83yF PMH HTN, HLD p/w fatigue and cyanosis. Reports that all day she has been feeling fatigued and was noted to have a blue color so her son called 911. On arrival she is cyanotic and hypoxic to 80-85% on NRB. Denies fevers, chills, chest pain, shortness of breath, cough, abdominal pain, nausea, vomiting, diarrhea, dysuria, hematuria. Patient denies any toxic ingestions or recent medication changes.
PMH / PSH
PMH: HTN, HLD
Medications: Celebrex, Meloxicam, Cyclosporine 0.05% 1 drop BID, Tolterodine, Pitvastatin, MVI, Omega 3
VS: 36.6, 90, 122/59, 25 80% on NRB
HEENT: NCAT, +periorbital and perioral cyanosis, OP clear, neck supple
Cardiovascular: RRR, no m/r/g
Pulmonary/Chest: Effort normal. No respiratory distress. No w/r/r
Abdominal: Soft, nt/nd, no r/g, normal BS
Extremities: Cyanosis to b/l hands and feet, warm to touch, no edema
Neurological: AAOx3, CN II-XII intact, strength and sensation intact
ABG: pH 7.484, PC02 32.8, P02 307, HC03 24.3 Lactate 1.8
WBC: 8.2, Neut 89%, Hgb 10.5, MCV 93.7, Hct 31.1, Plt 218
Na 141, K 4.7, Cl 103, BUN 35, Cr 1.0, Glucose 120, Ca 8.9, AG 12,
Bili Tot 0.4, Bili conj 0, Alk P 65, AST 18, ALT 22, Alb 3.4, Protein 6.1
CXR: No evidence for acute pulmonary pathology
What laboratory test will confirm your diagnosis?
A Co-Oximeter (Co-Ox) panel should be ordered which will report the percentages all the different types of hemoglobin currently present in the blood including MetHb (see More Info)
What is the treatment?
Methylene Blue given at 1-2mg/kg intravenously is the treatment for acquired MetHb (see More Info)
In this patient with acute onset cyanosis, hypoxemia on pulse oximeter without improvement on supplement oxygen, and a normal P02 on arterial blood gas analysis, suspicion for methemoglobinemia (MetHb) should immediately be raised. MetHb occurs when the iron in hemoglobin is oxidized from the ferrous (Fe2+) state into the ferric (Fe3+) state, thus making the heme molecule unable to bind new oxygen. In addition, it also causes an increased affinity for the already bound oxygen in the remaining heme sites, thereby causing a shift in the oxygen hemoglobin dissociation curve to the left and decreased oxygen delivery to tissues. Of note, when this patient’s blood was drawn, a chocolate brown color was noted, which is another hallmark of MetHb. This is also what causes the blue hue of cyanosis in patients with high levels of MetHb, not tissue hypoxia.
In order to confirm the diagnosis, a Co-Oximeter (Co-Ox) panel should be ordered which will report the percentages all the different types of hemoglobin currently present in the blood including MetHb. This patient’s level came back above the reportable range, indicating that it was very high. In healthy people, there is normally ~1% of methemoglobin in the blood. This is because auto-oxidation of hemoglobin (Hb) to MetHb occurs daily at a slow rate converting 0.5 to 3 % of the available Hb to MetHb with the subsequent reduction of MetHb back to Hb to maintain a steady-state level of MetHb. Pathologic MetHb occurs with higher levels and can be congenital or acquired. We will focus on acquired MetHb as this accounts for the majority of emergency department visits.
Acquired MetHb can be caused by a variety medications, most notably dapsone and cetacaine spray, as well as, environmental factors such as nitrogen-based fertilizers and nitrogenous waste from animal and human sources which contaminate shallow water wells. In addition, foods with high nitrate contents such as cauliflower, carrots, spinach, and broccoli, hot dogs and sausages. Elevated methemoglobin and carboxyhemoglobin levels are also seen in burn victims secondary to inhalation of oxides of nitrogen from combustion. In this patient, no identifiable cause of her MetHb was found.
Be wary of the fact that pulse oximeters are not accurate in the setting of elevated MetHb levels. Pulse oximeters were made to be used in patients who only have oxyhemoglobin and deoxyhemoglobin circulating in their blood. Pulse oximeters work by transmitting two wavelengths of light, 660 and 940 nm, which are selectively absorbed by deoxyhemoglobin and oxyhemoglobin respectively. Their ratios are calculated to produce a percentage of oxygenated blood based on the amount of absorption of each wavelength. In the presence of MetHb, which absorbs light at both wavelengths, this ratio is thrown off and the pulse oximeter reading is inaccurate. At very high levels of MetHb the pulse oximeter reading will plateau at around 85% regardless of the true percentage of oxyhemoglobin in the blood. This is why the co-oximeter panel is helpful in these cases as it transmits four different wavelengths of light based on the specific absorptions of oxyhemoglobin, deoxyhemoglobin, carboxyhemoglobin and methemoglobin to then give the true proportions of each in the blood.
Methylene Blue given at 1-2mg/kg intravenously is the treatment for acquired MetHb. Methylene Blue works by acting as an electron donor converting the iron in heme from its ferric (Fe+3) state back to its original ferrous (Fe+2) state. It is only indicated in patients with MetHb levels over 20-30% or patients who are very symptomatic. Rapid improvement in cyanosis and symptoms should be seen after administration of methylene blue. If this does not happen, a second dose may be given or consider that the offending agent has not been removed. The patient may require decontamination of the gut and/or skin cleansing. In severe refractory cases, exchange transfusion or hyperbaric oxygen may also be considered. Please consult your local poison center. Be aware that methylene blue causes a transient decrease in the pulse oximetry reading because its blue color has excellent absorbance at 660 mm, the same as deoxyhemoglobin.
This patient rapidly improved with 1 dose of methylene blue and was discharged the next day.
- Barker SJ, Tremper KK, Hyatt J: Effects of methemoglobinemia on pulse oximetry and mixed venous oximetry. Anesthesiology. 1989;70:112–117.
- Prchal JT. Clinical features, diagnosis, and treatment of methemoglobinemia. In: UpToDate, Post TW (Ed), UpToDate, Waltham, MA. (Accessed on May 16, 2017)
- Price D. Methemoglobinemia. In: Goldfrank LR, Flomenbaum NE, Lewin NA, Weisman RS, Howland MA, Hoffman RS, eds. Goldfrank’s Toxicologic Emergencies. 6th ed. Old Tappan, NJ: Appleton & Lange; 1998: 1507-1523