Acute Crit Care.  2021 Aug;36(3):185-200. 10.4266/acc.2021.00108.

The Efficacy of vitamin C, thiamine, and corticosteroid therapy in adult sepsis patients: a systematic review and meta-analysis

• Somagutta MKR
• Pormento MKL
• Khan MA
• Hamdan A
• Hange N
• KC M
• Pagad S
• Jain MS
• Lingarajah S
• Sharma V
• Kaur J
• Emuze B
• Batti E
• Iloeje OJ

• KMID: 2519445
• DOI: http://doi.org/10.4266/acc.2021.00108

Abstract

Background
Previous studies have suggested favorable outcomes of hydrocortisone, ascorbic acid (vitamin C), and thiamine (HAT) therapy in patients with sepsis. However, similar results have not been duplicated in sequential studies. This meta-analysis aimed to reevaluate the value of HAT treatment in patients with sepsis.
Methods
Electronic databases were searched up until October 2020 for any studies that compared the effect of HAT versus non-HAT use in patients with sepsis.
Results
Data from 15 studies (eight randomized controlled trials [RCTs] and seven cohort studies) involving 67,349 patients were included. The results from the RCTs show no significant benefit of triple therapy on hospital mortality (risk ratio [RR], 0.99; P=0.92; I²=0%); intensive care unit (ICU) mortality (RR, 0.77; P=0.20; I²=58%); ICU length of stay (weighted mean difference [WMD], 0.11; P=0.86; I²=37%) or hospital length of stay (WMD: 0.57; P=0.49; I²=17%), and renal replacement therapy (RR, 0.64; P=0.44; I²=39%). The delta Sequential Organ Failure Assessment (SOFA) score favored treatment after a sensitivity analysis (WMD, –0.72; P=0.01; I²=32%). However, a significant effect was noted for the duration of vasopressor use (WMD, –25.49; P<0.001; I²=46%). The results from cohort studies have also shown no significant benefit of HAT therapy on hospital mortality, ICU mortality, ICU length of stay, length of hospital stay, the delta SOFA score, the use of renal replacement therapy, or vasopressor duration.
Conclusions
HAT therapy significantly reduced the duration of vasopressor use and improved the SOFA score but appeared not to have significant benefits in other outcomes for patients with sepsis. Further RCTs can help understand its benefit exclusively.

Keyword

ascorbic acid; HAT therapy; septic shock; steroids; thiamine; vitamin C

Figure

• 

  Figure 1. Preferred reporting items for systematic reviews and meta-analyses flow diagram.

• 

  Figure 2. Forest plot showing results of triple therapy from randomized controlled trials (RCTs) and cohorts studies on the hospital mortality. HAT: hydrocortisone, ascorbic acid (vitamin C), and thiamine; CI: confidence interval; df: degrees of freedom.

• 

  Figure 3. Forest plot showing results of triple therapy from randomized controlled trials (RCTs) and cohort studies on the intensive care unit. HAT: hydrocortisone, ascorbic acid (vitamin C), and thiamine; CI: confidence interval; df: degrees of freedom.

• 

  Figure 4. Forest plot showing results of triple therapy from randomized controlled trials (RCTs) and cohorts studies on the intensive care unit length of stay. HAT: hydrocortisone, ascorbic acid (vitamin C), and thiamine; SD: standard deviation; IV: weighted mean difference; CI: confidence interval; df: degrees of freedom.

• 

  Figure 5. Forest plot showing results of triple therapy from randomized controlled trials (RCTs) and cohorts studies on delta Sequential Organ Failure Assessment (SOFA) score. HAT: hydrocortisone, ascorbic acid (vitamin C), and thiamine; SD: standard deviation; IV: weighted mean difference; CI: confidence interval; df: degrees of freedom.

• 

  Figure 6. Forest plot showing results of triple therapy from randomized controlled trials (RCTs) and cohort studies on delta Sequential Organ Failure Assessment (SOFA) score without the studies of Karimpour et al. [43] and Marik et al. [39]. HAT: hydrocortisone, ascorbic acid (vitamin C), and thiamine; SD: standard deviation; IV: weighted mean difference; CI: confidence interval; df: degrees of freedom.

• 

  Figure 7. Forest plot showing results of triple therapy from randomized controlled trials (RCTs) and cohort studies on hospital length of stay. HAT: hydrocortisone, ascorbic acid (vitamin C), and thiamine; SD: standard deviation; IV: weighted mean difference; CI: confidence interval; df: degrees of freedom.

• 

  Figure 8. Forest plot showing results of triple therapy from randomized controlled trials (RCTs) and cohort studies on renal replacement therapy. HAT: hydrocortisone, ascorbic acid (vitamin C), and thiamine; CI: confidence interval; df: degrees of freedom.

• 

  Figure 9. Forest plot showing results of triple therapy from randomized controlled trials (RCTs) and cohort studies on duration of vasopressors. HAT: hydrocortisone, ascorbic acid (vitamin C), and thiamine; SD: standard deviation; IV: weighted mean difference; CI: confidence interval; df: degrees of freedom.

Reference

1. Abraham E. New definitions for sepsis and septic shock: continuing evolution but with much still to be done. JAMA. 2016; 315:757–9.

2. Angus DC, van der Poll T. Severe sepsis and septic shock. N Engl J Med. 2013; 369:840–51.

3. Beesley SJ, Lanspa MJ. Why we need a new definition of sepsis. Ann Transl Med. 2015; 3:296.

4. Allegranzi B, Bagheri Nejad S, Chraiti MN, Castillejos GG, Kilpatrick C, Kelley E. Report on the burden of endemic health care-associated infection worldwide. Geneva: World Health Organization;2011.

5. Rudd KE, Johnson SC, Agesa KM, Shackelford KA, Tsoi D, Kievlan DR, et al. Global, regional, and national sepsis incidence and mortality, 1990-2017: analysis for the Global Burden of Disease Study. Lancet. 2020; 395:200–11.

6. Marik PE, Farkas JD. The changing paradigm of sepsis: early diagnosis, early antibiotics, early pressors, and early adjuvant treatment. Crit Care Med. 2018; 46:1690–2.

7. Galley HF, Howdle PD, Walker BE, Webster NR. The effects of intravenous antioxidants in patients with septic shock. Free Radic Biol Med. 1997; 23:768–74.

8. Wilson JX. Mechanism of action of vitamin C in sepsis: ascorbate modulates redox signaling in endothelium. Biofactors. 2009; 35:5–13.

9. Kuhn SO, Meissner K, Mayes LM, Bartels K. Vitamin C in sepsis. Curr Opin Anaesthesiol. 2018; 31:55–60.

10. Mandl J, Szarka A, Bánhegyi G. Vitamin C: update on physiology and pharmacology. Br J Pharmacol. 2009; 157:1097–110.

11. Heo HJ, Lee CY. Protective effects of quercetin and vitamin C against oxidative stress-induced neurodegeneration. J Agric Food Chem. 2004; 52:7514–7.

12. May JM, Harrison FE. Role of vitamin C in the function of the vascular endothelium. Antioxid Redox Signal. 2013; 19:2068–83.

13. Zhou G, Kamenos G, Pendem S, Wilson JX, Wu F. Ascorbate protects against vascular leakage in cecal ligation and puncture-induced septic peritonitis. Am J Physiol Regul Integr Comp Physiol. 2012; 302:R409–16.

14. Costa NA, Azevedo PS, Polegato BF, Zornoff LA, Paiva SA, Minicucci MF. Thiamine as a metabolic resuscitator in septic shock: one size does not fit all. J Thorac Dis. 2016; 8:E471–2.

15. Moskowitz A, Donnino MW. Thiamine (vitamin B1) in septic shock: a targeted therapy. J Thorac Dis. 2020; 12(Suppl 1):S78–83.

16. Donnino MW, Andersen LW, Chase M, Berg KM, Tidswell M, Giberson T, et al. Randomized, double-blind, placebo-controlled trial of thiamine as a metabolic resuscitator in septic shock: a pilot study. Crit Care Med. 2016; 44:360–7.

17. Costa NA, Gut AL, de Souza Dorna M, Pimentel JA, Cozzolino SM, Azevedo PS, et al. Serum thiamine concentration and oxidative stress as predictors of mortality in patients with septic shock. J Crit Care. 2014; 29:249–52.

18. Woolum JA, Abner EL, Kelly A, Thompson Bastin ML, Morris PE, Flannery AH. Effect of thiamine administration on lactate clearance and mortality in patients with septic shock. Crit Care Med. 2018; 46:1747–52.

19. Artigas A, Carlet J, Garnacho J, Niederman M, Torres A. 24th international symposium on infections in the critically ill patient. Med Sci. 2019; 7:23.

20. Erstad BL, Brophy GM, Martin SJ, Haas CE, Devlin JW, Welage LS, et al. Key articles and guidelines relative to intensive care unit pharmacotherapy: 2009 update. Pharmacotherapy. 2009; 29:1228–69.

21. Annane D. The role of ACTH and corticosteroids for sepsis and septic shock: an update. Front Endocrinol (Lausanne). 2016; 7:70.

22. Schumer W. Steroids in the treatment of clinical septic shock. Ann Surg. 1976; 184:333–41.

23. Keh D, Trips E, Marx G, Wirtz SP, Abduljawwad E, Bercker S, et al. Effect of hydrocortisone on development of shock among patients with severe sepsis: the HYPRESS randomized clinical trial. JAMA. 2016; 316:1775–85.

24. Marik PE, Pastores SM, Annane D, Meduri GU, Sprung CL, Arlt W, et al. Recommendations for the diagnosis and management of corticosteroid insufficiency in critically ill adult patients: consensus statements from an international task force by the American College of Critical Care Medicine. Crit Care Med. 2008; 36:1937–49.

25. Annane D, Sébille V, Charpentier C, Bollaert PE, François B, Korach JM, et al. Effect of treatment with low doses of hydrocortisone and fludrocortisone on mortality in patients with septic shock. JAMA. 2002; 288:862–71.

26. Sprung CL, Annane D, Keh D, Moreno R, Singer M, Freivogel K, et al. Hydrocortisone therapy for patients with septic shock. N Engl J Med. 2008; 358:111–24.

27. Keh D, Boehnke T, Weber-Cartens S, Schulz C, Ahlers O, Bercker S, et al. Immunologic and hemodynamic effects of “lowdose” hydrocortisone in septic shock: a double-blind, randomized, placebo-controlled, crossover study. Am J Respir Crit Care Med. 2003; 167:512–20.

28. Moskowitz A, Andersen LW, Huang DT, Berg KM, Grossestreuer AV, Marik PE, et al. Ascorbic acid, corticosteroids, and thiamine in sepsis: a review of the biologic rationale and the present state of clinical evaluation. Crit Care. 2018; 22:283.

29. Marik PE. Hydrocortisone, ascorbic acid and thiamine (HAT therapy) for the treatment of sepsis: focus on ascorbic acid. Nutrients. 2018; 10:1762.

30. Singer M, Deutschman CS, Seymour CW, Shankar-Hari M, Annane D, Bauer M, et al. The third international consensus definitions for sepsis and septic shock (Sepsis-3). JAMA. 2016; 315:801–10.

31. Stang A. Critical evaluation of the Newcastle-Ottawa scale for the assessment of the quality of nonrandomized studies in meta-analyses. Eur J Epidemiol. 2010; 25:603–5.

32. Wells GA, Shea B, O’Connell D, Peterson J, Welch V, Losos M, et al. The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses. Ottawa: Ottawa Hospital Research Institute;2000.

33. Luo D, Wan X, Liu J, Tong T. Optimally estimating the sample mean from the sample size, median, mid-range, and/or midquartile range. Stat Methods Med Res. 2018; 27:1785–805.

34. Wan X, Wang W, Liu J, Tong T. Estimating the sample mean and standard deviation from the sample size, median, range and/or interquartile range. BMC Med Res Methodol. 2014; 14:135.

35. Patsopoulos NA, Evangelou E, Ioannidis JP. Sensitivity of between-study heterogeneity in meta-analysis: proposed metrics and empirical evaluation. Int J Epidemiol. 2008; 37:1148–57.

36. DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials. 1986; 7:177–88.

37. Mathes T, Kuss O. A comparison of methods for meta-analysis of a small number of studies with binary outcomes. Res Synth Methods. 2018; 9:366–81.

38. Sadaka F, Grady J, Organti N, Donepudi B, Korobey M, Tannehill D, et al. Ascorbic acid, thiamine, and steroids in septic shock: propensity matched analysis. J Intensive Care Med. 2020; 35:1302–6.

39. Marik PE, Khangoora V, Rivera R, Hooper MH, Catravas J. Hydrocortisone, vitamin C, and thiamine for the treatment of severe sepsis and septic shock: a retrospective before-after study. Chest. 2017; 151:1229–38.

40. Mitchell AB, Ryan TE, Gillion AR, Wells LD, Muthiah MP. Vitamin C and thiamine for sepsis and septic shock. Am J Med. 2020; 133:635–8.

41. Litwak JJ, Cho N, Nguyen HB, Moussavi K, Bushell T. Vitamin C, hydrocortisone, and thiamine for the treatment of severe sepsis and septic shock: a retrospective analysis of real-world application. J Clin Med. 2019; 8:478.

42. Fujii T, Luethi N, Young PJ, Frei DR, Eastwood GM, French CJ, et al. 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. 2020; 323:423–31.

43. Karimpour H, Bahrami A, Amini S, Rezaei M, Amini-Saman J, Shahbazi F. Effects of a high dose of vitamin C along with thiamine in critically-ill patients with septic shock: a preliminary study. J Pharm Res Int. 2019; 29:1–7.

44. Wani SJ, Mufti SA, Jan RA, Shah SU, Qadri SM, Khan UH, et al. Combination of vitamin C, thiamine and hydrocortisone added to standard treatment in the management of sepsis: results from an open label randomized controlled clinical trial and a review of the literature. Infect Dis (Lond). 2020; 52:271–8.

45. Kim WY, Jo EJ, Eom JS, Mok J, Kim MH, Kim KU, et al. Combined vitamin C, hydrocortisone, and thiamine therapy for patients with severe pneumonia who were admitted to the intensive care unit: propensity score-based analysis of a before-after cohort study. J Crit Care. 2018; 47:211–18.

46. Iglesias J, Vassallo AV, Patel VV, Sullivan JB, Cavanaugh J, Elbaga Y. Outcomes of metabolic resuscitation using ascorbic acid, thiamine, and glucocorticoids in the early treatment of sepsis: the ORANGES trial. Chest. 2020; 158:164–73.

47. Moskowitz A, Huang DT, Hou PC, Gong J, Doshi PB, Grossestreuer AV, et al. Effect of ascorbic acid, corticosteroids, and thiamine on organ injury in septic shock: the ACTS randomized clinical trial. JAMA. 2020; 324:642–50.

48. Vail EA, Wunsch H, Pinto R, Bosch NA, Walkey AJ, Lindenauer PK, et al. Use of hydrocortisone, ascorbic acid, and thiamine in adults with septic shock. Am J Respir Crit Care Med. 2020; 202:1531–9.

49. Mohamed ZU, Prasannan P, Moni M, Edathadathil F, Prasanna P, Menon A, et al. Vitamin C therapy for routine care in septic shock (ViCTOR) trial: effect of intravenous vitamin C, thiamine, and hydrocortisone administration on inpatient mortality among patients with septic shock. Indian J Crit Care Med. 2020; 24:653–61.

50. Long MT, Frommelt MA, Ries MP, Murray M, Osman F, Krause BM, et al. Early hydrocortisone, ascorbate and thiamine therapy for severe septic shock. Crit Care Shock. 2020; 23:23–34.

51. Chang P, Liao Y, Guan J, Guo Y, Zhao M, Hu J, et al. Combined treatment with hydrocortisone, vitamin C, and thiamine for sepsis and septic shock: a randomized controlled trial. Chest. 2020; 158:174–82.

52. Sevransky JE, Rothman RE, Hager DN, Bernard GR, Brown SM, Buchman TG, et al. Effect of vitamin C, thiamine, and hydrocortisone on ventilator- and vasopressor-free days in patients with sepsis: the VICTAS randomized clinical trial. JAMA. 2021; 325:742–50.

53. Barabutis N, Khangoora V, Marik PE, Catravas JD. Hydrocortisone and ascorbic acid synergistically prevent and repair lipopolysaccharide-induced pulmonary endothelial barrier dysfunction. Chest. 2017; 152:954–62.

54. Berger MM. Do micronutrient deficiencies contribute to mitochondrial failure in critical illness? Curr Opin Clin Nutr Metab Care. 2020; 23:102–10.

55. Hwang SY, Ryoo SM, Park JE, Jo YH, Jang DH, Suh GJ, et al. Combination therapy of vitamin C and thiamine for septic shock: a multi-centre, double-blinded randomized, controlled study. Intensive Care Med. 2020; 46:2015–25.

56. Shi R, Tie H. Benefit of hydrocortisone, thiamine, and vitamin C for patients with sepsis or septic shock? Too early to draw conclusions. Crit Care. 2020; 24:431.

57. Rowe TA, McKoy JM. Sepsis in older adults. Infect Dis Clin North Am. 2017; 31:731–42.

58. Kim J, Arnaout L, Remick D. Hydrocortisone, ascorbic acid, and thiamine (HAT) therapy decreases oxidative stress, improves cardiovascular function, and improves survival in murine sepsis. Shock. 2020; 53:460–7.

59. Petsakul S, Morakul S, Tangsujaritvijit V, Kunawut P, Singhatas P, Sanguanwit P. Effects of thiamine on vasopressor requirements in patients with septic shock: a prospective randomized controlled trial. BMC Anesthesiol. 2020; 20:280.

60. Martin GS, Mannino DM, Moss M. The effect of age on the development and outcome of adult sepsis. Crit Care Med. 2006; 34:15–21.

61. Starr ME, Saito H. Sepsis in old age: review of human and animal studies. Aging Dis. 2014; 5:126–36.