I don’t know about you all but I’m constantly working on finding new ways to treat my septic shock patients who, based on the numbers from larger studies, have a mortality rate between 25-35%. I have used methylene blue on various occasions for post-CPB vasoplegia but would it possibly work in septic shock? UPDATE: This page was initially created on 12/28/19. We now have SOME data. Last update 03/15/23.
Methylene Blue in Septic Shock Increases the BP
When the CITRIS-ALI study was published just a few months ago they used plasma biomarkers as a method to prove that ascorbic acid in this patient population worked. You know, the study where they gave Vitamin C to patients with acute lung injury and it failed to show its primary endpoint which was SOFA/biomarker changes but….. had a statistically significant decrease in mortality and people scoffed that that since it wasn’t the primary endpoint. The study that I am posting today provided methylene blue to patients with severe sepsis and measured TNF-α, IL-1, IL-2 receptor, IL-6, IL-8. As I typed this I realized that I am such a nerd. It’s a Sunday and I’m typing about interleukins. I digress.
Those endpoints weren’t changed by giving these patients methylene blue. You know what did change? The mean arterial pressure on these patients. You know what makes patients survive? Requiring small vasopressor doses and having an improved blood pressure. By no means does this small study mean I’m changing my practice, but I am at least going to think outside the box a little more often in my refractory shock patients who absolutely cannot die on me.
Also, I am working on a comprehensive vasopressor post HERE.
Methylene Blue in A Small Sepsis RCT
Today, I’m going to be discussing an article that was published in the March issue of Critical Care. March 13th to be exact. It is titled “Early adjunctive, methylene blue in patients with septic shock: a randomized controlled trial. Ibarra-Estrada and some other legends in the field put together a small RCT looking at using Methylene Blue as an adjunct to other vasopressors in patients with septic shock. I really like this trial. That’s my first bias. It may have to do with the fact that it is great work but also with the fact that I am quite the fan of Glenn Hernandez. He is an intensivist that has put out fantastic publications in the past.
Amongst those is the ANDROMEDA SHOCK trial which looked at capillary refill time versus lactate in patients with septic shock. I have covered the ANDROMEDA SHOCK trial on my lactic acidosis post in the past. I’ll leave a link to that in the show notes. This was one of my favorite trials, as not only did they show that you did not necessarily need to use lactate to assess resuscitation in your patient but also that capillary refill testing is quite useful, perhaps even better.
The ANDROMEDA SHOCK 2 trial is currently in the works. To be quite frank, these teams do really good work. The way that they assessed fluid responsiveness in patients who were enrolled in the ANDROMEDA SHOCK trial, but also in this particular methylene blue trial were quite sophisticated. I’ll get some more of that in a moment. Before I go further down this post, keep in mind that this is not medical advice and I recommend you read this article for yourself before you trust me.
Here is how the typical sepsis management goes: Patient shows up with suspected sepsis, they get blood cultures, antibiotics, fluids. If the fluids do not get the job done at restoring perfusion, then the patients get vasopressors. We all know the drill, norepinephrine is the first line vasopressors for most and then at some point clinicians add vasopressin so on and so forth. Obviously it’s much more complicated that than but that’s beyond the scope of this post.
Methylene Blue Mechanism for Sepsis
But what if there is something that we already have in our toolbox that we can use to benefit these patients? Something we already know that works for another type of distributive shock known as post-op vasoplegia? After all, mechanistically speaking, both post-op vasoplegia and sepsis have a significant component of abnormalities within nitric oxide metabolism. This is where methylene blue comes out to play.
To quote to paper “methylene blue is a specific inhibitor or the inducible nitric oxide synthase” and “soluble guanylate cyclase”. What this does is restore the behavior of the blood vessels when there’s too much nitric oxide around hence causing a vasopressors-like effect. In 2019 I covered two papers (listed above) that were published in 2001 and 2002. These showed possible benefits to methylene blue but here we are in 2023 before the excitement finally is coming back.
Exploring the Paper
Let’s get started on reviewing what took place during this clinical trial. This is an investigator initiated, parallel, double blinded, randomized controlled trial. It was performed at an academic institution in Mexico. The particular unit was a MedSurg ICU. By definition, the patients had to be in septic shock. They also had to be enrolled in the trial within 24 hours of presentation. One of the things that one has to be very very cognizant of when even thinking about administering methylene blue to a patient is their home meds. You see, methylene blue interacts with SSRIs and causes serotonin syndrome. When we provide methylene blue in the Cardiothoracic ICU, we are very diligent about ensuring that the patient is not on these types of medications. There are other interactions listed in the exclusion criteria of the paper that they avoided as well.
Dosing of Methylene Blue in Sepsis/Septic Shock
The dosing of methylene blue in this population is different than what we typically use in the cardiothoracic ICU. The reason for this is because post operative vasoplegia typically resolves in less time than septic shock. Usually within 6 hours. Here, they used an infusion of 100 mg of methylene blue over six hours, once a day for a total of three doses/days. This was in addition to the normal sepsis management. I always have to tip my hat to the authors, especially in this team, for how they assessed for fluid responsiveness. They performed frequent echocardiogram’s on these patients, pulse pressure, variation, tidal volume challenges, and respiratory variation of carotid peak-flow velocity. I have to admit that I do not perform the latter two of those in my practice routinely. In other words, this was the best fluid resuscitation that a patient can receive per the current practice recommendations.
They were able to enroll a total of 91 patients in the study. This is not a sufficient quantity of patients in order to appropriately power a number of outcomes such as mortality, which is why the authors recommend performing a larger RCT sooner rather than later.
Let’s take a look at the outcomes.
Their primary outcome was the time to vasopressor discontinuation in hours. This outcome ended up being statistically significant. The methylene blue group had vasopressors discontinued at a median of 69 hours. The control group, however, had a discontinued at a median of 94 hours.
The secondary outcome was the vasopressor free days at 28 days. Here, the methylene blue was also beneficial where the median was 23.9 vasopressors-free days versus 19.5 in the control group. A median difference of one day. Right off the bat, without continuing looking at the other secondary all comes one can deduce that the ICU length of stay should to be shorter in the methylene blue group.
As the patients got out of shock earlier, one would hope that the cumulative fluid balance would be less in the methylene blue group. This ended up being true. Turns out that there was a mean difference of approximately 750 mL between the two groups which ended up being statistically significant. There was no difference when it comes to days on mechanical ventilation, nor mortality but this is where a more appropriately powered study could be helpful as there were trends towards improvement in both of these categories.
It was pretty clear cut, however, that there was an improvement in the ICU length of stay with the methylene blue group, being a median of 1.5 days shorter as well as hospital length of stay where the methylene blue group was discharged a median of 2.7 days sooner.
I need to get back to the mortality outcome, however. These clinicians did a phenomenal job of identifying these patients and starting them on the appropriate therapies very soon in the course of their illness. In addition, the used the best that we know of today for fluid responsiveness. It seems like they were on top of every one of these patients, whether it be in the methylene blue group or in the control group. What’s disappointing here is that the mortality in the control group was 46%.
This mortality is higher than what we’ve seen in other septic shock trials such as the PROMISE, PROCESS, and ARISE trials. To be fair, the APACHE score was higher here than the PROMISE trial which had approximately 30% mortality. But still, these are the patients that you and I are likely taking care of. Is the best we could currently do a mortality that’s hovering around 40%? Sepsis mortality, despite the best optimization we can do is still incredibly high. The methylene blue group had a 33% mortality at 28 days. This is better than the control group but this is not statistically significant. This is why larger studies need to take place because the study is not powered for a mortality benefit.
Limitations
There are numerous limitations to the study, which the authors freely admit. This is why it’s important to always read the paper for yourself, as opposed to trusting what I actually say here.
Adverse Effects of Methylene Blue in Septic Shock
The adverse effects were things that are common to those of us who are used to administering methylene, blue and other clinical scenarios. 93% of patients had a green/blue discoloration of their urine. There are numerous pictures on the Internet which show this. It’s funny because if one were to do a blinded or CT on methylene blue, they would have to hide the urine to not know who is in which group. There was also an expected difference in methemoglobin saturation between the two groups. This did not cause any clinical effects. There was also no change in the ejection fraction, PF ratio, renal function, and LFTs.
Wrapping it up.
All in all, I commend these authors for exploring a relatively inexpensive therapy to treat patients with septic shock. There is a lot of research going on with therapeutics, such as angiotensin II, which, to be honest, is extremely expensive, so not every institution has it in stock. At times, it is important to reach within the therapeutics that we already have our institutions, and potentially seek new ways to use them in order to benefit our patients. More research on methylene blue is definitely necessary, but this is a fantastic step in the right direction.
Citations Regarding Methylene Blue in Sepsis & Septic Shock
Kirov MY, Evgenov OV, Evgenov NV, Egorina EM, Sovershaev MA, Sveinbjørnsson B, Nedashkovsky EV, Bjertnaes LJ. Infusion of methylene blue in human septic shock: a pilot, randomized, controlled study. Crit Care Med. 2001 Oct;29(10):1860-7. doi: 10.1097/00003246-200110000-00002. PMID: 11588440.
Link to Abstract
Memis D, Karamanlioglu B, Yuksel M, Gemlik I, Pamukcu Z. The influence of methylene blue infusion on cytokine levels during severe sepsis. Anaesth Intensive Care. 2002 Dec;30(6):755-62. doi: 10.1177/0310057X0203000606. PMID: 12500513.
Link to Article
Link to FULL FREE PDF
Ibarra-Estrada M, Kattan E, Aguilera-González P, Sandoval-Plascencia L, Rico-Jauregui U, Gómez-Partida CA, Ortiz-Macías IX, López-Pulgarín JA, Chávez-Peña Q, Mijangos-Méndez JC, Aguirre-Avalos G, Hernández G. Early adjunctive methylene blue in patients with septic shock: a randomized controlled trial. Crit Care. 2023 Mar 13;27(1):110. doi: 10.1186/s13054-023-04397-7. PMID: 36915146; PMCID: PMC10010212.
Link to Article
Link to FULL FREE PDF
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