Back in 2017 the sepsis world had a rather strong reaction to a paper published by Paul Marik that suggested that a combination of steroid, vitamin C and Thiamine could cure sepsis. The data, published in Chest , was met with scepticism on social media(4,5,6,10,12,13) but also with interest in other circles perhaps due to the enthusiasm expressed by the lead authors (1,4).
Marik’s data was a before/after study which as we all know is an imperfect method for testing therapeutic interventions, which was one of several reasons for the scepticism(4). One impact of Marik’s work was the development of several randomised controlled trials to test the regime, some of which we have covered before on St emlyn’s and other blogs (6,9,11,14), and a further trial has been published this week (7). The abstract is below, but as always we strongly recommend that you read the full paper yourself.
What type of study is this?
It’s a randomised controlled trial which is the right study design for an intervention trial. It’s a multicentre study (14 centres) with blinding of the trial interventions. These are all good things to see and notably very different to the initial observational studies which would inevitably be more exposed to bias. Patients were randomised using block randomisation and stratification to try and ensure similar randomisation ratios at different sites. Block randomisation is a useful tool in these circumstances. You can read more about block randomisation here(8).
Tell me about the patients.
They included adult patients with a diagnosis of sepsis who required vasopressors on the ICU. As with all sepsis trials that does mean that it was a whole range of different pathologies, severities and patient groups. Table 1 in the paper shows this variation and there are a few differences between the groups that may influence the results.
What about the intervention?
Patients randomized to the intervention received ascorbic acid (1500mg), hydrocortisone (50mg), and thiamine (100mg) every 6 hours for 4 days or until intensive care unit (ICU) discharge. Patients in the control group wer a placebo (saline).
What about the outcomes?
In a disease such as sepsis I’m really interested in mortality as an outcome but in this trial the primary outcome was a change in the SOFA score in the first 72 hours. I can see why that was chosen on the basis of past studies and claims about how this group of drugs work, and perhaps we might expect to see an improvement in SOFA score to be a pre-requisite for mortality improvement, but they are not entirely the same (although mortality was a secondary outcome). The secondary outcomes were those we usually see in ICU trials (e.g. length of stay, renal support etc.).
What did they find?
They enrolled 205 patients from 4569 screened (more on this later). There were a number of protocol violations (e.g. given steroids in non-intervention group). In terms of the main outcome of change in SOFA score there was no statistical difference and in fact the outcomes were better in the non-intervention group (mean difference, −0.8; 95%CI, −1.7 to 0.2; P = .12). Similar findings occured for renal failure (31.7% in the intervention group vs 27.3% in the placebo group; adjusted risk difference, 0.03; 95% CI, −0.10 to 0.17; P = .58) and for mortality (34.7% vs 29.3%; hazard ratio, 1.3; 95% CI, 0.8-2.2; P = .26).
What does this all mean?
This paper once again finds little evidence and no real signal for the effectiveness of thiamine, steroids and vitamin C in sepsis patients when tested in a placebo controlled randomised controlled trial. However, there will be those who will question whether this is what Marik originally suggested. Notably the intervention/randomisation took place some time after the patients were identified, although this was tested and there did not seem to be any time effect (although the numbers get quite small for early interventions).
Similarly many patients were excluded because they were already on steroids, one of the reasons for the small number recruited as compared to those screened (following trials like ADRENAL), so perhaps the intervention should have been the three drugs vs. mineralocorticoids. Having said that we might still have expected to see some signal here and there is none.
The bottom line.
Evidence for the effectiveness of vitamin C, thiamine and steroids in combination remains elusive and cannot be routinely recommended.
- Early management of severe sepsis: concepts and controversies Paul E. Marik PMID: 24889440 DOI: 10.1378/chest.13-2104
2. Vitamin C, Hydrocortisone, and Thiamine for the Treatment of Severe Sepsis and Septic Shock: A Retrospective Analysis of Real-World Application
Jane J. Litwak,1 Nam Cho,2,3 H. Bryant Nguyen,2,4 Kayvan Moussavi,5 and Thomas Bushell2,3,* J Clin Med. 2019 Apr; 8(4): 478. Published online 2019 Apr 9. doi: 10.3390/jcm8040478
3. Ascorbic Acid, Corticosteroids and Thiamine in Sepsis (ACTS) protocol and statistical analysis plan: a prospective, multicentre, double-blind, randomised, placebo-controlled clinical trial.Moskowitz A, Yankama T, Andersen LW, Huang DT, Donnino MW, Grossestreuer AV; ACTS Clinical Trial Investigators.BMJ Open. 2019 Dec 17;9(12):e034406. doi: 10.1136/bmjopen-2019-034406.PMID: 31852712
7. Effect of Ascorbic Acid, Corticosteroids, and Thiamine on Organ Injury in Septic Shock The ACTS Randomized Clinical Trial
Ari Moskowitz, MD1,2; David T. Huang, MD, MPH3,4; Peter C. Hou, MD5; et alJonathan Gong, MD6; Pratik B. Doshi, MD7,8; Anne V. Grossestreuer, PhD2,9; Lars W. Andersen, MD, MPH, PhD, DMSc2,10,11; Long Ngo, PhD12; Robert L. Sherwin, MD13; Katherine M. Berg, MD1,2; Maureen Chase, MD, MPH2,9; Michael N. Cocchi, MD2,14; Jessica B. McCannon, MD15; Mark Hershey, MD16; Ayelet Hilewitz, MD17; Maksim Korotun, MD17; Lance B Becker, MD6; Ronny M Otero, MD18; Junior Uduman, MD19; Ayan Sen, MD, MSc20; Michael W. Donnino, MD1,2,9; for the ACTS Clinical Trial Investigators JAMA. 2020;324(7):642-650. doi:10.1001/jama.2020.11946
8. Block Randomisation https://www-bmj.com.manchester.idm.oclc.org/content/343/bmj.d7139
9. Fowler AA III, Truwit JD, Hite RD, et al. Effect of vitamin C infusion on organ failure and biomarkers of inflammation and vascular injury in patients with sepsis and severe acute respiratory failure: the CITRIS-ALI randomized clinical trial. JAMA. 2019; 322(13):1261-1270. doi:10.1001/jama.2019.11825
11. Fowler AA 3rd, Truwit JD, Hite RD, et al. Effect of Vitamin C Infusion on Organ Failure and Biomarkers of Inflammation and Vascular Injury in Patients With Sepsis and Severe Acute Respiratory Failure: The CITRIS-ALI Randomized Clinical Trial. JAMA. 2019;322(13):1261‐1270. doi:10.1001/jama.2019.11825 PMID: 31573637 NCT02106975
14. Chang P, Liao Y, Guan J, et al. Combined treatment with hydrocortisone, vitamin C, and thiamine for sepsis and septic shock (HYVCTTSSS): A randomized controlled clinical trial. Chest. 2020;S0012-3692(20)30552-3. doi:10.1016/j.chest.2020.02.065 PMID: 32243943