Methemoglobinemia presents distinct signs and symptoms depending on its blood concentration level. The normal concentration of methemoglobin in the blood is only 1%, beyond which pathologies may already set in to play if left unabated.

The following system-wise physical presentations are commonly seen in patients suffering from methemoglobinemia:

• General Appearance: Patients may present with pallor and confusion due to the underlying anemia and inadequate brain oxygenation.
• Integumentary system: The bluish discoloration of the skin or cyanosis represents the heralding sign because it appears at a low desaturation level of more than 1.5% plasma methemoglobin. This could be the only presenting sign for methemoglobinemia upon birth.
• Head and neck: Pallor of the conjunctiva may mean severe anemia which could mask the cyanotic signs of methemoglobinemia.
• Chest and heart: Patients may complain of shallow breathing and bradyarrhythmia when methemoglobin becomes severe at blood levels exceeding 50-70%.
• Abdomen: Metabolic acidosis may ensue and destabilize electrolytes and cause functional constipation, ileus and abdominal distention.
• Extremities: Muscle weakness and fatigue due to lack of cell oxygenation may be observed in cases of methemoglobinemia. Thread like pulses are noticeable with late complications of arrhythmia.
• Neurologic: When methemoglobin levels exceeds 50% in the serum, signs of delirium and coma may start to ensue because of the chronic oxygen deprivation of the brain.

• Anemia

  Publication type, MeSH terms, Substance, Supplementary concept Publication type Case Reports MeSH terms Adult Amnion* Anemia, Hemolytic, Congenital/chemically induced* Anemia, Hemolytic, Congenital/diagnosis* Anemia, Hemolytic, Congenital/therapy Cesarean [ncbi.nlm.nih.gov]

  However, patients with severe anemia may experience symptoms at much lower levels, because oxygen-carrying capacity is compromised both by true anemia and by functional anemia due to methemoglobinemia [ 2, 20 ]. [link.springer.com]

• Fatigue

  Symptoms Associated With Methemoglobin Blood Concentrations 3 Methemoglobin Concentration, g/dL Total Hemoglobin, % Symptoms None 1.5-3.0 10-20 Cyanotic skin discoloration 3.0-4.5 20-30 Anxiety, lightheadedness, headache, tachycardia 4.5-7.5 30-50 Fatigue [doi.org]

  Symptoms may include headache, dizziness, fatigue, shortness of breath, nausea, vomiting, rapid heartbeat, loss of muscle coordination, and blue-colored skin. [icd9data.com]

  A 47-year-old female with medical history of vulvar cancer and HIV undergoing chemoradiation was sent by the oncology clinic to the emergency department for worsening dyspnea, fatigue, hypoxia to 78% on room air, and gradual onset of cyanosis over the [ncbi.nlm.nih.gov]

  Extremities: Muscle weakness and fatigue due to lack of cell oxygenation may be observed in cases of methemoglobinemia. Thread like pulses are noticeable with late complications of arrhythmia. [symptoma.com]

• Chocolate-Brown Colored Blood

  All patients manifested cyanosis, low oxygen saturation and chocolate-brown-colored blood despite supplemental oxygen therapy. [ncbi.nlm.nih.gov]

  The main symptoms are: cyanosis, which describes a bluish color of the skin, especially the lips and fingers chocolate-brown colored blood It’s because of cyanosis that some people call methemoglobinemia “baby blue syndrome.” [healthline.com]

  The heart (615 g) contained approximately 650 mL of chocolate-brown colored blood and exhibited slight myocardial fibrosis and calcification. The coronary artery showed no abnormal findings, including stenosis. [omicsonline.org]

• Dyspnea

  Cyanosis, hypoxia, and dyspnea resolved, and the MetHb level decreased to 5.4% on the day of discharge. Benzocaine is a frequent cause of iatrogenic methemoglobinemia. [ncbi.nlm.nih.gov]

• Tachypnea

  Methemoglobin Blood Concentrations 3 Methemoglobin Concentration, g/dL Total Hemoglobin, % Symptoms None 1.5-3.0 10-20 Cyanotic skin discoloration 3.0-4.5 20-30 Anxiety, lightheadedness, headache, tachycardia 4.5-7.5 30-50 Fatigue, confusion, dizziness, tachypnea [doi.org]

  […] methemoglobinemia The signs of methemoglobinemia depend on the degree of methemoglobin present. 10-20% – cyanosis, blue or gray appearing skin, lips, and nail beds 20-30% – lightheadedness, anxiety, headache, tachycardia 30-50% – fatigue, confusion, dizziness, tachypnea [pharmacyjoe.com]

  […] percentage of methemoglobin in blood : asymptomatic 3 – 15 % grayish skin color 15 - 30 % cyanosis and chocolate brown blood 30 – 50 % dyspnea, headache, fatigue, dizziness, syncope, with oxygen saturation as low as 80 %, as seen in our case 50 – 70 % tachypnea [jpgo.org]

  Other clinical effects are consistent with hypoxia and include anxiety, lightheadedness, headache and tachycardia at MetHb levels of 20-30%; fatigue, confusion, dizziness and tachypnea at 30-50% and coma, seizures, dysrhythmias and acidosis at levels [ijccm.org]

  This discoloration increases with the concentration of methemoglobin, as do the manifestations of irritability, tachypnea, and altered mental status. 20 In the absence of respiratory symptoms, history of cardiovascular disease, abnormal pulse, or abnormal [pediatrics.aappublications.org]

• Vomiting

  RESULTS: The common symptoms were giddiness, vomiting and headache. Treatment included thorough skin wash, intravenous fluid and methylene blue in 111 children. [ncbi.nlm.nih.gov]

  Level * Signs and Symptoms † Methemoglobin Level (%) ‡ Coma 55 Cyanosis, acquired methemoglobinemic 10 to 20 Death 70 Dizziness 55 Heart failure 55 Lethargy 55 Muscle weakness 30 Nausea 30 None Respiratory arrest 55 Seizure 55 Stupor 55 Tachycardia 30 Vomiting [jaoa.org]

  Symptoms may include headache, dizziness, fatigue, shortness of breath, nausea, vomiting, rapid heartbeat, loss of muscle coordination, and blue-colored skin. [icd9data.com]

• Nausea

  Table Methemoglobinemia Common Signs and Symptoms by Methemoglobin Level * Signs and Symptoms † Methemoglobin Level (%) ‡ Coma 55 Cyanosis, acquired methemoglobinemic 10 to 20 Death 70 Dizziness 55 Heart failure 55 Lethargy 55 Muscle weakness 30 Nausea [jaoa.org]

  Symptoms may include headache, dizziness, fatigue, shortness of breath, nausea, vomiting, rapid heartbeat, loss of muscle coordination, and blue-colored skin. [icd9data.com]

  When the children were examined, additional complaints included nausea, vomiting, and headache. [cdc.gov]

• Failure to Thrive

  […] to thrive Intellectual disability Seizures Symptoms of hemoglobin M disease include: Bluish coloring of the skin Symptoms of acquired MetHb include: Bluish coloring of the skin Headache Giddiness Altered mental state Fatigue Shortness of breath Lack [nlm.nih.gov]

  Symptoms Cyanosis, headache, fatigue, seizures, mental retardation, and failure to thrive among infants may occur. Diagnosis Methemoglobin is confirmed by arterial blood gas (ABG) studies and pulse oximetry. [symptoma.com]

  Symptoms Symptoms of type 1 MetHb include: Bluish coloring of the skin Symptoms of type 2 MetHb include: Developmental delay Failure to thrive Intellectual disability Seizures Symptoms of hemoglobin M disease include: Bluish coloring of the skin Symptoms [huronregional.org]

• Cyanosis

  In the second case a six-hour-old 3300 gram, full-term male neonate born by spontaneous vaginal delivery was admitted to NICU for central cyanosis. The neonate was noted to have central cyanosis with respiratory distress. [ncbi.nlm.nih.gov]

  Heterozygotes have 50% enzyme activity and no cyanosis; homozygotes who have elevated methemoglobin levels above 1.5% have clinical cyanosis. [emedicine.com]

• Acrocyanosis

  […] non-draft ICD-10-CM) 2017 (effective 10/1/2016) : No change 2018 (effective 10/1/2017) : No change 2019 (effective 10/1/2018) : No change Cyanosis R23.0 ICD-10-CM Diagnosis Code R23.0 Cyanosis 2016 2017 2018 2019 Billable/Specific Code Type 1 Excludes acrocyanosis [icd10data.com]

• Headache

  Symptoms Associated With Methemoglobin Blood Concentrations 3 Methemoglobin Concentration, g/dL Total Hemoglobin, % Symptoms None 1.5-3.0 10-20 Cyanotic skin discoloration 3.0-4.5 20-30 Anxiety, lightheadedness, headache, tachycardia 4.5-7.5 30-50 Fatigue [doi.org]

  Symptoms may include headache, dizziness, fatigue, shortness of breath, nausea, vomiting, rapid heartbeat, loss of muscle coordination, and blue-colored skin. [icd9data.com]

  RESULTS: The common symptoms were giddiness, vomiting and headache. Treatment included thorough skin wash, intravenous fluid and methylene blue in 111 children. [ncbi.nlm.nih.gov]

• Seizure

  Neonates treated with lidocaine for seizures must be monitored for the occurrence of methemoglobinemia. [ncbi.nlm.nih.gov]

  Concentration, g/dL Total Hemoglobin, % Symptoms None 1.5-3.0 10-20 Cyanotic skin discoloration 3.0-4.5 20-30 Anxiety, lightheadedness, headache, tachycardia 4.5-7.5 30-50 Fatigue, confusion, dizziness, tachypnea, increased tachycardia 7.4-10.5 50-70 Coma, seizure [doi.org]

  Complications: The three main complications are shock, seizure, and death. [symptoma.com]

• Confusion

  Symptoms Associated With Methemoglobin Blood Concentrations 3 Methemoglobin Concentration, g/dL Total Hemoglobin, % Symptoms None 1.5-3.0 10-20 Cyanotic skin discoloration 3.0-4.5 20-30 Anxiety, lightheadedness, headache, tachycardia 4.5-7.5 30-50 Fatigue, confusion [doi.org]

  The resultant tissue hypoxia from MetHgb caused profound confusion, cyanosis, and myocardial infarction. [ncbi.nlm.nih.gov]

  Chocolate brown or otherwise discolored blood during phlebotomy Several years ago I encountered a 60 y/o male s/p transesophageal echocardiogram (TEE) who developed sudden cyanosis, tachycardia and confusion at the end of his procedure. [pharmacyjoe.com]

  Patients with lesser levels of toxic exposure can present with typical symptoms of acute hypoxia, confusion, dizziness, somnolence, and the appearance of cyanosis. [cancertherapyadvisor.com]

  With levels above 25% the following symptoms may be present: Cyanosis unaffected by oxygen administration Blood that is dark or chocolate in color that will not change to red in the presence of oxygen Headache Weakness Confusion Chest pain When methemoglobin [encyclopedia.com]

• Altered Mental Status

  Methemoglobin levels of 50 to 70% are associated with cardiac arrhythmias, altered mental status, seizures and metabolic acidosis. Levels above 70% may be fatal. [clinlabnavigator.com]

  His cyanosis and altered mental status promptly resolved after intravenous administration of methylene blue. In patients with methemoglobinemia, pulse oximetry tends to overestimate the actual oxygen saturation and is not entirely reliable. [aaaai.org]

  Main symptoms include central cyanosis not responding to oxygen, and in severe cases altered mental status, convulsions and coma leading to death when level rises to 70%. [jpgo.org]

  mental status; delirium, seizures, coma Metabolic - Profound acidosis At methemoglobin fractions exceeding 70%, death usually results. [emedicine.medscape.com]

• Irritability

  Abstract The authors herein report a 5-year-old child who presented with massive hemolysis, irritability, and cyanosis. [ncbi.nlm.nih.gov]

  Physical examination revealed an irritable child (weight 13 kg, body length 84 cm). He was pale and jaundiced and his lips were cyanotic. [link.springer.com]

  These products are used to relieve pain from a variety of conditions, such as teething, canker sores, and irritation of the mouth and gums. [fda.gov]

  Refractory cases of methemoglobinemia may occasionally require exchange transfusion therapy. » Case Report A boy aged 18 months, was referred as suspected unknown poisoning and presented in pediatric emergency with a history of vomiting, excessive irritability [ijccm.org]

Symptoms

Observing the symptoms is often the fastest way to determine the decline and severity of the methemoglobinemia. Observing vital signs such as oxygen saturation and pulse can be vital in the case of rapid onset following exposure to a toxin or chemical.

Laboratory tests

In cases of hereditary methemoglobinemia, arterial blood gas (ABG) levels are typically helpful in diagnosing the condition.
In cases of acquired methemoglobinemia, some laboratory tests that would be performed would include:

• Complete blood count (CBC)
• Arterial blood gases (ABGs)
• Peripheral blood smear 
• Lactate dehydrogenase (LDH)
• Reticulocyte count 
• Bilirubin
• Pulse oximetry
• Haptoglobin

Imaging Studies

Imaging studies would not typically be necessary, but might be done later in the course of the condition to determine the extent of damage to organ systems such as the heart or neurological system.

• Polyps

  The reported case describes methemoglobinemia that occurred in association with the use of topical benzocaine spray and lozenges in a previously healthy 51-year-old female who had undergone colon surgery to remove a bleeding polyp. [ncbi.nlm.nih.gov]

The most commonly mentioned treatment is the use of methylene blue, which is a reduction compound [10]. 

The prognosis of methemoglobinemia is dependent on several factors. The severity of the case is one factor. Mild cases tend to have a better prognosis.

When the condition is caught early, as in a case study following use of a topical anaesthetic, aggressive intervention can result in a favourable prognosis. Methemoglobin levels at or above 70% have higher rates of fatalities and involve more extensive organ damage that can be irreversible, resulting in a much less favourable prognosis.

Complications:

The three main complications are shock, seizure, and death. There has been evidences linking maternal methemoglobinemia from prenatal nicotine exposure to unexplained fetal and infant death [9].The risk and extent of complications depends on the severity of the case.

Methemoglobinemia can be acquired through exposure to many different things including dyes, silver nitrates, nitrous oxide, local anaesthetics [1], dapsone [2], and other chemicals.

One case report describes the reaction of a 60-year-old patient to a topical anaesthetic sprayed in the throat prior to intubation for surgery [3]. Another case study similarly reported methemoglobinemia acquired post-surgically in a 36-year-old patient who received a topical anaesthetic for diagnostic purposes [4].

Hereditary methemoglobinemia has two types. In one type the red blood cells lack a necessary enzyme. This is due to the genetic defect that is transmitted via an autosomal-recessive gene that renders the cytochrome P5 reductase deficient and ineffective in reducing methemoglobin in the plasma [5]. In the second type the enzyme is present but fails to work in the body.

Incidence

Two types of methemoglobinemia exist: hereditary and acquired. The incidence varies based on type. Acquired methemoglobinemia is typically due to exposure to exposure to certain drugs or toxins.

Age

Inherited methemoglobinemia can be present at birth, while acquired methemoglobinemia can occur at any time during one’s life, particularly after exposure to certain chemicals or toxins.

Sex

There are no major differences in occurrence of methemoglobinemia between males and females, except in the case of individuals with G6PD deficiencies since this deficiency is x-linked.

Methemoglobinemia occurs when methemoglobin levels are increased in the body. Even though methemoglobin is a form of haemoglobin, it is unable to carry and/or deliver oxygen to cells and tissues. This condition does not preclude a drop in erythrocyte count but is functionally anaemic; thus, methemoglobinemia can essentially lead to functional anemia [6].

A deficient pathway in the reduction of methemoglobin to haemoglobin plays a hand in the pathophysiology of methemoglobinemia [7]. Without oxygen cells and tissues become hypoxic and can die off if the condition is not reversed. When cells of the cardiac and neurological system begin to die off, symptoms such as bluish colouring of the skin, seizures, and shortness of breath can occur. At methemoglobin levels beyond 15%, cardiac and neurologic signs wills start to surface while levels above 70% may no longer be compatible with life [8].

Types

Hereditary methemoglobinemia is passed down from a parent. In this type, there are two subtypes. In the first type red blood cells lack the necessary enzyme cytochrome b5 reductase. In the second type the enzyme is present but does not work in the body as it should.

Methemoglobinemia is a complex condition. Acquired methemoglobinemia cannot typically be predicted and prevented ahead of time. Hereditary methemoglobinemia can be potentially prevented through genetic counselling for couples with a family history of methemoglobinemia who are considering having children of their own.

Methemoglobinemia is a disorder of the blood where methemoglobin, which is a type of hemoglobin, is found in abnormally high amounts in the blood. Anything over one percent is considered to be a high concentration of methemoglobin. Hemoglobin’s important task is distributing oxygen to the cells of the body.

Methemoglobin, however, cannot release oxygen, which results in less oxygen getting to vital organs and tissues, resulting in hypoxia, meaning the cells are not getting enough oxygen to function properly, and are at risk of dying due to this complication.

Symptoms are proportional to the percentage of methemoglobin. Generally, above the level of 15% patients experience cardiac and neurological symptoms and levels over 70% tend to be fatal.

Definition

Methemoglobinemia is clinical disease where methemoglobin levels are abnormally high in the blood stream.

Cause

Methemoglobinemia can be acquired through exposure with medications like anaesthetics, dapsone, dyes and other compounds. An autosomal-recessive gene causing cytochrome P5 reductase deficiency is the cause of inherited methemoglobinemia.

Symptoms

Cyanosis, headache, fatigue, seizures, mental retardation, and failure to thrive among infants may occur.

Diagnosis

Methemoglobin is confirmed by arterial blood gas (ABG) studies and pulse oximetry.

Treatment and follow-up

Patients suffering from severe methemoglobinemia can benefit from the administration of methylene blue dyes that reverses the methemoglobin in the system. Special precautions are taken for G6PD patients for they are unable to metabolize the dye.

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4. McGinley, L., Gornichec, R. Methemoglobinemia: A Bariatric Case Study. Bariatric Nursing and Surgical Patient Care. 2007: 2: 291-294
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9. Lavezzi AM, Mohorovic L, Alfonsi G, Corna MF, Matturri L. Brain iron accumulation in unexplained fetal and infant death victims with smoker mothers--the possible involvement of maternal methemoglobinemia. BMC Pediatr. Jul 6 2011; 11:62.
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