111. Pulm PEEPs Pearls: Methylene Blue

Furf and Monty are back today with another Pulm PEEPs Pearls episode, and discussing the use of methylene blue for patients with septic shock. They review the clinical scenarios when this comes up, the mechanism, some key data, and some … Continue reading →

Episode Transcript

(00:16):
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

(00:36):
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

(00:58):
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

(01:19):
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

(01:39):
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

(02:00):
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.

(02:21):
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

(02:41):
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,

(03:03):
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

(03:24):
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

(03:46):
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.

(04:08):
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

(04:29):
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.

(04:50):
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,

(05:13):
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

(05:33):
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.

(05:53):
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

(06:16):
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

(06:36):
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

(06:58):
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.

(07:22):
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.

(07:43):
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

(08:04):
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

(08:24):
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.

(08:45):
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

(09:06):
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

(09:27):
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

(09:48):
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

(10:09):
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

(10:31):
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,

(10:51):
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

(11:13):
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

(11:34):
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

(11:54):
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

(12:15):
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

(12:35):
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

(12:55):
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

(13:15):
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

(13:35):
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,

(13:58):
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,

(14:21):
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.

(14:42):
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

(15:02):
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

(15:24):
tune back in two weeks for our next
episode.