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Date: September 11th, 2019

Reference: Putzu et al. The Effect of Vitamin C on Clinical Outcome in Critically Ill Patients: A Systematic Review with Meta-Analysis of Randomized Controlled Trials. Critical Care Medicine. June 2019.

Guest Skeptics: Dr. Erin Willard is a PGY-3 Emergency Medicine Resident, Department of Emergency Medicine, University of Arkansas for Medical Sciences.

Dr. Carly Eastin is an Associate Professor, Division of Research and Evidence Based Medicine, Department of Emergency Medicine, University of Arkansas for Medical Sciences.

Case: A 45-year-old female in the emergency department is being admitted to the intensive care unit (ICU) for septic shock secondary to urinary tract infection (UTI). She has been given fluids, antibiotics, and is currently maintaining adequate mean arterial pressure (MAP) on low-dose vasopressors. You are ready to call the ICU and get her admitted. But you remember seeing in the news there was a study claiming vitamin C could cure sepsis. You wonder if giving vitamin C will affect her outcome?

Background: There was a huge buzz in the media a few years ago about a vitamin C cocktail (vitamin C, hydrocortisone and thiamine) as a possible cure for sepsis. This was because of a well-known critical care physician Dr. Paul Marik.

Dr. Paul Marik

Dr. Marik published a retrospective before and after study that included a vitamin C cocktail reporting an impressive number needed to treat of 3 to prevent one death due to sepsis.

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

We reviewed Dr. Marik’s observational study on SGEM#174. A dozen skeptics commented about the validity of the study including my EBM mentor Dr. Andrew Worster who started BEEM and Legend of Emergency Medicine Dr. Jerome Hoffman.

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

A number of clinical trials are currently underway in an attempt to replicated Dr. Marik’s findings. The existing evidence to support vitamin C use in patients with septic shock is weak and has been summarized in a systematic review meta-analysis. 

Clinical Question: Does the administration of vitamin C to an adult critically ill ICU patient or cardiac surgery patients decrease mortality?

Reference: Putzu et al. The Effect of Vitamin C on Clinical Outcome in Critically Ill Patients: A Systematic Review with Meta-Analysis of Randomized Controlled Trials. Critical Care Medicine. June 2019.

  • Population: Randomized trials examining critically ill adult ICU or cardiac surgery patients
    • Exclusions: Inappropriate setting (cardiac or ICU) or study design (RCT), pediatrics, non-critically ill
  • Intervention: Any type of vitamin C formulation or regimen
  • Comparison: Placebo or no therapy
  • Outcome:
    • Primary outcome: Mortality at the longest follow-up available
    • Secondary outcomes: Acute kidney injury, supraventricular tachycardia, ventricular arrhythmia, stroke, ICU and hospital length of stay.

Authors’ Conclusions:“In a mixed population of ICU patients, vitamin C administration is associated with no significant effect on survival, length of ICU or hospital stay. In cardiac surgery, beneficial effects on postoperative atrial fibrillation, ICU or hospital length of stay remain unclear. However, the quality and quantity of evidence is still insufficient to draw firm conclusions, not supporting neither discouraging the systematic administration of vitamin C in these populations. Vitamin C remains an attractive intervention for future investigations aimed to improve clinical outcome.”

Quality Checklist for Therapeutic Systematic Reviews:

  1. The clinical question is sensible and answerable. Yes
  2. The search for studies was detailed and exhaustive. Yes
  3. The primary studies were of high methodological quality. Unsure
  4. The assessment of studies were reproducible. Yes
  5. The outcomes were clinically relevant. Yes
  6. There was low statistical heterogeneity for the primary outcomes. No
  7. The treatment effect was large enough and precise enough to be clinically significant. No

Key Results: They included 44 randomized studies with 16 from the ICU setting (n=2,857) and 2 from cardiac surgery (n=3,598).

No statistical difference in mortality with the administration of vitamin C.

  • Primary Outcome: Mortality
    • ICU: No statistical difference 28% in the vitamin C group vs 29% in the control group. RR 0.90 (95% CI 0.74-1.10; p=0.31)
    • Cardiac Surgery: No statistical difference in post-operative mortality
  • Secondary Outcomes:
    • ICU: No statistical difference in AKI, ICU or hospital LOS
    • Cardiac Surgery: Less post-operative atrial fibrillation, ICU and hospital LOS. No statistical difference in AKI, stroke or ventricular arrhythmias.

1) Focused Question: We would have preferred to have a much more focused question. This SRMA looked at critically ill patient whether they were in the ICU or post-operative cardiac surgery patients. There is a possibility that vitamin C could have a patient oriented benefit identified through a SRMA. However, the heterogeneity of the included population could hide any subgroup demonstrating efficacy. We would have like to have the question of whether or not in patients suffering from severe sepsis or septic shock would have a mortality benefit from the administration of vitamin C.

2) Quality of Trials: One of the weaknesses of a SRMA is the quality of the included trials. The vast majority (36/44) of the included trials were deemed to be of high-risk of bias. There is this hierarchy of evidence-based medicine where SRMA are considered better than randomized control trials. However, we would have more confidence in a well designed multi-centered, blinded, randomized, placebo-controlled trial than a SRMA containing poor quality studies. Mashing low quality studies in a meat grinder does not get us any closer to the “truth”.

3) Heterogeneity: The statistical heterogeneity represented by the I2metric was moderately high. This relates to the 1stnerdy point and the variety of patients included in the study. There was also a great deal of variability in vitamin C regimen (dose and route of administration). If the result demonstrated benefit this would strength our confidence in the effect of vitamin C in a variety of critically ill patients at a variety of dosages. Because they failed to demonstrate efficacy we still do not know if there is a mortality or other benefit to vitamin C.

4) Harm: As with many studies, there was limited data on harm of the intervention. Most of the studies included in this SRMA did not systematically assess advents due to vitamin C administration. While it is probably safe it would be intellectually inaccurate to claim safety.

5) Burden of Proof: In epistemology the burden of proof is on those making the claim. Advocates of vitamin C claim that it provides a patient-oriented benefit. Research studies are set up with a null hypothesis (no effect). Evidence needs to be presented to reject the null hypothesis. At this point in time the burden in support of vitamin C has not been met. That does not mean we can make the claim that vitamin C does not work but rather we do not have sufficient evidence to warrant rejecting the null.

Comment on Authors’ Conclusion Compared to SGEM Conclusion: We agree that there appears to be no mortality benefit but that the secondary outcomes should only be viewed as hypothesis generating.

SGEM Bottom Line: There is not enough evidence to support the routine use of vitamin C in critically ill patients.

Dr. Erin Willrd

Case Resolution: You remember that there is no good evidence that vitamin C treatment in critically ill patients like sepsis has benefit and chose not to this therapy. The patient is transitioned to the floor the following day and ultimately discharged home without end-organ damage.

Clinical Application: Vitamin C may prove beneficial in the prevention of post-operative supraventricular arrhythmia. However, the available evidence has significant limitations and should be viewed as hypothesis generating for our cardiology colleagues.  Further high-quality research is needed in this area before we can confidently reject the null hypothesis.

Dr. Carly Eastin

What Do I Tell My Patient? We are going to admit you to the ICU and give you IV antibiotics for your serious infection. You may have heard in the media about vitamin C being a cure for sepsis (severe infections). We hope that is true but at this time we do not have good enough evidence to routinely give it to patients.

Keener Kontest: Last weeks’ winner was Dr. Terrance Creighton, a PGY II, Emergency Medicine Resident at Detroit Medical Center. He knew William Einthoven published the first ECG depicting atrial fibrillation?

List to the SGEM podcast to hear this weeks’ question. If you think you know the answer, send an email to  TheSGEM@gmail.com with keener in the subject line. The first correct answer will receive a cool skeptical prize.

Other FOAMed Resources:

  • The 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
  • EMCrit: Metabolic sepsis resuscitation: the evidence behind Vitamin C
  • Pharmacy Joe: Vitamin C, Hydrocortisone, and Thiamine for Severe Sepsis and Septic Shock
  • Everyday EBM: Vitamin C in Sepsis – Splashes in the Popular Press
  • 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?

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