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.

Thiamine and Renal Failure in Septic Shock Patients

Every possible option to decreased morbidity, mortality, and costs are worth looking at in my book. The study that I am reviewing at this moment was published in 2017. I am ashamed that I had not run into it until today. It's challenging to stay up to date in everything. I digress.

Some would quickly bash this study for it being small (n=70) and a post-hoc secondary analysis of a pilot study. I am not going to do that. Why not? Well first of all, I do not participate in research myself. Just reading and enjoying these studies. Also, thiamine has no side effects described in the literature. Third, it is an inexpensive medication. Fourth, if it does turn out to decrease the incidence of acute kidney injury and the need for renal replacement therapy, aren't you going to feel guilty for not adopting these strategies for your patients? I hate resorting to that but my responsibility is for patients. What happens if this data is wrong? Nothing. What happens if this data is right and no one does anything for several years? Many patients may suffer.

This article is completely free and I encourage you to download it and read it for yourself. Amongst the points illustrated by the authors, they mention that it's not only perfusion that injures the kidneys during sepsis. There are other factors listed in the article. The way that it is postulated that thiamine works for these patients is by assisting in the mitochondrial dysfunction. Data that I have found not listed in this article shows that thiamine deficiency could have an incidence between 20-70% of critically ill patients. 

What they found was 21% of the patients in the placebo arm of the trial went on to need dialysis. Just one patient, or 3% in the thiamine group went on to require this. The authors note that acidosis was the primary indication for dialysis in 66% of the patients who required it. I personally would like to dig deeper into these numbers as there is some data that thiamine administration helps decrease lactic acidosis. 

This data should make you wonder if the strategy that many clinicians take of providing more IV fluids to patients whose renal function deteriorates is the correct strategy. Are we going to look in the mirror in a decade and want to punch our past selves in the face?   

- EJ

Link to Abstract

Link to Full Article

ADDENDUM: The prospective RCT is going to be completed in July 2022. Here is the link to clinicaltrials.gov's study details here: LINK

Moskowitz A, Andersen LW, Cocchi MN, Karlsson M, Patel PV, Donnino MW. Thiamine as a renal protective agent in septic shock. A secondary analysis of a randomized, double-blind, placebo-controlled trial. Anns Am Thorac Soc. 2017;14(5):737–41.

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.

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.

Thiamine on Lactate Clearance and Mortality

https://journals.lww.com/ccmjournal/Citation/2018/11000/Effect_of_Thiamine_Administration_on_Lactate.5.aspx

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.

Marik Protocol for Septic Shock: Looking at Vitamin C

Hydrocortisone, Ascorbic Acid and Thiamine
(HAT Therapy) for the Treatment of Sepsis. Focus on Ascorbic Acid

Controversies. Controversies. Controversies. I tell you, the behaviors of Intensivists when it comes to king septic patients IV Vitamin C for sepsis are quite perplexing. We had a cheap drug, less than;$20 a day that MAY help treat sepsis and people don’t even bother to try it out. I know I use it because if it saves lives, why not try? Let’s say that the trials show a mortality benefit, two years have already passed since the first trial. Think of all the additional lives you could have saved but didn’t because your ego was in the damned way. If Marik is wrong, nothing bad happened. But if he’s right, you’re going to beat yourself up.

-EJ 



Link to Abstract

Link to 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.