The concept of metabolic resuscitation has been around for several years. Unfortunately, the data for the utilization of 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 thereafter. There have been numerous limitations to those RCT’s, but everyone can agree that it’s not as beneficial to everyone as we would like. I’ve gone deeper into that topic HERE. In this post, I will be discussing using vitamin B12 in septic shock.
As I would always mention in posts, podcasts, and videos related to metabolic resuscitation, I really 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 all are from the United States. I’ll try to find the citations for you all but sepsis accounts for almost 20% of the world deaths. The rest of the world will not have the financial resources to be able to administer the next monoclonal antibody agent or whatever that will be the “next big thing” for sepsis. They’re going to benefit more from something more reasonable which is why 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 I guess 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 obviously the 5000mcg. Well, 5000mcg is 5mg. Here, patients were given 5gm. That’s whole lot more. Why did the authors choose to go with 5gm as their dose? Here I am going to have to speculate certain things. First, the aforementioned cyanokit is already 5gm. This is convenient as it is already prepared and can be purchased. No fancy compounding pharmacy needed. Second, There’s plenty of data out there for a lack of harm utilizing this dose, again, because of cyanokit. As a matter of fact, 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 on the study protocol on clinicaltrials.gov HERE.
Why Should Vitamin B12 Work for Septic Shock?
At this point we all have been beat over the head with the fact that 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 the pathophysiology of this 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 take a 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. Phase 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 definitely 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.
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 any type of significant endpoints. Right off the bat we can throw mortality, length of stay, and such out the door.
That being said, their primary outcome is not something useful for our clinical practice. It’s nerdy phase 2 study type stuff so that phase 3 is a successful study. I’ll spare you the details and some time in your life. 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 for 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 then 3 hours after.
With regards to the H2S level, there was a change that was statistically significant. Check plus. Regarding the norepinephrine dose, the authors also found a benefit here. The norepinephrine dose decreased in a statistically significant manner 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 but this was not statistically significant. I guess 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 also decreases 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 not as inexpensive we’d like IV vitamin B12 to be. At a grand a pop, it better do more than make our vasopressor requirements decrease faster. Sure, this may be a positive study (for a phase 2). People may think and get excited that this is the next big thing. I’d like to get excited, too. But the price really 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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