Vasopressors and Vitamin C in Sepsis Explained Clearly

November 19, 2019 0 By Ewald Bahringer

welcome to another MedCram lecture
we’re going to talk about vasopressin and some exciting new information about
vasopressin so what our vasopressors vasopressors are substances that we put
into people’s bodies because their blood pressure is too low the use of
vasopressin be complex and if you want more information and a more
pathophysiological basis for this information I encourage you to visit med
cram comm for the entire series I’m going to talk about this specifically in
the sense of sepsis so sepsis is when you have an infection
that causes your body to go into a low blood pressure state because there’s
vasodilation there’s usually increased cardiac output at the very beginning and
your immune system basically goes wild and you have this hypotension and you
give fluids in these situations but still sometimes the blood pressure
doesn’t get up to where it needs to which is a map of 65 and you’ve got to
give vasopressors so the reason why you’ve got to actually give patients
vasopressors is because they don’t have enough endogenous vasopressors of their
own and the two big vasopressors that you should know about norepinephrine and
epinephrine and of course these are secreted from the adrenal gland as it
turns out in the biosynthesis pathway norepinephrine goes to epinephrine but
if we go backwards actually norepinephrine is simply synthesized
from a compound called dopamine and dopamine in turn is synthesized from
a compound called dopa specifically it’s l-dopa and of course l-dopa you may know
this is synthesized from something called tyrosine this is the synthetic
pathway that the body goes through to make the final product which is
epinephrine the problem is this there’s just not enough of it and that’s why we
have to give more in patients with sepsis
well if we look at the enzymes along here there is something called tyrosine
hydroxylase and there’s a very specific vitamin that’s implicated in the
activity of tyrosine hydroxylase and that is vitamin C now vitamin C is named
a vitamin because it comes from the term vital amine because it’s one of those
amines that was vital for the human body to have and humans with just a few other
mammals are the only mammals that cannot synthesize their own vitamin C and
that’s why it’s called the vitamin of course as we just mentioned so many
years ago and actually this has been looked at for several years the question
is whether or not the addition of vitamin C would help push this pathway
down to the final product which are the vasopressors norepinephrine and
epinephrine and would help with micro vascular problems in terms of perfusion
in septic shock and so that’s what we’re gonna look at today because there’s been
some interesting studies that have come out that have looked at just that
patients in septic shock who have been given high doses of vitamin C so what
Marik and his colleagues did and published in chest a 2060 and got the
reference there at the bottom is they basically looked at 47 patients that had
the standard treatment and then they looked at the 47 patients after a
specific time point that did not have the standard treatment but in fact had
something called the Merrick protocol so we have standard here and then we had
something called the Merrick protocol so what is the Merrick protocol
well the Merrick protocol is actually pretty straightforward it is vitamin C
and it is 1500 milligrams IV Q six hours and this is for four days or until the
patient the intensive care unit the next thing
that that is given is thymine and it’s 200 milligrams IV Q 12 hours this is
also given for those four days and the reason why this is given is it’s to help
prevent a formation of kidney stones and crystallization in the kidneys and this
is a low risk of doing it but they wanted to make sure that it did not
happen and they’ve done safety trials and they looked at this in it and it
just didn’t happen the other one that they gave was hydrocortisone 50
milligrams IV Q six hours and this was given up to seven days if they need it
and then remember hydrocortisone is a steroid that closely resembles both the
glucocorticoid and mineral corticoid activity of the adrenal cortex and so it
was thought actually in early goal-directed therapy that giving
hydrocortisone in patients who needed vasopressors was good but there’s been
some studies that have shown that hydrocortisone by itself is maybe not
completely everything that you need and so these three together or what was done
as opposed to just standard therapy and these 47 patients here were consecutive
and these 47 patients here were consecutive after this break and so
that’s how the study was done it was not a randomized placebo-controlled trial so
let’s take a look and see what the results were from standard therapy which
is listed here on the left versus the marek protocol which we’ve just
described in those 47 patients so the first thing we’re gonna look at is
hospital mortality so how many people died in the conventional group it was 19
patients that died out of the 47 patients so that works out to be about
40% whereas in the merit protocol there was 4 out of 47 patients that died and
that’s only about 9% so there was a huge difference there and the p-value on that
will just squeeze it in over here was significant at 0.001 now what
the ICU length of stay the ICU length of stay was actually four but it was
anywhere between four and ten days in the intensive care unit was in the
treatment group it was a verge of four but the range was three to five days and
that was not statistically significantly different here’s the real key though
vasopressors how much exogenously suppressors were needed in the standard
group in terms of hours there was about fifty four point nine hours of
vasopressors that was the average use per patient now if vitamin C is gonna
work it’s the thing that’s going to actually cause your body to make
norepinephrine and epinephrine we think based on the biological pathway and this
is where we saw the biggest difference because the average hours of use for
vasopressors in the treatment group was only eighteen point three hours and that
was very statistically significant less than 0.001 now if we can get blood
pressure up more quickly then we can also save the patient from acute renal
failure and we saw that again in the standard group we saw 11 out of 30
patients or about 33% of them going into renal replacement therapy which means
dialysis or acute kidney injury however in the marek protocol group only 3 out
of 31 patients or only about 10% needing renal replacement therapy and that was
statistically significant at 0.02 now what about the sofa scores what’s a sofa
score it’s basically a measurement of illness and if you see a big change in
sofa scores that means you’re seeing a big change in how fast that patient is
getting better so what was the change in sofa score at 72 hours only 0.9 whereas
in the merit protocol group it was 4.8 and that was statistically significant
finally how fast did we see procalcitonin levels come down and so
this is not as intuitive right because we’re looking at blood pressure
improvement not necessarily clearance of procalcitonin but you can
imagine that if you have better perfusion to the areas that are infected
you’re gonna get procalcitonin clearance improved and that’s exactly what we saw
so in the control group we saw about a thirty three point nine percent
clearance of procalcitonin whereas in the Merrick protocol we saw at eighty
six point four percent clearance and that again was statistically significant
so here we have it again the America call vitamin C 1500 milligrams IV Q six
times four days or until ICU discharge number two is thiamine two hundred
milligrams IV q twelve hours times four days or ICU discharge and then three
hydrocortisone fifty milligrams IV Q six times seven days or I see you discharged
so what were the advantages or the disadvantages or let’s say the good
things are the bad things about this study so some of the good things is that
the two groups were very similar so it’s probably that these changes these
differences that we see in these two groups are probably real and these were
consecutive patients the other thing about this is let’s face it
vitamin C thiamine hydrocortisone these are not exactly dangerous medications
right they’ve been in use there’s been some studies that have shown this dose
of vitamin C with thymine it’s pretty safe and I think this is the key here
now what are some of the bad things when I say bad what are some of the
limitations of this study it’s the same limitations that will see with anything
that’s not a randomized placebo-controlled trial and that is
it’s not a randomized controlled trial that’s the highest level of evidence and
we still need to have that it’s a small study okay we need to have a bigger
study but interestingly it’s a small study yet it still show pretty
significant difference which is pretty impressive this is a single Center study
so maybe there was something about the patients at this hospital that would
have benefited from vitamin C that maybe your Hospital might not benefit from
vitamin C but it’s hard to say that and again as we said it’s not controlled
it’s not randomized so there’s all sorts of biases that can come in right if you
know your to do a trial and now you’re about to
start in on the 47 people that you’re about to try your new treatment on you
might treat them better right and so you might be seeing improve results from
that so we really need to have a randomized controlled trial and it’s got
to be a large study and it’s got to be multi center that’s really what we need
here that being said however the question is would you use this protocol
at your hospital and that’s another interesting discussion now for that
analysis this is what I look at look there’s only two possibilities on either
side either I use it in my ICU or I don’t use it in my ICU and either it
turns out that after we study this thing it either works or it doesn’t work so I
don’t know if it works right now or not but I do have a choice of whether or not
I can use it or not and so what are the four possibilities if I look at this if
I use it or if I don’t use it so if I use it and it works then I’ve saved
people and I didn’t expose anybody to adverse events if it doesn’t work and I
used it the question is is did I cause any harm question of harm and there is
good evidence that this is safe and so therefore there is no harm okay other
than the fact that you’re spending money on a medication that’s not going to work
now if it works and I don’t use it then there’s people that I lost because I
wasn’t using it during the time that I didn’t know it worked right and if it
doesn’t work and I’m not using it obviously there’s no harm because I
didn’t use it right didn’t save any people so the question is is where do
you want to operate on this two by two punnett square we don’t know if it works
or doesn’t work it seems like it works and so I’ve used it in my ICU and the
reason why I’ve done it is because I would rather be in this category than in
this category it’s kind of a personal decision you have to look at the risks
and the benefits I don’t see big downside and giving people high dose
of vitamin C because the studies have shown that it’s pretty safe so there’s
not much to lose so the worst you can be if you decide to use it is the worst
thing that you can be is in this category and in this situation you’re
not causing much harm but as it turns out it may not work if you decide not to
use it the worst thing that can happen is that you might lose people that you
could have treated that you didn’t treat so this discussion kicks off a talk
about vasopressors how they’re used what’s the safe way to use them whether
or not you need a central line and for that I invite you to join me at Meg cram
comm for discussion on faze oppressors in terms of vitamin C and vasopressors I
would be remiss if I did not thank my friend and outstanding nurse tim taylor
who works with me in the intensive care unit for his enthusiasm and his
championing the whole cause of vitamin C in our ICU thanks for joining us