwell than one would expect from the severity of the ‘cyanosis’ present and, secondly, the cyanosis is unresponsive to oxygen therapy. Knowledge of the chemicals that cause methaemoglobinaemia will also assist in the diagnosis. Standard pulse oximetry is unreliable in the presence of methaemoglobinaemia, recording haemoglobin oxygen saturation values between 82% and 85% when methaemoglobin concentrations are between 30% and 100%. Arterial blood gas analysis shows normal partial pressures of oxygen and carbon dioxide, even in the presence of high methaemoglobin concentrations, since these parameters reflect dissolved gas in the sample and are not affected by methaemoglobinaemia. If there is significant tissue hypoxia, a metabolic acidosis may be present. Analysers incorporating a co-oximeter will measure methaemoglobin concentrations directly to confirm the diagnosis.
Keywords aminobenzene; cyanosis; dapsone; haemoglobin oxidation; hypoxia; lidocaine; nitrobenzene; organic nitrites
Methaemoglobin Methaemoglobin is formed when ferrous haemoglobin iron (II) is oxidized to ferric iron (III), which cannot participate in oxygen transport. Methaemoglobin concentrations are normally maintained at around 1% total haemoglobin by the action of a nicotinamide adenine dinucleotide (NADH)-dependent methaemoglobin reductase for which the physiological electron carrier is cytochrome b5.1 Excess methaemoglobin causes tissue hypoxia, not only because methaemoglobin is incapable of binding oxygen but also because the oxidation of one or more iron atoms in the haem tetramer distorts the tetramer structure, so that the remaining non-oxidized haem subunits bind oxygen avidly but release it less efficiently.1
Management Even though methaemoglobin cannot bind oxygen, it is appropriate to administer high flow oxygen to symptomatic patients with methaemoglobinaemia to maximise oxygen saturation of residual normal ferrous haemoglobin. Methylthioninium chloride (methylene blue), acts as an electron donor to reduce methaemoglobin (Figure 1). In otherwise healthy individuals, methaemoglobin concentrations less than 30% usually do not require specific therapy, since such patients have only minor or no symptoms and methaemoglobin will be reduced over several hours by the intrinsic activity of methaemoglobin reductase. However, an anaemic patient may experience symptoms of hypoxia at methaemoglobin concentrations below 30% since even in the absence of methaemoglobinaemia their overall oxygen transporting capacity is reduced. Such patients, or otherwise healthy individuals with methaemoglobin concentrations greater than 30%, warrant treatment with methylthioninium chloride (methylene blue) 1-2 mg/kg (the dose depending on the severity of features) intravenously over
Poisons causing methaemoglobinaemia Poisoning with a number of oxidizing drugs and chemicals may be complicated by methaemoglobinaemia.1–3 Two important chemical groups in this regard are organic nitrites (e.g. amyl and isobutyl nitrite) and amino- or nitro-derivatives of benzene (e.g aniline, dapsone and lidocaine). Organic nitrites are sold as ‘room odorizers’. Inhalation causes profound, though transient, vasodilatation with the intent of enhancing sexual pleasure or inducing a transient ‘high’. Substantial absorption, which may occur after prolonged inhalation or ingestion, precipitates methaemoglobin formation.4,5
Sally Bradberry BSc MRCP is Assistant Director of the National Poisons Information Service (Birmingham Unit) at City Hospital, Birmingham, UK. Competing interests: none declared.
MEDICINE 35:10
552
© 2007 Elsevier Ltd. All rights reserved.
Complications of poisoning
The reduction of methaemoglobin by methylene blue NADP +
NADPH Methaemoglobin reductase
H
N
H3C
N
S
N
+ N
H3C
CH3
CH3
CH3
N
S
N
CH3
CH3
CH3
Methylene blue
Leucomethylene blue
(oxidised)
(reduced)
Haemoglobin (FeII)
Methaemoglobin (FeII)
NADP+, oxidized form of nicotinamide-adenine dinucleotide phosphate; NADPH, reduced form of nicotinamide-adenine dinucleotide phosphate.
Figure 1
5–10 minutes as a 1% solution (methylthioninium chloride can also be diluted with 0.9% saline for infusion). If the methaemoglobin concentration is greater than 50%, methylthioninium chloride 2 mg/kg should be administered. Symptomatic improvement usually occurs within 30 minutes. If there is evidence of continuing chemical absorption or prolonged methaemoglobin formation, a second dose of methylthioninium chloride 1–2 mg/kg may be required. High doses (typically in excess of 20 mg/kg) of methylthioninium chloride can initiate severe intravascular haemolysis and doses as low as 4 mg/kg may exacerbate the haemolytic effect of oxidizing chemicals. Severe renal impairment is an absolute contraindication to methylthioninium chloride administration since it is eliminated predominantly renally. Methylthioninium chloride will also be less effective where nicotinamide adenine dinucleotide phosphate (NADPH) availability is reduced, as occurs in the presence of glucose-6-phosphate dehydrogenase (G-6-P-D) deficiency and haemolysis, and when the chemical initiating methaemoglobin formation itself utilizes NADPH in cyclical methaemoglobin production, as occurs with, for example, dapsone and aniline. ◆
eds. Hemoglobin: molecular, genetic and clinical aspects. Philadelphia: WB Saunders, 1986: 634–62. 2 Eyer P, Klimmek R. Blood and blood-forming organs. In: Marquardt H, Schäfer SG, McClellan RO, Welsch F, eds. Toxicology. San Diego, California: Academic Press, 1999: 349–69. 3 Kiese M. The biochemical production of ferrihemoglobinforming derivatives from aromatic amines, and mechanisms of ferrihemoglobin formation. Pharmacol Rev 1966; 18: 1091–161. 4 Bradberry SM, Whittington RM, Parry DA, Vale JA. Fatal methemoglobinemia due to inhalation of isobutyl nitrite. J Toxicol Clin Toxicol 1994; 32: 179–84. 5 Shesser R, Mitchell J, Edelstein S. Methemoglobinemia from isobutyl nitrite preparations. Ann Emerg Med 1981; 10: 262–64. 6 Wuertz RL, Frazee Jr WH, Hume WG, et al. Chemical cyanosis-anemia syndrome: diagnosis, treatment and recovery. Arch Environ Health 1964; 9: 478–91. 7 Demirel H, Koster VS, Koot MJ, et al. Methemoglobinemia as an uncommon cause of cyanosis. N J Med 1999; 55: 19–22. 8 Bradberry SM, Gazzard B, Vale JA. Methemoglobinemia caused by the accidental contamination of drinking water with sodium nitrite. J Toxicol Clin Toxicol 1994; 32: 173–78. 9 Harrison MR. Toxic methaemoglobinaemia. A case of acute nitrobenzene and aniline poisoning treated by exchange transfusion. Anaesthesia 1977; 32: 270–72. 10 Harris JC, Rumack BH, Peterson RG, McGuire BM. Methemoglobinemia resulting from absorption of nitrates. JAMA 1979; 242: 2869–71.
References 1 Bunn HF, Forger BG. Hemoglobin oxidation: methemoglobin, methemoglobinemia and sulfhemoglobinemia. In: Benn HF, Forger BG,
MEDICINE 35:10
553
© 2007 Elsevier Ltd. All rights reserved.
Methaemoglobinaemia
Amino- and nitro-derivatives of benzene are particularly potent methaemoglobin-formers because once absorbed they are activated to a metabolite that enters a cyclical process of methaemo globin production such that even small exposures can result in clinically significant methaemoglobinaemia.1–3
Sally Bradberry
Features Methaemoglobinaemia is characterized by grey-blue central ‘cyanosis’, which is usually asymptomatic at methaemoglobin concentrations less than 20% of total haemoglobin. This discoloration is caused predominantly by the slate-grey colour imparted by the methaemoglobin pigment rather than the presence of deoxygenated haemoglobin. At increasing methaemoglobin concentrations, features reflect impaired oxygen transport to, and liberation at, body tissues. Headache, weakness and fatigue predominate at methaemoglobin concentrations below 30%,6 while nausea,7,8 dizziness,7 anxiety, chest pain and dyspnoea7 may be observed at concentrations of 30–50%.6 Impaired consciousness6,9 and seizures10 are likely at methaemoglobin concentrations exceeding 60% and concentrations approaching 80% are life-threatening.
Abstract Methaemoglobin is formed when ferrous haemoglobin iron (II) is oxidized to ferric iron (III), which cannot participate in oxygen transport. Methaemoglobin-forming chemical groups of particular importance in poisoning are organic nitrites (e.g. amyl and isobutyl nitrite) and aminoor nitro-derivatives of benzene (e.g. aniline, dapsone and lidocaine). An asymptomatic, apparent ‘cyanosis’ is the earliest clinical feature, occurring when approximately 15% of total haemoglobin is replaced by methaemoglobin. Progressive manifestations of tissue hypoxia ensue at increasing methaemoglobin concentrations and concentrations approaching 80% may be fatal.
Diagnosis Two clinical observations may help. First, the victim is often less unwell than one would expect from the severity of the ‘cyanosis’ present and, secondly, the cyanosis is unresponsive to oxygen therapy. Knowledge of the chemicals that cause methaemoglobinaemia will also assist in the diagnosis. Standard pulse oximetry is unreliable in the presence of methaemoglobinaemia, recording haemoglobin oxygen saturation values between 82% and 85% when methaemoglobin concentrations are between 30% and 100%. Arterial blood gas analysis shows normal partial pressures of oxygen and carbon dioxide, even in the presence of high methaemoglobin concentrations, since these parameters reflect dissolved gas in the sample and are not affected by methaemoglobinaemia. If there is significant tissue hypoxia, a metabolic acidosis may be present. Analysers incorporating a co-oximeter will measure methaemoglobin concentrations directly to confirm the diagnosis.
Keywords aminobenzene; cyanosis; dapsone; haemoglobin oxidation; hypoxia; lidocaine; nitrobenzene; organic nitrites
Methaemoglobin Methaemoglobin is formed when ferrous haemoglobin iron (II) is oxidized to ferric iron (III), which cannot participate in oxygen transport. Methaemoglobin concentrations are normally maintained at around 1% total haemoglobin by the action of a nicotinamide adenine dinucleotide (NADH)-dependent methaemoglobin reductase for which the physiological electron carrier is cytochrome b5.1 Excess methaemoglobin causes tissue hypoxia, not only because methaemoglobin is incapable of binding oxygen but also because the oxidation of one or more iron atoms in the haem tetramer distorts the tetramer structure, so that the remaining non-oxidized haem subunits bind oxygen avidly but release it less efficiently.1
Management Even though methaemoglobin cannot bind oxygen, it is appropriate to administer high flow oxygen to symptomatic patients with methaemoglobinaemia to maximise oxygen saturation of residual normal ferrous haemoglobin. Methylthioninium chloride (methylene blue), acts as an electron donor to reduce methaemoglobin (Figure 1). In otherwise healthy individuals, methaemoglobin concentrations less than 30% usually do not require specific therapy, since such patients have only minor or no symptoms and methaemoglobin will be reduced over several hours by the intrinsic activity of methaemoglobin reductase. However, an anaemic patient may experience symptoms of hypoxia at methaemoglobin concentrations below 30% since even in the absence of methaemoglobinaemia their overall oxygen transporting capacity is reduced. Such patients, or otherwise healthy individuals with methaemoglobin concentrations greater than 30%, warrant treatment with methylthioninium chloride (methylene blue) 1-2 mg/kg (the dose depending on the severity of features) intravenously over
Poisons causing methaemoglobinaemia Poisoning with a number of oxidizing drugs and chemicals may be complicated by methaemoglobinaemia.1–3 Two important chemical groups in this regard are organic nitrites (e.g. amyl and isobutyl nitrite) and amino- or nitro-derivatives of benzene (e.g aniline, dapsone and lidocaine). Organic nitrites are sold as ‘room odorizers’. Inhalation causes profound, though transient, vasodilatation with the intent of enhancing sexual pleasure or inducing a transient ‘high’. Substantial absorption, which may occur after prolonged inhalation or ingestion, precipitates methaemoglobin formation.4,5
Sally Bradberry BSc MRCP is Assistant Director of the National Poisons Information Service (Birmingham Unit) at City Hospital, Birmingham, UK. Competing interests: none declared.
MEDICINE 35:10
552
© 2007 Elsevier Ltd. All rights reserved.
Complications of poisoning
The reduction of methaemoglobin by methylene blue NADP +
NADPH Methaemoglobin reductase
H
N
H3C
N
S
N
+ N
H3C
CH3
CH3
CH3
N
S
N
CH3
CH3
CH3
Methylene blue
Leucomethylene blue
(oxidised)
(reduced)
Haemoglobin (FeII)
Methaemoglobin (FeII)
NADP+, oxidized form of nicotinamide-adenine dinucleotide phosphate; NADPH, reduced form of nicotinamide-adenine dinucleotide phosphate.
Figure 1
5–10 minutes as a 1% solution (methylthioninium chloride can also be diluted with 0.9% saline for infusion). If the methaemoglobin concentration is greater than 50%, methylthioninium chloride 2 mg/kg should be administered. Symptomatic improvement usually occurs within 30 minutes. If there is evidence of continuing chemical absorption or prolonged methaemoglobin formation, a second dose of methylthioninium chloride 1–2 mg/kg may be required. High doses (typically in excess of 20 mg/kg) of methylthioninium chloride can initiate severe intravascular haemolysis and doses as low as 4 mg/kg may exacerbate the haemolytic effect of oxidizing chemicals. Severe renal impairment is an absolute contraindication to methylthioninium chloride administration since it is eliminated predominantly renally. Methylthioninium chloride will also be less effective where nicotinamide adenine dinucleotide phosphate (NADPH) availability is reduced, as occurs in the presence of glucose-6-phosphate dehydrogenase (G-6-P-D) deficiency and haemolysis, and when the chemical initiating methaemoglobin formation itself utilizes NADPH in cyclical methaemoglobin production, as occurs with, for example, dapsone and aniline. ◆
eds. Hemoglobin: molecular, genetic and clinical aspects. Philadelphia: WB Saunders, 1986: 634–62. 2 Eyer P, Klimmek R. Blood and blood-forming organs. In: Marquardt H, Schäfer SG, McClellan RO, Welsch F, eds. Toxicology. San Diego, California: Academic Press, 1999: 349–69. 3 Kiese M. The biochemical production of ferrihemoglobinforming derivatives from aromatic amines, and mechanisms of ferrihemoglobin formation. Pharmacol Rev 1966; 18: 1091–161. 4 Bradberry SM, Whittington RM, Parry DA, Vale JA. Fatal methemoglobinemia due to inhalation of isobutyl nitrite. J Toxicol Clin Toxicol 1994; 32: 179–84. 5 Shesser R, Mitchell J, Edelstein S. Methemoglobinemia from isobutyl nitrite preparations. Ann Emerg Med 1981; 10: 262–64. 6 Wuertz RL, Frazee Jr WH, Hume WG, et al. Chemical cyanosis-anemia syndrome: diagnosis, treatment and recovery. Arch Environ Health 1964; 9: 478–91. 7 Demirel H, Koster VS, Koot MJ, et al. Methemoglobinemia as an uncommon cause of cyanosis. N J Med 1999; 55: 19–22. 8 Bradberry SM, Gazzard B, Vale JA. Methemoglobinemia caused by the accidental contamination of drinking water with sodium nitrite. J Toxicol Clin Toxicol 1994; 32: 173–78. 9 Harrison MR. Toxic methaemoglobinaemia. A case of acute nitrobenzene and aniline poisoning treated by exchange transfusion. Anaesthesia 1977; 32: 270–72. 10 Harris JC, Rumack BH, Peterson RG, McGuire BM. Methemoglobinemia resulting from absorption of nitrates. JAMA 1979; 242: 2869–71.
References 1 Bunn HF, Forger BG. Hemoglobin oxidation: methemoglobin, methemoglobinemia and sulfhemoglobinemia. In: Benn HF, Forger BG,
MEDICINE 35:10
553
© 2007 Elsevier Ltd. All rights reserved.