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 TheSGEM@gamil.com 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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