Skip to main content

Advertisement

Springer Nature Link
Log in

Combination therapy of vitamin C and thiamine for septic shock: a multi-centre, double-blinded randomized, controlled study

  • Original
  • Published:
Intensive Care Medicine Aims and scope Submit manuscript

Abstract

Purpose

To evaluate the effects of early combination therapy with intravenous vitamin C and thiamine on recovery from organ failure in patients with septic shock.

Methods

The ascorbic acid and thiamine effect in septic shock (ATESS) trial was a multi-centre, double-blind, randomized, controlled trial conducted in four academic emergency departments, enrolling adult patients with septic shock from December 2018 through January 2020. Patients were randomly assigned in a 1:1 ratio to either the treatment group [intravenous vitamin C (50 mg/kg, maximum single dose 3 g) and thiamine (200 mg) administration every 12 h for a total of 48 h] or the placebo group (identical volume of 0.9% saline with the same protocol). The primary outcome was Δ Sequential Organ Failure Assessment (SOFA) score (SOFA score at enrolment–SOFA score after 72 h). Eighteen secondary outcomes were predefined, including shock reversal and 28-day mortality.

Results

A total of 111 patients were enrolled, of which 53 were assigned to the treatment group and 58 were assigned to the placebo group. There was no significant difference in ΔSOFA scores between the treatment group and the placebo group [3, interquartile range (IQR) − 1 to 5 vs. 3, IQR 0–4, respectively, p = 0.96]. Predefined secondary outcomes were also not significantly different between the groups.

Conclusion

In this study, vitamin C and thiamine administration in the early phase of septic shock did not improve organ function compared with placebo, despite improvements in vitamin C and thiamine levels.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
$34.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Singer M, Deutschman CS, Seymour CW, Shankar-Hari M, Annane D, Bauer M, Bellomo R, Bernard GR, Chiche JD, Coopersmith CM, Hotchkiss RS, Levy MM, Marshall JC, Martin GS, Opal SM, Rubenfeld GD, van der Poll T, Vincent JL, Angus DC (2016) The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA 315:801–810

    Article  CAS  Google Scholar 

  2. Vincent JL, Jones G, David S, Olariu E, Cadwell KK (2019) Frequency and mortality of septic shock in Europe and North America: a systematic review and meta-analysis. Crit Care 23:196

    Article  Google Scholar 

  3. Vincent J-L (2018) How I treat septic shock. Intensive Care Med 44:2242–2244

    Article  CAS  Google Scholar 

  4. De Backer D, Cecconi M, Lipman J, Machado F, Myatra SN, Ostermann M, Perner A, Teboul J-L, Vincent J-L, Walley KR (2019) Challenges in the management of septic shock: a narrative review. Intensive Care Med 45:420–433

    Article  Google Scholar 

  5. Coopersmith CM, De Backer D, Deutschman CS, Ferrer R, Lat I, Machado FR, Martin GS, Martin-Loeches I, Nunnally ME, Antonelli M, Evans LE, Hellman J, Jog S, Kesecioglu J, Levy MM, Rhodes A (2018) Surviving sepsis campaign: research priorities for sepsis and septic shock. Intensive Care Med 44:1400–1426

    Article  Google Scholar 

  6. Donnino MW, Carney E, Cocchi MN, Barbash I, Chase M, Joyce N, Chou PP, Ngo L (2010) Thiamine deficiency in critically ill patients with sepsis. J Crit Care 25:576–581

    Article  CAS  Google Scholar 

  7. Iglesias J, Vassallo AV, Patel VV, Sullivan JB, Cavanaugh J, Elbaga Y (2020) Outcomes of metabolic resuscitation using ascorbic acid, thiamine, and glucocorticoids in the early treatment of sepsis: the ORANGES trial. Chest 158:164–173

    Article  CAS  Google Scholar 

  8. Carr AC, Shaw GM, Fowler AA, Natarajan R (2015) Ascorbate-dependent vasopressor synthesis: a rationale for vitamin C administration in severe sepsis and septic shock? Crit Care 19:418

    Article  Google Scholar 

  9. Berger MM, Oudemans-van Straaten HM (2015) Vitamin C supplementation in the critically ill patient. Curr Opin Clin Nutr Metab Care 18:193–201

    Article  CAS  Google Scholar 

  10. Amrein K, Oudemans-van Straaten HM, Berger MM (2018) Vitamin therapy in critically ill patients: focus on thiamine, vitamin C, and vitamin D. Intensive Care Med 44:1940–1944

    Article  Google Scholar 

  11. May JM, Harrison FE (2013) Role of vitamin C in the function of the vascular endothelium. Antioxid Redox Signal 19:2068–2083

    Article  CAS  Google Scholar 

  12. Moskowitz A, Donnino MW (2020) Thiamine (vitamin B1) in septic shock: a targeted therapy. J Thorac Dis 12:S78–S83

    Article  Google Scholar 

  13. Fujii T, Luethi N, Young PJ, Frei DR, Eastwood GM, French CJ, Deane AM, Shehabi Y, Hajjar LA, Oliveira G, Udy AA, Orford N, Edney SJ, Hunt AL, Judd HL, Bitker L, Cioccari L, Naorungroj T, Yanase F, Bates S, McGain F, Hudson EP, Al-Bassam W, Dwivedi DB, Peppin C, McCracken P, Orosz J, Bailey M, Bellomo R, Investigators VT (2020) Effect of vitamin C, hydrocortisone, and thiamine vs hydrocortisone alone on time alive and free of vasopressor support among patients with septic shock: the vitamins randomized clinical trial. JAMA 323:423–431

    Article  Google Scholar 

  14. Chang P, Liao Y, Guan J, Guo Y, Zhao M, Hu J, Zhou J, Wang H, Cen Z, Tang Y, Liu Z (2020) Combined treatment with hydrocortisone, vitamin C, and thiamine for sepsis and septic shock: a randomized controlled trial. Chest 158:174–182

    Article  CAS  Google Scholar 

  15. Fowler AA 3rd, Truwit JD, Hite RD, Morris PE, DeWilde C, Priday A, Fisher B, Thacker LR 2nd, Natarajan R, Brophy DF, Sculthorpe R, Nanchal R, Syed A, Sturgill J, Martin GS, Sevransky J, Kashiouris M, Hamman S, Egan KF, Hastings A, Spencer W, Tench S, Mehkri O, Bindas J, Duggal A, Graf J, Zellner S, Yanny L, McPolin C, Hollrith T, Kramer D, Ojielo C, Damm T, Cassity E, Wieliczko A, Halquist M (2019) 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 322:1261–1270

    Article  Google Scholar 

  16. Hwang SY, Park JE, Jo IJ, Kim S, Chung SP, Kong T, Shin J, Lee HJ, You KM, Jo YH, Kim D, Suh GJ, Kim T, Kim WY, Kim YJ, Ryoo SM, Choi SH, Shin TG, Korean Shock Society I (2019) Combination therapy of vitamin C and thiamine for septic shock in a multicentre, double-blind, randomized, controlled study (ATESS): study protocol for a randomized controlled trial. Trials 20:420

    Article  Google Scholar 

  17. Rhodes A, Evans LE, Alhazzani W, Levy MM, Antonelli M, Ferrer R, Kumar A, Sevransky JE, Sprung CL, Nunnally ME, Rochwerg B, Rubenfeld GD, Angus DC, Annane D, Beale RJ, Bellinghan GJ, Bernard GR, Chiche JD, Coopersmith C, De Backer DP, French CJ, Fujishima S, Gerlach H, Hidalgo JL, Hollenberg SM, Jones AE, Karnad DR, Kleinpell RM, Koh Y, Lisboa TC, Machado FR, Marini JJ, Marshall JC, Mazuski JE, McIntyre LA, McLean AS, Mehta S, Moreno RP, Myburgh J, Navalesi P, Nishida O, Osborn TM, Perner A, Plunkett CM, Ranieri M, Schorr CA, Seckel MA, Seymour CW, Shieh L, Shukri KA, Simpson SQ, Singer M, Thompson BT, Townsend SR, Van der Poll T, Vincent JL, Wiersinga WJ, Zimmerman JL, Dellinger RP (2017) Surviving sepsis campaign: international guidelines for management of sepsis and septic shock: 2016. Intensive Care Med 43:304–377

    Article  Google Scholar 

  18. Ferreira FL, Bota DP, Bross A, Melot C, Vincent JL (2001) Serial evaluation of the SOFA score to predict outcome in critically ill patients. JAMA 286:1754–1758

    Article  CAS  Google Scholar 

  19. Marik PE, Khangoora V, Rivera R, Hooper MH, Catravas J (2017) Hydrocortisone, vitamin C, and thiamine for the treatment of severe sepsis and septic shock: a retrospective before-after study. Chest 151:1229–1238

    Article  Google Scholar 

  20. Annane D, Renault A, Brun-Buisson C, Megarbane B, Quenot JP, Siami S, Cariou A, Forceville X, Schwebel C, Martin C, Timsit JF, Misset B, Ali Benali M, Colin G, Souweine B, Asehnoune K, Mercier E, Chimot L, Charpentier C, Francois B, Boulain T, Petitpas F, Constantin JM, Dhonneur G, Baudin F, Combes A, Bohe J, Loriferne JF, Amathieu R, Cook F, Slama M, Leroy O, Capellier G, Dargent A, Hissem T, Maxime V, Bellissant E, Network C-T (2018) Hydrocortisone plus fludrocortisone for adults with septic shock. N Engl J Med 378:809–818

    Article  CAS  Google Scholar 

  21. Jentzer JC, Vallabhajosyula S, Khanna AK, Chawla LS, Busse LW, Kashani KB (2018) Management of refractory vasodilatory shock. Chest 154:416–426

    Article  Google Scholar 

  22. Ostermann M, Joannidis M (2016) Acute kidney injury 2016: diagnosis and diagnostic workup. Crit Care 20:299

    Article  Google Scholar 

  23. Zavada J, Hoste E, Cartin-Ceba R, Calzavacca P, Gajic O, Clermont G, Bellomo R, Kellum JA, Investigators AKI (2010) A comparison of three methods to estimate baseline creatinine for RIFLE classification. Nephrol Dial Transpl 25:3911–3918

    Article  CAS  Google Scholar 

  24. Fowler AA 3rd, Syed AA, Knowlson S, Sculthorpe R, Farthing D, DeWilde C, Farthing CA, Larus TL, Martin E, Brophy DF, Gupta S, Medical Respiratory Intensive Care Unit N, Fisher BJ, Natarajan R (2014) Phase I safety trial of intravenous ascorbic acid in patients with severe sepsis. J Transl Med 12:32

    Article  Google Scholar 

  25. Hemila H, Chalker E (2019) Vitamin C can shorten the length of stay in the ICU: a meta-analysis. Nutrients. https://doi.org/10.3390/nu11040708

    Article  Google Scholar 

  26. Langlois PL, Manzanares W, Adhikari NKJ, Lamontagne F, Stoppe C, Hill A, Heyland DK (2019) Vitamin C administration to the critically ill: a systematic review and meta-analysis. JPEN J Parenter Enteral Nutr 43:335–346

    Article  CAS  Google Scholar 

  27. Putzu A, Daems AM, Lopez-Delgado JC, Giordano VF, Landoni G (2019) The effect of vitamin C on clinical outcome in critically ill patients: a systematic review with meta-analysis of randomized controlled trials. Crit Care Med 47:774–783

    Article  Google Scholar 

  28. Donnino MW, Andersen LW, Chase M, Berg KM, Tidswell M, Giberson T, Wolfe R, Moskowitz A, Smithline H, Ngo L, Cocchi MN, Center for Resuscitation Science Research G (2016) Randomized, Double-Blind, Placebo-Controlled Trial of Thiamine as a Metabolic Resuscitator in Septic Shock: A Pilot Study. Crit Care Med 44:360–367

    Article  CAS  Google Scholar 

  29. Miyamoto Y, Aso S, Iwagami M, Yasunaga H, Matsui H, Fushimi K, Hamasaki Y, Nangaku M, Doi K (2020) Association between IV thiamine and mortality in patients with septic shock: a nationwide observational study. Crit Care Med. https://doi.org/10.1097/CCM.0000000000004394

    Article  Google Scholar 

  30. de Grooth HJ, Elbers PWG, Vincent JL (2020) Vitamin C for sepsis and acute respiratory failure. JAMA 323:792

    Article  Google Scholar 

Download references

Funding

This work was supported by a National Research Foundation of Korea grant funded by the Korean government (No. 2018R1C1B6006821).

Author information

Author notes

  1. Sung Yeon Hwang, Seung Mok Ryoo, Tae Gun Shin and Won Young Kim contributed equally to this work.

Authors and Affiliations

  1. Department of Emergency Medicine, Samsung Medical Centre, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul, 06351, Korea

    Sung Yeon Hwang, Jong Eun Park, Ik Joon Jo & Tae Gun Shin

  2. Department of Emergency Medicine, Asan Medical Centre, University of Ulsan College of Medicine, 88 Olympic-ro 43-gil, Songpa-gu, Seoul, 138-736, Korea

    Seung Mok Ryoo, Youn-Jung Kim & Won Young Kim

  3. Department of Emergency Medicine, Seoul National University Bundang Hospital, Songnam, Korea

    You Hwan Jo & Dong-Hyun Jang

  4. Department of Emergency Medicine, Seoul National University College of Medicine, Seoul, Korea

    You Hwan Jo, Dong-Hyun Jang, Gil Joon Suh & Taegyun Kim

  5. Statistics and Data Centre, Samsung Medical Centre, Seoul, Korea

    Seonwoo Kim & Hyun Cho

  6. Department of Emergency Medicine, Yonsei University College of Medicine, Seoul, Korea

    Sung Phil Chung

  7. Department of Emergency Medicine, Guro Hospital, Korea University Medical Centre, Seoul, Korea

    Sung-Hyuk Choi

Authors
  1. Sung Yeon Hwang
    View author publications

    You can also search for this author inPubMed Google Scholar

  2. Seung Mok Ryoo
    View author publications

    You can also search for this author inPubMed Google Scholar

  3. Jong Eun Park
    View author publications

    You can also search for this author inPubMed Google Scholar

  4. You Hwan Jo
    View author publications

    You can also search for this author inPubMed Google Scholar

  5. Dong-Hyun Jang
    View author publications

    You can also search for this author inPubMed Google Scholar

  6. Gil Joon Suh
    View author publications

    You can also search for this author inPubMed Google Scholar

  7. Taegyun Kim
    View author publications

    You can also search for this author inPubMed Google Scholar

  8. Youn-Jung Kim
    View author publications

    You can also search for this author inPubMed Google Scholar

  9. Seonwoo Kim
    View author publications

    You can also search for this author inPubMed Google Scholar

  10. Hyun Cho
    View author publications

    You can also search for this author inPubMed Google Scholar

  11. Ik Joon Jo
    View author publications

    You can also search for this author inPubMed Google Scholar

  12. Sung Phil Chung
    View author publications

    You can also search for this author inPubMed Google Scholar

  13. Sung-Hyuk Choi
    View author publications

    You can also search for this author inPubMed Google Scholar

  14. Tae Gun Shin
    View author publications

    You can also search for this author inPubMed Google Scholar

  15. Won Young Kim
    View author publications

    You can also search for this author inPubMed Google Scholar

Consortia

Korean Shock Society (KoSS)

Corresponding authors

Correspondence to Tae Gun Shin or Won Young Kim.

Ethics declarations

Conflicts of interest

The authors declare no competing interests.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary file1 (DOCX 40 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Hwang, S.Y., Ryoo, S.M., Park, J.E. et al. Combination therapy of vitamin C and thiamine for septic shock: a multi-centre, double-blinded randomized, controlled study. Intensive Care Med 46, 2015–2025 (2020). https://doi.org/10.1007/s00134-020-06191-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00134-020-06191-3

Keywords