Association of Vitamin C, Thiamine, and Hydrocortisone Infusion With Long-term Cognitive, Psychological, and Functional Outcomes in Sepsis Survivors
Authors: Williams Roberson Shawniqua , Nwosu Samuel , Collar Erin M. , Kiehl Amy L. , Harrison Fiona E. , Bastarache Julie , Wilson Jo Ellen , Mart Matthew F. , Sevransky Jonathan E. , Ely E. Wesley , Lindsell Christopher J. , Jackson James C. ,   VICTAS Investigators, Nugent Katherine , Spainhour Christine , Polito Carmen , Moore Brooks , Negrin Lovie , Khan Akram , Kea Bory , Krol Olivia , Haq Ebaad , Pinkert Vincent , Nguyen Kelly , Brown Samuel M , Bledsoe Joseph , Peltan Ithan , Applegate Darrin , Armbuster Brent , Montgomery Quinn , Brown Katie , Daw Austin , Gong Michelle , Aboodi Michael , Chen Jen-Ting (Tina) , Hope Aluko , Gummadi Swarna , Lopez Brenda , Hinson Jeremiah , Hager David , Ricketts Erin , Clare Johnathan , McBryde Breana , Clements Casey M. , Gajic Ognjen , Kashyap Rahul , Vanmeter Derek , Busse Laurence , McBride Mary , Ginde Adit , Moss Marc , Finck Lani , Howell Michelle , McKeehan Jeffrey , Higgins Carrie , Barksdale Aaron , Kalin Dan , Kruse Derek , Hilz Katlyn , Qadir Nida , Chang Steven Y. , Beutler Rebecca , Tam Andrea , Harris Estelle S. , Youngquist Scott T. , Middleton Elizabeth A. , Davidov Ervin , Plante Amber , Belsky Justin , Siner Jonathan , Wira Charles , Brokowski Carolyn , Steingrub Jay , Smithline Howard , Thorton-Thompson Sherell , Fowler Alpha , Miller Stephen , Narron Kyle , Pusckarich Michael A. , Prekker Matthew E. , Hendrickson Audrey , Quinn James , Wilson Jennifer , Levitt Joseph , Mann Rosen , Visweswaran Anita , Gentile Nina , Marchetti Nathaniel , Reimer Hannah , Guirgis Faheem , Jones Lisa , Black Lauren , Henson Morgan , Meyer Nuala J. , Greenwood John C. , Ittner Caroline , Rivers Emanuel , Jayaprakash Namita , Gardner-Gray Jayna , Hurst Gina , Pflaum Jacqueline , Jaehne Anja Kathrin , Gill Jasreen , Cook Aaron , Janz David R , Vonderhaar Derek , Romaine Connie , Wilkerson R. Gentry , McCurdy Michael T. , Beach Dana , Lasko Kyra , Gill Richard , Price Katherine , Dickson Lisa , Duggal Abhijit , Mace Sharon E. , Hite R. Duncan , Hastings Andrei , Haukoos Jason , Dougla Ivor , Trent Stacy , Lyle Carolynn , Cupelo Alicia , Gravitz Stephanie , Hiller Terra , Oakes Judy , LoVecchio Frank , Quiroga Pedro , Danley Shiloh , Mulrow Mary , Encinas Amanda , Goodwin Andrew , Hall Gregory , Grady Abigail , Exline Matthew , Terndrup Thomas , Pannu Sonal , Robart Emily , Karow Sarah , Files D. Clark , Smith Lane , Gibbs Kevin , Flores Lori , Pastores Stephen M. , Shaz David J. , Kostelecky Natalie , Chase Chad , Wilkins Elizabeth (Liz) , Gaieski David , Baram Michael , Schwegler Daniel , Renzi Nicole , Mosier Jarrod M. , Hypes Cameron , Salvagio Campbell Elizabeth , Hooper Michael , Sill Joshua , Mitchell Kate , Hudock Kristin , Lyons Michael , Gordner Kari , Ahmad Yousef , Studer Autumn , Davis Jacqueline , Barrett Matthew , Nomura Jason , Knox Jennifer , Park Pauline , Co Ivan , McSparron Jakob , Hyzy Robert , McDonough Kelli , Hanna Sinan , Self Wesley H. , Semler Matthew W. , Hays Margaret , Bartz Racquel , Limkakeng Alexander , Sweeney Katherine , Woodburn Rachael , Goyal Munish , Zaaqoq Akram , Moriarty Theresa , Oropello John , Zhang Ziya 
Published: February 2023

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