Background:
Vitamin C is an essential water-soluble nutrient which cannot be synthesised or stored by humans. It is a potent antioxidant with anti-inflammatory and immune-supportive roles. Previous research has indicated that vitamin C levels are depleted in critically ill patients. In this study we have assessed plasma vitamin C concentrations in critically ill patients relative to infection status (septic shock or non-septic) and level of inflammation (C-reactive protein concentrations). Vitamin C status was also assessed relative to daily enteral and parenteral intakes to determine if standard intensive care unit (ICU) nutritional support is adequate to meet the
vitamin C needs of critically ill patients.
Methods:
Forty-four critically ill patients (24 with septic shock, 17 non-septic, 3 uncategorised) were recruited from the Christchurch Hospital Intensive Care Unit. We measured concentrations of plasma vitamin C and a proinflammatory biomarker (C-reactive protein) daily over 4 days and calculated patients’ daily vitamin C intake from the enteral or total parenteral nutrition they received. We compared plasma vitamin C and C-reactive protein concentrations between septic shock and non-septic patients over 4 days using a mixed effects statistical model, and we compared the vitamin C status of the critically ill patients with known vitamin C bioavailability data using a
four-parameter log-logistic response model.
Results:
Overall, the critically ill patients exhibited hypovitaminosis C (i.e., < 23 ?mol/L), with a mean plasma vitamin C concentration of 17.8 ± 8.7 ?mol/L; of these, one-third had vitamin C deficiency (i.e., < 11 ?mol/L). Patients with hypovitaminosis C had elevated inflammation (C-reactive protein levels; P < 0.05). The patients with septic shock had lower vitamin C concentrations and higher C-reactive protein concentrations than the non-septic patients (P < 0.05). Nearly 40% of the septic shock patients were deficient in vitamin C, compared with 25% of the non-septic patients. These low vitamin C levels were apparent despite receiving recommended intakes via enteral and/or parenteral nutritional therapy (mean 125 mg/d).
Conclusions:
Critically ill patients have low vitamin C concentrations despite receiving standard ICU nutrition. Septic shock patients have significantly depleted vitamin C levels compared with non-septic patients, likely resulting from increased metabolism due to the enhanced inflammatory response observed in septic shock.
Commentary:
This study demonstrates that ALL critically ill patients are vitamin C deficient; It should be noted that this finding has been known for over 20 years. In addition, the study by Carr et al demonstrated that 40% of patients with septic shock had vitamin C levels diagnostic of biochemical SCURVY. Furthermore, low serum levels are associated with severe cellular deficiency. In critically ill patients, vitamin C levels have been inversely associated with disease severity and the risk of organ failure and death. The likely cause of the vitamin C deficient is metabolic consumption. Considering the role of Vitamin C plays in a multitude of biochemical reactions and pathways relevant to sepsis, these findings provide a strong rationale for treating all septic patients with intravenous vitamin C.
Paul Marik
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Very interesting to know more information about Vitamin C and the levels in septic patients. I would suggest caution in over-interpreting the results. Just because you are deficient in something does not mean replacing it has a net benefit.
I would argue that the results are not a strong rationale for treating all septic patients with IV Vitamin C. However, it is a strong rationale for conducting a high-quality, blinded, placebo controlled, multi centre trial.
As scientists we must use the scientific method to answer our questions. The question we all want to know is will replacement of Vitamin C result in a net benefit. The null hypothesis is that it will make no difference. Until we have good evidence that it provides a patient oriented outcome we should “don’t just do something, stand there”. https://www.ncbi.nlm.nih.gov/pubmed/29327445
If Vitamin C has such a significant positive patient oriented impact on patients with sepsis it should not take a very big study to demonstrate the effect. I hope this study is conducted and demonstrates a benefit. Until such results are published I remain skeptical.
Just because you are deficient in something does not mean replacing it has a net benefit? Absolutely. I’m going to stop treating hypokalemia, hypomagnesemia, or hypophosphatemia until we have some multi-center RCTs showing that treatments are worthwhile. In fact, I don’t think there are any RCTs showing mortality benefit from measuring electrolytes, so I’m going to stop checking them entirely.
Hey Josh, good to hear from you.
It is hard to know if your tongue is in your cheek based on a text?
You did not really answer the issue but brought up something else.
Are you opposed to a properly conducted RCT to determine if there is a net benefit to Vitamin C in sepsis?
Hi Ken, always a pleasure. Yeah, maybe a bit too much sarcasm. Let me flesh out my position slightly: #1. More RCTs on vitamin C are certainly needed, and I’m delighted that they are coming soon. It will be nice to have more clarity on this issue, one way or the other. (I have no COI here, just trying to extricate people from ICU.) However, that’s nothing particularly unique about Vitamin C. We need more studies about virtually every aspect of critical care medicine. It’s hard to think of any subject where we can say “I know everything about this, no further studies are needed.” Except for hetastarch maybe – that’s poison, we need to stop wasting time studying it. #2. My opinion is that based on currently available evidence, the benefits of hydrocortisone/ascorbate/thiamine outweigh the risks for patients with septic shock. This isn’t solely on the basis of Marik’s study, it’s based on a numerous studies at multiple levels. This is obviously debatable and a wide range of opinions exist on this topic. I think that it’s entirely reasonable for clinicians to use vitamin C while simultaneously awaiting additional information (#1). #3. Nearly all treatments in critical care are… Read more »
Doesn’t this recent study suggest that all critical care patients be given Vitamin C. Why? Because all critical care patients are deficient. Does it have to be more complicated than that?
Unfortunately Pete, it is more complicated.
Just because a patient is deficient in something does not mean it is a net benefit to correct the abnormality. There are many examples in medicine where we have acted on this thinking only to find out with high-quality research there was no benefit and even sometimes harm.
What is not complicated is a properly designed RCT which I understand from Josh are currently underway.
What is your best example to illustrate your point? I just can’t see why you wouldn’t give Vitamin C to somebody who is deficient. Perhaps other interventions you are thinking of are more harmful, and the benefit less well defined. So I want to compare your example to Vitamin C and see if it holds up.
Actually any example I provide would not provide any proof whether or not providing vitamin C to patients is beneficial. The question is does IV vitamin C given to septic patients result in a patient oriented outcome? The burden of proof is on those making the positive claim. As a scientist, researcher, clinician, critical appraiser and skeptic that burden has not been met.
two examples of things which are low in critical illness which don’t really benefit from routine repletion would be ionized calcium and vitamin D. A good reference on this is https://www.ncbi.nlm.nih.gov/pubmed/26836894. So not everything which is low necessarily needs to be repleted. However, thiamine and ascorbate are water-soluble vitamins which makes them extraordinarily safe — so they’re in some ways in a different category compared to calcium and vitamin D. Also there is other evidence/rationale for their use (https://emcrit.org/pulmcrit/metabolic-sepsis-resuscitation/).
Thanks for your response. I know we both want the best for patients. Glad to hear there are RCTs coming on Vitamin C. I hope they show patient oriented benefit and will be happy to review on the SGEM to cut the knowledge translation down. #1) I too have no COI in the matter. We agree that more clarity would be helpful. #2) We differ on the available evidence to change practice. We have a long history in medicine of adopting a therapy based on physiological, animal and observational studies only to find out in proper RCTs they do not have benefit and sometimes even have harm. I understand why some physicians would find it reasonable to use this therapy. I cannot recommend it be used for all septic patients based on the existing data. #3) I am not making the argument we should not provide any therapy unless we have multi-cantered RCTs demonstrating benefit. I agree that is unrealistic. There are limits to what we can study for a variety of reasons. This is not one of them. You are asking for a new therapy to be used. We adopted the white coats ~100 years ago for credibility. To… Read more »
Thanks, I’ll take a lime martini. Second round is on me.
Compared to Vitamin C, Angiotensin-II sounds sexy because of the hyphenated Roman numerals. And better ads in NEJM, not to mention free dinners at SCCM.
But seriously, having been in medicine for over 30 years now, I see treatments going in and out of vogue, fiercely defended, then gradually falling out of favor…. and then coming back in. lidocaine, Bretyllum, procainamide, to amodarone, and back to lidocaine or preferably procainamide again, for example.
Without people to push the boundaries, we’d still be giving saline 125/hr to everyone. Without skeptics, we would have never stopped it! Without dialogue, sometimes painfully, those of us on the sidelines would not be able to make good choices between the two.
So I’m glad to see both viewpoints and dialogue, here. And glad to see prospective RCT’s on metabolic resuscitation are underway!
A number of skeptics covered the observational study done by Dr. Marik
SGEM#174: Don’t Believe the Hype
http://thesgem.com/2017/04/sgem174-dont-believe-the-hype-vitamin-c-cocktail-for-sepsis/
I can see from information on YouTube that there are at least two doctors who have tried the protocol and had success. And I know of a few more who have tried it. What I really wonder is how many times is it being tried overall and what are the outcomes? Is it possible that it has been tried hundreds of times already but just not reported? There are so many cases of sepsis that its use for 100 cases seems possible.
Pete, You are correct. Hundreds of patients have been treated across the world. Many centers have incorporated this protocol as part of their routine care.
Is there any way to write up the results of these various trials? It wouldn’t be a traditional publication but it might have some influence if doctors around the world have used it on hundreds of patients with success. I know everybody wants RCTs and they are underway, but I am just thinking of how to get to the answer sooner.
Pete: that was my plan. I have given the spreadsheet that I used to collect data to a couple of folks, hoping to develop a registry of all treated patients. Unfortunately this has not happened. Seems like we will need to wait for the results of the RCT’s. Furthermore, it would appear that without a RCT many physicians remain skeptical.
Observational trials are just the plural of anecdote. We all hope that the protocol proves to be true and results in a patient oriented outcome. Before we incorporate something into routine care we need to know if it works. If it has such a large effect size it will not take a big study to demonstrate the benefit.
Regardless of how many people have been treated and how many centres have incorporated the protocol into their routine care, as a scientist Dr. Marik you know that does not answer the question if it works.
Searched and found 11 trials ongoing
https://clinicaltrials.gov/ct2/results?cond=vitamin+C+sepsis&term=&cntry=&state=&city=&dist=
noted Paul.
a potential problem is getting everyone on board. i can give the starting doses (? 2gm vit C (?), and 200 mg of B1, thiamine. but does that help much if its not continued “upstairs”?
thank you, paul.
tom
Why get everyone on board when there is not enough evidence to support the treatment?
“What counts is not what sounds plausible, not what we would like to believe, not what one or two witnesses claim, but only what is supported by hard evidence rigorously and skeptically examined”. (Carl Sagan)
this proves how pts get better with devouring limes w honey. great that there is recent literature
The NPR story about sepsis speaks about development of early warning systems for sepsis. Do such systems get tested by RCTs?
https://www.npr.org/sections/health-shots/2018/02/22/583846656/synergy-between-nurses-and-automation-could-be-key-to-finding-sepsis-early
I am a sepsis widow. My 40 year old husband, Jeff, died from sepsis on 10-20-2012. Our babies were 9 months and 3. When he triaged, he presented with 103.6 fever, resp. rate of 24 and shaking uncontrollably. He was diagnosed with the flu and left dying for 8 hours before going into septic shock and the hospital finally catching on that he had sepsis(2 Dr. missed it). 16 hours later he was gone. I have tried hard to raise awareness, partnering with Sepsis Alliance and hosting an annual 5K in his memory. I know I wish Dr. would have tried vitamin C or ECMO-anything on him! God bless you all for your efforts. I know you can’t win them all!
A good reminder of why we have to build strong systems of care that don’t miss sick patients, AND when they are really sick, not be afraid to forge ahead, pull out the stops, and try to save them. Because they are someone’s family member, not just another ‘n’ in a study, or a platitude to watch them as they die.
[…] of sepsis symptoms [R]. The studies of ascorbic acid treatment have led to a discovery that 40% (in this study) were deficient in the vitamin, so much so they were clinically diagnosed with […]