The concept of metabolic resuscitation has been around for several years. Unfortunately, the data for using ascorbic acid, thiamine, and glucocorticoids has not been as robust as we would like. There have been challenges replicating the miraculous data seen in the first trial in every subsequent trial performed after that. There have been numerous limitations to those RCTs, but everyone can agree that they could be more beneficial to everyone. I’ve gone deeper into that topic HERE. In this post, I will discuss using vitamin B12 in septic shock.
As I always mentioned in posts, podcasts, and videos about metabolic resuscitation, I want these therapies to work. After all, using cheap and readily available products such as vitamin C, thiamine, glucocorticoids, and now vitamin b12 in septic shock should be something we are all rooting for. The demographics of those who read the content I create show that 85% of you are from the United States. I’ll try to find the citations for you all, but sepsis accounts for almost 20% of deaths worldwide. The rest of the world will not have the financial resources to administer the next monoclonal antibody agent or the “next big thing” for sepsis. They’re going to benefit more from something more reasonable, so I am happy researchers are still experimenting with things we have on the shelf.
Cyanokit is an IV high-dose vitamin B12 formulation that has been on the market for several years. The purpose of this therapy is for the treatment of cyanide poisoning. There have been several case reports since then of people using this B12 formulation for septic shock here and there. In addition, there is data for its use in patients with severe vasoplegia after cardiac surgery, which I briefly discussed several years ago in THIS POST. I’ve spoken to colleagues who have this therapy available for their patients, and the main comment I’ve heard is how expensive it is. So that cheap and readily available does not apply here.
What is the Vitamin B12 Dose used in Septic Shock?
The authors provided the patients with 5gm of IV vitamin B12. For context, the over-the-counter variants of vitamin B12 come in 5000, 1000, and 500mcg. Of these, the largest is the 5000mcg. Well, 5000mcg is 5mg. Here, patients were given 5gm. That’s a whole lot more. Why did the authors choose to go with 5gm as their dose? Here I am going to have to speculate on certain things. First, the cyanokit above is already 5gm. This is convenient as it is already prepared and can be purchased. No fancy compounding pharmacy is needed. Second, There’s plenty of data out there for lack of harm utilizing this dose because of cyanokit. If you type in cyanokit into the search bar for the paper, it is not mentioned once. Digging in a bit deeper, Cyanokit is mentioned in the study protocol on clinicaltrials.gov HERE.
Why Should Vitamin B12 Work for Septic Shock?
At this point, we all have been beaten over the head because septic shock is a distributive type of shock. This means that the patients vasodilate. If we look at the basic hemodynamics equation that I repetitively teach people is that MAP = CO x SVR. SVR stands for systemic vascular resistance. In septic shock, the problem is that the SVR hits the ground. They vasodilate too much.
Patel et al. cite several articles discussing this pathophysiology, but the bottom line is that too much nitric oxide (NO) and hydrogen sulfide (H2S) are produced. These create the vasodilation/drop in SVR that we see in our patients with septic shock. What vitamin B12 SHOULD do in patients with septic shock is that it “scavenges and prevents NO and H2S formation and has the potential to recuse capillary leak, to promote capillary membrane stabilization, and to accentuate recovery. All sounds mighty good to me! The reason why they created a study was to evaluate this theory.
The Intravenous Hydroxocobalamin in Septic Shock Trial
Understanding Clinical Trial Phases
Now that we have those foundations set let’s dive into the article. First of all, this is a phase 2 study. To make it easier to understand the phases, phase 1 is to see if the possible treatment will cause harm. Phase 2 is to see if the treatment has the desired effect. Phases 1 and 2 are usually with very small groups. The third phase is where they compare the treatment to the current standard of care. Stage 4 is where they look at the long-term benefits and side effects. Phase 2 studies are not designed to be revolutionary. They’re not powered for such.
So getting back to the type of study that this is, and it’s a mouthful, it is a phase 2 single-center, double-blind, allocation-concealed, placebo-controlled, parallel-group pilot randomized controlled trial. Say that five times fast. I’ll save you the endless Google searches as to what all that means, but this is the correct way to do this trial—great job by the authors.
Patient Selection
These patients were in septic shock. Fluids, cultures, antibiotics, and vasopressors were already on board. They were enrolled and received the study drug vs. placebo within 24 hours of admission. They enrolled a total of 20 patients. Remember, this is a phase 2 pilot study. This acknowledges that they weren’t trying to recruit a ton of patients. Also, being academically honest, 20 patients isn’t enough to power significant endpoints. Right off the bat, we can throw mortality, length of stay, and such out the door.
Outcomes
That said, their primary outcome could be more helpful for our clinical practice. It’s nerdy phase 2 study-type stuff, so phase 3 is successful. I’ll spare you the details and some time in your life. I just wanted to let you know that you’re welcome. The secondary outcome is where we find if the treatment has the desired effect. You know, the part that makes this a phase 2 trial. Here, they measured a change in the monobromobimane-reactive H2S (hydrogen sulfide) levels. I’d like to see the look on the faces of the lab personnel should I call to see if this is available at my shop. They checked that level before infusion and 30 minutes after infusion. In addition, they noted the norepinephrine dose at randomization, 1 minute before the B12 was given, 30 minutes after, and 3 hours later.
Concerning the H2S level, there was a statistically significant change. Check plus. Regarding the norepinephrine dose, the authors also found a benefit here. The norepinephrine dose decreased statistically significantly from 1 minute before the start of the infusion up to 30 minutes after the infusion. There was also a decrease from the 30-minute mark up to 3 hours, which was not statistically significant. We can call this a catecholamine-sparing agent.
There were no differences in the tertiary outcomes, which included mortality, length of stay, etc. I mentioned earlier that this is expected in a phase 2 trial. Thankfully, no adverse effects were noted.
Where do we go from here? When can we use this in clinical practice?
This paper proved that using IV Vitamin B12 in septic shock decreases the H2S levels and catecholamine utilization. Here’s the catch, though. The price of cyanokit is $985 per dose per the average wholesale price listed on UpToDate.com on 02/28/23. This is more expensive than we’d like IV vitamin B12 to be. At a grand a pop, it better do more than decrease our vasopressor requirements faster. This may be a positive study (for phase 2). People may think and get excited that this is the next big thing. I want to get excited, too. But the price needs to come down, and the phase 3 trial hopefully is a game changer. Our patients need it.
Citations for Vitamin B12 in Septic Shock
Patel JJ, Willoughby R, Peterson J, Carver T, Zelten J, Markiewicz A, Spiegelhoff K, Hipp LA, Canales B, Szabo A, Heyland DK, Stoppe C, Zielonka J, Freed JK. High-Dose IV Hydroxocobalamin (Vitamin B12) in Septic Shock: A Double-Blind, Allocation-Concealed, Placebo-Controlled Single-Center Pilot Randomized Controlled Trial (The Intravenous Hydroxocobalamin in Septic Shock Trial). Chest. 2023 Feb;163(2):303-312. doi: 10.1016/j.chest.2022.09.021. Epub 2022 Sep 26. PMID: 36174744.
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