IV Vitamin C in Sepsis: It Should Help Decrease Vasopressor Doses and Duration

The VITAMINS trial didn’t pan out was not a positive study as it was conducted. I’ve already provided my take on that with my main argument being that they took too long to initiate the study drug (median time >25 hours, not including the time to arrive in the ICU). Sepsis management is expedient, you and I see it every day. Waiting over a day is not being expedient.

I’m seeing a benefit in my clinical practice, as admittedly worthless as my opinion is on the grand scheme of evidence. But when something doesn’t make sense from a results standpoint, you need to go back to the basics and wonder what happened.

Here are some things we absolutely know: 88% of patients in septic shock have hypovitaminosis C and 38% of septic shock patients have severe vitamin C deficiency. What many of you may not know, and I’m here to help you understand why I’m so surprised by the findings of the VITAMINS trial, is that vitamin c is a co-factor to the creation of endogenous catecholamines. That means that without vitamin c, your body isn’t going to produce the appropriate amounts of dopamine, norepinephrine, and epinephrine. It also is necessary for the production of vasopressin. It’s as simple as that. 38% of people will not produce appropriate endogenous catecholamines. The fact that administering exogenous vitamin c did not decrease time that the patients were receiving vasopressors in the study makes me wonder why. I am aware that there was a delay of >24 hours to start the therapies in the study but is there more I'm missing. Hopefully you can take some basic biochem away from this post as to why it should work (although it didn't in the study).

A 🎩 tip to the authors.

-EJ




Link to Article

Link to FULL FREE PDF

Carr, A.C.; Shaw, G.M.; Fowler, A.A.; Natarajan, R. Ascorbate-dependent vasopressor synthesis: A rationale for vitamin C administration in severe sepsis and septic shock? Crit. Care 2015, 19, e418.

Although great care has been taken to ensure that the information in this post is accurate, eddyjoemd, LLC shall not be held responsible or in any way liable for the continued accuracy of the information, or for any errors, omissions or inaccuracies, or for any consequences arising therefrom.

VITAMINS Trial: Timing was overlooked

You all know my bias. It shouldn't be a surprise given my body of work: I wanted this to be a positive study. I wanted patients to benefit from this therapy and SURVIVE. I cannot understand the vitriol I have received in my direct messages when I shared my initial take on the study. I’m prepared to deal with more. Bring it!

Ultimately, there's no difference in the the endpoints, whether primary or secondary. No need to go through them in depth. That’s what the data says, that’s what the study concluded. Hat tip to the authors. It is what it is. I can agree with their conclusions based on the study conducted. But clinicians should not take the study as the end of HAT therapy. It would be scientifically irresponsible to do so. The study had a fatal flaw that doomed it from the beginning. Let me explain why. I practice real world medicine. I am not a trialist. I do the best I can every day with what I have.

Here's a take on how I care for septic shock patients for some perspective. There are plenty of nurses and physicians who work with me currently and have worked with me in the past following along on IG who can vouch for my style of practicing medicine.

This is NOT MEDICAL ADVICE. Do not do what I do because I say so. This post is not all 100% all inclusive for every nuisance. Every pt is different. That is your disclaimer.

1. I get a call from a colleague: ED physician, hospitalist, or surgeon regarding a patient who is in septic shock. At this point they have already gotten antibiotics and fluids bc everyone is excellent at this.
2. I go see the patient IMMEDIATELY
3. I assess, as quickly as possible with my limited tools a guesstimate on their fluid status
4. I start vasopressors EARLY while fluid resuscitating
5. pt arrives in the ICU, central line placed, arterial line placed, EV1000 hooked up.
6. I camp out at the nurses station next to the patient with them in my line of sight.
7. I watch how the patient behaves to my interventions, how the vasopressors go up, if they go up
8. As the vasopressor requirement increases, says NE around 10mcg, I start feeling uneasy. Especially how quickly their requirement increases.
9. I pull the trigger after 10-15mcg of NE to start vasopressin, hydrocortisone 50mg IV q6h, vitamin C 1500mg IV q6h and thiamine 200mg IV q12hours. I hit click, click, click, click, on an order set I created for myself on my EMR.
10. I keep on monitoring the patient closely to assess their response and provide additional fluids and learn more about their physiology.
Thing I do on the side: airway, bedside echo, talk to family and patient, management of other sick patients happen in this time period as needed. This post is not all-inclusive.

Needless to say, all of this happens WITHIN 6 HOURS. One has a general idea, within 6 hours of the patient being in septic shock, a pathology that has a 25-40% mortality rate depending on the study, what is the likelihood of the patient turning the corner.

What can we all agree on regarding management for sepsis: early antibiotics make a difference. Early source control makes a difference. Early fluids are better than late fluids. Early vasopressor administration is showing to be better than late (data for that coming soon).

Here’s my main problem with the study:
- Time for patients to get randomized: I CAN'T FIND THIS DATA
- Time from ICU admission to randomization: 13.7 hours (IQR 7.1-19.3 hrs).
- Median time for patients to receive study study from randomization: 12.1 hours (IQR, 5.7-19 hours).
13.7 + 12.1 = 25.8 hours PLUS time for patients to get randomized!
For those who don't know what IQR means: click here

Why in the world did they take so long to start the study drugs?

That's my problem with the study. My larger problem with the study is the fact that, since it was published in JAMA, a very high impact factor journal, clinicians are going to take it as gospel and dismiss the therapy entirely. If they would have provided the study drugs appropriately, there may have been a difference in outcomes. Since they didn't, patients who could have potentially benefitted will not.
Or maybe I'm just wrong.

-EJ



Link to FULL FREE ARTICLE


Fujii T, Luethi N, Young PJ, et al. Effect of Vitamin C, Hydrocortisone, and Thiamine vs Hydrocortisone Alone on Time Alive and Free of Vasopressor Support Among Patients With Septic Shock: The VITAMINS Randomized Clinical Trial. JAMA. Published online January 17, 2020.

Although great care has been taken to ensure that the information in this post is accurate, eddyjoemd, LLC shall not be held responsible or in any way liable for the continued accuracy of the information, or for any errors, omissions or inaccuracies, or for any consequences arising therefrom.

IV Vitamin C in Sepsis and "Fictitious Hyperglycemia"

I’m plenty fired up for the VITAMINS trial that’s going to be published on the 17th. That’s the first large RCT looking at Vitamin C, Thiamine, and Hydrocortisone in Septic Shock. If the trial turns out to be positive, which I really hope it does, then we will really need to know about this limitation as our utilization will definitely increase worldwide.

From burn data and providing high dose vitamin C in that population, and I’m taking about doses >50gm/day, they have noted a cross reactivity in certain point of care blood glucose monitors where the ascorbic acid, due to having to do with glucose having a similar molecular structure to ascorbic acid with six-carbon molecules.

This seems to confuse the POC machine and the readings could be falsely >30%. Ultimately, those designing the studies for 1.5gm IV q6 hours have known this and have been checking to see if there’s a difference between the lab numbers and the POC numbers. As of the time of publication, they found no significant difference. We still need to keep this in mind, though. In the burn population someone died of iatrogenic hypoglycemia 😔. A 🎩 tip to the authors and those who answered the questions.

-EJ



Link to Website

Flannery AH, Bastin MLT, Magee CA, Bensadoun ES. Vitamin C in sepsis: when it seems too sweet, it might (literally) be. Chest. 2017;152(2):450–1.

Although great care has been taken to ensure that the information in this post is accurate, eddyjoemd, LLC shall not be held responsible or in any way liable for the continued accuracy of the information, or for any errors, omissions or inaccuracies, or for any consequences arising therefrom.

Thiamine, Ascorbic Acid and Corticosteroids: The Mechanisms by which they should help in Sepsis

Want some nerdy stuff? Well this is some nerdy stuff! I'm taking a nice deep look at this figure. I am not going to lie to you at this moment, October 19th, and tell you I know what all this means, because I don't. But people who are more intelligent that I am have suggested that these are the mechanisms by which thiamine, ascorbic acid, and corticosteroids should help in the treatment of septic patients. I have a lot to learn.

I hope I don't get dinged for copyright stuff but honestly if this offends you, let me know. I will take it down. I will likely go deeper into this article at a later time. Wanted to share this image with you right now, though.





Link to Abstract

Link to FREE FULL Article

Moskowitz, A.; Andersen, L.W.; Huang, D.T.; Berg, K.M.; Grossestreuer, A.V.; Marik, P.E.; Sherwin, R.L.; Hou, P.C.; Becker, L.B.; Cocchi, M.N.; et al. Ascorbic acid, corticosteroids, and thiamine in sepsis: A review of the biologic rationale and the present state of clinical evaluation. Crit. Care 2018, 22, 283.

Although great care has been taken to ensure that the information in this post is accurate, eddyjoemd, LLC shall not be held responsible or in any way liable for the continued accuracy of the information, or for any errors, omissions or inaccuracies, or for any consequences arising therefrom.

IV Vitamin C and ARDS: CITRIS-ALI

Here's my bias before I even read the article. I want to see a positive response in providing Vitamin C/ascorbic acid in patients who have Acute Respiratory Distress Syndrome. Why? Because I want me patients to do better with treatments that are inexpensive and easy to manufacture rather than the latest immunologic that ends in -mab and costs tens of thousands of dollars. If before you read this summary, you already think that Vitamin C is a bunch of bullpoop, you need some deep reflections in the mirror. You SHOULD want it to work. Now whether it does or doesn't is different and that's where the data comes in to play.

Ultimately, I'm sure I am going to write far more than what IG will allow me to write do you're more than likely going to have to go to my blog to read my thoughts.

The Study Drugs
Before we even get started, we need to look at the study drugs, or lack thereof. The cocktail that was used in the Marik trial that was monumental in finding a mortality benefit in sepsis included ascorbic acid at 1.5gm q6, thiamine 200mg, and steroids. There is a rationale as to why these three go together that Dr. Marik explains far better than I could ever explain. The three are necessary today. Heck, even Gianfranco Meduri has been using steroids for ARDS for years and it's not part of this study. Red flag number one. Not hating on the authors, I am just saying. Haven't finished reading on it yet. Reserve the right to change my mind. In fact, a quick search shows there's no mention of the word "thiamine" in the entire paper.

Outcomes
The primary outcome was modified sofa scores at 96 hours and biomarkers.
I am not going to go over the secondary outcomes but there are 46 of them. They're covering ALL the bases! Good job.

They enrolled 167 patients. This is remarkable that they were able to enroll this many patients in these 7 centers from 9/14 until 11/17.

Results
Let's talk results. That's why you're here. Are you going to start giving vitamin C to your patients with ARDS, yes or no?

Primary outcome: mSOFA and biomarkers: NO DIFFERENCE.
Secondary outcomes: 43 of 46 had NO DIFFERENCE.

But here is the kicker. The three secondary outcomes that had a difference are pretty important.
1. All-cause mortality (p=0.03). 46.3% in the placebo group vs. 29.8% in the Vitamin C group
2. ICU-free days (p=0.03). Patients were transferred out of the ICU faster in the Vitamin C group
3. Hospital-free days (p=0.04) 22.6 in the vitamin C group vs 15.5 in the placebo

Think of all the money that could be saved by this inexpensive vitamin in shortening time in the hospital. $6 a dose, if I'm not mistaken.

No difference in the biomarkers? Well, this may be my off-kilter idea but maybe we are looking or do not full understand our biomarkers.

There were NO adverse effects that occurred during the trial! I've had many people talk about kidney stones, renal dysfunction, terrible side effects of vitamin C. Well, there were none.

Now, there are many limitations in this study. The authors admit to that full and well. Physicians like myself who are on the pro-vitamin C side will interpret the data the way I just did. Those who are contrarians on the matter will be able to look at the numbers and interpret it differently. They will point out all the flaws in the study and throw the findings of the endpoints in the trash. I may be completely off base with my interpretation of these results, but I want to do EVERYTHING that's reasonable to take care of my patients. And if that means spending $24 a day on Vitamin C, I will do it.

If you were the patients on the ventilator with ARDS, would you want the doctor treating you to give you vitamin C?

-EJ




Link to Abstract

Although great care has been taken to ensure that the information in this post is accurate, eddyjoemd, LLC shall not be held responsible or in any way liable for the continued accuracy of the information, or for any errors, omissions or inaccuracies, or for any consequences arising therefrom.

Ascorbic Acid, Thiamine, and Steroids in Septic Shock: Propensity Matched Analysis

Link to Article

Another day, another Vitamin C article. This one came out just two weeks ago, it’s not free, and the results are a bit strange. There are larger trials in the works. If I were part of the group of these authors, I’d be itchy to get my data out ASAP as well. Just 31 patients in each arm of this trial. Heck, even I could replicate this trial in my 20 bed MSICU if I wanted to over 1.5 years. The problem is that my bias admittedly is for the cocktail to work. I am wide openly admitting that, everyone. I have a bias. I want it to work bc I want my patients to live.  

There are numerous parts of this study that seem strange to me. 

1. the ICU mortality of the control arm is 42%. This number should not be quite as high based on the latest data. That could lead the p-value of 0.004 to be perhaps a bit too small. But considering that they used the same strategies to manage septic shock these pts in both arms, it’s still valid for that institution. 

2. The duration of the vasopressors were longer in the experimental arm. This makes NO sense as Vitamin C is a co-factor in the endogenous creation of catecholamines. Heck, even the authors admitted this was strange. 

3. There was no significant difference in hospital mortality. They probably needed a high n to get this to show a difference. The hospital medicine and palliative teams must be great at getting code status’ changed so that people don’t bounce back to the unit. 

4. Pts did not get off of the ventilator faster. Word on the street is that there’s preliminary data suggesting that it helps this process that just isn’t out yet. Stay tuned. 

Lastly, everyone is worried about renal failure. No difference in AKI here, folks. In fact, I am yet to see one report in any of these trials talking about renal calculi secondary to vitamin C in sepsis. 

What are your thoughts on the matter? Is your shop using this yet? Are you a believer or a skeptic?

Although great care has been taken to ensure that the information in this post is accurate, eddyjoemd, LLC shall not be held responsible or in any way liable for the continued accuracy of the information, or for any errors, omissions or inaccuracies, or for any consequences arising therefrom.

Ascorbic acid, corticosteroids, and thiamine in sepsis: a review of the biologic rationale and the present state of clinical evaluation

Link to Article

Direct download to full FREE PDF

Although great care has been taken to ensure that the information in this post is accurate, eddyjoemd, LLC shall not be held responsible or in any way liable for the continued accuracy of the information, or for any errors, omissions or inaccuracies, or for any consequences arising therefrom.

Vitamin C Can Shorten the Length of Stay in the ICU: A Meta-Analysis

Link to Abstract

Full PDF available once you click the link above.

Although great care has been taken to ensure that the information in this post is accurate, eddyjoemd, LLC shall not be held responsible or in any way liable for the continued accuracy of the information, or for any errors, omissions or inaccuracies, or for any consequences arising therefrom.