Dear Editor,
We are writing to discuss our findings and perspectives from a series of cases involving acquired methemoglobinemia, a rare but life-threatening condition that requires prompt diagnosis and treatment. Methemoglobinemia is caused by the oxidation of hemoglobin from its ferrous (Fe
2+) to ferric (Fe
3+) form. The ferric iron causes an allosteric shift in the hemoglobin molecule, diminishing the affinity of heme units for oxygen, shifting the oxygen dissociation curve to the left, limiting oxygen delivery to tissues, known as the Darling-Roughton effect, which is akin to carbon monoxide poisoning. Methemoglobin cannot transport oxygen, resulting in functional anemia [
1]. Exposure to oxidizing substances, such as insecticides, local anesthetics, nitrates, and rare hereditary enzymatic deficits may cause this illness. A famous example is the Fugate family of Kentucky, popularly referred to as the "Blue People of Kentucky," who had a genetic abnormality that caused congenital methemoglobinemia, which resulted in blue-tinged skin [
2]. Acquired methemoglobinemia can manifest acutely and, depending on the methemoglobin levels, can range from mild cyanosis to severe hypoxia, arrhythmias, and even death. Preexisting anemia can further exacerbate the effects of methemoglobinemia.
Here, we outline the cases of four patients who presented to the emergency department with central cyanosis and unexplained hypoxemia. The patients had a characteristic chocolate-brown blood color, a saturation gap between arterial blood gas analysis and pulse oximetry, and elevated methemoglobin levels, which were confirmed by co-oximetry (
Table 1).
TREATMENT
All the patients received an intravenous infusion of methylene blue (1 mg/kg over 30 minutes), vitamin B complex, and vitamin C (1 g three times daily). However, patient 1 was 5 months pregnant, and the injection of methylene blue was carefully evaluated owing to the known teratogenic potential. She suffered a spontaneous abortion the next day, and her hemoglobin level decreased to 6.4 g/dL, necessitating blood transfusions. All the patients except patient 3 recovered fully and were discharged safely.
MANAGEMENT
Methylene blue is the principal treatment for methemoglobinemia, acting as a cofactor for the NADPH-dependent methemoglobin reductase pathway, which reduces methemoglobin to leukomethylene blue. This reduced chemical acts as an electron donor converting methemoglobin to hemoglobin [
3]. Methylene blue, which acts as both an oxidizing agent and a monoamine oxidase A inhibitor, can also have serious adverse effects:
• Excessive methemoglobinemia or hemolysis from overdose or altered metabolism.
• Risk of serotonin syndrome in patients on serotonergic medications [
4].
• Green or blue discoloration of urine, which patients should be informed about prior to treatment.
The use of methylene blue during pregnancy requires extreme caution due to the possible harm to the fetus [
5,
6]. Additionally, its administration in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency is controversial but not strictly contraindicated. The risk of hemolysis is significant at doses exceeding 5 mg/kg, more than twice the standard dose [
3].
Ascorbic acid, a potent reducing agent, complements methylene blue and serves as an antioxidant. In resistant cases, alternative modalities such as exchange transfusion or hyperbaric oxygen therapy may be required [
3]. Dyshemoglobinemias like sulfhemoglobinemia are to be considered in patients nonresponsive to methylene blue [
7].
CONCLUSION
This case series highlights the various manifestations and management challenges of methemoglobinemia, emphasizing the significance of increased clinical suspicion and thorough history taking for hazardous exposures and genetic defects (
Table 2) in patients with unexplained hypoxemia or cyanosis [
7]. Co-oximetry is the confirmatory test for methemoglobinemia. Methylene blue, ascorbic acid and adjunct therapy such as exchange transfusions can effectively treat acquired methemoglobinemia. Early detection and a multidisciplinary approach are essential for improving patient outcomes.
NOTES
-
Ethics statement
Written informed consents were obtained from the patients.
-
Author contributions
Conceptualization: MAAS, VS, SB; Data curation: MAAS, VS, SB; Formal analysis: MAAS, VS; Methodology: MAAS, VS; Validation: MJ; Writing–original draft: MAAS; Writing–review & editing: all authors. All authors read and approved the final manuscript.
-
Conflicts of interest
The authors have no conflicts of interest to declare.
-
Funding
The authors received no financial support for this study.
-
Data availability
Data analyzed in this study are available from the corresponding author upon reasonable request.
Table 1.Clinical characteristics and laboratory findings of methemoglobinemia cases
Table 1.
|
Characteristic |
Patient 1 |
Patient 2 |
Patient 3 |
Patient 4 |
|
Age (yr) |
25 |
40 |
46 |
27 |
|
Sex |
Female |
Male |
Female |
Male |
|
Brief history |
Attempted self-abortion |
Self-harm |
Accidental ingestion |
Self-harm |
|
Causative agent |
Indoxacarb containing pesticide |
Amish B (GM Biocides; herbal bug killer containing alkaloids, terpenes, lactones) |
Nitrate containing preservative in pickles |
Amish B (GM Biocides; herbal bug killer containing alkaloids, terpenes, lactones) |
|
Underlying condition |
Pregnancy |
None |
Diabetes mellitus, ischemic heart disease |
None |
|
pH |
7.389 |
7.418 |
7.090 |
7.370 |
|
PaCO2 (mmHg) |
34.4 |
35.9 |
34.5 |
25.0 |
|
PaO2 (mmHg) |
180 |
207 |
298 |
145 |
|
HCO3 (mEq/L) |
19.4 |
22.8 |
15.4 |
14.5 |
|
Lactate (mmol/L) |
3.6 |
3.0 |
18.0 |
7.4 |
|
Methemoglobin (%) |
60.2 |
50.0 |
64.0 |
58.0 |
|
FiO2 (%) |
100 |
100 |
100 |
100 |
|
SpO2 (%) |
80 |
84 |
82 |
58 |
|
SaO2 (%) |
99 |
98 |
99 |
95 |
|
Hospital stay (day) |
5 |
3 |
3 |
4 |
|
Outcome |
Cured |
Cured |
Died |
Cured |
Table 2.Known causes of methemoglobinemia
Table 2.
|
Cause |
Description |
|
Genetic |
Cytochrome b5 reductase deficiency, variants of hemoglobin M |
|
Analgesic |
Phenazopyridine, phenacetin |
|
Antimicrobial |
Antimalarials (chloroquine, primaquine), dapsone, sulfamethoxazole |
|
Local anesthetic |
Benzocaine, lidocaine, prilocaine, dibucaine |
|
Nitrate/nitrite |
Amyl nitrite, isobutyl nitrite, sodium nitrite, ammonium nitrate, well water, silver nitrate, nitroglycerin |
|
Other |
Rasburicase |
REFERENCES
- 1. 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.
- 2. Phillips GS, Vatanchi M, Glick SA. The fugates of troublesome creek. JAMA Dermatol 2017;153:513.
- 3. Ludlow JT, Wilkerson RG, Nappe TM. Methemoglobinemia [updated 2023 Aug 28]. StatPearls [Internet]. StatPearls Publishing; [cited 2025 Mar 9]. Available from: https://www.ncbi.nlm.nih.gov/books/NBK537317/
- 4. Ramsay RR, Dunford C, Gillman PK. Methylene blue and serotonin toxicity: inhibition of monoamine oxidase A (MAO A) confirms a theoretical prediction. Br J Pharmacol 2007;152:946-51.
- 5. ProvayBlue® (methylene blue) injection USP, for intravenous use [Internet]. US Food and Drug Administration; 2016 [cited 2025 Mar 9]. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/204630s000lbl.pdf
- 6. Methylene blue in pregnancy and breastfeeding warnings [Internet]. Drugs.com; 2024 [cited 2025 Mar 9]. Available from: https://www.drugs.com/pregnancy/methylene-blue.html
- 7. Tintinalli JE, Ma OJ, Yealy DM, et al., editors. Tintinalli’s emergency medicine: a comprehensive study guide. 9th ed. Mc-Graw-Hill Education; 2020.
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