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SGEM#174: Don’t Believe the Hype – Vitamin C Cocktail for Sepsis

SGEM#174: Don’t Believe the Hype – Vitamin C Cocktail for Sepsis

Podcast Link: SGEM174

Date: April 6th, 2017

Reference: Marik et al. Hydrocortisone, Vitamin C and Thiamine for the Treatment of Severe Sepsis and Septic Shock: A Retrospective Before-After Study. Chest Dec 2016

Guest Skeptic: Dr. Jeremy Faust is an attending emergency physician at Brigham and Women’s Hospital in Boston Massachusetts and an instructor at Harvard Medical School. He’s the co-host of FOAMcast with co-host Dr. Lauren Westafer and he’s written about sepsis in the Annals of Emergency Medicine, EM Clinics of North America, and for mainstream audiences in Slate. 

Case: A 60 year-old man is admitted to the ICU with severe sepsis from pneumonia. He has a history of hypertension and diabetes. You are providing him with intravenous fluids and appropriate antibiotics. When speaking with the family his son asks about a vitamin C cure he just read about?

Background: We have covered sepsis many times on the SGEM (#44, 69, 90, 92 and 113). Most recently we covered the HYPRESS Trial on SGEM#168. The primary outcome was that hydrocortisone did not prevent the development of septic shock. The secondary outcomes also showed no difference in mortality.

There has been a huge buzz in the media about a vitamin C cocktail (vitamin C, hydrocortisone and thiamine) as a possible cure for sepsis. Many FOAMed sites have joined the conversation:

  • FOAM logoThe Bottom Line: An Orange a Day Keeps Sepsis at Bay?
  • EMLit of Note: Vitamin C for Sepsis
  • EMCrit: Paul Marik on the Metabolic Resuscitation of Sepsis
  • Pharmacy Joe: Vitamin C, Hydrocortisone, and Thiamine for Severe Sepsis and Septic Shock
  • Everyday EBM: Vitamin C in Sepsis – Splashes in the Popular Press
  • St. Emlyn’s: Vitamin SCepTiC?
  • REBEL EM: The Marik Protocol: Have We Found a “Cure” for Severe Sepsis and Septic Shock?
  • ZdoggMD: Vitamin C Cures Sepsis and other fake news?

For the scientific rationale why vitamin C therapy may help septic patients check out Josh Farkas’ post on PulmCrit.

People have searched and people have failed to find an effective treatment for sepsis (DC Angus JAMA 2011). A classic example is the story of recombinant activated protein C (ADDRESS NEJM 2005 and FDA).

Dr. Paul Marik is a well-known critical care physician and professor of medicine from the Eastern Virginia School of Medicine. Based on some information discussed in Josh Farkas’ post and specifically a paper by Fowler and colleagues, Dr. Marik had the idea to treat three patients suffering from septic shock with vitamin C as a life-saving measure (Fowler et al J Transl Med 2014). He also added some hydrocortisone for its theoretical synergistic effect.

Plrual of anecdoteAll three patients made a dramatic recovery with no reported residual organ dysfunction. From a statistical stand point three consecutive patients surviving from sepsis should not have been that unusual giving its known mortality rate. And of course the plural of anecdote is not data but hypothesis generating.

This did inspire Dr. Marik to design a study to investigate the hypothesis of vitamin C as a treatment for sepsis. He designed a retrospective before and after study that included intravenous vitamin C, hydrocortisone and thiamine. This was because they were unable to initiate a RCT at his hospital due to the perceived lack of clinical equipoise and it being unethical to withhold a potentially life saving treatment. However, Dr. Marik correctly did not include those first three patients in the data set. You can see an interview with Dr. Marik about this on YouTube.

Clinical Question: Does a vitamin C, hydrocortisone, and thiamine protocol decrease mortality in patients with severe sepsis or septic shock?

Reference: Marik et al. Hydrocortisone, Vitamin C and Thiamine for the Treatment of Severe Sepsis and Septic Shock: A Retrospective Before-After Study. Chest Dec 2016

  • Population: Adult patients admitted to the ICU with server sepsis or septic shock and a procalcitonin ≥2ng/ml (Sepsis and septic shock defined by the 1992 American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference definitions).
    • Exclusion: Patients less than <18 years of age, pregnant patients and patients with limitations of care.
  • Intervention: Vitamin C protocol (Vitamin C 1.5gm IV q6hr x four days or until ICU discharge, hydrocortisone 50mg IV q6h for seve days or until ICU discharge followed by a taper of three days and thiamine 200mg IV q12h for four days or until ICU discharge.
  • Comparison: Hydrocortisone 50mg q6hr IV per the current guidelines at the discretion of the attending physician.
  • Outcome:
    • Primary: Hospital survival
    • Secondary: Duration of vasopressor therapy, requirement for renal replacement therapy, change in serum procalcitonin and the SOFA score over first 72 hours

Authors’ Conclusions: Our results suggest that the early use of intravenous vitamin C, together with corticosteroids and thiamine may prove to be effective in preventing progressive organ dysfunction including acute kidney injury and reducing the mortality of patients with severe sepsis and septic shock. Additional studies are required to confirm these preliminary findings.”

checklistQuality Checklist for Observational Study:

  1. Did the study address a clearly focused issue? Yes
  2. Did the authors use an appropriate method to answer their question? Yes for demonstrating associations but no if wanting to demonstrate causation.
  3. Was the cohort recruited in an acceptable way? Unsure.
  4. Was the exposure accurately measured to minimize bias? Yes
  5. Was the outcome accurately measured to minimize bias? Yes
  6. Have the authors identified all-important confounding factors? Unsure
  7. Was the follow up of subjects complete enough? Yes
  8. How precise are the results? Unsure
  9. Do you believe the results? No
  10. Can the results be applied to the local population? Unsure
  11. Do the results of this study fit with other available evidence? Yes

checklistQuality Checklist for Chart Review (Worster et al Ann of EM 2005)

  1. Were the abstractors trained before data collection? Unsure
  2. Were the inclusion and exclusion criteria for case selection defined? Yes
  3. Were the variables defined? Yes
  4. Did the abstractors use data abstraction forms? Yes
  5. Was the abstractors’ performance monitored? Unsure
  6. Were the abstractors aware of the hypothesis/study objectives? Unsure
  7. Was the interobservere reliability discussed? No
  8. Was the interobservere reliability tested or measured? No
  9. Was the medical record database identified or described? Yes
  10. Was the method of sampling described? Yes
  11. Was the statistical management of missing data described? Unsure
  12. Was the study approved by the institutional or ethics review board? Yes

Key Results: There were 47 patients in the comparison group and 47 patients after in the vitamin C protocol treatment group.

 Mortality: 40.4% control group vs. 8.5% treatment group

  • Primary Outcome:
    • Mortality 19/47 (40.4%) Control Group vs. 4/47 (8.5%) Treatment Group
    • Absolute difference 31.9% NNT 3

Vit C Table

Screen Shot 2015-04-25 at 3.11.12 PMNormally the guest skeptic and I go through five points that threaten the validity of the study. This time it is going to be a little different.

Dr. Marik was asked some “tough questions” by Scott Weingart on EMCrit. One question was “Does [he] think there is any possibility his result could be false due to chance or systemic bias?”. His answer was:

  • “No.Why don’t the skeptics speak to the patients who have left our ICU alive and without residual organ failure?”

It seems like Dr. Marik might be committing a logical fallacy and making an appeal to emotion (argumentum ad passiones).  Rather than speaking to the patients who have left Dr. Marik’s ICU alive, I contacted some fellow skeptics from around the world to speak to the data as scientific skeptics.

We have skeptics from Canada, the USA, Australia and the UK. They are critical care physicians, academics, Physician Assistants, EBM experts, community EM physicians, and an EM pharmacist. These skeptics provide care in small rural hospitals all the way up to very large urban teaching centers.

I have asked each of them to introduce themselves, where they practice, provide one limitation of the study and whether or not they would change their practice based on this data.

Click on the names below to hear what these skeptics have to say about Dr. Marik’s study or listen to the whole SGEM podcast on iTunes.

  1. Andrew Worster (BEEM): Retrospective Study
  2. Salim Rezaie (REBEL EM): Association vs. Causation
  3. Rory Spiegel (EM Nerd): Lack of Randomization
  4. Lauren Westafer (FOAMCast): Lack of Blinding
  5. Chris Carpenter (EMA): Hawthorne/Observer Effect
  6. Chris Nickson (LITFL): External Validity
  7. Daniel Horner (St. Ellyn’s): Cost Effectiveness:
  8. Anand Swaminathan (EM Rap): Attention
  9. Chip Lange (TOTAL EM): Harm
  10. Meghan Groth (EM Pharm Girl): Synergistic Effects
  11. Jerome Hoffman (EMA): 30,000 Foot View

    Dr. Marik Grand Rounds 2014

    Dr. Marik Grand Rounds 2014

Comment on authors’ conclusion compared to SGEM Conclusion: We generally agree with the authors’ conclusions that the data suggests this treatment may (may not) prove to be effective and these preliminary results need confirmation.

SGEM Bottom Line: Vitamin C, hydrocortisone and thiamine was associated with lower mortality in severe septic and septic shock patients in this one small, single centre retrospective before-after study but causation has yet to be demonstrated.

Case Resolution: You continue with your intravenous fluids and antibiotics and the man recovers from his pneumonia and is discharged out of the ICU after four days doing well and expected to make a full recovery.

Clinical Application: While this provides some weak evidence of the effectiveness of a vitamin C cocktail it is not strong enough to reject the null hypothesis that there is no effect. Therefore, I will not be providing this treatment at this time based on this information.

What do I tell my patient? You tell the son you have read the original published study. It was a small observational study done at one hospital showing unusually good results. It demonstrated association not causation of vitamin C, hydrocortisone and thiamine reducing mortality. This is weak evidence but encouraging. Even the lead author of the study said the results were preliminary and needed to be confirmed. Our hospital is going to look at this information and decide if it is in the best interest of patients to use the treatment or not. For now, your dad will get the best medical care based on the best evidence.

Keener Kontest: Last weeks’ winner was Brenda Palsa. She is an RN from South Huron Hospital in Exeter, Ontario and it is her second win in a row. She knew the word lumbago is Latin for weakness of loins and thighs.

Listen to this weeks’ episode for the keener question. If you know the answer then send an email to with “keener” in the subject line. The first correct answer will receive a cool skeptical prize. 

Remember to be skeptical of anything you learn, even if you heard it on the Skeptics’ Guide to Emergency Medicine.

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  • Kirsty Challen
    • Karl Davis

      How does 40% mortality get one sad face and four happy? Doesn’t that make 2 sad and three happy?

      • davea0511

        It should. And there should be not sad faces for vitamin c group because the 4 deaths that occurred was *not* from sepsis.

    • davea0511

      The one mortality in the Vit C group was not related to sepsis. Your infographic seems so suggest that it was. Please fix.

  • Ken Milne
  • Ken Milne
    • Rohan Bussell

      Very interesting results Ken…Im very surprised that the abstainers are at 65%.
      If it was a brand new drug for morning sickness I would agree…but severe sepsis and septic shock patients are at a very high mortality risk visavis other causes of mortality. That is afterall why other methods of sepsis treatment were adopted before they were adequately studied.
      Far more is known about ascorbic acid than i think most of these practitioners realize.

    • Karl Davis

      OK, then the time for the RCT is immediately. Is there some reason we need to take a couple years to put together an RCT in a case like this? This is no mainstream situation where there is a great deal of mud in the water. 48 hours later the patients are either dead or alive, and current mortality rates are high, so this one should be lightning fast.

  • Ken Milne
    • Rohan Bussell

      The audio from Andrew Worster above did suggest that a prospective study is another option and I for one would welcome that. More retrospective studies will probably be forthcoming now that so many other sites have adopted the protocol…at least i hope they do additional retrospective studies and publish them.
      An RCT on this particular protocol will be a while coming and there is no particular reason for intensivists and resuscitationists to avoid this protocol if its reasonably believed it will save their patients.
      As Marik shows, if in doubt, do your own experiment on a dying patient and see for yourself.

  • Ken Milne

    Thank you to all the skeptics who contributed to this episode and made it the best global #FOAMed this week.

  • Felipe M.

    Shame on you, evidence-Talibans!. Please read yourselves: “Our hospital is going to look at this information and decide if it is in the best interest of patients to use the treatment or not”. It’s NOT the best interest of patients, it’s the best interest of your intellectual arrogance.
    The treatment is practically devoid of side effects and almost free!! We all do much worse stuff (and much more expensive) in the name of evidence with no real clinical benefit whatsoever, every day. The worst thing that can happen to your pneumonia patient is what was meant to happen anyway, with Marik combo or without.
    If later on the way a properly designed RCT satisfies your evidence thirst and proves Marik wrong, then stop using it and feel even more full of yourselves. Until then, give the damn thing a chance. I’d give it to myself.

    • Rohan Bussell

      “Shame on you, evidence-Talibans!”
      I think theres an element of truth to this, but at the same time you cant blame allopathic medicine for being very hesitant to accept something ‘new’ because there have been so many drugs and treatments that have turned out to be harmful.
      What I would say though is that ascorbic acid is not ‘new’ and that means that I think people are caught being habitually skeptical instead of well informed.
      The most obvious reason for this is that the Phase 1 safety trial for 50mg/kg/day vs 200mg/kg/day has already been completed with positive results. This already refutes Chip Langes criticism.
      Secondly, whilst it is correct that this retrospective study is insufficient on its own to prove to other sites that it cures sepsis, it has to be recognized that Dr Marik has reproduced this more than 100 times at his own site and it is therefore, in effect his own laboratory. His site has decided that it is no longer ethical to wait for an RCT and Marik has himself suggested that this needs to be done at a site that is interested in the protocol but not ready to commit.
      Finally, most of the criticism will find satisfaction from the phase 2 trial being done by Fowler that is testing 200mg/kg/day of ascorbic acid. This will provide results on how the vitamin c is performing against sepsis by itself.

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  • Ken Milne
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  • Rohan Bussell

    Yes, its about time a reputable physician had the guts to do something like this…it has the potential to just open the flood gates on the use of IV Vit C in allopathic medicine.
    Also good to point out that Marik himself didnt pull this out of thin air, he based it on recent work done on the use of ascorbic acid (vit c) and thiamine (vit b1) with sepsis. He also referred to the fact that there is a large body of work going back to 1949…in fact I know that the work goes back to experiments and research from the 1930s.

  • Karl Davis

    There are two kinds of ICU’s on this topic, the ones that tried and and report that it’s highly successful, and those who refuse to try it. The third category, where they tried and and say it doesn’t work, contains zero sites.
    Dr. Marik continues to use it to the present day and continues to have 8-9% all cause mortality and less than 1% mortality from sepsis specifically, while other places brag that they have gotten their sepsis-specific mortality rates under 20%, like it’s the greatest thing in the world, and ignore that Marik’s place and 50-100 other ICU’s are at 1/2 their mortality.
    The “I’m waiting for more evidence” crowd should win a Nobel Prize in ignoring the elephant in the room. What does it take to get people to try this? Maybe we need to see the UN report that Pakistan has better sepsis survival than the US before we move on it?
    I would like to see the Mayo clinic use it on half of their patients and not the other half, and report the results when they hit a 99% confidence interval, or when they reject it. If it wins, I would like to see it split into about 12 variations, not necessarily in a well controlled study, but as a series of parallel experiments to see what’s better. Should we always use 1.5 grams? Should the first dose be 2 grams, then 500 mg for each successive 6 hours? Does bode weight matter? Gender? Is 50 mg hydrocortisone best, vs. 40 mg or 60 mg? In a matter of months we should be able to step past validating this and fine-tune it.

  • Lawrence Lynn

    All of this is possible because thought leaders use guessed, inflationary and unvalidated set of thresholds as the “true state” for sepsis and hyped their own mortality reduction relative to historical controls when the actual controls showed no difference.

    Indeed, the denominator in sepsis is as inflated as German mark was in the 30s. Quote whatever mortality % you want. Without a solid denominator it means little because it takes a whealbarrel of “sepsis” today to buy a loaf of bread.

    This is what happens when the science itself is pathologic (Langmuir). Did they think others would not also simply bypass the controls and compare to the past producing their own mortality reduction miracle.

    I always did like Thiamine for sepsis if the patient was potentially malnourished or drank a little beer and I have no idea if Vit C works. However, that is the point. We really can’t learn anything if everbody is spinning. It’s like watching Fox and CNN.

    Many of those so quick to demand “science” have done the politically correct thing in the past and remained silent as each new silly set of static thresholds was rolled out as a scientific standard to define the true state (the denominator).

    In fact these guesses become their data. They don’t record and analyze the game films so they can learn what actually happened. Rather they are so intellectually arrogant that they only record and study the very threshold violations they guessed.

    This Vit C study is a wake up call. Read the work of Langmuir. Pathological science look very scientific and can go on for decades when a fundamental mistake was made, like using a one size fits all set of static thresholds for the true state of something which is actually comprised of a set of very different dynamic pattern phenotypes.

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  • Ken Milne

    This episode was referred to in the July issue of Emergency Medicine News.

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  • davea0511

    The mortality from the experimental group was not from sepsis. You need to revise everything you said that suggests that it was.

  • davea0511

    Depends on the doctor. These doctors are on the side of “don’t sue me … I have an excuse, and the 3rd largest industry behind me (Pharmaceuticals, food/drink is #1, and oil is #2)”.

  • davea0511

    So I just have to shout baloney at your rating of NO for interobserver reliability discussion, testing and measurement. Check out this video of 3 independent nurses: If these aren’t interobservers then I don’t know what is, and their reports are all independently glowing … each time saying “we, our, us” … they’re talking about what they all saw and observed independently, and where do you get off assuming that they didn’t check each other’s testing and measurements (and hell yes, they recorded a number of parameters regarding patient progress). So basically you failed as an investigator of this investigation bigtime, and as a result the only thing you had a right to assign “NO” to in your above analysis was that you didn’t believe it. Says more about you than the protocol. I’m sure glad you’ll never be my practitioner.

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  • Advanced…

    Contra arguments are less than weak. Suggest you all read Tom Levy, MD, JD, who wrote Primal Panacea. Especially Chapter 7. The Seven Medical Lies that kill. Our medical director uses 50 to 150 grams..not mg..but Grams. BTW, who created the RCT? It was the founder of orthomolecular medicine, Abram Hoffer, PhD, MD who proved the effectiveness of very high doses IV vitamin C and niacin for positive treatment of schizophrenia. But, you all do not know that.

  • Bob

    NIH seems to think there’s something to it – thoughts?

    • Ken Milne

      This is the study we did the structured critical review. It had an ePublication in 2016 and now it looks like it is out in print. It does not change our assessment. We are waiting for more and better information on this topic.