Articles, Blog

Sepsis Treatment & Vitamin C – Trials & Updates (Septic Shock)

November 25, 2019


welcome to another MedCram lecture
we’re gonna talk about some really interesting developments with vitamin C
in septic shock and if you’ve been following this you’ll know that there is
a paper that was published in chests awhile ago by the author of Marik who
looked at vitamin C and hydrocortisone and thiamine in the treatment of septic
shock that was vasopressor dependent basically what he did real quickly is he
looked at 47 patients before they initiated the protocol and then 47
patients after he initiated the protocol and the results were that the mortality
rate before they initiated the protocol was forty point four percent mortality
and afterwards it dropped to a whopping eight point five percent mortality so
statistically significant though not a randomized placebo-controlled trial and
so this really put vitamin C on the map for septic shock and of course you got a
lot of criticism because people started to use vitamin C in septic shock and
there really wasn’t a randomized placebo-controlled trial however his
point was is that there really isn’t a lot of risk in using vitamin C and so
this war between should we use it should we not use it has been going back and
forth for some period of time in the meantime there is a randomized
placebo-controlled trial which we’ll talk about coming up called victus which
is looking at multi-centered study however something really interesting has
come up recently regarding this topic and that thing is an unlikely
publication called the citrus aali or Ali trial that was published in JAMA and
this will be in the link below that really has raised some eyebrows here in
terms of vitamin C because this is a randomized placebo-controlled trial in
fact the M here was not forty seven and forty seven but rather one hundred and
sixty seven patients it was a multicenter trial and again it was a
randomized placebo-controlled trial so what happened here well patients were
enrolled that were in septic shock but they were not started on vitamin C until
they were within 48 hours of a RDS and that was defined as a PF ratio of less
than 300 so they didn’t get vitamin C in septic shock they had to wait until they
were in a RDS and that’ll become clear as to why that was in the trial in just
a little bit the other distinction was instead of getting the traditional
Merrick protocol of 1500 milligrams of vitamin C Q six hours they actually got
just fifty milligrams I say just because they did not get hydrocortisone and they
did not get thiamine they just got 50 milligrams per kilogram of vitamin C IV
so if you think about a typical 70-kilogram man that would be three
thousand five hundred milligrams every six hours which was about three times
the dose that Marik’s study got that was published in chest okay and they looked
at a number of endpoints and here is where the problem is so there are
secondary endpoints and there’s primary endpoints and the study was powered to
look at the primary endpoints so what were the primary endpoints the first
primary endpoint was the change in sofa score that’s a score that looks at the
severity of illness the other thing they looked at was CRP and finally another
compound called thrombomodulin now in terms of secondary endpoints well there
was about 46 secondary endpoints and the reason why there were so many endpoints
is that’s typically what people do when they have studies like this because they
want to generate more hypotheses to see what else could be abnormal so you
really can’t draw conclusions from secondary endpoints you can only really
draw conclusions from primary endpoints because usually there’s so many
secondary endpoints that you’re going to look at that if you look at 50 different
endpoints and in this case there was 46 of them one or two of them are bound to
become statistically significant just because you’re looking at so
many of them well as it turns out one of their secondary endpoints and here’s
where the problem was is mortality and your like mortality shouldn’t that be a
primary endpoint well here’s the problem this study was funded by the NIH and I
got to give you a little bit of background this was really not a septic
shock study this was a nard study and this is what happened the NIH was
wanting to fund studies for a RDS and the problem is is that there’s only
three things that has been shown to improve survival in a RDS and you can go
ahead and look at make REM calm for lectures on what those three things are
but briefly they are prone positioning low tidal volume and paralysis in
patients with PF ratios of less than 150 and so the NIH took a little different
standpoint they said you know what we’re willing to fund studies since we’re
having such a hard time finding mortality benefits and studies let’s go
for hypothesis generating studies and let’s look for some smaller things let’s
look for sofa score let’s look for some intermediate markers let’s look for some
surrogates and so that’s why the authors decided to look for change in sofa CRP
and thrombomodulin this is also the reason why they decided to look at a RDS
instead of just sepsis so in other words what they did is yeah we’ll take the
septic shock patients but we’ll wait for them to be an A RDS before we start the
high-dose vitamin C so because of the way the funding was given and because of
the preconditions for funding that’s what made the study kind of awkward in
that they waited for a RTS before starting it instead of starting it way
back here at septic shock and it’s kind of the reason why we have the flip flop
well here are the results when they looked at the primary outcome for the
primary endpoints there was no statistical significant benefit
whatsoever there was no change no change in sofa scores no change in CRP no
change in thrombomodulin between those that got vitamin C and those that got
placebo however and sit down for this there was a huge secondary mortality
benefit for those that were on vitamin C well I shouldn’t say huge there was a
difference in those that got the c-arm the mortality was 29.8% greater
than the 8% that we saw in Marik’s protocol study but remember this was
started away later than septic shock showed up in the other thing that they
saw was the mortality in the placebo so this is the vitamin C group and in the
placebo group the mortality was forty six point three percent and this was
statistically significant of a p-value of 0.01 so not borderline but pretty
specific so what do you do now what do you do when you have a primary endpoint
that shows no change and yet through some mechanism that is unknown we have a
mortality benefit this was a 28-day mortality benefit in those that were on
vitamin C and it gets even better than that because if you look at the actual
graph of survival or indeed mortality the placebo the mortality rose very
quickly at the beginning so this is placebo but the vitamin C Group did not
and then after it was stopped it then reached and plateaued off and so during
this period of time when vitamin C was being infused there was this pretty
sizable difference between those that were not getting the vitamin C and those
that were getting the vitamin C during that period of time and so this of
course has raised a firestorm and people are debating because here we have a
randomized placebo-controlled trial that shows a mortality benefit but because
the study was not powered to look at mortality because it was a secondary
endpoint and you didn’t and we did not correct for these multiple secondary
endpoints mortality falls out and so why would it be then that the primary
endpoints were not statistically significant well one of the explanations
that have been tossed around and I’ll include a link to a really nice website
that goes through this is that it’s possible that the vitamin C grew
was benefited so much that because less people died more people with bad sofa
scores or less improving sofa scores were included in the analysis whereas
those that were on the placebo those patients died the worst ones and that
made the sofa scores in that group look better because the worst ones were
eliminated or the worst ones that were not improving the best were eliminated
and that’s why there might have been no statistical significance so take a look
at those links it’s a new update I think it’s very fascinating but as I mentioned
in the middle of this is victus should be coming out in the next few months so
if you want some more information about how to treat septic shock and a RDS
please join us at MIT cram comm for all the latest and online instructional
videos thanks for joining us

10 Comments

  • Reply Nurse Stefan November 24, 2019 at 5:31 pm

    fascinating! Saved! Discussing this with colleagues tomorrow.

  • Reply Blue Line Rider November 24, 2019 at 5:33 pm

    nice update

  • Reply MedCram - Medical Lectures Explained CLEARLY November 24, 2019 at 5:34 pm

    Thanks for watching. Much more about sepsis and shock treatment at our website: https://www.medcram.com/courses/shock-and-sepsis-explained-clearly

  • Reply o0Avalon0o November 24, 2019 at 6:05 pm

    I could listen to you guys all day. It's channels like this that inspire me to keep learning & work hard!

  • Reply evans ekhator November 24, 2019 at 6:41 pm

    High dose of Vit C has been used for years to cure so many diseases and ailments.

  • Reply Stop the Philosophical Zombies November 24, 2019 at 8:08 pm

    Would you consider doing a video on Metformin?

  • Reply Jeremiah Roark November 24, 2019 at 9:00 pm

    I love the idea of using something that appears to have low side effects. Will hospitals start implementing this in the future? I sure hope

  • Reply Md Mazidul Haque November 25, 2019 at 12:25 am

    Thanks for making this video free for us.
    Good job.

  • Reply polaris911 November 25, 2019 at 5:31 am

    is this why, for the past year, my pharmacy is always compounding huge doses of ascorbic acid?!

  • Reply Mehboob Islam November 25, 2019 at 8:31 am

    So… they let patients die just to check the efficacy of a drug by not providing the patients the medical care that they need ( on time ) all this for the betterment of science?!

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