Marik Vitamin C Sepsis Protocol

You may remember the controversy about Paul Marik's suggestions that a combination of Vitamin C, steroids and Thiamine (sometimes known as HAT ¹ ) is a cure all for sepsis. There were some rather dramatic claims that this combination would reduce sepsis deaths to zero, and that it is a simple yet safe panacea to sepsis.

The #FOAMed world was rather sceptical about this, not least because the data was essentially a before and after service evaluation ² (with all the accompanying methodological issues), single centre and subject to multiple confounders. Despite this there was a lot of interest based on some fairly interesting pathophysiological arguments ^2–4 about why it might work. These were best described by Marik himself at the critical care reviews meeting back in 2017. If you missed that lecture then it's still available online and I'd really recommend you watch it below.

Marik's original study was pretty weak and is reviewed here in detail on the REBELEM site ^5,6 . It was small at just 94 patients and single centre and so it's right to be rather suspicious of these results. Despite this I am aware of several clinician who changed their practice to include the cocktail on the basis of 'what harm can it do, and they might be right'. I'm not so keen on that rationale to be honest. What we need is data.

The VITAMINS trial is one of several planned studies ^7–10 to look at the Marik protocol as a randomised controlled trial with the results being live streamed from the critical care reviews conference in Belfast on 17/1/2020. I'll be there and will update the blog as the results come out. You can watch the live stream below.

The VITAMINS trial, or more correctly 'The VitamIn C, HydrocorTisone and ThiAMINe in Patients With Septic Shock Trial (VITAMINS Trial) – A Prospective, Feasibility, Pilot, Multi-centre, Randomised, Open-label Controlled Trial' (Ed – that's really a dodgy acronym), is the first large trial to test the Marik protocol in a general sepsis ICU population. You can read the study protocol here, and the predetermined statistical review plan here ⁹ .

The results are published in JAMA today ¹¹ .

What kind of study is this?

It's a randomised controlled trial which is exactly what we need to determine with the protocol works in practice. However, this is listed as a feasibility study. The numbers are quite small and so it may not (in fact we don't expect) it to be definitive.

What are the interventions?

The treatment group received Vitamin C Ascorbic acid 1.5g every 6 hours i.v. while in ICU, until shock resolution for a maximum of ten days PLUS
Thiamine 200mg every 12 hours i.v. while in ICU, until shock resolution for a maximum of ten days PLUS Hydrocortisone 50mg every 6 hours i.v while in ICU, until shock resolution or for a maximum of 7 days, then tapered or stopped.

The control arm received Hydrocortisone 50mg every 6 hours i.v while in ICU, until shock resolution or for a maximum of 7 days, then tapered or stopped.

Tell me about the patients.

These were septic patients on the ICU. To get into the trial they had to be over 18 with the following parameters. The aim was to recruit 216 patients.

Blood lactate >2 mmol/L, despite adequate fluid resuscitation AND
need for continuous vasopressor therapy to keep mean arterial pressure (MAP) >65 mmHg for >2 hours

There were a bunch of standard exclusions too (e.g.pregnancy, DNR etc.) which seem reasonable and not too exclusive.

Patients were recruited in Australia, New Zealand and Brazil.

What about the outcomes?

The primary outcome was time alive and free of vasopressors at day 7 (168 hours) after randomization.

This was defined by the patient being alive at discontinuation of all vasopressors for at least 4 hours in the presence of a MAP>65 mmHg for the same 4 hour period as recorded in the ICU charts and censored at 7 days.

Primary outcome was time that patients had spent free (>4hrs) of vasopressors at 7 days. Sample size was increased to 216 after the first 60 pts, in order to achieve 90% power for a 25hr decrease in vasopressor time (considered clinically significant) #VITAMINStrial #CCR20
— Gabriel Beecham (@GBeecham) January 17, 2020

There are 10 additional secondary outcomes, but interestingly I can't see any patient orientated functional outcomes. Perhaps they will come later, but a 6 month functional score would be helpful. They did look at mortality data up to 90 days and also at hospital and ICU mortality rates.

So what are the main results?

They estimated that they would need 216 patients in the study and recruited 216. 786 were screened but excluded on predetermined criteria.

In terms of the primary outcome of time alive and free of vasopressor use the outcomes were 122.1 hours in the intervention group vs. 124.6 hours in the control group. This was not clinically nor statistically significant. Patients were similar at baseline. About 40% were ventilated at enrolment.

So basically there is no difference in outcome between the two groups for the primary outcome.

There was no difference in outcome at 28 days, 90 days, ICU mortality or hospital mortality.

There will be some in the FOAMed world who may be feeling smug about this after the initial controversy about the original study. At St Emlyn's we don't think that's right. There was a perfectly reasonable patho-physiological argument for doing this study. We should celebrate that it has been done and use the findings impartially, wisely and with kindness to all of those who had led us to this point.

You should also read the excellent editorial in JAMA.

The response from Paul Marik was more robust than anything I've ever seen. He questioned the protocol in the study, stating that they did not follow his protocol and the study was designed to fail. Strong words delivered with a great deal of emotion. However, the evidence here is not supportive of the treatment. We would argue that if there remains equipoise on the specific protocol designed by Marik, then we still need a trial to demonstrate this.

@tomoko_ICU acknowledges that timing will need to be investigated in future studies. Median time of treatment duration was only ~3 days, but clear criteria for stopping treatment: pressors being off for 4 consecutive hrs, pts leaving ICU, or 10 days treatment. #CCR20 #VITAMINS
— Alicia Waite (@_aacw) January 17, 2020

The clinical bottom line

Although this was only a feasibility trial this is pretty conclusive that the treatment effects suggested in observational studies are not repeated when tested by a higher scientific method. The rather ambitious claims that this regimen would change the world of sepsis management has not been seen in the results and we cannot recommend it as routine care.

However, there are still important questions about timing and patient selection and we look forward to the results of other trials that are currently recruiting.

References

1.

Marik P. Hydrocortisone, Ascorbic Acid and Thiamine (HAT Therapy) for the Treatment of Sepsis. Focus on Ascorbic Acid. Nutrients. November 2018:1762. doi:10.3390/nu10111762
2.

Marik PE, Khangoora V, Rivera R, Hooper MH, Catravas J. Hydrocortisone, Vitamin C, and Thiamine for the Treatment of Severe Sepsis and Septic Shock. Chest. June 2017:1229-1238. doi:10.1016/j.chest.2016.11.036
3.

Marik PE. Vitamin C for the treatment of sepsis: The scientific rationale. Pharmacology & Therapeutics. September 2018:63-70. doi:10.1016/j.pharmthera.2018.04.007
4.

Badeaux JE, Martin JB. Emerging Adjunctive Approach for the Treatment of Sepsis. Critical Care Nursing Clinics of North America. September 2018:343-351. doi:10.1016/j.cnc.2018.05.002
6.

Marik P, Khangoora V, Rivera R, Hooper M, Catravas J. Hydrocortisone, Vitamin C, and Thiamine for the Treatment of Severe Sepsis and Septic Shock: A Retrospective Before-After Study. Chest. 2017;151(6):1229-1238. doi:10.1016/j.chest.2016.11.036
7.

Moskowitz A, Andersen LW, Huang DT, et al. Ascorbic acid, corticosteroids, and thiamine in sepsis: a review of the biologic rationale and the present state of clinical evaluation. Crit Care. October 2018. doi:10.1186/s13054-018-2217-4
8.

Hager DN, Hooper MH, Bernard GR, et al. The Vitamin C, Thiamine and Steroids in Sepsis (VICTAS) Protocol: a prospective, multi-center, double-blind, adaptive sample size, randomized, placebo-controlled, clinical trial. Trials. April 2019. doi:10.1186/s13063-019-3254-2
9.

Fujii T, Udy A, Deane A, et al. Vitamin C, Hydrocortisone and Thiamine in Patients with Septic Shock (VITAMINS) trial: study protocol and statistical analysis plan. Crit Care Resusc. 2019;21(2):119-125. https://www.ncbi.nlm.nih.gov/pubmed/31142242.
10.

Moscowitz A. Ascorbic Acid, Corticosteroids and Thiamine in Sepsis (ACTS) protocol and statistical analysis plan: a prospective, multicentre, double-blind, randomised, placebo-controlled clinical trial. BMJ Open. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6937040/. Published 2018. Accessed 2019.

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Simon Carley MB ChB, PGDip, DipIMC (RCS Ed), FRCS (Ed)(1998), FHEA, FAcadMed, FRCEM, MPhil, MD, PhD is Creator, Webmaster, owner and Editor in Chief of the St Emlyn's blog and podcast. He is visiting Professor at Manchester Metropolitan University and a Consultant in adult and paediatric Emergency Medicine at Manchester Foundation Trust. He is co-founder of BestBets, St.Emlyns and the MSc in emergency medicine at Manchester Metropolitan University. He is an Education Associate with the General Medical Council and is an Associate Editor for the Emergency Medicine Journal. His research interests include diagnostics, MedEd, Major incidents & Evidence based Emergency Medicine. He is verified on twitter as @EMManchester

Marik Vitamin C Sepsis Protocol

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