A thirty year old woman attending a funeral presents accidentally drinks a bitter liquid that was stored in a cola can. Upon presentation to the emergency department two hours later, her only complaint is shortness of breath. The bottle from which she drank is not available in the ED.
Vital signs on admission are: BP 130/70, P 120, R 24, T afebrile. Her lungs are clear, and her heart examination is normal. The only impressive finding is deep cyanosis of the trunk, face and extremities.
The pulse oximeter reads 90% on room air and the arterial blood is noted to be brown when drawn for a blood gas. The blood gas reveals pH 7.45, pCO2 35, pO2 575, O2 saturation 100%. The blood specimen run on a cooximeter reveals a methemoglobin level of 50%.
Antidotal therapy was administered with complete resolution of the cyanosis and dyspnea within fifteen minutes. The patient was observed overnight without recurrence.
What is methemoglobinemia?
Despite popular use, the term methemoglbinemia is actually a misnomer as no free methemoglobin exists in the blood (it is within the red blood cells). It results from the oxidation of the iron moiety of deoxyhemoglobin from a ferrous (2+) to a ferric (3+) state. The methemoglobin remains unless actively reduced back to the ferrous state. The same oxidative process normally occurs when oxygen binds to ferrous hemoglobin, but upon dissociation of the oxygen the ferrous state is regained. Methemoglobin cannot be further oxidized (to a 4+ state), so oxygen cannot be loaded and the red cells cannot carry their full complement of oxygen.
Since oxidizing agents are always generating methemoglobin in the body, several mechanisms for the active reduction back to hemoglobin have developed. NADH methemoglobin reductase is quantitatively the most important and uses NADH generated during glycolysis as the electron donor. Nonenzymatic reduction, using ascorbic acid or glutathion as antioxidants, plays a small role in reducing methemoglobin levels. Finally, a third, normally unimportant system which uses NADPH obtained from the hexose monophosphate shunt as the reducing agent exists. This third system is accelerated and made quantitatively important when the antidote, methylene blue, is administered.
How is methemoglobinemia recognized and diagnosed?
Although not commonly seen, patients with cyanosis in whom there is no sign of or cause for hypoxemia should be evaluated for methemoglobinemia. Methemoglobin, due to it's altered characteristics, appears very dark in the visible light spectrum. While patients may require 5 g/dL of deoxyhemoglobin to appear cyanotic, it only requires 1.5 g/dL of methemoglobin to produce similar findings. In a normal non-anemic person, this is approximately 10% of total hemoglobin (normal hemoglobin is 15g/dL). It should be noted that symptoms of hypoxemia are usually worse than expected for a corresponding degree of anemia since the oxygen dissociation curve is shifted toward the left, reducing oxygen unloading to tissue. The finding of dark "chocolate brown" blood upon obtaining arterial blood, especially if not made red by exposure to oxygen, is frequently cited as a quick test for methemoglobinemia.
Caution must be used when interpreting a pulse oximeter or blood gas result in such patients. The pulse oximeter relies on the absorption of light of two different wavelengths to separate out oxy- form de-oxyhemoglobin. It is unable to separate out methemoglobin, and tends to report it as oxyhemoglobin. As in this patient, the oxygen saturation is reported as normal or nearly normal. The blood gas analysis uses the dissolved oxygen (pO2 ) which is normal, to calculate the expected oxygen saturation. Therefore both of these tests would lead the interpreter astray. The only currently available method to determine hemoglobin species other than deoxyhemoglobin and oxyhemoglobin is cooximetry. Cooximetry utilized four or more wavelengths to pick apart the different hemoglobin species including carboxy- and methemoglobin.
How is methemoglobinemia treated?
Indications for antidotal therapy with methylene blue include signs of hypoxia such as acidosis, altered mental status, cardiac dysrhythmias or ischemia. In addition, most agree that patients with significantly elevated methemoglobin levels of about 30% need antidotal therapy. Methylene blue, 1 mg/kg (or 0.1 ml/kg of the standard 1% solution), is administered intravenously. Methylene blue, after activation by NADPH, acts as a reducing agent to non-enzymatically restore ferrous hemoglobin. Caution must be taken to give the correct amount of antidote, since at high doses methylene blue is an oxidizing agent.
As with this patient, most respond rapidly to antidotal therapy and remain normal. Failure to respond may be due to several factors, the most common of which is continuing oxidation. This may be due to a large continually absorbing gastrointestinal load, or to an oxidizing agent with a long half life (such as dapsone). Other antidotes used with less success include ascorbic acid as a reducing compound and hyperbaric oxygen therapy, which eliminates the need for hemoglobin but does not restore the ferrous state. Exchange transfusion has also been performed.
Which substances cause methemoglobinemia?
The list of agents is huge and constantly growing. Here are a few (the patient actually ingested a phenol based preservative which was left in a cola can):
Chemicals:
ammonium nitrate (cold packs)
phenols
aniline derivatives
chlorates (matches)
amyl (butyl, isobutyl) nitrite ("poppers")
meat preservatives (sausage)
well water in kids (nitrates nitrites in gut)
Medication/drug:
phenazopyridine (Pyridium)
dapsone
phenacetin (forms apap)
antimalarials (chloroquine)
naphthalene
"caines" (not cocaine)
antianginals (nitroglycerin)
Interesting further reading:
Curry S. Methemoglobinemia. Ann Emerg Med 1982; 11:214-221 (despite it's age, the definitive work)
Barker SJ, Tremper KK, Hyatt J. Effects of methemoglobinemia on pulse oximetry and mixed venous oximetry. Anesthesiology 1989;70:112-117.
There are thousands of case reports (too many to list). See a text such as Goldfrank's Toxicologic Emergencies for a more extensive bibliography.