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 more extensive studies, have a mortality rate between 25-35%. I have used methylene blue occasionally for post-CPB vasoplegia, but would it 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 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 failed to show its primary endpoint, SOFA/biomarker changes, but….. had a statistically significant decrease in mortality, and people scoffed that since it wasn’t the primary endpoint. The study I am posting today provided methylene blue to patients with severe sepsis and measured TNF-α, IL-1, IL-2 receptor, IL-6, and 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 were kept the same by giving these patients methylene blue. Would you happen to know what did change? The mean arterial pressure on these patients. Do you understand what makes patients survive? Requiring small vasopressor doses and having improved blood pressure. By no means does this small study mean I’m changing my practice, but I will at least 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 tiny RCT to use Methylene Blue as an adjunct to other vasopressors in patients with septic shock. I like this trial. That’s my first bias. It may have to do with the fact that it is excellent work and that I am quite a 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 functional, perhaps even better.
The ANDROMEDA SHOCK 2 trial is currently in the works. These teams do excellent 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, was quite sophisticated. I’ll get some more of that in a moment. Before I go further down this post, remember 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: The patient shows up with suspected sepsis, and they get blood cultures, antibiotics, and 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 vasopressor for most, and then at some point, clinicians add vasopressin so on and so forth. It’s much more complicated then, 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 into play.
To quote to paper, “methylene blue is a specific inhibitor or the inducible nitric oxide synthase” and “soluble guanylate cyclase.” This restores the behavior of the blood vessels when there’s too much nitric oxide around, hence causing a vasopressors-like effect. 2019 I covered two papers (listed above) published in 2001 and 2002. These showed possible benefits to methylene blue, but here we are in 2023 before the excitement finally comes 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 aware 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 diligently ensure 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 differs from what we typically use in the cardiothoracic ICU. 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 three doses/days. This was in addition to the everyday sepsis management. I always have to tip my hat to the authors, especially in this team, for how they assessed 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 must admit that I do not perform the latter two in my practice routinely. In other words, this was the best fluid resuscitation that a patient could receive per the current practice recommendations.
They were able to enroll a total of 91 patients in the study. There needs to be a sufficient quantity of patients to appropriately power several 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 vasopressors discontinued at a median of 94 hours.
The secondary outcome was the vasopressor-free days at 28 days. Here, methylene blue was also beneficial; the median was 23.9 vasopressors-free days versus 19.5 in the control group—a median difference of one day. Without looking at the other secondary outcomes, one can deduce that theta should ICU length of stay 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. There was a mean difference of approximately 750 mL between the two groups, which was statistically significant. There was no difference between days of mechanical ventilation and mortality, but a more appropriately powered study could be helpful as there were trends toward improvement in both categories.
It was clear cut, however, that there was an improvement in the ICU length of stay with the methylene blue group, a median of 1.5 days shorter, and 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 identifying these patients and starting them on the appropriate therapies very soon during their illness. In addition, they used the best we know today for fluid responsiveness. They were on top of all of these patients, whether in the methylene blue or control groups. 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. The APACHE score was higher here than the PROMISE trial, which had approximately 30% mortality. But still, these are the patients you and I are likely caring for. Is the best we could currently do a mortality hovering around 40%? Despite the best optimization we can do, Sepsis is still incredibly high. The methylene blue group had a 33% mortality at 28 days. This is better than the control group but is not statistically significant. More extensive studies are needed 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 essential to always read the paper for yourself instead of trusting what I say here.
Adverse Effects of Methylene Blue in Septic Shock
The adverse effects were familiar to those administering methylene blue and other clinical scenarios. 93% of patients had a green/blue discoloration of their urine. Numerous pictures on the Internet show this. It’s funny because if one were to do a blinded RCT on methylene blue, they would have to hide the urine not to 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.
Overall, 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 only some institutions have it in stock. At times, it is essential to reach within the therapeutics we already have in our institutions and seek new ways to use them to benefit our patients. More research on methylene blue is 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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