Endemic in populations of Mediterranean and African descent
Etiology
Hereditary/Congenital Methemoglobinemia
Hemoglobin M Disease
General Comments: usually autosomal dominant
Hb Ms
Hb MIwate
Hb MBoston
Hb MHyde Park
Hb MSaskatoon
Hemoglobin E Disease
Hb E beta-thalassemia patients have been demonstrated to have increased methemoglobin levels
NADH Cytochrome b5 Reductase (cyb5R) Deficiency
General Comments
Autosomal recessive
Mechanism: decreased enzymatic reduction of methemoglobin back to normal hemoglobin
Type I Cytochrome b5 Reductase (cyb5R) Deficiency: most common type (represents 85-90% of cases)
Endemic in specific Native American tribes (Navajo, Athabaskan Alaskans) and Yakutsk people of Siberia
Cytochrome b5 reductase (cyb5R) deficiency is limited to red blood cells
Type II Cytochrome b5 Reductase (cyb5R) Deficiency: represents 10-15% of cases
Cytochrome b5 reductase (cyb5R) deficiency in multiple tissues (including red blood cells, liver, fibroblasts, and brain)
Clinical features
Severe central nervous symptoms (encephalopathy, microcephaly, hypertonia, athetosis, opisthotonos, strabismus, mental retardation, growth retardation)
Cyanosis: evident at an early age
Type III Cytochrome b5 Reductase (cyb5R) Deficiency
Cytochrome b5 reductase (cyb5R) deficiency in red blood cells, white bood cells, platelets
Clinical features: cyanosis is the only symptom
Type IV Cytochrome b5 Reductase (cyb5R) Deficiency
Cytochrome b5 reductase (cyb5R) deficiency is limited to red blood cells
Clinical features: cyanosis is the only symptom
NADPH-Flavin Reductase Deficiency
May also cause methemoglobinemia
Cytochrome b5 Deficiency
Rare
Anesthetics
General Comments: while skin/mucosal breaches may increase absorption of the anesthetic agents, methemoglobinemia may occur due to either a previously-undiagnosed methemoglobin reductase enzyme deficiency or idiosyncratic toxicity
Ingestion of High Nitrite/Nitrate Foods: beets, spinach, carrots, borage, chard
Ingestion of Nitrite-Contaminated Well Water: cases have been reported where well water has been contaminated by nitrite runoff from fertilized farm fields
Ingestion of Nitrites in Packaged Foods
Inhaled Nitric Oxide (iNO) (see Nitric Oxide, [[Nitric Oxide]]): however, in clinical trials of iNO in ARDS, clinically significant methemoglobinemia was not observed
Isobutyl Nitrite (Inhaled “Rush”, “Poppers”) (see Isobutyl Nitrite, [[Isobutyl Nitrite]])
Isosorbide Dinitrate (see Isosorbide, [[Isosorbide]])
Methyl Nitrite
Nitroglycerin (see Nitroglycerin, [[Nitroglycerin]])
Nitroprusside (Nipride) (see Nitroprusside, [[Nitroprusside]])
Cyclophosphamide (Cytoxan) (see Cyclophosphamide, [[Cyclophosphamide]])
Flutamide (Eulexin) (see Flutamide, [[Flutamide]])
Ifosfamide (Ifex) (see Ifosfamide, [[Ifosfamide]]): due to interaction between 4-thiofosfamide metabolite and glutathione -> resulting in oxidative stress
Other Drugs/Toxins
2,4-Dinitrophenol: weight loss agent
Acetaminophen (Tylenol) (see Acetaminophen, [[Acetaminophen]])
Significant methemoglobinemia may be seen with Dapsone use to treat dermatitis herpetiformis or pneumocystis jirovecii
Risk is probably dose-related
Induction of Dapsone Tolerance: cimetidine (see Cimetidine, [[Cimetidine]]) may be used to chronically enhance Dapsone tolerance, as it is a selective inhibitor of N-hydroxylation and chronically lowers methemoglobin levels by >25%
Ingestion of Fava Beans in a Patient with G6PD Deficiency (see Favism, [[Favism]])
Herbicides/Pesticides
Aluminum Phosphide
Indoxacarb
Paraquat (Dipyridylium) (see Paraquat, [[Paraquat]])
Indigo Carmine: intravenous dye used during urologic surgery (it is rapidly filtered by the kidneys and turns the urine blue)
Menadione (“Vitamin K3”): nutritional supplement (it is an analog of 1,4-naphthoquinone)
At high doses, methylene blue functions as an oxidant: it can cause acute hemolysis in patients with G6PD deficiency -> further decreasing oxygen delivery
At high doses, methylene blue can also paradoxically cause methemoglobinemia
Metoclopramide (Reglan) (see Metoclopramide, [[Metoclopramide]])
Naphthalene (see Naphthalene, [[Naphthalene]]): moth balls
Naphthoquinone: plants with compounds derived from naphthoquinone are used in China and South America for their medicinal properties
Nitroethane: nail polish remover
Nitrofurans: anti-microbials
Furazolidone
Furylfuramide
Nifuratel
Nifuroxazide
Nifurquinazol
Nifurtimox
Nifurtoinol
Nifurzide
Nitrofurantoin (Macrodantin) (see Nitrofurantoin, [[Nitrofurantoin]])
Phenazopyridine (Pyridium) (see Phenazopyridine, [[Phenazopyridine]])
Phenylamine: psychoactive stimulant used as a recreational drug
Rasburicase (Elitek) (see Rasburicase, [[Rasburicase]])
Patients with low inherited or acquired catalase activity may be at risk for methemoglobinemia after rasburicase administration: due to the formation of hydrogen peroxide
Some authors recommend the measurement of catalase activity before administering rasburicase
Smoke Inhalation (see Smoke Inhalation, [[Smoke Inhalation]]): due to inhalational exposure to oxidants
Silver Sulfadiazine (Silvadene) (see Silver Sulfadiazine, [[Silver Sulfadiazine]])
Toxic Mushrooms (see Toxic Mushrooms, [[Toxic Mushrooms]]): for gyromitrin-containing mushrooms
Zopiclone (Imovane, Zimovane) (see Zopiclone, [[Zopiclone]])
Miscellaneous Other Conditions
Cirrhosis (see End-Stage Liver Disease, [[End-Stage Liver Disease]]): red blood cells in cirrhotic patients undergo severe oxidative stress, especially in the setting of bleeding complications: levels of methemoglobin are significantly higher in the red blood cells of bleeding cirrhotics than in non-bleeding cirrhotics [MEDLINE]
Post-Splenectomy: increased methemoglobin levels have been observed in patients following splenectomy
Sepsis (see Sepsis, [[Sepsis]]): methemoglobin levels may increase in sepsis [MEDLINE]
May be related to synthesis of nitric oxide that occurs in sepsis: nitric oxide is converted to methemoglobin and nitrate
Physiology
Normal Methemoglobin Physiology
Auto-Oxidation of Hemoglobin to Methemoglobin: in normal individuals, hemoglobin is auto-oxidized to methemoglobin at the rate of 0.5-3% per day
Methemoglobin levels of <1-3% are considered normal
Potential Chemical Mechanisms to Reduce Methemoglobin Back to Hemoglobin
NADH-Dependent Reaction Catalyzed by Cytochrome b5 Reductase (b5R): this is the only physiologically important mechanism under normal conditions (accounting for clearance of 95-99% of the methemoglobin that is produced under normal circumstances)
Generation of NADPH by Glucose-6-Phosphate Dehydrogenase (G6PD) in the Hexose Monophosphate Shunt within the Red Blood Cell: this mechanism is not natively physiologically active, as it requires an extrinsically-administered electron acceptor (such as methylene blue and riboflavin)
This mechanism becomes important in the treatment of methemoglobinemia: methylene blue accelerates the NADPH-dependent methemoglobin reduction pathway
Note: G6PD deficiency is a risk factor for acquired methemoglobinemia
Pathophysiology in Patient with Methemoglobinemia
Oxidation of Iron in Hemoglobin from the Ferrous (Fe2+) to the Ferric (Fe3+) State: results in a “functional anemia” and consequent decreased oxygen delivery to tissues
Ferric Hemes of Methemoglobin are Unable to Bind Oxygen
Left-Shifting of Hemoglobin Dissociation Curve: due to increased oxygen affinity by the remaining ferrous hemes in the hemoglobin tetramer
Left shifting results in impaired oxygen unloading at the tissues
Predisposition of Premature Neonates and Infants to Methemoglobinemia
Factors Increasing Risk of Methemoglobinemia in Premature Neonates/Infants <4 mo of Age
Propensity of fetal hemoglobin to more easily oxidize than adult hemoglobin
Low levels of NADH reductase at birth: NADH reducase levels increase to adult levels by 4 mo of age
Higher gastric pH with increased basterial conversion of dietary nitrates to nitrites
Association of methemoglobinemia with gastroenteritis illnesses in infants: this may be related to increased stool loss of bicarbonate
Diagnosis
Pulse Oximetry
Decreased SpO2
When Methemoglobin is <30%: pulse oximetry will overestimate the percentage of oxyhemoglobin in presence of methemoglobin by an amount roughly equal to 50% of the amount of methemoglobin present
In presence of 20% methemoglobin and a SpO2 of 90%: percentage of oxyhemoglobin will be 80%
When Methemoglobin is >30%: pulse oximetry will plateau at about 85%
Note that severity of the cyanosis does not correspond to the pulse oximetry reading
Principle of Pulse Oximetry: pulse oximeter only measures the relative absorbance of 2 light wavelengths (660 nm and 940 nm) to differentiate oxyhemoglobin from deoxyhemoglobin
Methemoglobin increases absorption of both light wavelengths (although moreso at 940 nm): therefore, it optically interferes with the pulse oximetry
Newer Generation Multi-Wavelength Pulse Oximeters: while these are being developed, their accuracy is still being investigated
Arterial Blood Gas (ABG)
Appearance of Blood in ABG Syringe: chocolate or brown-blue color
pO2: normal
Note that the pO2 reflects the plasma oxygen content and does not reflect the oxygen-carrying capacity of hemoglobin
Co-Oximetry SaO2: normal
“Saturation Gap” (occurs in methemoglobinemia): difference between SpO2 measured from pulse oximetry and the SaO2 calculated from co-oximetry
Co-Oximetry
Principle: co-oximeter is a simplified spectrophotometer that can measure the relative absorbance of 4 different wavelengths of light
It quantifies the percentages of methemoglobin (absorbs at 631 nm), carboxyhemoglobin, oxyhemoglobin, and deoxyhemoglobin
Newer co-oximeters can also measure sulfhemoglobin, which may be confused with methemoglobin on older devices
Normal Range of Methemoglobin: <1-3%
Relationship of Percentage of Methemoglobin to Clinical Symptoms: clinical symptoms are correlated with the precentage of methemoglobin
False-Positive Results
May occur in presence of sulhemoglobinemia
May occur in the presence of methylene blue
May occur in the presence of lipemia
Inaccuracy: may occur with the use of blood substitutes
Evelyn-Malloy Assay of Methemoglobin
Technique
Addition of cyanide, which binds to positively charged methemoglobin -> eliminates the peak at 630-635 nm
Subsequent addition of ferricyanide -> converts entire specimen to cyanomethemoglobin, which allows measurement of total hemoglobin concentration
Specificity: more specific than co-oximetry for detection of methemoglobin
Clinical Utility: this assay is a good confirmatory test and is especially useful after methylene blue administration
Potassium Cyanide Test
Distinguishes between methemoglobin and sulfhemoglobin
Methemoglobin reacts with cyanide to form cyanomethemoglobin: bright red color change
Sulfhemoglobin does not react with cyanide: lack of bright red color change
Drop Test
Technique: place 1-2 drops of blood onto white filter paper -> in the presence of significant methemoglobinemia, blood will remain dark (ie: will not oxygenate as normal blood would)
May accelerate process by gently blowing 100% onto the blood drop on the filter paper
Aeration of Tube of Blood with 100% Oxygen
Technique: bubble 100% oxygen through blood -> in the presence of significant methemoglobinemia, blood will remain dark (ie: will not oxygenate as normal blood would)
Hemoglobin Electrophoresis
May be used to identify hemoglobin M
Clinical Manifestations
Congenital Methemoglobinemia
Type I Cytochrome b5 Reductase Deficiency-Related Methemoglobinemia
General Comments: functional deficiency of cytochrome b5 reductase is limited to red blood cells
Methemoglobin Level: usually 10-35%
Asymptomatic Cyanosis (see Cyanosis, [[Cyanosis]]): usually the only clinical manifestation and is often present from birth
Cyanosis is clinically apparent when methemoglobin levels exceed 8-12% (at a normal hemoglobin concentration): equivalent to >1.5 g/dL
Polycythemia (see Polycythemia, [[Polycythemia]]): rarely observed
Type II Cytochrome b5 Reductase Deficiency-Related Methemoglobinemia
General Comments: cytochrome b5 reductase is deficient in all cells
Cyanosis (see Cyanosis, [[Cyanosis]]): often present from birth
Developmental Abnormalities
Mental Retardation
Death Within First Year of Life
Acquired Methemoglobinemia
General Comments
Relationship of Clinical Symptoms to Methemoglobin Level
Influence of Heterozygous State for Cytochrome b5R Deficiency: although patients heterozygous for cytochrome b5R deficiency may develop methemoglobinemia more readily than normals, most acquired methemoglobinemia cases occur in patients who are not heterozygous for cytochrome b5R deficiency
Influence of Anemia: the clinical symptoms of methemoglobinemia are exacerbated in the presence of anemia
Appearance of Chocolate-Brown Blood in the Bronchoscopic Field of View: may be observed in cases that occur during bronchoscopy (or during other videoscopic procedures)
Bluish-brown coloration of skin and mucous membranes
Cyanosis is clinically apparent when methemoglobin levels exceed 8-12% (at a normal hemoglobin concentration): equivalent to >1.5 g/dL
Note: in contrast, a deoxyhemoglobin level of 5 g/dL is required to produce clinical cyanosis
In patients with severe anemia, a higher percentage of methemoglobin is required for cyanosis to be clinically apparent
These patients are more likely to exhibit signs of hypoxemia and have less degrees of cyanosis, as compared to non-anemic patients
The clinical symptoms of methemoglobinemia are exacerbated in the presence of anemia
Lack of Response of Cyanosis to Supplemental Oxygen (in Absence of Cardiopulmonary Disease): hallmark of methemoglobinemia
While cyanosis in most pulmonary diseases will respond to supplemental oxygen, cyanosis in cardiac disease with a right-to-left intra-cardiac shunt usually do not respond to oxygen administration
Dyspnea/Respiratory Distress (see Dyspnea, [[Dyspnea]])
Renal Manifestations
Lactic Metabolic Acidosis (see Lactic Acidosis, [[Lactic Acidosis]])
Treatment
Treatment of Congenital Methemoglobinemia
Ascorbic Acid (Vitamin C) (see Vitamin C, [[Vitamin C]]): may cosmetically decrease cyanosis
Riboflavin (Vitamin B2) (see Vitamin B2, [[Vitamin B2]]): may cosmetically decrease cyanosis
Methylene Blue (see Methylene Blue, [[Methylene Blue]]): may cosmetically decrease cyanosis
Treatment of Hemoglobin M Disease-Associated Methemoglobinemia
No effective treatment
Treatment of Acquired Methemoglobinemia
Withdraw or Avoid the Drug or Offending Agent
Recommended
Dietary avoidance of orally ingested precipitant agents
Removal of clothing that may contain the agent
Withdrawal/avoidance alone may be adequate in an asymptomatic patient with methemoglobin <20%
Supplemental Oxygen
Recommended
Dextrose-Containing Intravenous (IV) Fluid
The NADPH-dependent methemoglobin reductase enzyme system requires glucose for the clearance of methemoglobin
Correction of Metabolic Acidosis
Bicarbonate therapy may be necessary (especially in cases in infants)
Pharmacology: reduces methemoglobin (by serving as an artificial electron transporter) via a NADPH-dependent pathway
Results in rapid clinical improvement
Indications: methylene blue is considered the preferred treatment for patients with the appropriate indications
Hypoxic Symptoms
Methemoglobin >20-30%: these levels are considered life-threatening
Methemoglobin 10% In Setting of Significant Co-Morbid Disease or End-Organ Dysfunction (Cardiac Ischemia, etc): treatment of this group should be considered
Contraindications
Glucose-6-Phosphate Dehydrogenase (G6PD) Deficiency (see Glucose-6-Phosphate Dehydrogenase Deficiency, [[Glucose-6-Phosphate Dehydrogenase Deficiency]]): methylene blue is ineffective in this group (since it requires NADPH generated by G6PD) and these patients are at high risk for hemolysis after administration
G6PD Deficiency is found in African-Americans, Mediterranean Descent, Southeast Asians
Use of Other Serotonergic Agents (see Serotonin Syndrome, [[Serotonin Syndrome]]): since methylene blue functions as a reversible monoamine oxidase (MAO) inhibitor (see Monoamine Oxidase Inhibitors, [[Monoamine Oxidase Inhibitors]]), it may preceipitate the serotonin syndrome
Administration: 1-2 mL/kg (of 1% solution) IV over 5 min
Latency: resolution typically occurs within 1 hr (often within 20 min)
Re-Treatment: treatment can be repeated in 1 hr if methemoglobin level remains elevated
Serial Monitoring of Methemoglobin Level (by Evans-Malloy Method)
Co-oximetry cannot be used to follow serial methemoglobin levels after methylene blue dosing, since methylene blue is erroneously “read” as methemoglobin
Serial monitoring of methemoglobin levels is recommended, due to prolonged absorption of the offending drug from topical sites/GI tract
Some cases may manifest significant rebound methemoglobinemia up to 18 hrs later
Dapsone undergoes enterohepatic recirculation: re-treatment may be necessary
Adverse Effects/Cautions
Blue Discoloration of Skin After Administration: methylene blue can impart a blue discoloration to the skin after administration -> note that this does not imply treatment failure
Excessive Dosing: cumulative doses >7 mg/kg can cause hemolysis, dyspnea, and chest pain
Interference with Pulse Oximetry: since methylene blue interferes with subsequent pulse oximetry, must not rely on improving SpO2 as a marker for successful treatment
Technique: permits tissue oxygenation to occur through oxygen dissolved in plasma, rather than through hemoglobin-bound oxygen
Indications
Methemoglobinemia with Either Resistance to Methylene Blue or Contraindications to Its Use
G6PD Deficiency
Methemoglobinemia Associated with Aniline Derivatives: may be resistant
PRBC Transfusion/Exchange Transfusion (see Packed Red Blood Cells, [[Packed Red Blood Cells]])
Indications
Methemoglobinemia with Either Resistance to Methylene Blue or Contraindications to Its Use
G6PD Deficiency
Methemoglobinemia Associated with Aniline Derivatives: may be resistant
Other Agents
Cimetidine (Tagamet) (see Cimetidine, [[Cimetidine]]): may be used in the setting of dapsone to increase tolerance to this agent
N-Acetylcysteine (see N-Acetylcysteine, [[N-Acetylcysteine]]): although has been effective in some studies, not currently approved for the treatment of methemoglobinemia
Riboflavin (Vitamin B2) (see Vitamin B2, [[Vitamin B2]])
References
Failure of methylene blue treatment in toxic methemoglobinemia. Association with glucose-6-phosphate dehydrogenase deficiency. Ann Intern Med 1971;75:83-6
Toxic methemoglobinemia after topical anesthesia for transesophageal echocardiography. J Am Soc Echocardiogr. Nov-Dec 1996;9(6):874-6
Acute effects of inhaled nitric oxide in adult respiratory distress syndrome. Eur Respir J 1998; 12:1164-1171
Effects of inhaled nitric oxide in patients with acute respiratory distress syndrome: results of a randomized phase II trial. Crit Care Med 1998; 26:15-23
Elevated methemoglobin in patients with sepsis. Acta Anaesthesiol Scand. Jul 1998;42(6):713-6 [MEDLINE]
Innovations in mechanical ventilation. Current Opin Crit Care 1999; 5:43-51
Inhalation of nitric oxide in acute lung injury: results of a European multicentre study. Intensive Care Med 1999; 25:911-919
Inhaled nitric oxide in ARDS: modulator of lung injury? Intensive Care Med 1999; 25:1024-1026
Metoclopramide-induced methemoglobinemia in a patient with co-existing deficiency of glucose-6-phosphate dehydrogenase and NADH-cytochrome b5 reductase: failure of methylene blue treatment Haematologica 2001;86:659
Toxicol Review 2003: 22: 13-27
J Am Soc Echocardiograpy 2003: 16: 170-175
Recognition and management of methemoglobinemia and hemolysis in a G6PD-deficient patient on experimental anticancer drug Triapine. Am J Hematol 2006;81:210-1 [MEDLINE]
Methemoglobinemia and transesophageal echo. Proc West Pharmacol Soc. 2007;50:134-5
Level of oxidative stress in the red blood cells of patients with liver cirrhosis. Indian J Med Res. Sep 2007;126(3):204-10 [MEDLINE]
Infection and the Risk of Topical Anesthetic Induced Clinically Significant Methemoglobinemia after Transesophageal Echocardiography. Echocardiography. Aug 31 2009
Coma, metabolic acidosis, and methemoglobinemia in a patient with acetaminophen toxicity. J Popul Ther Clin Pharmacol. 2013;20(3):e207-11. Epub 2013 Sep 6 [MEDLINE]
