Acquired Methemoglobinemia- Causes, Symptoms, Diagnosis, and Treatment

Introduction:

Acquired methemoglobinemia is a medical emergency condition where the methemoglobin in the blood is elevated. Methemoglobin is a form of hemoglobin that does not bind with oxygen. When its concentration is elevated, the oxygen-carrying capacity of hemoglobin is reduced. Therefore prompt recognition and treatment are necessary to avoid complications, including death. Unnecessary therapy in mild cases can result in hemolysis (destruction of red blood cells), especially if a patient has glucose-6-phosphate dehydrogenase (G6PD) deficiency.

What Are the Causes of Methemoglobinemia?

Methemoglobinemia occurs when the iron is in the oxidized ferric form instead of the usual reduced ferrous form. It can be acquired or congenital. Congenital or genetic causes are rare, and in most cases, it is acquired from certain medications, chemicals, or food. In healthy individuals, normal methemoglobin levels should be less than 1 %. When it is more than the normal level, the protective enzyme system commonly present in the red blood cells rapidly reduces the methemoglobin to hemoglobin.

Thus, the methemoglobin levels are maintained at less than one percent of the total hemoglobin concentration. When exposed to certain chemicals or oxidizing drugs, it may lead up to a thousandfold increase in the methemoglobin formation rate. Infants under six months of age have lower levels of a methemoglobin reductase enzyme in their red blood cells. Hence there is an increased risk if they are exposed to these chemicals.

The most common medication associated with acquired methemoglobinemia are :

• Local anesthetics (Lidocaine, Prilocaine, Benzocaine).

• Dapsone (used in pneumocystis infection), Chloroquine.

• Aniline dyes, Metoclopramide, chlorates, bromates.

• Nitrobenzene (additives to prevent the meat from getting spoiled).

• Nitrates.

Nitrates are primarily present in the fertilizers, which may leak into the ground and cause water contamination (well water). Benzocaine present in baby teething gels or sore throat lozenges can cause methemoglobinemia. Other causes include dehydration, sepsis, and topical anesthetics containing Benzocaine or Prilocaine.

What Are the Different Signs and Symptoms of Methemoglobinemia?

Symptoms are proportional to the methemoglobin level. At levels up to 20 %, blood and skin color changes can occur. When the levels rise above 20 %, neurologic and cardiac symptoms are seen as a symptom of hypoxia (reduced blood oxygen level). Levels higher than 70 % are usually fatal.

• Less than 10 %- No symptoms.

• 10 % to 20 % - Slight discoloration of the skin.

• 20 % to 30 % - Anxiety, headache, increased heartbeat, and lightheadedness.

• 30 % to 50 % - Difficulty in breathing, weakness, confusion, and chest pain.

• 50 % to 70 % - Arrhythmia (abnormal rate and rhythm of the heartbeat), altered mental status, delirium, seizures, coma, and acidosis (too much acid in the body fluids).

• Greater than 70 % - High mortality.

Other than these symptoms, there can be bluish discoloration, pallor of the skin or conjunctiva, skeletal abnormalities, and mental retardation. Patients with comorbidities such as anemia, heart diseases, lung disease, sepsis, or the presence of abnormal hemoglobin may experience moderate to severe symptoms at much lower levels.

How to Diagnose Methemoglobinemia?

• To Rule Out Hemolysis -

1. Complete blood count (CBC).

2. Reticulocyte count.

3. Lactate dehydrogenase (LDH) levels.

4. Indirect bilirubin level.

5. Haptoglobin level.

• To Test for Organ Failure and General Dysfunction -

1. Liver function test (LFT).

2. Electrolyte concentration.

3. Blood urea nitrogen.

4. Creatinine.

• Urine pregnancy test.

• Heinz body preparation (indicates the oxidative injury to red blood cells).

• Hemoglobin electrophoresis (to identify hemoglobin M).

• Specific enzyme assays.

• Bedside Tests - Examination of blood color on white filter paper. A characteristic chocolate brown color compared to normal bright red color is suspective of methemoglobinemia.

• Check serum levels of nitrites or other drugs.

• The Oxygen-Carrying Capacity of Blood May Be Determined Using -

1. Arterial blood gas determination.

2. Co-oximetry.

3. Pulse oximetry-refractory hypoxemia (inadequate arterial oxygen despite optimum levels of oxygen breathed) and saturation gap (greater than 5 %) are diagnostic clues of methemoglobinemia.

• Other Studies-

1. Potassium cyanide test.

2. CT (computed tomography) of the head.

3. Chest radiography (to exclude lung or heart disease).

4. Echocardiography (to know the presence of congenital heart disease).

What Is the Treatment for Methemoglobinemia?

Early clinical recognition of methemoglobinemia is necessary for treatment. Severe cases can be life-threatening and necessitate emergency therapy. Chronic mild methemoglobinemia may be completely asymptomatic, and there is no need for any treatment. Treatment is advisable for patients who have suffered acute exposure to an oxidizing agent and have 20 % or higher methemoglobin levels. Initial care includes:

• Administration of supplemental oxygen.

• Determination of underlying etiology (drug or chemical).

• Removal of offending oxidizing substance.

• Methylene blue (contraindicated in G6PD deficiency). Benign side effects include green or blue discoloration of urine. As an oxidizing agent, methylene blue can cause hemolysis (destruction of red blood cells) in high doses or if ineffectively reduced. Hence, it should be used cautiously and judiciously in infants and patients with G6PD-deficiency, but it is not contraindicated.

• Exchange transfusion (removing the patient's blood and replacing it with donor blood or plasma).

• Hyperbaric oxygen treatment.

• Intravenous hydration and bicarbonate (for metabolic acidosis).

• Other medications- Include Ascorbic acid (Vitamin C) up to 10 g per dose intravenously, Riboflavin, Cimetidine (inhibits the conversion of dapsone to its metabolite form), and N-acetylcysteine.

• Dietary measures - Avoid precipitants in food or drink.

What Are the Other Differential Diagnosis?

The bluish skin may also be seen in:

• Argyria (excessive exposure to silver or silver dust).

• Sulfhemoglobinemia (excess sulfhemoglobin, a greenish derivative of hemoglobin seen even in low levels in the blood).

• Heart failure.

• Anemia.

• Asthma.

• Polycythemia.

• Peripheral cyanosis.

• Cyanotic congenital heart disease.

• Acrodermatitis enteropathica.

• Amiodarone-induced skin pigmentation.

Conclusion:

The prognosis in mild cases of methemoglobinemia is very favorable. Mostly, the patients respond well to treatment and can be discharged after a brief observation period. Anyone with persistent symptoms after initial treatment or underlying medical condition should be considered for admission. The patient will be counseled to avoid exposure in the future. In severe cases, the prognosis is determined by the degree of end-organ damage. Complications, including death, can occur in patients with significant comorbidities.