Update: What is the evidence for use of high-dose vitamin C in critically ill patients with sepsis?
Introduction
Sepsis and septic shock are life-threatening medical conditions with an increased risk of end-organ damage and mortality.1 To reduce the clinical and economic burden of these conditions, an exploration into nontraditional therapeutic approaches that are safe, effective, inexpensive, and readily available has been encouraged in the literature. Vitamin C, also known as ascorbic acid (AA), is one such therapy whose potent antioxidant effects are postulated to halt the propagation of organ injury and dysfunction in sepsis, especially when combined with anti-inflammatory therapies such as thiamine and corticosteroids to produce synergistic effects. In addition to its antioxidant effects, AA serves important roles in several metabolic processes, including the biosynthesis of neurotransmitters, epinephrine, and cortisol, and has also been shown to decrease capillary permeability and improve immune system function.2 Thiamine likewise plays an important role in metabolic processes including glucose metabolism and ATP synthesis, and supplementation has been shown to decrease lactate levels and alleviate organ dysfunction. Patients with sepsis are generally deficient in AA and thiamine, further supporting the use of these agents in this population.
A frequently asked question (FAQ) was published in May 2017 (available here) with information on the use of AA in critically ill patients with sepsis or septic shock.3 At the time the 2017 FAQ was published, the author found that the existing literature generally supported high-dose intravenous (IV) AA as a means to decrease the dose and duration of vasopressors and improve hospital survival without increasing adverse effects. However, the published literature at the time was limited to 2 small (N<25) randomized controlled trials (RCTs) and 1 retrospective study. Higher-quality studies exploring AA in this population have recently emerged, prompting an update of the previous FAQ publication.2,4-7
Literature Review
An updated search of the PubMed database was conducted in June 2021 to identify RCTs evaluating clinical outcomes with AA in the management of patients with sepsis and septic shock. The majority of recently published RCTs have already been pooled in meta-analyses (MAs) and are therefore not summarized individually in this update.2,4,5 Across the literature, IV AA was administered at a dose of 6 grams daily in divided doses (3 g every 12 hours or 1.5 g every 6 hours), usually in combination with IV thiamine 200 mg twice daily or as part of an IV HAT (hydrocortisone [50 mg every 6 hours]/AA/thiamine) regimen.2,4-7 Less common adjunct treatments used in combination with AA were vitamin E and N-acetylcysteine.4 In some studies, hydrocortisone use was allowed in both intervention and control groups, potentially confounding the results in those cases.4,6,7 Otherwise, the control groups utilized placebo or no treatment.2,4,5 Across trials, treatment with AA was started within 24 hours of recognition of sepsis or intensive care unit (ICU) admission, and in most cases within 12 hours.2,4-7 The duration of AA therapy spanned between 4 to 7 days or until ICU discharge.
Overall, newer evidence has not demonstrated significant survival advantages nor notable improvements in the duration of hospitalization, ICU stay, or vasopressor use with AA combinations with hydrocortisone and/or thiamine in patients with sepsis or septic shock.2,4-7 In 2 MAs of 6 and 7 RCTs, in-hospital and long-term mortality were similar with AA-based therapy versus control (placebo, no treatment, or hydrocortisone).2,4 The length of hospital and ICU stay were also similar between groups in both analyses. One of the analyses found a statistically significant reduction in the duration of vasopressor use with AA plus thiamine, however, the clinical significance of a 17 hours reduction versus placebo is uncertain.2 A third slightly older MA that pooled data from 4 RCTs and 6 retrospective studies found no significant difference in the duration of vasopressor use between IV AA-containing therapies and placebo, and similarly did not identify a survival advantage or reduction in hospital or ICU length of stay with regimens containing IV AA.5 In 2 MAs, IV AA-containing regimens did not significantly impact the risk of developing acute kidney injury.
Since the publication of the aforementioned MAs, 2 additional RCTs evaluating IV AA in critically ill patients with suspected or confirmed sepsis have been published.6,7 In both trials, IV AA was administered as part of a HAT regimen in the intervention group. In the first trial, Hussain et al (2021) compared HAT to hydrocortisone alone in 94 Egyptian patients with septic shock.6 In-hospital mortality at 28 days and ICU mortality were similar between groups, as was the time on mechanical ventilation. A 1-day reduction in the duration of vasopressor use reached statical significance in favor of HAT therapy, although the clinical significance of this change is uncertain.
Next, Sevransky et al (2021) compared HAT to placebo in 501 patients with acute respiratory and/or cardiovascular dysfunction caused by suspected infection.7 Open-label corticosteroids were prescribed to approximately one-third of patients in each group. In this trial, consecutive ventilator- and vasopressor-free days in the first 30 days were similar between groups, as was mortality at 30 and 180 days. This trial was terminated early for administrative reasons, and may therefore have been underpowered to detect a difference in outcomes between groups. In both RCTs, numerical reductions in mortality generally trended in favor of HAT.6,7
Summary
Despite the theoretical advantages of AA supplementation in patients with sepsis and septic shock and early positive evidence of clinical benefit, newer, higher quality data from RCTs and MAs have overwhelming failed to demonstrate a survival or hospital/ICU length of stay advantage with IV AA-containing regimens versus hydrocortisone alone, placebo, or no treatment. Since most trials use IV AA in combination with other antioxidant/anti-inflammatory treatments, the confounding effects of these additional therapies should be considered. Reductions in the duration of vasopressor use in favor of regimens that contain AA on average range from 17 hours to 1 day, reaching statistical significance in comparisons with hydrocortisone (1 RCT) and placebo or no treatment (1 MA). Interestingly, the seemingly negative data have not slowed research in this area, and regimens that IV AA continue to be explored in patients with sepsis and septic shock. The results of these ongoing trials may help identify populations that may benefit from therapy.
| Table 1. Clinical outcomes with intravenous ascorbic acid in patients with sepsis or septic shock.2,4-7 | ||||
|---|---|---|---|---|
| Citation/ Design | Population | Interventions | Primary outcome* | Other outcomes |
| Meta-analyses |
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| Ge 20212 MA of 7 RCTs | 868 patients with sepsis or septic shock | IV AA + thiamine Control (placebo or no treatment) | In-hospital mortality: similar between treatment and control groups (OR, 1.11; 95% CI, 0.79 to 1.56) | The duration of the following outcomes was similar between IV AA and control groups: ICU stay: WMD, -0.00 days; 95% CI, -1.11 to 1.11 Hospital stay: WMD, 0.42 days; 95% CI, -1.04 to 1.87 Vasopressor use: WMD, -17.73 hours; 95% CI, -29.76 to -4.98 |
| Zayed 20214 MA of 6 RCTs | 839 patients with sepsis or septic shock | IV HAT Control (placebo, routine treatments that may have included HCT, or no treatment) | Long-term mortality: similar between groups (RR, 1.05; 95% CI, 0.85 to 1.30) | The risk of the following outcomes was similar between IV AA and control groups: ICU mortality: RR, 1.03; 95% CI, 0.73 to 1.44 AKI: RR, 1.05; 95% CI, 0.80 to 1.37 Hospital LOS: MD, 0.53 days; 95% CI, -1.00 to 2.05 ICU LOS: MD, 0.11; 95% CI, -0.88 to 1.09 ICU free days on day 28: MD, -0.21; 95% CI, -2.65 to 2.23 |
| Wei 20205 MA of 10 studies (4 RCTs and 6 retrospective cohort) | 1671 patients with sepsis | IV AA (3 RCTs and 1 retrospective study) IV AA + thiamine (1 retrospective study) IV HAT regimen (4 retrospective studies) IV AA + vitamin E, + N-acetylcysteine (1 RCT) Therapies used in control groups were not specified | The risk of the following outcomes was similar between IV AA and control groups: 28-day mortality: OR, 0.84; 95% CI, 0.43 to 1.65 ICU mortality: OR, 0.79; 95% CI, 0.51 to 1.25 In-hospital mortality: OR, 0.76; 95% CI, 0.47 to 1.22 Duration of vasopressor use: SMD, -0.87 days; 95% CI, -2.27 to 0.52 ICU LOS: SMD, 0.03 days; 95% CI, -0.09 to 0.15 Hospital LOS: SMD, 0.10 days; 95% CI, 0.-30 to 0.51 AKI: OR, 1.12; 95% CI, 0.67 to 1.89 |
|
| Clinical trials |
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| Hussein 20216 RCT, SC (Egypt) It is unclear if patients and/or investigators were blinded to treatment. | 94 patients with septic shock | IV HAT IV HCT IV HCT was provided for 7 days or until ICU discharge; IV AA and thiamine were provided for 4 days or until ICU discharge | In-hospital mortality at 28 days: similar between HAT and HCT groups (36.2% vs 44.7%, respectively; p=0.4005) ICU mortality: similar between HAT and HCT groups (29.7% vs 40.4%, respectively; p=0.2799) | Duration on vasopressors: reduced with HAT vs HCT (4 days vs 5 days, respectively; p=0.0100) Time on mechanical ventilation: ~5.4 days in each group (p=0.9888) |
| Sevransky 20217 RCT, MC, DB The trial was terminated early for administrative reasons. | 501 patients with acute respiratory and/or cardiovascular dysfunction caused by suspected infection with planned ICU admission | IV HAT Placebo All interventions were given every 6 hrs for 96 hrs, until discharge from the ICU, or death OL HCT was prescribed to approximately one-third of patients in each group | Consecutive ventilator- and vasopressor-free days in the first 30 days: similar with HAT (median 25 days [IQR, 0 to 29]) vs placebo (26 days [IQR, 0 to 28 days]; the median difference was -1 day (95% CI, -4 to 2 days; p=0.85) | Mortality at 30 days: similar with HAT vs placebo (22% vs 24%, respectively) Mortality at 180 days: similar with HAT vs placebo (40.5% vs 37.8%, respectively; difference, 2.7 days; 95% CI, ‑11.3 to 5.8) |
| *Wei et al did not identify a primary outcome for their meta-analysis. Abbreviations. AA=ascorbic acid; AKI=acute kidney injury; DB=double blind; HAT=hydrocortisone/ascorbic acid/thiamine; HCT=hydrocortisone; ICU=intensive care unit; IQR=interquartile range; IV=intravenous; LOS=length of stay; MA=meta-analysis; MC=multicenter; MD=mean difference; OL=open label; OR=odds ratio; RCT=randomized controlled trial; RR=relative risk; SC=single center; SMD=standardized mean difference; WMD=weighed mean difference. |
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References
- Lee YR, Vo K, Varughese JT. Benefits of combination therapy of hydrocortisone, ascorbic acid and thiamine in sepsis and septic shock: a systematic review. Published online May 26, 2021. Nutr Health. 2021;2601060211018371. doi:10.1177/02601060211018371
- Ge Z, Huang J, Liu Y, et al. Thiamine combined with vitamin C in sepsis or septic shock: a systematic review and meta-analysis. Eur J Emerg Med. 2021;28(3):189-195. doi:10.1097/MEJ.0000000000000812
- Afanasjeva J. What is the evidence for use of high-dose vitamin C in critically ill patients? University of Illinois at Chicago Drug Information Group. Published May 2017. Accessed June 16, 2021. https://dig.pharmacy.uic.edu/faqs/2017-2/may-2017-faqs/
- Zayed Y, Alzghoul BN, Banifadel M, et al. Vitamin C, thiamine, and hydrocortisone in the treatment of sepsis: a meta-analysis and trial sequential analysis of randomized controlled trials. Published online Jan 29, 2021. J Intensive Care Med. 2021;885066620987809. doi:10.1177/0885066620987809
- Wei XB, Wang ZH, Liao XL, et al. Efficacy of vitamin C in patients with sepsis: An updated meta-analysis. Eur J Pharmacol. 2020;868:172889. doi:10.1016/j.ejphar.2019.172889
- Hussein AA, Sabry NA, Abdalla MS, Farid SF. A prospective, randomised clinical study comparing triple therapy regimen to hydrocortisone monotherapy in reducing mortality in septic shock patients. Published online May 18, 2021. Int J Clin Pract. 2021;e14376. doi:10.1111/ijcp.14376
- Sevransky JE, Rothman RE, Hager DN, 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(8):742-750. doi:10.1001/jama.2020.24505
- ClincalTrials.gov. US National Library of Medicine; 2021. Accessed June 17, 2021. https://clinicaltrials.gov/ct2/home
Prepared by:
Katherine Sarna, PharmD, BCPS
Clinical Assistant Professor, Drug Information Specialist
University of Illinois at Chicago College of Pharmacy
July 2021
The information presented is current as of June 17, 2021. This information is intended as an educational piece and should not be used as the sole source for clinical decision-making.