Tox and Hound – Color Me Blue

by Christine Murphy

Alternative Uses for Methylene Blue

I like finding alternative uses for existing antidotes. Antidote research is very limited – let’s be honest, there isn’t a huge market out there for most antidotes. So, anytime an existing antidote’s use can be expanded to other indications, I think that is a win.

Methylene blue is one drug that has many uses. Most folks are aware of using methylene blue to treat methemoglobinemia. However, methylene blue can also be used to treat several conditions – most of which share one common underlying factor: vasoplegia.

What is vasoplegia?

Vasoplegia (a.k.a. vasoplegic syndrome) is essentially intractable hypotension. There are no uniform criteria for identifying this, but most references use the term to describe severe hypotension despite catecholamine therapy. Patients have decreased systemic vascular resistance and some papers report a mean arterial pressure < 50 and cardiac index of > 2.5 L/min x m² as diagnostic criteria.^​1,2​ Basically, they are super sick.

How does methylene blue treat vasoplegia?

Vasoplegia is mediated by the nitric oxide (NO) cascade. NO is upregulated during periods of stress by many factors. In the endothelium, NO formation is increased in response to bradykinin, acetylcholine, and histamine. Cytokines increase the formation of NO in vascular smooth muscle. Once NO is formed, soluble guanylate cyclase (sGC) interacts with NO to convert GTP to cGMP, ultimately leading to vasodilation (see Figure 1). By inhibiting sGC activity, methylene blue prevents cGMP-dependent smooth muscle relaxation and vasodilation, allowing vasoconstriction in response to circulating catecholamines to occur. It is important to point out that methylene blue itself is not a vasoconstrictor.

What’s the evidence?

There are several alternative uses of methylene blue described in the literature. This discussion is going to focus on methylene blue use in patients with vasoplegia from cardiopulmonary bypass surgery and sepsis, as well as use in treating anaphylaxis, dialysis induced hypotension, and, of course, toxicologic applications.

Cardiac bypass surgery

The strongest evidence for using methylene blue to treat vasoplegia comes from the surgical literature. In cardiac surgery patients requiring cardiopulmonary bypass (CPB) an estimated 5-25% of patients develop vasoplegia. If prolonged, vasoplegia is associated with complications and a mortality rate up to 25%.^​3​ Methylene blue improves hemodynamics^​1,4,5​, and several authors have reported decreased morbidity and mortality in patients with post CPB vasoplegia.^​6–8​ Some controversy exists, however, about whether methylene blue should be used early before the development of refractory shock or only as a rescue therapy.^​9–12​

Sepsis

Methylene blue has been investigated as a treatment for sepsis-related vasoplegia. Several observational studies^{​13–17​} and a few randomized controlled studies with a small number of participants in each study^​18,19​, support the use of methylene blue for sepsis-induced vasoplegia. Unsurprisingly, there are also many case reports describing the use of methylene blue in a variety of vasoplegic septic patients^​20,21​ including one pediatric case^​22​ and one patient who received a methylene blue infusion of 0.5 mg/kg/hour for 120 hours.^​23​ A small prospective study also found that septic patients receiving methylene blue for refractory hypotension had less renal tubular injury.^​24​ More research is definitely needed on this front.

Anaphylaxis

While not widely studied, it is estimated that 3-5% of all anaphylaxis cases are refractory to standard therapies.^​25​ Clinical effects of anaphylaxis and associated angioedema are triggered in part by histamine and platelet activating factor’s initiation of the nitric oxide cascade (see Figure 1). The use of methylene blue to reverse refractory anaphylaxis and anaphylaxis-related angioedema has been reported in several case reports/case series.^{​26–31​} In reported cases, a variety of agents are documented as causing refractory anaphylaxis including latex, contrast dye, bendamustine, protamine, menses, diapirone, and aprotinin. Most of the literature describes cases of intractable anaphylactic shock that are sometimes associated with angioedema. One case by Bauer, et al describes reversal of unrelenting anaphylaxis (e.g., wheezing, urticaria) without hypotension.^​25​ Supporting these cases is in vitro data demonstrating methylene blue reversal of histamine-induced vasodilation of human arteries.^​32​ Collectively, this literature led several authors to include methylene blue as a recommended treatment for refractory anaphylaxis.^​25,30​

Hemodialysis

Some patients with ESRD can develop significant hypotension while undergoing routine hemodialysis. While they aren’t technically vasoplegic (as in they don’t have catecholamine resistant hypotension), the hypotension they experience is thought to be primarily due to dialysis-induced NO production. In one study by Peer et al., patients prone to hypotension during dialysis were pre-treated with methylene blue. These patients developed fewer instances of intra- and post-dialytic hypotension.^​33​ Patients treated during dialysis with a continuous infusion also had fewer episodes of intradialytic hypotension. Those patients with hypotension during hemodialysis also had higher levels of nitric oxide production compared to those without intradialytic episodes of hypotension. Interestingly, methylene blue increased blood pressure in normotensive dialysis patients, but there was no change in normal healthy controls. Patients with intradialytic hypotension receiving methylene blue also had increases in both systolic and diastolic blood pressures.

What about toxicology patients?

While basic and clinical research supporting methylene blue in the treatment of vasoplegia from cardiopulmonary bypass, sepsis, anaphylaxis and dialysis is available, the literature supporting its use in overdose-related vasoplegia is limited to case reports. Several case reports outline successful use of methylene blue in patients with refractory shock following overdoses.^{​34–39​} In most of these cases, cardioactive drugs were involved and high dose insulin therapy was not always maximized, but the cases do demonstrate improved hemodynamics following/temporal relationship with methylene blue administration. There are also two published case reports of vasoplegia from metformin overdose describing successful treatment with methylene blue.^​40,41​

Ifosfamide

Ifosfamide-induced encephalopathy is one of those alternative toxicologic uses of methylene blue alluded to in the intro that doesn’t involve vasoplegia. Ifosfamide, an alkylating agent, is used to treat solid tumors. One of the most serious side effects of use is encephalopathy, the incidence of which is estimated to be 20-60%.^​42​ If a patient develops encephalopathy, treatment with ifosfamide is usually discontinued and patients with mild symptoms tend to recover in 48 hours. Methylene blue has been used successfully in several case reports and even in a small prospective trial to treat more serious episodes of ifosfamide encephalopathy.^{​43–45​} The mechanism by which ifosfamide causes encephalopathy is unknown, as is the mechanism by which methylene blue may work to treat/prevent the encephalopathy. For those that love mechanisms and theories, I give you Figure 2. Chloroacetylaldehyde, an ifosfamide metabolite, is thought to cause neurotoxicity directly as it has a structure similar to chloral hydrate. Additionally, it is theorized to inhibit complex I activity in the mitochondria, disrupting the NAD/NADH balance leading to an accumulation of chloroacetaldehyde because metabolism of this compound is dependent on NAD.^{​46–49​} Chloroacetylaldehyde is primarily formed by p450 enzymes but may be formed extra-hepatically by monoamine oxidases from chloroethylamine, another ifosfamide metabolite.^​50​ The chloroethylamine metabolite thialysine ketimine may also interfere with mitochondrial activity at the complex I site.^​48​ Methylene blue is hypothesized to restore mitochondrial function by oxidating NADH and preventing chloroacetylaldehyde formation by inhibiting monoamine oxidases.^​50​ Dosing varies in the cases reported of ifosfamide-induced encephalopathy with several authors recommending 50 mg IV x 6 doses/day and 4 doses/day at 50 mg/dose IV or orally for prophylaxis.^​44,51​ Thiamine supplementation (100 mg IV daily to every 4 hours) may also play a role with methylene blue in preventing ifosfamide-induced encephalopathy.^​51,52​ More research on this is needed.

When should I think about using methylene blue?

Let’s look at some toxicologic case scenarios where you might consider using methylene blue.

Case 1: A 60 yo female presents with severe salicylism. She was noted to be unresponsive and seizing prior to arrival. She is intubated and breathing over the vent at 35 breaths per minute. Her salicylate level is 113 mg/dL, her bicarb is undetectable, and her glucose is 120 g/dL. A post intubation chest x-ray demonstrated severe pulmonary edema and her EF is noted to be 20%. Nephrology agrees to dialyze her emergently. Unfortunately, prior to initiation of hemodialysis her blood pressure drops and despite quick administration of multiple vasopressors at escalating doses, her blood pressure continues to plummet to 40/20 mmHg every time dialysis is initiated.

In this case, you could make the argument that there is no alternative way to remove salicylate, and the patient needs hemodialysis. Starting methylene blue may be one option to help the vasopressors she is receiving work and improve her hemodynamics to the point she can tolerate hemodialysis.

Case 2: A 15 yo male was found huffing a can of keyboard cleaner by his mother. He startled when his mother opened the door and went into cardiac arrest. Standard ACLS protocols were followed and he had return of spontaneous circulation after two rounds of CPR. However, he is persistently hypotensive and every time a vasopressor is started, the patient develops ventricular tachycardia. When the vasopressor is stopped, the tachycardia resolves.

The patient in this case has huffing-related cardiac sensitization to catecholamines (see October 2018 Tox and Hound post “Dust to Dust” by Howard Greller). Finding an agent that can help improve his overall perfusion is needed. In this case, methylene blue may work to help stop existing vasodilation and as it isn’t a catecholamine, it shouldn’t be arrhythmogenic. 

Contraindications

There are two primary patient populations to be aware of when contemplating the use of methylene blue for one of these alternative indications – those with G6PD deficiency and those on concurrent serotonergic medications.

Methylene blue is an oxidizer and can cause hemolysis in patients with G6PD deficiency. (Dr. Steve Curry has an excellent discussion of the risks and benefits of methylene blue for treating methemoglobinemia in G6PD deficient patients in the comment section of his June 2018 Tox and Hound post, Methylene Blue Infusions). However, the severity of a patient’s G6PD deficiency varies depending on how it is expressed in each patient. I agree with Dr. Curry and avoid the use of methylene blue in patients with G6PD deficiency with one general exception – if the patient is critically ill with severe vasoplegia, and I have nothing left to offer to improve their hemodynamics, I would consider using methylene blue as a rescue agent. Hemolysis, if it occurs, is a legitimate concern, the effects of which can often be mitigated with a blood transfusion and supportive care. While admittedly there are no reports of G6PD-deficient patients with refractory shock treated with methylene blue, it’s worth a shot for the patient running out of options.

Another concern is the risk of serotonin syndrome from methylene blue. Methylene blue is a monoamine oxidase inhibitor. Cases of serotonin syndrome are described in the literature following administration of methylene blue in patients who are on other serotonergic medications. Many providers are aware of this potential interaction, are hypervigilant about the possibility of developing serotonin syndrome and quick to stop methylene blue administration. Symptoms are treated, and in the cases I reviewed where serotonin syndrome occurs after methylene blue has been used for vasoplegia, patients recovered. Yes, serotonin syndrome is fatal in some cases but usually those cases are when much higher doses of methylene blue are used in a patient using other serotonergic medications^​53​, or serotonin syndrome is not readily recognized and multiple serotonergic agents continue to be used. If a patient had vasoplegic syndrome and was on or even overdosed on an SSRI, I would readily consider using methylene blue as a rescue agent when other treatments had failed. I would be more cautious, however, if treating intractable anaphylaxis or anaphylaxis related angioedema in a normotensive patient on a significantly serotonergic medication, involving them in the decision-making process.

Bottom line, I agree with Dr. Curry that in certain situations, the risk of possibly causing one of these side effects may be outweighed by the risk of not perfusing vital organs or death.  

Methylene blue dosing

• No set dosing regimens for treating vasoplegia are available
• Most authors use 1-2 mg/kg IV bolus followed by an infusion of 0.5-2 mg/kg/hour; in some cases, only an IV infusion is used
• Single doses of > 3 mg/kg have been associated with hypotension and wheezing; this is per the package insert – limited data is available on this particular report, and it could reflect an actual allergic reaction to the methylene blue itself
• Most side effects are noted at doses > 7 mg/kg (cumulative dose)
• Severe hemolysis, hyperbilirubinemia, and death are reported with single doses of > 20 mg/kg
• See the package insert for more information

Pro tips

1. Methylene blue will cause a temporary, false lowering of pulse ox readings, especially when patients receive the bolus dose.
2. Regardless of how slow the infusion goes, patients report burning with infusion of methylene blue.
3. Hemodialysis circuits do not respond well to bolus dosing of methylene blue, but infusions have been used without significant issues.