Thread by @jeremyfaust

Does Vitamin C, Thiamine, and Hydrocortisone cure sepsis?

Is this "cocktail" the wonder drug that the media hype implied in 2017 based on ONE before-after retrospective study?

Answers from the 1st major international randomized control trial ARE HERE! @JAMA_current.

THREAD!

Let’s not bury the lede here.

*This trial is PROFOUNDLY negative*

The authors (Fujii et al) found the vitamin C cocktail to have NO effect on the primary outcome: time alive and vasopressor free days.

The authors also found no effect in 9 of 10 secondary outcomes including 28 day mortality, 90 day mortality, need for mechanical ventilation, renal replacement therapy (dialysis) and others (see below).

The only positive finding was a 1 point reduction in the SOFA score (sequential organ failure assessment). This is hardly game-changing and it is not a patient-centered outcome. It’s just some numbers.

The famous 2017 retrospective Marik study that took the world by storm told an painted an almost implausibly prettier picture. In that study, 40% of the patients died in the ICU before they rolled out the Vitamin C protocol. After they rolled it out, only 8.5% died. Staggering.

In today’s VITAMINS trial, that didn’t hold up. In fact, numerically but not statistically, more patients who received the vitamin C cocktail died at almost all time points than those in the control arm (who received hydrocortisone alone).

This is an unmitigated disaster.

Additionally, the vasopressor requirements of the patients who received the Vitamin C cocktail in the Marik study were reportedly much, much lower (left). In today’s JAMA study, no such finding was seen (right).

An accompanying editorial in JAMA practically calls for the 18 remaining Vitamin C cocktail trials to be halted for presumed futility. The author doesn’t go that far but he points out how much research funding is going towards this all, just based on the one Marik study from 2017

He points out that media hype and the overstating of the importance of data from low quality studies (like the before-and-after design of the now famous 2017 study) distracts researchers and funders from other promising leads. It also gives people false hope.

Here’s a summary of some of the research literature on the Vitamin C cocktail in sepsis, by the way, by my collaborator @LWestafer.

A few points. This trial wasn’t a blinded. As @LWestafer & I discuss on a new episode of @FOAMpodcast, blinding is always preferred in randomized trials. (For our analysis, check out podcasts.apple.com/us/podcast/foa…)

But...if anything, open label designs should’ve HELPED the intervention

The patients in both arms were quite sick. These were patients with septic shock using the Sepsis-3 definitions. These are the hardest patients to save. These are the patients who really need a therapy that works as well as the 2017 Marik data suggested was possible.

The patients in the intervention arm were sicker at baseline (worse APACHE III) while the patients in the control arm had somewhat higher lactates.

But the authors were able to look at whether these differences altered the unadulterated negativeness of this trial.

It didn’t.

On the plus side, randomization was good, adherence to and execution of the protocol was good.

Also, and this is important, *ALL* of the outcomes (both primary and secondary) as well as the statistical plan and strategy were announced ahead of time.

NO POSTGAME CHERRY PICKING.

Kudos to the international research collaborative that performed this trial. (@BellomoRinaldo @DogICUma etc). They started this project as a “passion project.” No funding (thus no blinding, which is something that takes time and money to accomplish).

They sought real answers.

The answers are not pretty. They are not the good news that we so badly need for sepsis.

It bears repeating that sepsis is a life-threatening condition that occurs when the body’s maladaptive response to infection causes life-threatning organ damage...

What we know is that severe cases of sepsis are best treated by early recognition, antibiotics, SOURCE CONTROL (all the antibiotics and pressors on Earth won’t save the patient with an infected medication port or a perforated appendicitis).

Rigid protocols also don’t help.

On the other hand, calling ALL infections sepsis (overtriage) is wrong and can really hurt both individuals and cause systemic harms as we misuse and squander our precious nonrenewable antibiotic resources.

Resistance is real and it’s only getting worse.

Finally, our current understanding of sepsis is probably wrong. Sepsis is one syndrome? Not likely, as @seymoc has shown. What we think of as sepsis is likely a few different conditions, each with its own potential targets for treatment.

I predict someday, medical scientists will look back upon 2020 as a time when we had *no clue* as to what we were talking about when it came to sepsis. Truthfully, I actually hope that’s the case because the status quo is NOT cutting it.

In summary, vitamin C-based cocktails are clearly not the game-changing answer that many hoped it might be--even skeptics like me and @LWestafer and @TheSGEM and @EM_Nerd and others were hoping it might help. We really do want to save more lives here.

If any of the remaining forthcoming trials shows any benefits at all, they’re likely to be very small ones. (Even that would be welcome news but only if consistently validated and appropriately applied.)

But these findings out today all but clinch it. We can confidently say...

Vitamin-C based cocktails (aka “metabolic resuscitation” or the “Marik protocol”) will not be the sepsis cure that you read about in the newspaper or heard about online or on the radio in 2017.

The search for better answers goes on.

We must find more effective sepsis treatments.

But the time has come.

We must now move on.

For more check out foamcast.org and read these new studies @JAMA_current.

Thanks for reading!
FIN.

Resources: VITAMINS trial is out in @JAMA_current ! Check out our take on Vit C + Thiamine + hydrocortisone in septic shock
foamcast.libsyn.com/vitamins-trial…
Blog: foamcast.org/2020/01/17/vit…
Listen:foamcast.libsyn.com/vitamins-trial…
Podcast: podcasts.apple.com/us/podcast/foa…
#FOAMed

FIN for real :)