An Even More Skeptical Guide to Vitamin C in Sepsis
I’ve been more than a little skeptical about the so called metabolic cure for sepsis for a while, but I wanted to wait until the results of the studies were back before passing judgement. I think we can now safely say that the wait is over.
There have been (at least) nine randomized trials of vitamin C in sepsis/septic shock. These trials differed in design, ranging from single center open-label trials, to large multinational placebo-controlled studies.
| Study | Inclusion | Sites | Blinding | Control | n |
|---|---|---|---|---|---|
| CITRIS-ALI | Sepsis & ARDS | 7 ICUs | Double blind | Placebo | 167 |
| VITAMINS | Septic shock | 10 ICUs | Open label | Hydrocortisone | 216 |
| HYVCTTSSS | Sepsis & septic shock | 1 ICU | Single blind | Placebo | 140 |
| ORANGES | Sepsis & septic shock | 1 ICU | Double blind | Placebo | 140 |
| ATESS | Septic shock | 4 EDs | Double blind | Placebo | 116 |
| ACTS | Septic shock | 14 ICUs | Double blind | Placebo | 200 |
| ViCTOR | Septic shock | 2 ICUs | Open label | Standard of care | 90 |
| Wani et al | Sepsis | 1 ICU | Open label | Standard of care | 100 |
| VICTAS | Septic shock | >43 ICUs | Double blind | Placebo | 501 |
They differed slightly in the intervention, though most used a similar cocktail to what was used in the original Marik study.
| Study | Hydrocortisone | Ascorbic acid | Thiamine |
|---|---|---|---|
| Marik et al | 50 mg q6 | 1.5 gm q6 | 200 mg BID |
| CITRIS-ALI | - | 50 mg/kg q6 | - |
| VITAMINS | 50 mg q6 | 1.5 gm q6 | 100 mg BID |
| HYVCTTSSS | 50 mg q6 | 1.5 gm q6 | 200 mg BID |
| ORANGES | 50 mg q6 | 1.5 gm q6 | 200 mg BID |
| ATESS | - | 50 mg/kg q6 | 200 mg BID |
| ACTS | 50 mg q6 | 1.5 gm q6 | 100 mg BID |
| Wani et al | 50 mg q6 | 1.5 gm q6 | 200 mg BID |
| ViCTOR | 50 mg q6 | 1.5 gm q6 | 200 mg BID |
| VICTAS | 50 mg q6 | 1.5 gm q6 | 100 mg BID |
These studies also looked at different primary endpoints (ICU mortality, hospital mortality, vasopressor free days, etc). Crucially, what these studies have in common is that none has come close to replicating the miraculous effect reported by Marik et al.
In fact all of these studies - except for ORANGES - were negative for their primary endpoints (ORANGES had two primary endpoints; only one was positive):
| Study | Primary Endpoint | Significant |
|---|---|---|
| CITRIS-ALI | ΔSOFA score | NO |
| VITAMINS | Vasopressor free days | NO |
| HYVCTTSSS | Hospital mortality | NO |
| ORANGES | ΔSOFA score, Time to resolution of shock | NO, YES |
| ATESS | ΔSOFA score | NO |
| ACTS | ΔSOFA score | NO |
| Wani et al | Hospital mortality | NO |
| ViCTOR | Hospital mortality | NO |
| VICTAS | Vasopressor & ventilator free days | NO |
Furthermore, if we look at mortality 4 studies show a decrease in mortality with HAT and 5 show an increase, though only one achieved statistical significance. It is worth noting that VICTAS was stopped early due to lack of efficacy.
| Study | Mortality Timeframe | Mortality (intervention) | Mortality (control) | OR | Significant Δmortality |
|---|---|---|---|---|---|
| CITRIS-ALI | 28 day | 29.8% | 45.8% | 0.65 | YES |
| VITAMINS | 28 day | 22.4% | 20.2% | 1.11 | NO |
| HYVCTTSSS | 28 day | 27.5% | 16.9% | 1.63 | NO |
| ORANGES | 28 day | 16.2% | 18.8% | 0.86 | NO |
| ATESS | 28 day | 20.8% | 15.5% | 1.34 | NO |
| ACTS | 30 day | 34.7% | 29.3% | 1.18 | NO |
| Wani et al | 28 day | 24.0% | 28.0% | 0.86 | NO |
| ViCTOR | 30 day | 57.8% | 53.5% | 1.08 | NO |
| VICTAS | 30 day | 22.2% | 24.1% | 0.92 | NO |
If we meta-analyze these studies, the effect on mortality is equally unambiguous.
Forrest Plot of mortality in randomized trials of Vitamin C in sepsis.
So what can we conclude based on this analysis?
First, vitamin C does not reduce mortality in patients with sepsis. What once appeared promising in an uncontrolled n=47 observational study, has not been replicated in nine randomized trials with an n=1638.
Second, while there may be some secondary effects such as faster resolution of shock or weaning from vasopressors, there is no evidence that this is anything more than the effect of corticosteroids.
Even if the metabolic cure is completely benign - and it probably is - over the last three years, we have dedicated a huge amount of resources to studying the utility of HAT in sepsis. It’s not just the tens of millions of dollars spent but then opportunity cost - how many promising critical care interventions were delayed because of vitamin C?
Finally, what can we learn about ourselves from this vitamin C mis-adventure?
we are quick to embrace vitamins; we tend to assume that 'natural' things must be safe (the so-called appeal-to-nature fallacy) unfortunately, not all ‘natural’ things are benign, especially at high dose.
we also fall for the normalization fallacy that ‘correcting’ derangements will ‘cure’ the associated disease; sadly most metabolic deficiencies are symptoms, not the cause of disease. Some of these abnormalities may even be adaptive, such as sequestering iron during infection.
while respecting expertise, we should be wary of eminence based medicine, which is not a substitute for a well conducted trial.
we genuinely want new therapies to work, but, as Carl Sagan cautioned, “extraordinary claims require extraordinary evidence”
Data/code availability:
You can download my raw data here.
The meta-analysis was done using R version 3.6.2 with the MetaFoR package.