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REVIEW ARTICLE
Year : 2019  |  Volume : 17  |  Issue : 4  |  Page : 125-128

Methemoglobinemia: When to suspect and how to treat


Department of Emergency Medicine, Christian Medical College, Vellore, Tamil Nadu, India

Date of Submission29-Oct-2019
Date of Decision12-Nov-2019
Date of Acceptance16-Nov-2019
Date of Web Publication12-Dec-2019

Correspondence Address:
Dr. Kundavaram Paul Prabhakar Abhilash
Department of Emergency Medicine, Christian Medical College, Vellore, Tamil Nadu
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/cmi.cmi_55_19

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  Abstract 

Methemoglobinemia is an altered state of the hemoglobin moiety resulting in impaired oxygen delivery to the tissues. It is a potentially fatal condition that occurs when the ferrous iron of heme is oxidized to ferric iron. Methemoglobinemia has been linked to a wide array of drugs, chemicals, and substances such as local anesthetics, industrial chemicals, and insecticides. Many of these compounds have no details of the composition and can result in severe methemoglobinemia. Clinical suspicion should be aroused with low oxygen saturation on pulse oximetry and the presence of chocolate-colored blood. Immediate administration of the antidote, methylene blue when indicated, effectively decreases methemoglobin levels to tolerable levels.

Keywords: Ascorbic acid, methemoglobinemia, MethHb, methylene blue


How to cite this article:
Abhilash KP. Methemoglobinemia: When to suspect and how to treat. Curr Med Issues 2019;17:125-8

How to cite this URL:
Abhilash KP. Methemoglobinemia: When to suspect and how to treat. Curr Med Issues [serial online] 2019 [cited 2020 Aug 13];17:125-8. Available from: http://www.cmijournal.org/text.asp?2019/17/4/125/272809




  Introduction Top


Methemoglobinemia is an altered state of the hemoglobin moiety resulting in impaired oxygen delivery to the tissues. It is a potentially fatal condition that occurs when the ferrous iron of heme is oxidized to ferric iron.[1],[2] This shifts the oxygen dissociation curve to the left, thereby decreasing the capacity of hemoglobin to deliver oxygen to the tissues. Effectively, patients with acutely increased levels of methemoglobin have a functional anemia, wherein the amount of functional hemoglobin capable of oxygen delivery to the tissues is less than the measured level of the total hemoglobin. Methemoglobinemia has been linked to a wide array of drugs, chemicals, and substances such as local anesthetics, industrial chemicals, and insecticides.[3],[4],[5],[6]


  Types of Methemoglobinemia Top


Methemoglobinemia can result from either congenital or acquired processes.

Congenital type

Congenital/hereditary forms of methemoglobinemia occur either due to an enzyme deficiency (autosomal recessive defects in the enzyme cytochrome b5 reductase) or due to autosomal dominant mutations in the genes that code for globin proteins, termed hemoglobin M. It is characterized by decreased enzymatic reduction of methemoglobin back to functional hemoglobin. Patients with hemoglobin M disease are generally asymptomatic and should be counseled about the benign nature of their condition. If treatment is required for this condition, there is no effective option available. Patients with the congenital methemoglobinemia may have methemoglobin levels of 20%–40%.[4],[7] They are usually cyanotic from birth but are asymptomatic with normal development. Increased frequency of disease has been found in Siberian Yakuts, Athabaskans, Eskimos, and Navajo.[8]

Acquired type

Acquired methemoglobinemia is more common and results from exposure to direct oxidizing agents. It can be fatal and typically results from the ingestion of specific drugs or agents that cause an increase in the production of methemoglobin [Table 1]. The common drugs with oxidizing effects are nitroglycerine, dapsone, sulfonamides, phenytoin, phenacetin, and local anesthetics. Many agrochemical compounds contain solvent that may result in severe methemoglobinemia that may even be fatal.[9],[10],[11] Many of these compounds have no details of the composition and can result in severe methemoglobinemia. Due to underdeveloped methemoglobin reduction mechanisms, neonates and infants are at a higher risk of methemoglobin accumulation when exposed to certain drugs.
Table 1: Common precipitating agents of acquired methemoglobinemia

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  When to Suspect Methemoglobinemia? Top


The following red flag signs should alert the physician to the possibility of methemoglobinemia.

  • Sudden onset of cyanosis with symptoms of hypoxia after the administration or ingestion of an agent that can cause methemoglobinemia
  • Hypoxia (low SpO2 on pulse oximeter) that does not improve with an increased fraction of inspired oxygen
  • Abnormal dark red, chocolate, or brownish coloration of the blood observed during phlebotomy.


Methemoglobinemia is a clinical diagnosis that is made based on history and presenting symptoms. The presence of hypoxemia refractory to supplemental oxygen therapy and of chocolate-colored blood strongly supports the diagnosis. The confirmatory test is an arterial or venous blood gas with Co-oximetry that can speciate the hemoglobin to determine the methemoglobin level in the blood.

Standard pulse oximeters use two wavelengths of light (660 nm and 940 nm) to calculate oxyhemoglobin percentage.[12],[13] These wavelengths detect methemoglobin as well, and light absorption by the methemoglobin confounds oxyhemoglobin percentage calculation and hence the “refractory hypoxemia,” which is often an important diagnostic sign. The commercially available pulse Co-oximeters use additional wavelengths of light to measure the total hemoglobin concentration and the methemoglobin and carboxyhemoglobin percentages and hence are more accurate in measuring oxygen saturation of the blood.[14]


  Clinical Features Top


Methemoglobinemia may be acute or chronic. The physiologic level of methemoglobin in the blood is 0%–2%.[1],[2] Normal healthy patients can tolerate methemoglobin concentrations of 10% to 20% but develop symptoms at levels above this. Methemoglobin levels above 70% may be fatal, though survival has been reported with a Methemoglobinemia (MetHb) level of 81%–91%[1],[6] Symptoms also depend on the rapidity of the formation of methemoglobin. Most patients with congenital/hereditary methemoglobinemia remain asymptomatic, but patients exposed to drugs and toxins resulting in acquired methemoglobinemia may be severely symptomatic.

Symptoms in patients with acquired methemoglobinemia result from an acute impairment in oxygen delivery to tissues

  • Methemoglobin level <20%: Asymptomatic
  • Methemoglobin level >20%: Patients may develop early symptoms of methemoglobinemia which are usually pale skin, lightheadedness, headache, tachycardia, fatigue, dyspnea, and lethargy. At these levels, the blood takes a characteristic “chocolate brown” appearance
  • Methemoglobin level >30%: patients become severely symptomatic with cyanosis, respiratory depression, altered sensorium, coma, shock, and seizures. Higher levels if untreated may be fatal.


Definite diagnosis of methemoglobinemia requires Co-oximetry of arterial or venous blood gas, which is a spectrophotometric method of identifying and measuring oxyhemoglobin, deoxyhemoglobin, carboxyhemoglobin, and methemoglobin levels.[13],[14],[15]


  Management Top


Treatment of acquired methemoglobinemia includes the removal of the inciting agent and supportive care. The antidote, methylene blue (tetramethylthionine chloride), should be administered at the earliest.[16],[17],[18] Supportive care includes high-flow oxygen delivered by the non-rebreather mask that increases oxygen delivery to tissues and enhances the natural degradation of methemoglobin. Gastric decontamination may be of limited benefit due to the substantial time gap between exposure to the inciting agent and development of methemoglobinemia.

Asymptomatic patient with a MetHb level is <20%

Discontinuation of the offending agent (s) is the most important step required for the management of these patients. Supportive care with oxygen may be considered, but no antidote is required.

Symptomatic patients or if the MetHb level is >20%

These patients require immediate administration of an antidote. The two commonly available and used antidotes for methemoglobinemia are methylene blue and ascorbic acid.

Methylene blue

Methylene blue accelerates the enzymatic reduction of methemoglobin by Nicotinamide adenine dinucleotide phosphate hydrogenase-methemoglobin reductase. It also reduces methemoglobin to leucomethylene blue, which directly reduces the oxidized ferric iron (Fe 3+) back to the ferrous (Fe 2+) state.

The initial dose of methylene blue is 1–2 mg/kg IV bolus. Repeat dose may be given after 1 h if the MetHb level still elevated (>20%). The response to the first dose is usually rapid and one dose is sufficient in most patients. Methylene blue is itself an oxidant when administered at doses >7 mg/kg and thus may cause methemoglobinemia in susceptible patients. Repeated doses may cause acute hemolysis and may worsen the methemoglobinemia. Nonpathologic side effect of methylene blue being urine discoloration can be normally expected. Methylene blue has drug interaction with seratonergics; hence caution should be exerted in pregnancy as there is a evidence for fetal risk.

Treatment failure

Methylene blue is contraindicated in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency and is ineffective in G6PD-deficient patients with methemoglobinemia.[19] Administering methylene blue to G6PD deficient patients is not only ineffective but may even be dangerous. This is because of the oxidant property of methylene blue which may precipitate acute hemolysis, thus further decreasing the functional hemoglobin levels. Patients exposed to oxidant drugs with long half-life like dapsone (t1/2: 50 h) may require repetitive doses of methylene blue, as the red blood cells are exposure to prolonged oxidant stress. Cimetidine, a selective inhibitor of N-hydroxylation, may be used in such patients to lower methemoglobin levels by upto 25%. Patients with a rare congenital deficiency of NADH-methemoglobin reductase, the enzyme required for methylene blue activation of methylene blue, may be resistant to treatment with methylene blue.[20] Treatment failure may also be seen in patients with sulfhemoglobinemia, as it does not respond to methylene blue but is clinically indistinguishable from methemoglobinemia.[21] Alternate therapy should be considered in these patients along with supportive care. In patients with severe methemoglobinemia or in clinically unstable patients, packed red blood cell transfusion or exchange transfusion should be considered.[22],[23],[24]

Ascorbic acid

Ascorbic acid or Vitamin C is a natural water-soluble vitamin and is a potent-reducing and antioxidant agent. It functions in fighting bacterial infections, in detoxifying reactions, and in the formation of collagen in the fibrous tissue, teeth, bones, connective tissue, skin, and capillaries. It can be used as an antidote to methemoglobin in settings where methylene blue is unavailable or is contraindicated.[25],[26] The dose is 10 g intravenously every 6 h or 300–1000 mg/day orally in divided doses. Ascorbic acid is slow to act and requires multiple doses over 24 h for the same effect as methylene blue.


  Conclusion Top


Methemoglobinemia can be caused by a wide variety of drugs and chemically with potentially new inciting agents being reported regularly. Many of these compounds have no details of the composition and can result in severe methemoglobinemia. Clinical suspicion should be aroused with low oxygen saturation on pulse oximetry and the presence of chocolate-colored blood. Immediate administration of the antidote, methylene blue when indicated, effectively decreases methemoglobin levels to tolerable levels.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interes



 
  References Top

1.
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Percy MJ, Lappin TR. Recessive congenital methaemoglobinaemia: Cytochrome b (5) reductase deficiency. Br J Haematol 2008;141:298-308.  Back to cited text no. 5
    
6.
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Burtseva TE, Ammosova TN, Protopopova NN, Yakovleva SY, Slobodchikova MP. Enzymopenic congenital methemoglobinemia in children of the republic of Sakha (Yakutia). J Pediatr Hematol Oncol 2017;39:42-5.  Back to cited text no. 8
    
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Bradberry SM. Occupational methaemoglobinaemia. Mechanisms of production, features, diagnosis and management including the use of methylene blue. Toxicol Rev 2003;22:13-27.  Back to cited text no. 9
    
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Perera M, Shihana F, Kularathne K, Dissanayake D, Dawson A. Acute methaemoglobinaemia after massive nitrobenzene ingestion. BMJ Case Rep 2009;2009. pii: bcr07.2008.0515.  Back to cited text no. 10
    
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Garg D, Edwin N. A case report of methemoglobinemia due to benzonitrile. J Clinic Toxicol 2012;2:131.  Back to cited text no. 11
    
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13.
Beutler E. Methemoglobinemia and other causes of cyanosis. In: Beutler E, Lichtman MA, Coller BS, Kipps TJ, editors. Williams Hematology. 5th ed. New York: McGraw-Hill; 1994. p. 654-62.  Back to cited text no. 13
    
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Haymond S, Cariappa R, Eby CS, Scott MG. Laboratory assessment of oxygenation in methemoglobinemia. Clin Chem 2005;51:434-44.  Back to cited text no. 14
    
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Chan ED, Chan MM, Chan MM. Pulse oximetry: Understanding its basic principles facilitates appreciation of its limitations. Respir Med 2013;107:789-99.  Back to cited text no. 15
    
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Joshi P. Toxidromes and their treatment. In: Fuhrman BP, Zimmerman J, editors. Pediatric Critical Care. 3rd ed. Philadelphia: Mosby Inc.; 2008. p. 1454-5.  Back to cited text no. 16
    
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do Nascimento TS, Pereira RO, de Mello HL, Costa J. Methemoglobinemia: From diagnosis to treatment. Rev Bras Anestesiol 2008;58:651-64.  Back to cited text no. 17
    
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Ash-Bernal R, Wise R, Wright SM. Acquired methemoglobinemia: A retrospective series of 138 cases at 2 teaching hospitals. Medicine (Baltimore) 2004;83:265-73.  Back to cited text no. 18
    
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Harvey JW, Keitt AS. Studies of the efficacy and potential hazards of methylene blue therapy in aniline-induced methaemoglobinaemia. Br J Haematol 1983;54:29-41.  Back to cited text no. 19
    
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Coleman MD, Rhodes LE, Scott AK, Verbov JL, Friedmann PS, Breckenridge AM, et al. The use of cimetidine to reduce dapsone-dependent methaemoglobinaemia in dermatitis herpetiformis patients. Br J Clin Pharmacol 1992;34:244-9.  Back to cited text no. 20
    
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Finch CA. Methemoglobinemia and sulfhemoglobinemia. N Engl J Med 1948;239:470-8.  Back to cited text no. 21
    
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Pritchett MA, Celestin N, Tilluckdhary N, Hendra K, Lee P. Successful treatment of refractory methemoglobinemia with red blood cell exchange transfusion. Chest J 2006;130:294S.   Back to cited text no. 23
    
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Lee KW, Park SY. High-dose vitamin C as treatment of methemoglobinemia. Am J Emerg Med 2014;32:936.  Back to cited text no. 26
    



 
 
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Abstract
Introduction
Types of Methemo...
When to Suspect ...
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