Background
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?
Population
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.
Intervention
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
Control
Standard ICU care + hydrocortisone 50 mg q6 hours X 7 days or until ICU discharge and followed by a 3 day tapper
Outcomes
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
Design
Retrospective, before-after clinical study of consecutive patients presenting to the ICU with severe sepsis or septic shock
Excluded
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 |
Strengths
- 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
Limitations
- 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
The Bottom Line: An Orange a Day Keeps Sepsis at Bay?
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?