- Identify a rare cause of hypoxia
- Evaluate and treatment someone with methemoglobinemia
Click here for a interactive 5 min version of the case on the Human Diagnosis Project.
60 yo woman with metastatic melanoma presents with new onset shortness of breath over the past month. She had previously been on nivolumab for her melanoma, which was complicated on severe immune-mediated enteritis. She was started on high dose steroids, infliximab and dapsone for PJP prophylaxis one month prior to presentation. Her shortness of breath has been slowly progressive and she was noted to have low oxygen saturations in the low 90s on several clinic visits. On the day of presentation, she noted some blue discoloration around her lips and finger-tips. She also reports worsening headaches, light-headedness and fatigue. She has no other medical history and takes no other medications. She is a nonsmoker.
On presentation, she is afebrile, RR in the low 20s, SaO2 84% on room air. On 8 L/min NC, her SaO2 was up to 90%. Her exam was notable for dusky skin and mucus membranes.
- BUN 24, Cr 0.4
- WBC – 18, Hgb 8.9, hct 27% (hct 37% 2 weeks ago), plt 264
- ABG – pH 7.43/34/87/25 on room air
How would you interpret her ABG and pulse oximetry?
She has a “saturation gap” – or a discrepancy between the oxygen saturation and expected PaO2.
The O2-hemoglobin dissociation curve describes the relationship between oxygen saturation (indirectly measured by SpO2) and PaO2. In this patient, a SpO2 of 90%, we would expect a PaO2 of ~ 60 mmHg.
What is your differential for this finding?
A saturation gap is strongly suggestive of methemoglobinemia. Methemoglobin (metHb), an oxidized hemoglobin, cannot bind O2 so patients are functionally anemic because fewer Hb molecules are available to transport O2.
Methemoglobin absorbs a distinct wavelength and pulse oximetry will show SpO2 of ~85% at metHb levels >20-30%3. Administration of high levels of oxygen will not correct the peripherally measured low SpO23.
Symptoms typically include1:
- Headache, dizziness, fatigue and weakness
- Paralysis, arrhythmias, coma and seizures at higher levels
The metHb level at which patients experience symptoms depends on concurrent anemia, cardiopulmonary comorbidities, other Hb abnormalities (e.g., sickle cell disease)1.
How would you diagnose this?
Co-oximetry additionally measures the levels of oxyhemoglobin (hemoglobin bound to O2), metHb, and carboxyhemoglobin (hemoglobin bound to carbon monoxide).
Venous blood co-oximetry showed a metHb level of 17% (normal is < 1%).
What is the most likely cause of her diagnosis?
Methemoglobinemia can be congenital, but more commonly it is a result of exposure to drugs and toxins. Most common causes include:
- Nitrites – e.g. nitroglycerin
- Dapsone (most common cause in patients presenting to the hospital, up to 42%)1
- Anti-malarials – e.g., primaquine, chloroquine
- Local anesthetics – e.g., prilocaine, benzocaine, lidocaine (second most common cause in patients presenting to a hospital, 20%)1
- Pyridium (case reports)
- Methylene blue1
- Aniline dyes
- Nitrobenzene (used as solvent in labs)
The most likely cause in this patient is dapsone. Dapsone-induced methemoglobinemia, in one study, accounted for 42% of all cases of inpatient methemoglobinemia.1 There is wide variability in the onset of methemoglobinemia from dapsone initiation.1
How would you manage this patient?
- Stop dapsone
- Give methylene blue 1 mg/kg (can be repeated in 30 min if metHb levels are still high)
- Repeat co-oximetry panel in 30 min (metHb level decreased to 9%)
How would you further work-up her anemia?
Acute anemia over 2 weeks is most likely from:
- Acute blood loss
- Hemolysis – LDH, haptoglobin, peripheral smear (schistocytes, spherocytes), coagulation markers
A reticulocyte index can differentiate between blood loss/destruction and hemodilution. Given the acuity, nutritional deficiences are less likely.Click for lab results.
What is the likely cause of her anemia?
Dapsone can cause a Heinz-body mediated hemolytic anemia. Heinz bodies are denatured hemoglobin precipitates and can indicate G6PD deficiency or exposure to oxidative stress. These RBCs have a shorter half life. Administration of methylene blue can exacerbate this hemolytic anemia.
Of note, in patients with G6PD deficiency, both dapsone and methylene blue can result in hemolysis. G6PD screen sent for this patient was negative, though it does not completely rule this out (since it was sent during hemolytic episode).
TAKE HOME POINTS:
- Suspect methemoglobinemia in patients with a cyanosis, a saturation gap and hypoxia that does not correct with oxygen. Co-oximetry panel confirms the diagnosis.
- Dapsone and topical anesthetics are the common causes of methemoglobinemia.
- Methylene blue can be used to treat patients with symptomatic and severe methemoglobinemia.
- Barclay JA, et al. Dapson-Induced Methemoglobinemia: a Primer for Clinicians. The Annals of Pharmacotherapy. 2011; 45:1130-1015.
- Costanzo LS. Respiratory Physiology. In: Costanzo, LS (ed). Physiology. Philadelphia, PA: Saunders Elsevier; 2018: 189-243.
- Benz, Jr EJ & Ebert BL. Hemoglobin Variants Associated with Hemolytic Anemia, Altered Oxygen Affinity, and Methemoglobinemias. In: Hoffman, R et al (eds). Hematology:Basic Principles and Practice. Philadelphia, PA: Elsevier; 2018: 608-615.