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Randomized Controlled Trial
. 2023 Feb 1;6(2):e230380.
doi: 10.1001/jamanetworkopen.2023.0380.

Association of Vitamin C, Thiamine, and Hydrocortisone Infusion With Long-term Cognitive, Psychological, and Functional Outcomes in Sepsis Survivors: A Secondary Analysis of the Vitamin C, Thiamine, and Steroids in Sepsis Randomized Clinical Trial

Shawniqua Williams Roberson  1   2   3 , Samuel Nwosu  4 , Erin M Collar  1   5 , Amy L Kiehl  1   5 , Fiona E Harrison  6   7 , Julie Bastarache  5   7 , Jo Ellen Wilson  1   8   9 , Matthew F Mart  1   5   9 , Jonathan E Sevransky  10   11 , E Wesley Ely  1   5   9 , Christopher J Lindsell  4 , James C Jackson  1   5   9 ; VICTAS Investigators
Collaborators, Affiliations
Randomized Controlled Trial

Association of Vitamin C, Thiamine, and Hydrocortisone Infusion With Long-term Cognitive, Psychological, and Functional Outcomes in Sepsis Survivors: A Secondary Analysis of the Vitamin C, Thiamine, and Steroids in Sepsis Randomized Clinical Trial

Shawniqua Williams Roberson et al. JAMA Netw Open. .

Erratum in

  • Error in the Byline.
    [No authors listed] [No authors listed] JAMA Netw Open. 2023 Apr 3;6(4):e2312173. doi: 10.1001/jamanetworkopen.2023.12173. JAMA Netw Open. 2023. PMID: 37079308 Free PMC article. No abstract available.

Abstract

Importance: Sepsis is associated with long-term cognitive impairment and worse psychological and functional outcomes. Potential mechanisms include intracerebral oxidative stress and inflammation, yet little is known about the effects of early antioxidant and anti-inflammatory therapy on cognitive, psychological, and functional outcomes in sepsis survivors.

Objective: To describe observed differences in long-term cognitive, psychological, and functional outcomes of vitamin C, thiamine, and hydrocortisone between the intervention and control groups in the Vitamin C, Thiamine, and Steroids in Sepsis (VICTAS) randomized clinical trial.

Design, setting, and participants: This prespecified secondary analysis reports the 6-month outcomes of the multicenter, double-blind, placebo-controlled VICTAS randomized clinical trial, which was conducted between August 2018 and July 2019. Adult patients with sepsis-induced respiratory and/or cardiovascular dysfunction who survived to discharge or day 30 were recruited from 43 intensive care units in the US. Participants were randomized 1:1 to either the intervention or control group. Cognitive, psychological, and functional outcomes at 6 months after randomization were assessed via telephone through January 2020. Data analyses were conducted between February 2021 and December 2022.

Interventions: The intervention group received intravenous vitamin C (1.5 g), thiamine hydrochloride (100 mg), and hydrocortisone sodium succinate (50 mg) every 6 hours for 96 hours or until death or intensive care unit discharge. The control group received matching placebo.

Main outcomes and measures: Cognitive performance, risk of posttraumatic stress disorder and depression, and functional status were assessed using a battery of standardized instruments that were administered during a 1-hour telephone call 6 months after randomization.

Results: After exclusions, withdrawals, and deaths, the final sample included 213 participants (median [IQR] age, 57 [47-67] years; 112 males [52.6%]) who underwent long-term outcomes assessment and had been randomized to either the intervention group (n = 108) or control group (n = 105). The intervention group had lower immediate memory scores (adjusted OR [aOR], 0.49; 95% CI, 0.26-0.89), higher odds of posttraumatic stress disorder (aOR, 3.51; 95% CI, 1.18-10.40), and lower odds of receiving mental health care (aOR, 0.38; 95% CI, 0.16-0.89). No other statistically significant differences in cognitive, psychological, and functional outcomes were found between the 2 groups.

Conclusions and relevance: In survivors of sepsis, treatment with vitamin C, thiamine, and hydrocortisone did not improve or had worse cognitive, psychological, and functional outcomes at 6 months compared with patients who received placebo. These findings challenge the hypothesis that antioxidant and anti-inflammatory therapy during critical illness mitigates the development of long-term cognitive, psychological, and functional impairment in sepsis survivors.

Trial registration: ClinicalTrials.gov Identifier: NCT03509350.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Williams Roberson reported receiving grants from the National Institute on Aging and the Brain and Behavior Research Foundation. Dr Bastarache reported receiving grants from the National Institutes of Health (NIH), US Department of Defense (DoD), and US Department of Veterans Affairs outside the submitted work. Dr Sevransky reported receiving grants from the Centers for Disease Control and Prevention (CDC) Foundation, DoD, CDC, and Regeneron as well as other funding to the institution from the Society of Critical Care Medicine outside the submitted work. Dr Lindsell reported receiving grants to the institution from the NIH, CDC, and DoD; other funding to the institution from Endpoint Health, bioMérieux, Entegrion Inc, AbbVie, and AstraZeneca; and personal fees from Bioscape Digital outside the submitted work as well as holding a patent for risk stratification in sepsis and septic shock issued to Cincinnati Children's Hospital Medical Center. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Recruitment, Randomization, and Flow of Participants in the VICTAS Study
aParticipants could meet multiple criteria; thus, exclusions were not mutually exclusive.
Figure 2.
Figure 2.. Adjusted Odds Ratios (aORs) for Improvement in 6-Month Cognitive Outcomes With Treatment
Participants in the intervention group had worse scores on the Weschler Adult Intelligence Scale IV Logical Memory I subtest (aOR, 0.49; 95% CI, 0.26-0.89), which measures immediate (short-term) memory. Effect sizes for scores on all other cognitive assessments except the Hayling Sentence Completion Test and the Controlled Oral Word Association Test (COWAT) were less than 1, suggesting a tendency toward worse cognitive outcomes with treatment. TICS indicates Telephone Interview for Cognitive Status.
Figure 3.
Figure 3.. Adjusted Odds Ratios (aORs) for 6-Month Psychological and Functional Outcomes With Treatment
Participants in the intervention group had higher odds of having a positive screening result for PTSD (aOR, 3.51; 95% CI, 1.18-10.40) and lower odds of receiving mental health care (aOR, 0.38; 95% CI, 0.16-0.89). Symptom burden (ie, the number of related symptoms reported) and functional capabilities were roughly equivalent between the groups. ADL indicates activities of daily living; EQ-5D-3L, EuroQoL 5-Dimensions 3-Level; FAQ, Functional Activities Questionnaire; ICU, intensive care unit; and PTSD, posttraumatic stress disorder.
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