Hey everybody.

Welcome back to Palm peeps.

We are gonna be doing a Palm peeps pearls episode today.

We're very excited about this segment.

For those of you haven't heard these episodes before, this is more just a short form casual episode between Monte and I to talk about a topic in pulmonary and critical care.

Go over some of the highlights, wet your beak a little bit, give you some resources to read.

Today, we're gonna be talking about methylene blue and septic shock.

This has been around for more than a century, but stirs a lot of debate and there's more recent data and more recent usage.

So we wanted to dive into it a little bit.

I should say that this episode, these episodes require a decent amount of research, and this one was helped by a resident at UT Southwestern George Dumont.

George has been on an episode of Palm Heath before one of our BMJ Thorax journal clubs.

And so we thank him for his hard work with this.

Before we dive in, Monty, you're just getting back from chest.

Are you all recovered?

How was it?

Fur first of all, I missed you.

I missed my other half being there, but we did have the other pump peeps crew there with Luke, Tom, and Roopali, so that was great to see them.

It was great to actually meet George in person.

Right?

We had just done our BMJ thorax recording, which is all done virtually.

So it was great to see him in person and just catch up with a lot of trainees and peers and PCCM.

You always come back reenergized from those type of conferences.

I did say first though, you were reenergizing in your own way in Italy, but I said we were taking notes on who has the best pizza, whether it was the Deep Dish Chicago or the Yeah.

Italian pizza you were having every day.

Yeah.

100%.

They it's funny you just come back recharged.

I'm always both recharged and totally depleted after a conference like that.

Like, I love it, but I spend so much time talking to everybody.

I also need to hibernate for a little bit.

Actually, I was in London.

That's my I was gonna say you can correct it.

So London, you probably had better pizza than I had in London.

I'll say that for sure.

But we had a lot of fun.

It was a very good trip.

Alright.

Without further ado, this is supposed to be short form.

Let's talk about methylene blue.

This has been used for septic shock.

It's a topic that's coming up more recently, so we wanted to dive into it a little bit.

Absolutely first.

And we're all in the ICU.

Septic shock always is a high stakes environment.

You wanna do as best as you can, as fast as you can.

But I think, inevitably, if someone's not responding as quick as you want to, someone on the team, resident, fellow, APP, pharmacist may say, what about methylene blue?

So our purpose today is to talk about that.

When do we actually reach for it, and what does the current evidence say?

Absolutely.

We have done some episodes on sepsis before.

This is not a sepsis episode.

But sepsis in one minute, just so we have the background for this, we know sepsis is a subject shock as a condition of persistent hypotension, hypoperfusion, decreased oxygen delivery to the cells compared to their oxygen demand.

The surviving sepsis campaign would say that you need vasopressors to maintain a map above 65 after adequate fluid resuscitation and an elevated lactate representing that those cells are not getting adequate oxygenation.

And I in teaching it would just say an imbalance of O two delivery versus O two usage or demand of the cells.

So that's our sort of septic, our bread and butter that we're seeing in the ICU.

Exactly right for freight.

And I think we're all very, comfortable with our very standard approaching broad spectrum antibiotics, aggressive fluid resuscitation at thirty cc's per kilogram, and reaching for our first mainstay of a suppressor, which is norepinephrine or Levothyroid.

Current guidelines say if we're on norepinephrine and patients' match are not rated in 65, our second agent that we may pull out is vasopressin.

But once we start thinking about norepinephrine and vasopressin and think about adding a potential third vasopressor, some cases fourth, that there's a mixed component.

Are we really into that refractory territory?

And at this time, someone may say, what about methylene blue?

It's not even in the standard bundles for vasopressors at most institutions, but but what do we do about it?

And when do we try to use it?

Yeah, absolutely.

So this is usually this patient who's on two, three, four pressors.

I usually think about this for the patient who's clearly in a vaso distributive process, like very much septic, high temperature.

You have some suspicion of a bad infection going on.

Certainly, we often see mixed shock in the ICU.

But I I think really when you're getting that third, fourth presser, obviously there's some cardiac dysfunction, but we're really focusing on this vasodistributive septic patient.

And here's where often methylene blue will be floated.

So methylene blue for the background is a nitric oxide, cyclic GMP antagonist.

People will say casually that it's a free radical oxygen scavenger, like that you have oxygen free radicals and it's helping scavenge them.

That's not quite exactly right, but it by working on this nitric oxide and cyclic GMP pathway, we are removing excess nitric oxide, which we know happens during vasoplegic sepsis and profound vasodistributive shock.

So by decreasing that, we think we can help reverse some of that profound vasodilation.

Perfect.

Your point was taken.

Right?

This is really someone who you're thinking of vaso vasodilort sorry.

Vasodilation component.

So as you said, methylene blue inhibits inducible nitric oxide synthase and guanylate cyclase, but really it's supposed to help blunt that vasodilation and help restore vascular tone.

So some may say in theory, it makes the vasculature more responsive to catecholamines.

Yeah, absolutely.

And honestly, the first time I ever encountered it and often when it's used more routinely is in patients who are in that more vasoplegic coming out of the OR state.

So there are some of these patients who come out of the OR often after maybe a cardiovascular surgery or cardiovascular bypass, especially if they were on some medications going into a procedure.

Famously, ACE inhibitors are thought about for this.

And they just can't maintain time.

It looks like you have resumption of your cardiac function, but you have this vasoplegic state.

And this is where methylene blue, maybe not was first used, but maybe more commonly was coming up in the hospital.

Now, I think in the last for many years, but more with a resurgence in the last five, ten years for refractory vasoplegic shock, people are thinking about methylene blue in the ICU.

So I think most of us in the pulmonary critical care really only consider this in catecholamine refractory vasoplegic shock.

So this is really the patient's max dose leave of fed already on vasopressin at max dose.

Obviously in the ICU, we use it more as a hormone replacement and not a titratable drip, but they're still hypotensive.

And I would say even more to the point, I don't think people are ever thinking about methylene blue in sepsis in the ICU currently until people are really on a third breast or the, whether that be phenylephrine or angiotensin two sort of being the most common ones that we might add.

Exactly right.

For afraid that the purpose today is not to not and we hope you don't think that we are saying methylene blues in the current guidelines.

It's not, but we just we wanna talk about it, understand the mechanism of action, really understand what are some clinical outcomes, and talk about the evidence so that we could potentially use it as an extra tool off our tool belt in these refractory cases.

The mechanism makes sense.

Small study suggests methylene blue can improve map and help wean off pressers, but really how convincing is the evidence for?

Yeah.

Yeah.

Let's we should dive into the evidence a bit.

And but to your point, Monty, I think we have to think about it at the bedside too.

So that's why we're talking about this now.

I always say with the residents and the fellows, medicine is a three pillared science and approach.

We have the physiology.

We like to understand how things work.

We have the empiricism.

That's the evidence.

If someone comes with a good idea and proves it in a rigorous way, we're going to use that because we know it benefits patients.

And then we have the, what do you do at the bedside at 2AM when someone is in front of you and they're just not doing well.

And it's not always that easy to run to a specific portion of evidence or to think through in detail, the physiology, you have to have some sense of the physiology, but without being able to act right then and be able to do something in the ICU to save that patient.

So we're trying to unite the three of those in thinking about methylene boot for these patients.

So multiple recent meta analyses and systematic reviews have tried to do this to say, we've studied this a bunch in small environments.

How can we look at methylene blue as an adjunctive therapy for septic shock?

And they've tried to look at outcomes like math, the duration of total vasopressors, some mortality, and some impact on some other organ systems that we care about in the ICU, like p to f ratio.

Yeah.

Perfect.

And I think, as you said, some more recent meta analysis, even in 2025, some that were done in 2024.

So I think most of the the studies are small, single center, and there's a lot of heterogeneity and inadequate number of studies with low levels of evidence.

But what we do know from the meta analysis, and there's some systematic reviews as well, some quick hits on what you just mentioned.

Methylene blue can increase MAT by about one to 10 millimeter sorry.

One to 10 millimeters of mercury.

Some have found that it can shorten total vasopressor duration up to roughly thirty one hours.

This is just from one meta analysis study.

As you mentioned, Bert, right, not thinking about it, but this p to f ratio, there's been a small bump in p to f ratio.

And then two things that we're looking at, two primary outcomes that we should be looking at in large studies.

What about hospital stay, and what about mortality?

So possibly a reduction in hospital stay up to two days.

And some pool data has looked at methylene blue potentially causing lower short lower short term mortality.

But, again, the caveat that these studies, there are a lot of heterogeneity, inadequate number of studies.

So I think all of these studies are gonna end where we are we are when there was, like, some signaling there, but we need further large multicenter RCTs to really have great evidence for us to continue to work with.

Yeah.

Absolutely.

Thank you for reviewing through that.

I think that the signal is, maybe not clear, but reproducible and multiple of these that there does seem to be some improvement in map and a signal towards some improvement in the outcomes that we care about in the ICU.

Although not all of them, not like to say your ventilator day is obviously mortality and duration of vasopressors is important to us.

So if we're going to use a therapy, we're not a 100% sure about the efficacy.

The other side of that is always the safety.

So safety is something that people get nervous about in the SEO, especially if there's a medication you haven't used before and you're already with a sick patient.

So for methylene blue, let's talk about some of the common side effects.

So I'll say we usually do just for dosing.

So people know one to three mg per kg, IB bolus, and then.

Often you're assessing the response based on that bolus.

So you're giving it once seeing if it worked.

And then if it working well, you can either repeat the bolus or start a methylene blue infusion.

My process is usually to do a bolus assess dynamic dynamic metrics of perfusion and a map.

And then see if I think it worked, then I will go for a methylene blue infusion.

Monty, what are some of the side effects that you're looking out for?

Yeah.

So I read it in exact what you were saying.

That was like a really good learning point.

Right?

Because when we get other standard vasopressors, we're not doing boluses of them.

Right?

We're starting the drips.

Our colleagues are titrating them up or down.

So this is unique in that sense too, but I like how you approach it bolus.

Is it working?

Is it not working?

And then reassess whether or not you start a continuous infusion.

But to answer your question for some serious adverse events, even though they're rare, we need to be on the lookout for hemoglobinemia, serotonin syndrome if patients are on SSRIs, and the classic pulse ox artifacts that we can see.

And, Farf, I think someone's gonna ask, what does it change the color of the urine?

Have you seen that?

Yeah.

A 100%.

You're gonna know this happens.

I feel like you can do your little ICU quiz of regular urine, bloody urine, green urine from popafol, and blue urine from methylene blue.

Nothing to be worried about.

I do think it's always interesting that methylene blue is both a cause of, and a cure for methemoglobin anemia.

Just that really interesting physiology that we can dump dive into on another episode.

But yeah, these are the things we worry about.

I don't worry about them too much.

Like the serotonin syndrome has come up for me mostly because I'm only considering it in these ultra sick patients.

Right.

So if somebody is on an SSRI at home, I am a little less worried about the theoretical side effect of serotonin syndrome.

If they're in four press or multi organ system failure, refractory shock.

And so I'll usually still go ahead and use it.

Okay.

We've talked about methylene boot a lot.

We've talked about the potential efficacy, a little squidgy there, some of the safety.

So let's talk about guidelines because we should follow what our societies say and what we think the best integration of the evidence is.

And I wanna be a 100% clear that the surviving sepsis campaign of 2021 does not recommend methylene blue be used routinely for septic shock.

So it's important for us to keep that in mind.

This is not currently within the guidelines for managing patients with sepsis.

That's right.

For no other major critical care societies include methylene blue in any standard protocols.

But as we said, a potential, tool from our tool belt that we can think about for the right patient in the right context.

But we're really concerned about refractory shock, vasodilatory, and even with then it's somewhat of a caveat of with multidisciplinary discussions amongst all team members.

Absolutely.

So to sum it up, methylene blue is mechanistically rational for patients with refractory vasoplegic septic shock, and you're acting on that nitric oxide pathway to decrease vasodilation.

It can raise MAP and reduce other vasopressor requirements.

This seems to be the most consistent effect in some of the studies that we have talked about.

Effects on mortality and major outcomes are variable, remain very low certainty at best, possibly some positive impact.

Generally, we think this is safe.

You should be talking with your ICU pharmacist when you're giving it, and you should be monitoring for some of the major side effects that we talked about.

And this is firmly a rescue therapy that is not part of standard sepsis management.

Absolutely, Ferf.

And we should be under our fifteen minutes of methylene blue today, but I think just a good reminder, reminding us kinda why this may work in certain patients.

Obviously, though, we will need better data before this earns or if it deserves to earn a place in guideline driven care, but had fun talking with you about this today, Fer.

Yes.

Absolutely.

You too.

This episode was written, edited, and produced by myself, Montemayor, and George Dumont.

Thank you all for listening and tune tune back in two weeks for our next episode.