Basics
Description
- Iron molecule in hemoglobin is oxidized from ferrous (Fe2+) to ferric (Fe3+) state resulting in a form of hemoglobin that cannot transport oxygen.
- Oxygen-carrying capacity of blood is reduced and cyanosis is generally present with significant levels.
- Normal methemoglobin levels are ≤1%; symptoms usually occur with levels >20%.
- More serious with coexisting anemia
- Methemoglobin:
- Decreases total oxygen-carrying capacity (functional anemia)
- Shifts hemoglobin oxygen-dissociation curve to the left, impairing O2 release to tissues
- Maintained at physiologic level (1 " “2%) by nicotinamide adenine dinucleotide (NADH)-methemoglobin (cytochrome B5) reductase in red blood cells (RBCs)
- Congenital methemoglobinemia:
- NADH-methemoglobin (cytochrome B5) reductase deficiency (homozygous or heterozygous)
- Heterozygous hemoglobin M and other abnormal hemoglobins
- Acquired methemoglobinemia results from oxidant stress on RBCs:
- Some methemoglobin-inducing agents are direct oxidants (e.g., nitrites)
- Many substances produce oxidant injury via N-hydroxylamine metabolites.
- Methemoglobinemia may be delayed relative to initial substance exposure.
- Many methemoglobin-inducing agents also cause Heinz body hemolytic anemia (HA):
- Caused by oxidant injury of RBC proteins
- Glucose-6-phosphate dehydrogenase (G6PD) " “deficient patients have higher risk.
- Patients with methemoglobinemia should be worked up for HA.
- Methemoglobinemia may serve as marker for genetic abnormalities:
- Heterozygous NADH-methemoglobin (cytochrome B5) reductase deficiency
Etiology
- Cyanide (CN) antidote kit:
- Induces methemoglobinemia via amyl and sodium nitrite
- CN will preferentially complex with methemoglobin, which can then be chelated by sodium thiosulfate.
- Nitrates/nitrites:
- Nitrites (NO2)
- Nitrates (NO3) (e.g., nitroglycerine, via metabolic conversion to nitrites)
- Nitric oxide (NO)
- Dyes:
- Aniline dyes
- Methylene blue (excessive)
- Antiparasitic drugs (high potential for MetHb formation):
- Dapsone
- Primaquine
- Chloroquine
- Local anesthetics (high potential for MetHb formation):
- Benzocaine
- Lidocaine
- Prilocaine
- Analgesics:
- Phenazopyridine (Pyridium)
- Phenacetin
- Antibiotics:
- Nitrofurantoin
- Sulfones
- Sulfonamides
- Others:
- Metoclopramide
- Naphthalene (mothballs)
- Paraquat (herbicide)
- Arsine gas (AsH3)
- Chlorates (ClO4)
- Phenols (e.g., dinitrophenol, hydroquinone)
Diagnosis
Signs and Symptoms
- Central cyanosis, refractory to oxygen administration:
- Cyanosis evident at methemoglobin (MetHb) of 10 " “15% of total hemoglobin in nonanemic patient (or 1.5 g of MetHb/dL blood)
- Dyspnea/tachypnea
- Chest pain/dysrhythmias
- Syncope
- Altered mental status with levels >50%
History
- Exposure to methemoglobin-inducing agent
- All substances ingested and time(s) of ingestion
- G6PD deficiency
- Medical conditions vulnerable to impaired oxygen delivery (e.g., coronary artery disease)
Physical Exam
- Cyanosis
- Emphasis on mental status and cardiovascular findings
- Icterus or dark-colored urine with accompanying HA
Essential Workup
- Pulse oximetry is inaccurate in methemoglobinemia:
- MetHb interferes with pulse oximetry measurement of hemoglobin oxygen saturation.
- Saturation decreases to ¢ ˆ ¼85% with increasingly more severe methemoglobinemia.
- Pulse oximetry cannot be used to guide management.
- ABG for:
- Methemoglobin level
- Carboxyhemoglobin level
- PaO2 and PaCO2
- ECG
Diagnosis Tests & Interpretation
Lab
- Blood classically described as chocolate colored
- CBC with manual differential count and smear analysis for evidence of HA
Imaging
CXR to rule out other pulmonary pathology ‚
Differential Diagnosis
- Hypoxia:
- CHF
- COPD
- Pulmonary embolism
- Irritant gas exposure
- Blue discoloration:
- Hypoxia
- Sulfhemoglobinemia
- CN poisoning
- Hydrogen sulfide poisoning
- Excess methylene blue administration
- Tellurium toxicity
- Skin contact/staining with blue dye
Treatment
Pre-Hospital
- Bring to hospital all substances patient may have ingested.
- Question witnesses and observe scene for household products and other potential coingestants:
- Document and relay findings to emergency medical staff.
- Commercial or industrial sites:
- Obtain relevant material safety data sheets (MSDSs) if available to identify commercial or chemical products.
- Avoid dermal exposures.
Initial Stabilization/Therapy
- ABCs:
- Cardiac monitor
- Isotonic crystalloids as needed for hypotension
- Naloxone, thiamine, and dextrose (D50W) as indicated for altered mental status
- Supplemental oxygen
Ed Treatment/Procedures
- Decontamination:
- If owing to acute ingestion/overdose within previous 1 " “2 hr, and protective airway reflexes are intact, administer 50 " “100 g of activated charcoal PO.
- Remove source of oxidant stress.
- Methylene blue:
- Indications:
- Asymptomatic with levels >30%
- Symptomatic patients with levels >10 " “20%, especially if comorbid diseases are present
- Expect transient worsening of saturations on pulse oximetry after methylene blue is administered:
- Interferes with pulse oximetry measurement and no specific intervention required
- Use with caution in patients with glucose-6 pyruvate decarboxylase deficiency:
- If no improvement with methylene blue, consider that source of oxidant stress is not eliminated, or that sulfhemoglobinemia is present:
- Sulfhemoglobin is sulfur molecule bound to hemoglobin. Presents similar to methemoglobin, but is self-limited and not responsive to methylene blue.
- RBC transfusion:
- May be necessary to increase blood oxygen-carrying capacity
- Consider in the presence of HA.
- Exchange transfusion:
- Especially with neonates/infants
- Hyperbaric oxygen therapy:
- Increases oxygen delivery to tissues by allowing more oxygen to be dissolved in the blood, independent of hemoglobin.
- Use in life-threatening methemoglobinemia if immediately available.
- Children may develop significant methemoglobinemia from apparently minor ingestions.
- Symptoms delayed several hours after ingestion, so prolonged observation necessary
- Neonates are also at higher risk of methemoglobinemia (owing to decreased stores of NADH methemoglobin reductase).
Medication
- Dextrose 50%: 25 g (50 mL) (peds: 0.5 " “1 g/kg of dextrose) IV for hypoglycemia
- Methylene blue: 0.1 " “0.2 mL/kg 1% solution IV over 5 min (adults and peds)
- May repeat if no improvement in 1 hr
- Doses of 0.3 to 1 mg/kg IV have been effective in neonates. Has been used IO over 3 " “5 min.
- Naloxone: 0.4 " “2 mg (peds: 0.1 mg/kg) IV, may repeat up to 10 mg for suspected opioid intoxication
- Thiamine: 100 mg (peds: 1 mg/kg) IM or IV
Follow-Up
Disposition
Admission Criteria
- Severely symptomatic patients
- Patients requiring multiple doses of methylene blue
- Dapsone may cause prolonged recurrent methemoglobinemia
Discharge Criteria
Methemoglobin levels <20% and falling with no symptoms or comorbid disease ‚
Issues for Referral
Toxicology consult for significant exposures ‚
Followup Recommendations
Occupational medicine referral for work-related exposures ‚
Pearls and Pitfalls
- Pulse oximetry is inaccurate in methemoglobinemia.
- Obtain an ABG.
- Administer methylene blue for significant levels/symptoms.
A special thanks to Dr. Gerald Maloney who contributed to the previous edition. ‚
Additional Reading
- Barclay ‚ JA, Ziemba ‚ SE, Ibrahim ‚ RB. Dapsone-induced methemoglobinemia: A primer for clinicians. Ann Pharmacother. 2011;45:1103 " “1115.
- Bradberry ‚ SM, Aw ‚ TC, Williams ‚ NR, et al. Occupational methaemoglobinaemia. Occup Environ Med. 2001;58:611 " “615.
- Guay ‚ J. Methemoglobinemia related to local anesthetics: A summary of 242 episodes. Anesth Analg. 2009;108:837 " “845.
- Price ‚ D. Methemoglobin inducers. In: Flomenbaum ‚ NE, Goldfrank ‚ LR, Hoffman ‚ RS, et al., eds. Goldfranks Toxicologic Emergencies. 9th ed. New York, NY: McGraw-Hill; 2011.
- Wright ‚ RO, Lewander ‚ WJ, Woolf ‚ AD. Methemoglobinemia: Etiology, pharmacology, and clinical management. Ann Emerg Med. 1999;34:646 " “656.
Codes
ICD9
289.7 Methemoglobinemia ‚
ICD10
- D74.0 Congenital methemoglobinemia
- D74.8 Other methemoglobinemias
- D74.9 Methemoglobinemia, unspecified
- D74 Methemoglobinemia
SNOMED
- 38959009 Methemoglobinemia (disorder)
- 267550008 Congenital methemoglobinemia (disorder)
- 295315008 Acquired methemoglobinemia