While early recognition and treatment of sepsis has improved outcomes, mortality rates continue to be high. In low income countries, septic patients suffer mortality rates as high as 60%. Sepsis has been associated with vitamin c deficiency, with lower levels of vitamin c being associated with higher mortality rates. Prior studies targeting pathophysiological effects of sepsis have failed. In order to have a significant global impact on sepsis, therapies should be inexpensive, safe, and readily available. Marik et al. study ICU patients with severe sepsis and septic shock treated with hydrocortisone, vitamin c, and thiamine.

Clinical Question

Does the combination of hydrocortisone, vitamin c and thiamine reduce mortality in patients with severe sepsis and septic shock?


Treatment population consisted of consecutive adult patients between January 2016 and July 2016 admitted to the EVMS critical care medicine service with severe sepsis or septic shock and a procalcitonin of >/= 2 ng/ml.


Standard ICU care plus:
Hydrocortisone 50 mg q6 hours x7 days or until ICU discharge and followed by a 3 day tapper
IV vitamin C 1.5g q6 hours x4 days or until ICU discharge
IV thiamine 200 mg q12 hours x4 days or until ICU discharge


Standard ICU care + hydrocortisone 50 mg q6 hours X 7 days or until ICU discharge and followed by a 3 day tapper


Primary: Hospital survival
Secondary: Duration of vasopressor therapy, requirement of renal replacement therapy in patients with AKI, ICU length of stay, change in serum procalcitonin over 72 hours, change in SOFA score over 72 hours


Retrospective, before-after clinical study of consecutive patients presenting to the ICU with severe sepsis or septic shock


Pregnant patients
Age <18 Procalcitonin of <2 ng/ml in first 24 hours of ICU stay Patients with limitation of care

Primary Results

  • 94 patients included in study
  • Baseline characteristics were similar between groups

Critical Results

Treated Control
Hospital Mortality 4 (8.5%) 19 (40.4%) p < 0.001
ICU LOS 4 (3-5) 4 (4-10)
Duration of vasopressors (hr) 18.3 +/- 9.8 54.9 +/- 28.4 p < 0.001
RRT for AKI 3/31 (10%) 11/30 (33%) p < 0.02
Delta SOFA (72 hr) 4.8 +/- 2.4 0.9 +/- 2.7 p < 0.001
Procalcitonin Clearance (72 hr) 86.4% (80.1-90.8) 33.9% (-62.4-64.3) p < 0.001


  • Study addressed a clear question and was focused on a clinically important outcome
  • Baseline characteristics of control and treatment arms are similar
  • Patients were consecutively enrolled


  • Utilized methodology (before and after) can only demonstrate association, not causality
  • Small sample size
  • Single center study reducing external validity
  • There was no blinding performed (either patients, providers or outcome assessors) which introduces significant bias
  • Treatment and control occurred during different seasons
  • Not every hospital is able to perform procalcitonin measurements

Author's 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.”

Our Conclusions

This before-after study is a thought provoking and hypothesis generating study for the use of vitamin c, thiamine, and corticosteroid in combination for the treatment of patients with severe sepsis and septic shock. If reproduced in a large RCT it may have important implications for the future treatment of severer sepsis and septic shock.

Potential Impact To Current Practice

Early adopting hospitals around the country and the world have started to use the combination of hydrocortisone, vitamin c, and thiamine in their treatment of septic patients. Depending on where you work, there may be a push to start using this protocol prior to methodologically sound studies demonstrating its benefit.

Bottom Line

The combination of hydrocortisone, vitamin c, and thiamine may (or may not) reduce the mortality rate of patients with severe sepsis and septic shock. The methodology in this study does not allow for a definitive answer.

Read More

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REBEL EM: The Marik Protocol: Have We Found a “Cure” for Severe Sepsis and Septic Shock?

EMLit of Note: Vitamin C for Sepsis

PulmCrit: Metabolic Sepsis Resuscitation – The Evidence Behind Vitamin C

EMCrit: Paul Marik on the Metabolic Resuscitation of Sepsis

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

MDCalc: First Scurvy, Now Sepsis: Is Vitamin C the New Old Wonder Drug?