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June - 2017


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Hydrocortisone, Vitamin C, and Thiamine for the Treatment of Severe Sepsis and Septic Shock: A Retrospective Before-After Study

P Marik, V Khangoora, R Rivera, M Hooper, J Catravas CHEST, 2017, 151(6):1229-1238


We don't usually include retrospective before and after studies in JC, but this analysis of a three pronged novel sepsis treatment - vitamin C, thiamine, and “moderate-dose” hydrocortisone - has gained a lot of attention, and generated a lot of debate about the intersection of social media and science.

In this retrospective before and after study;

  • After cohort (6 months) 47 patients with severe sepsis or septic shock and a PCT>= 2ng/ml were treated with IV vitamin C (1.5 g every 6 h), IV thiamine (200 mg every 12 h), and IV hydrocortisone (50 mg every 6 h)
  • Before cohort 47 patients from 7-months earlier, of whom 60% received hydrocortisone 
  • Hospital mortality 40.4% before vs 8.5% after, propensity adj OR 0.13 (95% CI, 0.04-0.48)
  • Duration vasopressor support reduced by 2/3, need for RRT decreased (37% vs 10%)

There are obvious limitations;

  • Before and after studies cannot adjust for time or process dependent confounders, and therefore should be considered as pilot data.
  • The first 3 patients in the after period were excluded, the reason is unclear
  • The evidence for the presence, duration, magnitude, and importance of vitamin C and thiamine deficiency in critical illness is not well established. Also, the effect of replacement is not well described, i.e. select those with low values or all, dose, duration
  • A three pronged treatment is open to criticism regarding which component is effective
  • Baseline hospital mortality was high , and the treatment effect large. In the past these sort of effects have not been reproduced in larger RCTs.
  • Other studies (APC, vitamin D, insulin, growth hormone, steroids) have failed to validate single centre positive results in larger studies

However there has been a lot of interest in the result, and their are biological mechanisms that could explain an effect. Given this, a sensible course could be to use this as hypothesis generating, and design observational then if warranted interventional studies to investigate this novel treatment regime.



BACKGROUND: The global burden of sepsis is estimated as 15 to 19 million cases annually,

with a mortality rate approaching 60% in low-income countries.


METHODS: In this retrospective before-after clinical study, we compared the outcome

and clinical course of consecutive septic patients treated with intravenous vitamin C,

hydrocortisone, and thiamine during a 7-month period (treatment group) with a control

group treated in our ICU during the preceding 7 months. The primary outcome was hospital

survival. A propensity score was generated to adjust the primary outcome.


RESULTS: There were 47 patients in both treatment and control groups, with no significant

differences in baseline characteristics between the two groups. The hospital mortality was

8.5% (4 of 47) in the treatment group compared with 40.4% (19 of 47) in the control group

(P < .001). The propensity adjusted odds of mortality in the patients treated with the vitamin

C protocol was 0.13 (95% CI, 0.04-0.48; P . .002). The Sepsis-Related Organ Failure

Assessment score decreased in all patients in the treatment group, with none developing

progressive organ failure. All patients in the treatment group were weaned off vasopressors, a

mean of 18.3  9.8 h after starting treatment with the vitamin C protocol. The mean duration

of vasopressor use was 54.9  28.4 h in the control group (P < .001).


CONCLUSIONS: Our results suggest that the early use of intravenous vitamin C, together with

corticosteroids and thiamine, are effective in preventing progressive organ dysfunction,

including acute kidney injury, and in reducing the mortality of patients with severe sepsis and

septic shock. Additional studies are required to confirm these preliminary findings.


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