Continuous Methylene Blue Infusions for Treating Recurrent Methemoglobinemia
by Steve Curry
Banner – University Medical Center Phoenix
University of Arizona College of Medicine – Phoenix
A 2012 report out of Oregon serves as one of many examples reminding us that some serious cases of methemoglobinemia require more than a single injection of methylene blue in the ED or ICU. I thought this might be a good opportunity to describe our approach to this problem.
This Feb 10, 2012 issue of MMWR describes two men who drank what they believed to be 2C-E, a.k.a. 4-ethyl-2,5-dimethoxyphenethylamine.
As an aside, whenever we see phenylalkylamines with oxygen or halogen substitutions on the benzene ring, there commonly, but not always, is an increase in serotonergic and, thus, illusionogenic/hallucinogenic activity. And this may explain such actions by 2C-E, as well.
But these men did not experience pleasurable illusions or hallucinations and, instead, developed serious methemoglobinemia along with hemolytic anemia as a result of the ingested product containing aniline. Although the MMWR mistakenly reports methemoglobin fractions (percents) as concentrations (expanded upon, below), I want to focus on how we treat recurrent methemoglobinemia at our center, in Phoenix.
But first of all, what is commonly meant by methemoglobinemia that is recurrent? This is most commonly used to describe clinical situations in which a single dose of methylene blue produces only a transient and sometimes incomplete effect, with methemoglobin fractions never falling to near zero, and/or rebounding back up into a range of concern. Remember that methemoglobin “levels” are most commonly reported as fractions of total hemoglobin concentration, and we normally walk around with <2% methemoglobin. So, if my total hemoglobin concentration is 15 g/dL, then, for example, at 10% methemoglobinemia I would have 1.5 g/dL methemoglobin and, presumably, about 13.5 g/dL oxyhemoglobin in arterial blood at sea level (minus some endogenously-produced carboxyhemoglobin). Methemoglobin fractions in non-anemic patients first produce noticeable cyanosis around 10% because of methemoglobin’s dark color. A V/Q mismatch, hypoventilation, shunting, higher altitude, etc., will also cause a rise in deoxyhemoglobin and fall in oxyhemoglobin concentration, for a given methemoglobin fraction, of course.
We see methemoglobinemia regularly on our service, and the most common etiology in older children and adults is topical benzocaine. In all but a couple instances that I recall, when treating benzocaine-induced methemoglobinemia, a single IV injection of methylene blue at 2 mg/Kg (0.2 cc of 1% methylene blue OR 0.4 cc of 0.5% methylene blue per Kg body weight) has resulted in normalization of methemoglobin fractions within 15 to 30 minutes without significant rebound, though we regularly watch for such for a few hours.
On the other hand, we also see cases of methemoglobinemia from other causes in which methemoglobin fractions only transiently decline and then rebound following a dose of methylene blue. Our differential diagnosis of a partial or poor response to methylene blue comprises:
- unrecognized G-6-PD deficiency.
- coexistent sulfhemoglobinemia, which commonly occurs with methemoglobinemia.
- the patient is blue for another reason (e.g., blue dye on the skin from new jeans/towels – I’ve seen this twice).
- NADPH methemoglobin reductase deficiency.
- blue from too much methylene blue (usually acute doses significantly > 7 mg/Kg).
- ingestion or exposure to a large dose of an etiologic agent or to a very strong oxidant with a long half-life.
It is the latter situation (#6) I will address here. Whenever we see methemoglobinemia that improves, but keeps bouncing back, three agents most commonly come to mind: aniline, nitrobenzene, and dapsone. In this recently reported case, aniline was responsible. This is not to say these are the only three possible etiologies, but these are the three we see most commonly that produce this scenario. One of my former fellows, George Braitberg, was also faced with this dilemma in a patient exposed to copper glycine, a veterinary product.
Let’s briefly take a look at how aniline even produces methemoglobinemia. You may recall that methemoglobin, in simplest terms, is normal hemoglobin in which ferrous (Fe2+) iron has been oxidized to the ferric (Fe3+) state. Below is a simplistic explanation of how aniline achieves this end.
A fraction of aniline is oxidized to phenylhydroxylamine by CYP2E1, the same P450 that oxidizes acetaminophen to NAPQI and that oxidizes a portion of ethanol. The phenylhydroxylamine, in turn, is believed to quickly donate an electron to oxygen (to form the superoxide anion) while being converted to the nitroso moiety. The superoxide anion goes on to form other compounds, including H2O2, that are responsible for oxidizing iron in hemoglobin to form methemoglobin, and for oxidizing protein in hemoglobin to cause a hemolytic anemia. Meanwhile, the nitroso moiety is reduced back to phenylhydroxylamine, and the cycle continues. This futile cycling allows for lots of methemoglobin formation for a given amount of aniline. Eventually other pathways will lead to elimination of aniline and the intermediates, but after an aniline ingestion, this can take a few days.
The para-amino groups of dapsone (above) undergo the same reactions in that dapsone is converted to dapsone hydroxylamine and then to the nitroso with subsequent cycling and oxygen radical formation.
Methylene Blue Mechanism of Action
Next, let’s very briefly review, in an admittedly simplified way, how methylene blue lowers methemoglobin levels. Take a look at the figure below.
We begin with an oxidant (e.g., drug) that oxidizes ferrous iron in hemoglobin to form ferric methemoglobin. The enzyme cytochrome b5 reductase (a.k.a. NADH methemoglobin reductase; diaphorase I) is normally active and uses electrons from NADH and an electron carrier intermediate, cytochrome b5, to reduce ferric methemoglobin back to normal ferrous hemoglobin. Methemoglobinemia occurs when we produce methemoglobin faster than cytochrome b5 reductase can reduce it.
But we have another potential pathway of methemoglobin reduction. NADPH methemoglobin reductase uses electrons from NADPH to reduce methemoglobin, but also requires an electron carrier intermediate. Since no intermediate is normally present, this enzyme is normally inactive. However, methylene blue serves as the intermediate and markedly turns on this enzymatic reduction.
Methylene Blue Continuous Infusions
Regardless of etiology (e.g., dapsone, aniline, copper), if methemoglobin fractions rebound higher than about 10 to 15% and are rising in the absence of anemia after an initial treatment with 2 mg methylene blue/Kg IV, we give another 1 mg methylene blue/Kg IV. If yet another rebound occurs, we prepare a continuous infusion of methylene blue and begin at a rate of 0.1 mg/Kg/hr, which typically runs for 3 to 5 days and, sometimes, longer (especially in the case of aniline and dapsone). Methemoglobin fractions are monitored, and when they are less than about 2% (without serious anemia), we turn the infusion off and watch for a rebound. If they rise again, then the infusion is restarted after another bolus, if needed. I have had to use higher infusion rates, at times, in order to keep methemoglobin fractions in the safe range, but 0.1 mg/Kg/hr usually takes care of it. Every day we attempt to lower the infusion rate to the lowest effective dose – that which keeps methemoglobin levels down (and oxyhemoglobin levels up) in the safe range. Some papers have suggested that methylene blue may not work well for aniline-induced methemoglobinemia because of decreased erythrocytic uptake of methylene blue in the face of the phenylhydroxylamine, but we have found continuous infusions to be effective for aniline toxicity. Transfusions may be needed for significant hemolysis which commonly doesn’t really become a problem for 2-3 days.
A few tips and precautions to be aware of:
1 – Creating the infusion solution
Using the 10 cc vials of 0.5% or, if you are lucky enough to find them, 1% methylene blue will save you and/or the pharmacy a lot of headache in preparing the infusion. Let’s think this through. If I were to give straight 1% methylene blue as an infusion and wanted to give 0.1 mg/Kg/hr, I would be infusing 0.01 cc 1% methylene blue per Kg per hr. A person weighing, say, 100 Kg, then, would receive 1 cc of 1% methylene blue per hour. And if I want to mix up an IV bag for a 24 hour infusion, I would need 24 cc of 1% methylene blue. Breaking open 24 vials, 1 cc each, is a headache and makes quite a mess compared to using two to three multidose vials, each containing 10 cc 1% methylene blue. And double the volume if you are using 0.5% methylene blue for injection. Because of lack of availability of the 1% product, we currently use 10 cc glass vials of 0.5% methylene blue to mix infusions.
We prepare 250 cc methylene blue solutions for infusion by adding methylene blue to D5W to create a methylene blue concentration of 1 mg/mL. Our continuous infusion rate, then, will begin at 0.1 mg/Kg/hr, which is 0.1 cc/Kg/hr.
2 – Continuous methylene blue infusions in the face of renal failure
Methylene blue exhibits an elimination half-life of 5-6 hours. Methylene blue is partly eliminated in the urine as the parent compound and as its redox pair, leukomethylene blue. After a single dose of methylene blue IV to a person with normal renal function, roughly a third appears in the urine, most within 24 hours. First the urine is dark blue and then, of course, becomes progressively more green as urine methylene blue concentrations fall, before turning yellow again.
I haven’t found studies reporting elimination kinetics of methylene blue in the face of renal failure, so no specific dosing adjustments are found in the literature except for precautions of use in such patients. For oliguric or anuric patients with renal failure we generally drop the infusion rate by 30 to 50%, but this is not based on formal studies, and simply represents our practice and experience. Again, we seek the lowest effective infusion rate daily by monitoring methemoglobin and oxyhemoglobin concentrations with multiwavelength cooximetry daily, every few hours, if the patient appears stable.
3 – Don’t trust improvement in cyanosis, alone
Recurrent or refractory methemoglobinemia is commonly accompanied by oxidant-induced hemolysis. Heinz bodies can be seen with special staining (not on a Wright’s stain of blood, such as with a CBC), but spherocytes, bite cells, and in severe cases, schistocytes are found.
This hemolysis may be relatively rapid in onset, such as with chlorates, or more commonly appears after a day or two. About 1.5 g/dL of methemoglobin is required in capillary blood to appear cyanotic (thus cyanosis appears at about 10% methemoglobin in a person with a total hemoglobin of about 15 g/dL). A fall in total hemoglobin concentration from hemolysis may result in anemia severe enough for cyanosis to disappear from declining methemoglobin concentrations, despite worsening oxygen carrying capacity from falling oxyhemoglobin concentrations. And during this time, methemoglobin fractions (percents) might be falling, staying the same or even rising.
Thus cyanosis may disappear while oxygen carrying capacity and delivery worsen and become life-threatening. One must always follow total hemoglobin concentrations, oxyhemoglobin concentrations AND methemoglobin fractions in making clinical moves that maintain adequate oxygen delivery.
4 – Methylene blue-induced serotonin syndrome
Methylene blue is an MAO inhibitor, and the literature describes cases of serotonin syndrome following methylene blue administration in patients taking other serotonergic drugs, such as SSRIs. If a person who happened to be taking an SSRI was suffering from life-threatening methemoglobinemia, we would not hesitate to give methylene blue, understanding and acknowledging the risks of producing serotonin syndrome, as the risk of death from methemoglobinemia far outweighs the risk of death from serotonin syndrome. And if such a patient tolerated the initial 2 mg/Kg dose of methylene blue IV without difficulty, we certainly would not hesitate to begin a continuous infusion if we felt that it was required.
Other Treatment Options for Refractory Methemoglobinemia
When you are up against the wall and can’t keep the methemoglobin fractions down, other measures can be tried. While it is not the purpose of this post to discuss these in detail, I feel compelled to at least mention some options.
Ascorbic acid probably works too slowly to do any good in the acute situation, but is pretty benign. Riboflavin in large doses displays an action similar to methylene blue by acting as a redox pair, but relies on the same pathway for activity (NADPH methemoglobin reductase), making it unexpected to work in the face of methylene blue failure. If dapsone is the etiology, we use high-dose cimetidine to inhibit CYP450, so to prevent formation of dapsone hydroxylamine. Repeat dose charcoal has also been reported to shorten the normally long elimination half-life of dapsone. Hyperbaric oxygen can buy 2-3 hours of time, especially if you need to type and crossmatch a relatively large volume of blood for transfusions. However, non-cross-matched O negative blood may be your only option when the patient is moribund and not responding to methylene blue.
That’s it. The intent was not to make this an entire overview of methemoglobinemia, contraindications to methylene blue, etc., but just to explain how we use continuous methylene blue infusions. I hope this information might help you someday.
I’ve seen methemoglobemia twice in two years of IM residency so far – both from rasburicase given for TLS in unknowingly G6pd deficient patients. The issue I ran into each time was pharmacy’s reluctance to give me methylene blue. Their concern is always a worsening oxidative crisis.
Is there any good data on the >7 mg/kg dosage that I can show them in case this happens again?
Hi Bill,
The topic of treatment of methemoglobinemia in patients with G6PD deficiency could easily take up an entire post (or three). But I’ll make some general statements with an understanding that there are no controlled trials evaluating methylene blue therapy in human beings with G6PD deficiency. Here are the main concepts and observations. I don’t know what you know, so I may make some statements that are obviously apparent to you.
First, G6PD deficiency predisposes to hemolysis, but is a minor factor in predisposing to methemoglobinemia. We need NADPH, made in the HMP shunt via G6PD, in order to reduce oxidized glutathione dimers (GSSG) to reduced glutathione (GSH). If we allow an oxidant to oxidize and denature hemoglobin or other essential proteins, the denaturation is generally irreversible and leads to hemolysis. Thus G6PD is essential for maintaining adequate stores of GSH which inactivates many oxidants.
Second, the main way we keep methemoglobin fractions low is to allow methemoglobin to form, but quickly reduce it via cytochrome b5 reductase, using NADH generated in glycolysis. We normally have a reducing capacity a few hundred times greater than background methemoglobin formation. Thus, the presence of G6PD deficiency and a possible somewhat increased formation of methemoglobin is pretty insignificant compared to our methemoglobin reducing capacity. Nevertheless, a G6PD deficient patient can certainly develop methemoglobinemia like anyone else, and rasburicase is a drug that can cause methemoglobinemia in most any patient, and is especially good at causing hemolysis in patients with G6PD deficiency.
Third, methylene blue works to reduce methemoglobin using NADPH generated in the HMP shunt via G6PD. A person with serious G6PD deficiency, then, is predisposed to hemolysis and would be expected to have a minimal response to methylene blue if they also happen to have methemoglobinemia.
Fourth, methylene blue exists as a redox pair with leukomethylene blue. That is, methylene blue can accept electrons to oxidize things, including hemoglobin and other proteins, in the face of low GSH stores. So, methylene blue is one of the drugs that can cause hemolysis in G6PD deficient patients.
Thus, for many, many, many decades, the caution has been that a patient with G6PD deficiency who happens to acquire methemoglobinemia should not be treated with methylene blue. It would be expected that they would not respond to methylene blue with much of a lowering of methemoglobin (low NADPH levels), and that the hemolysis (low NADPH causing low GSH levels) potentially caused by methylene blue would worsen oxygen carrying capacity even more.
But all of this is complicated by the simple term, G6PD deficiency. Of the hundreds of mutations that produce G6PD deficiency, there is great variation in their severity. And, most importantly, there are two general categories. The G6PD deficiency we see most commonly in the U.S., such as that commonly found in black males, but also found in most any race, mainly affects older red cells. One could argue, then, that methylene blue would work in younger red cells and would not hemolyze those cells. What fraction of red cells would be resistant to methylene blue therapy and possibly undergo hemolysis? No one knows in any given individual who is seriously ill and needs immediate therapy.
On the other hand, the second major type of G6PD deficiency, more commonly found in Mediterranean countries, affects red cells of all ages. These patients might theoretically hemolyze to death from methylene blue and experience no drop in methemoglobin levels at all.
We are left, then, with variations in severity of G6PD deficiency, variations in whether the deficiency affects all red cells or just progressively older red cells, and the lack of randomized trials in human beings to guide us. I avoid methylene blue in patients with G6PD deficiency. If a such a patient was dying from methemoglobinemia and not just mildly symptomatic, we would give blood. And if they were still in trouble and likely to die, we might try methylene blue as a last resort, knowing it won’t make transfused red cells hemolyze and will lower new formed methemoglobin levels in those transfused cells. But watch for hemolysis and attendant complications. Of course, on top of this are the theoretical options of hyperbaric oxygen (while arranging exchange transfusions which would allow methylene blue?) and high dose ascorbate (probably not effective).
Years ago Wright published a paper on incubating G6PD-deficient red cells with elevated methemoglobin fractions in N-acetylcysteine and claimed a reduction in methemoglobin levels (Wright 1998 PMID 9523930). However, the concentrations of NAC were sky-high compared to what can be given safely in vivo. We subsequently published a paper in which we gave IV NAC, using APAP dosing, after 4 mg/Kg sodium nitrite IV in human volunteers and found that, if anything, NAC actually increased methemoglobin levels slightly (Tanen 2000 PMID 10736124). So NAC appears off the board as an option in these patients.
Hope some of this might be helpful to you.