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

Alpha A. Fowler; Jonathon D. Truwit; R. Duncan Hite; Peter E. Morris; Christine Dewilde; Anna Priday; Bernard Fisher; Leroy R. Thacker; Ramesh Natarajan; Donald F. Brophy; Robin Sculthorpe; Rahul Nanchal; Aamer Syed; Jamie Sturgill; Greg S. Martin; Jonathan Sevransky; Markos Kashiouris; Stella Hamman; Katherine F. Egan; Andrei Hastings; Wendy Spencer; Shawnda Tench; Omar Mehkri; James Bindas; Abhijit Duggal; Jeanette Graf; Stephanie Zellner; Lynda Yanny; Catherine McPolin; Tonya Hollrith; David Kramer; Charles Ojielo; Tessa Damm; Evan Cassity; Aleksandra Wieliczko; Matthew Halquist

doi:10.1001/jama.2019.11825

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

Alpha A. Fowler, Jonathon D. Truwit, R. Duncan Hite, Peter E. Morris, Christine Dewilde, Anna Priday, Bernard Fisher, Leroy R. Thacker, Ramesh Natarajan, Donald F. Brophy, Robin Sculthorpe, Rahul Nanchal, Aamer Syed, Jamie Sturgill, Greg S. Martin, Jonathan Sevransky, Markos Kashiouris, Stella Hamman, Katherine F. Egan, Andrei HastingsWendy Spencer, Shawnda Tench, Omar Mehkri, James Bindas, Abhijit Duggal, Jeanette Graf, Stephanie Zellner, Lynda Yanny, Catherine McPolin, Tonya Hollrith, David Kramer, Charles Ojielo, Tessa Damm, Evan Cassity, Aleksandra Wieliczko, Matthew Halquist

Research output: Contribution to journal › Article › peer-review

526 Scopus citations

Abstract

Importance: Experimental data suggest that intravenous vitamin C may attenuate inflammation and vascular injury associated with sepsis and acute respiratory distress syndrome (ARDS). Objective: To determine the effect of intravenous vitamin C infusion on organ failure scores and biological markers of inflammation and vascular injury in patients with sepsis and ARDS. Design, Setting, and Participants: The CITRIS-ALI trial was a randomized, double-blind, placebo-controlled, multicenter trial conducted in 7 medical intensive care units in the United States, enrolling patients (N = 167) with sepsis and ARDS present for less than 24 hours. The study was conducted from September 2014 to November 2017, and final follow-up was January 2018. Interventions: Patients were randomly assigned to receive intravenous infusion of vitamin C (50 mg/kg in dextrose 5% in water, n = 84) or placebo (dextrose 5% in water only, n = 83) every 6 hours for 96 hours. Main Outcomes and Measures: The primary outcomes were change in organ failure as assessed by a modified Sequential Organ Failure Assessment score (range, 0-20, with higher scores indicating more dysfunction) from baseline to 96 hours, and plasma biomarkers of inflammation (C-reactive protein levels) and vascular injury (thrombomodulin levels) measured at 0, 48, 96, and 168 hours. Results: Among 167 randomized patients (mean [SD] age, 54.8 years [16.7]; 90 men [54%]), 103 (62%) completed the study to day 60. There were no significant differences between the vitamin C and placebo groups in the primary end points of change in mean modified Sequential Organ Failure Assessment score from baseline to 96 hours (from 9.8 to 6.8 in the vitamin C group [3 points] and from 10.3 to 6.8 in the placebo group [3.5 points]; difference, -0.10; 95% CI, -1.23 to 1.03; P =.86) or in C-reactive protein levels (54.1 vs 46.1 μg/mL; difference, 7.94 μg/mL; 95% CI, -8.2 to 24.11; P =.33) and thrombomodulin levels (14.5 vs 13.8 ng/mL; difference, 0.69 ng/mL; 95% CI, -2.8 to 4.2; P =.70) at 168 hours. Conclusions and Relevance: In this preliminary study of patients with sepsis and ARDS, a 96-hour infusion of vitamin C compared with placebo did not significantly improve organ dysfunction scores or alter markers of inflammation and vascular injury. Further research is needed to evaluate the potential role of vitamin C for other outcomes in sepsis and ARDS. Trial Registration: ClinicalTrials.gov Identifier: NCT02106975.

Original language	English
Pages (from-to)	1261-1270
Number of pages	10
Journal	JAMA - Journal of the American Medical Association
Volume	322
Issue number	13
DOIs	https://doi.org/10.1001/jama.2019.11825
State	Published - Oct 1 2019

Bibliographical note

Funding Information:
receiving an honorarium from Virginia Tech School of Medicine; grants from the National Heart, Lung, and Blood Institute (NHLBI); and study materials from McGuff Pharmaceuticals during the conduct of the study. Dr Truwit reports receiving grants from the National Institutes of Health (NIH) during the conduct of the study. Dr Hite reports receiving grants from NHLBI during the conduct of the study, grants from the Marcus Foundation, and grants from NHLBI outside the submitted work. Dr Morris reports receiving grants from NIH during the conduct of the study. Dr Thacker reports receiving grants from NIH during the conduct of the study. Dr Brophy reports receiving grants from NIH during the conduct of the study. Dr Sturgill reports receiving grants from NIH during the conduct of the study. Dr Martin reports receiving grants from NHLBI during the conduct of the study. Dr Sevransky reports receiving grants from NIH during the conduct of the study and grants from the Marcus Foundation outside the submitted work. Ms Egan reports receiving grants from Emory University during the conduct of the study. Dr Duggal reports receiving grants from NIH during the conduct of the study. Ms Graf reports receiving grants from Virginia Commonwealth University during the conduct of the study. Ms Zellner reports receiving grants from Virginia Commonwealth University during the conduct of the study. Ms Yanny reports receiving grants from the Medical College of Wisconsin during the conduct of the study. Ms McPolin reports receiving grants from the Medical College of Wisconsin during the conduct of the study. Ms Hollrith reports receiving grants from the Medical College of Wisconsin during the conduct of the study. Dr Damm reports receiving grants from the Medical College of Wisconsin during the conduct of the study. Mr Cassity reports receiving grants from NIH during the conduct of the study. No other disclosures were reported.

Funding Information:
Funding/Support: The study was supported by

Publisher Copyright:
© 2019 American Medical Association. All rights reserved.

ASJC Scopus subject areas

Medicine (all)

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10.1001/jama.2019.11825

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Fowler, A. A., Truwit, J. D., Hite, R. D., Morris, P. E., Dewilde, C., Priday, A., Fisher, B., Thacker, L. R., Natarajan, R., Brophy, D. F., Sculthorpe, R., Nanchal, R., Syed, A., Sturgill, J., Martin, G. S., Sevransky, J., Kashiouris, M., Hamman, S., Egan, K. F., ... 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 - Journal of the American Medical Association, 322(13), 1261-1270. https://doi.org/10.1001/jama.2019.11825

@article{e89a684e36ce44acaafe911087d46215,

title = "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",

abstract = "Importance: Experimental data suggest that intravenous vitamin C may attenuate inflammation and vascular injury associated with sepsis and acute respiratory distress syndrome (ARDS). Objective: To determine the effect of intravenous vitamin C infusion on organ failure scores and biological markers of inflammation and vascular injury in patients with sepsis and ARDS. Design, Setting, and Participants: The CITRIS-ALI trial was a randomized, double-blind, placebo-controlled, multicenter trial conducted in 7 medical intensive care units in the United States, enrolling patients (N = 167) with sepsis and ARDS present for less than 24 hours. The study was conducted from September 2014 to November 2017, and final follow-up was January 2018. Interventions: Patients were randomly assigned to receive intravenous infusion of vitamin C (50 mg/kg in dextrose 5% in water, n = 84) or placebo (dextrose 5% in water only, n = 83) every 6 hours for 96 hours. Main Outcomes and Measures: The primary outcomes were change in organ failure as assessed by a modified Sequential Organ Failure Assessment score (range, 0-20, with higher scores indicating more dysfunction) from baseline to 96 hours, and plasma biomarkers of inflammation (C-reactive protein levels) and vascular injury (thrombomodulin levels) measured at 0, 48, 96, and 168 hours. Results: Among 167 randomized patients (mean [SD] age, 54.8 years [16.7]; 90 men [54%]), 103 (62%) completed the study to day 60. There were no significant differences between the vitamin C and placebo groups in the primary end points of change in mean modified Sequential Organ Failure Assessment score from baseline to 96 hours (from 9.8 to 6.8 in the vitamin C group [3 points] and from 10.3 to 6.8 in the placebo group [3.5 points]; difference, -0.10; 95% CI, -1.23 to 1.03; P =.86) or in C-reactive protein levels (54.1 vs 46.1 μg/mL; difference, 7.94 μg/mL; 95% CI, -8.2 to 24.11; P =.33) and thrombomodulin levels (14.5 vs 13.8 ng/mL; difference, 0.69 ng/mL; 95% CI, -2.8 to 4.2; P =.70) at 168 hours. Conclusions and Relevance: In this preliminary study of patients with sepsis and ARDS, a 96-hour infusion of vitamin C compared with placebo did not significantly improve organ dysfunction scores or alter markers of inflammation and vascular injury. Further research is needed to evaluate the potential role of vitamin C for other outcomes in sepsis and ARDS. Trial Registration: ClinicalTrials.gov Identifier: NCT02106975.",

author = "Fowler, {Alpha A.} and Truwit, {Jonathon D.} and Hite, {R. Duncan} and Morris, {Peter E.} and Christine Dewilde and Anna Priday and Bernard Fisher and Thacker, {Leroy R.} and Ramesh Natarajan and Brophy, {Donald F.} and Robin Sculthorpe and Rahul Nanchal and Aamer Syed and Jamie Sturgill and Martin, {Greg S.} and Jonathan Sevransky and Markos Kashiouris and Stella Hamman and Egan, {Katherine F.} and Andrei Hastings and Wendy Spencer and Shawnda Tench and Omar Mehkri and James Bindas and Abhijit Duggal and Jeanette Graf and Stephanie Zellner and Lynda Yanny and Catherine McPolin and Tonya Hollrith and David Kramer and Charles Ojielo and Tessa Damm and Evan Cassity and Aleksandra Wieliczko and Matthew Halquist",

note = "Funding Information: receiving an honorarium from Virginia Tech School of Medicine; grants from the National Heart, Lung, and Blood Institute (NHLBI); and study materials from McGuff Pharmaceuticals during the conduct of the study. Dr Truwit reports receiving grants from the National Institutes of Health (NIH) during the conduct of the study. Dr Hite reports receiving grants from NHLBI during the conduct of the study, grants from the Marcus Foundation, and grants from NHLBI outside the submitted work. Dr Morris reports receiving grants from NIH during the conduct of the study. Dr Thacker reports receiving grants from NIH during the conduct of the study. Dr Brophy reports receiving grants from NIH during the conduct of the study. Dr Sturgill reports receiving grants from NIH during the conduct of the study. Dr Martin reports receiving grants from NHLBI during the conduct of the study. Dr Sevransky reports receiving grants from NIH during the conduct of the study and grants from the Marcus Foundation outside the submitted work. Ms Egan reports receiving grants from Emory University during the conduct of the study. Dr Duggal reports receiving grants from NIH during the conduct of the study. Ms Graf reports receiving grants from Virginia Commonwealth University during the conduct of the study. Ms Zellner reports receiving grants from Virginia Commonwealth University during the conduct of the study. Ms Yanny reports receiving grants from the Medical College of Wisconsin during the conduct of the study. Ms McPolin reports receiving grants from the Medical College of Wisconsin during the conduct of the study. Ms Hollrith reports receiving grants from the Medical College of Wisconsin during the conduct of the study. Dr Damm reports receiving grants from the Medical College of Wisconsin during the conduct of the study. Mr Cassity reports receiving grants from NIH during the conduct of the study. No other disclosures were reported. Funding Information: Funding/Support: The study was supported by Publisher Copyright: {\textcopyright} 2019 American Medical Association. All rights reserved.",

year = "2019",

month = oct,

day = "1",

doi = "10.1001/jama.2019.11825",

language = "English",

volume = "322",

pages = "1261--1270",

number = "13",

}

Fowler, AA, Truwit, JD, Hite, RD, Morris, PE, Dewilde, C, Priday, A, Fisher, B, Thacker, LR, 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 - Journal of the American Medical Association, vol. 322, no. 13, pp. 1261-1270. https://doi.org/10.1001/jama.2019.11825

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. / Fowler, Alpha A.; Truwit, Jonathon D.; Hite, R. Duncan et al.
In: JAMA - Journal of the American Medical Association, Vol. 322, No. 13, 01.10.2019, p. 1261-1270.

Research output: Contribution to journal › Article › peer-review

TY - JOUR

T1 - Effect of Vitamin C Infusion on Organ Failure and Biomarkers of Inflammation and Vascular Injury in Patients with Sepsis and Severe Acute Respiratory Failure

T2 - The CITRIS-ALI Randomized Clinical Trial

AU - Fowler, Alpha A.

AU - Truwit, Jonathon D.

AU - Hite, R. Duncan

AU - Morris, Peter E.

AU - Dewilde, Christine

AU - Priday, Anna

AU - Fisher, Bernard

AU - Thacker, Leroy R.

AU - Natarajan, Ramesh

AU - Brophy, Donald F.

AU - Sculthorpe, Robin

AU - Nanchal, Rahul

AU - Syed, Aamer

AU - Sturgill, Jamie

AU - Martin, Greg S.

AU - Sevransky, Jonathan

AU - Kashiouris, Markos

AU - Hamman, Stella

AU - Egan, Katherine F.

AU - Hastings, Andrei

AU - Spencer, Wendy

AU - Tench, Shawnda

AU - Mehkri, Omar

AU - Bindas, James

AU - Duggal, Abhijit

AU - Graf, Jeanette

AU - Zellner, Stephanie

AU - Yanny, Lynda

AU - McPolin, Catherine

AU - Hollrith, Tonya

AU - Kramer, David

AU - Ojielo, Charles

AU - Damm, Tessa

AU - Cassity, Evan

AU - Wieliczko, Aleksandra

AU - Halquist, Matthew

N1 - Funding Information: receiving an honorarium from Virginia Tech School of Medicine; grants from the National Heart, Lung, and Blood Institute (NHLBI); and study materials from McGuff Pharmaceuticals during the conduct of the study. Dr Truwit reports receiving grants from the National Institutes of Health (NIH) during the conduct of the study. Dr Hite reports receiving grants from NHLBI during the conduct of the study, grants from the Marcus Foundation, and grants from NHLBI outside the submitted work. Dr Morris reports receiving grants from NIH during the conduct of the study. Dr Thacker reports receiving grants from NIH during the conduct of the study. Dr Brophy reports receiving grants from NIH during the conduct of the study. Dr Sturgill reports receiving grants from NIH during the conduct of the study. Dr Martin reports receiving grants from NHLBI during the conduct of the study. Dr Sevransky reports receiving grants from NIH during the conduct of the study and grants from the Marcus Foundation outside the submitted work. Ms Egan reports receiving grants from Emory University during the conduct of the study. Dr Duggal reports receiving grants from NIH during the conduct of the study. Ms Graf reports receiving grants from Virginia Commonwealth University during the conduct of the study. Ms Zellner reports receiving grants from Virginia Commonwealth University during the conduct of the study. Ms Yanny reports receiving grants from the Medical College of Wisconsin during the conduct of the study. Ms McPolin reports receiving grants from the Medical College of Wisconsin during the conduct of the study. Ms Hollrith reports receiving grants from the Medical College of Wisconsin during the conduct of the study. Dr Damm reports receiving grants from the Medical College of Wisconsin during the conduct of the study. Mr Cassity reports receiving grants from NIH during the conduct of the study. No other disclosures were reported. Funding Information: Funding/Support: The study was supported by Publisher Copyright: © 2019 American Medical Association. All rights reserved.

PY - 2019/10/1

Y1 - 2019/10/1

N2 - Importance: Experimental data suggest that intravenous vitamin C may attenuate inflammation and vascular injury associated with sepsis and acute respiratory distress syndrome (ARDS). Objective: To determine the effect of intravenous vitamin C infusion on organ failure scores and biological markers of inflammation and vascular injury in patients with sepsis and ARDS. Design, Setting, and Participants: The CITRIS-ALI trial was a randomized, double-blind, placebo-controlled, multicenter trial conducted in 7 medical intensive care units in the United States, enrolling patients (N = 167) with sepsis and ARDS present for less than 24 hours. The study was conducted from September 2014 to November 2017, and final follow-up was January 2018. Interventions: Patients were randomly assigned to receive intravenous infusion of vitamin C (50 mg/kg in dextrose 5% in water, n = 84) or placebo (dextrose 5% in water only, n = 83) every 6 hours for 96 hours. Main Outcomes and Measures: The primary outcomes were change in organ failure as assessed by a modified Sequential Organ Failure Assessment score (range, 0-20, with higher scores indicating more dysfunction) from baseline to 96 hours, and plasma biomarkers of inflammation (C-reactive protein levels) and vascular injury (thrombomodulin levels) measured at 0, 48, 96, and 168 hours. Results: Among 167 randomized patients (mean [SD] age, 54.8 years [16.7]; 90 men [54%]), 103 (62%) completed the study to day 60. There were no significant differences between the vitamin C and placebo groups in the primary end points of change in mean modified Sequential Organ Failure Assessment score from baseline to 96 hours (from 9.8 to 6.8 in the vitamin C group [3 points] and from 10.3 to 6.8 in the placebo group [3.5 points]; difference, -0.10; 95% CI, -1.23 to 1.03; P =.86) or in C-reactive protein levels (54.1 vs 46.1 μg/mL; difference, 7.94 μg/mL; 95% CI, -8.2 to 24.11; P =.33) and thrombomodulin levels (14.5 vs 13.8 ng/mL; difference, 0.69 ng/mL; 95% CI, -2.8 to 4.2; P =.70) at 168 hours. Conclusions and Relevance: In this preliminary study of patients with sepsis and ARDS, a 96-hour infusion of vitamin C compared with placebo did not significantly improve organ dysfunction scores or alter markers of inflammation and vascular injury. Further research is needed to evaluate the potential role of vitamin C for other outcomes in sepsis and ARDS. Trial Registration: ClinicalTrials.gov Identifier: NCT02106975.

AB - Importance: Experimental data suggest that intravenous vitamin C may attenuate inflammation and vascular injury associated with sepsis and acute respiratory distress syndrome (ARDS). Objective: To determine the effect of intravenous vitamin C infusion on organ failure scores and biological markers of inflammation and vascular injury in patients with sepsis and ARDS. Design, Setting, and Participants: The CITRIS-ALI trial was a randomized, double-blind, placebo-controlled, multicenter trial conducted in 7 medical intensive care units in the United States, enrolling patients (N = 167) with sepsis and ARDS present for less than 24 hours. The study was conducted from September 2014 to November 2017, and final follow-up was January 2018. Interventions: Patients were randomly assigned to receive intravenous infusion of vitamin C (50 mg/kg in dextrose 5% in water, n = 84) or placebo (dextrose 5% in water only, n = 83) every 6 hours for 96 hours. Main Outcomes and Measures: The primary outcomes were change in organ failure as assessed by a modified Sequential Organ Failure Assessment score (range, 0-20, with higher scores indicating more dysfunction) from baseline to 96 hours, and plasma biomarkers of inflammation (C-reactive protein levels) and vascular injury (thrombomodulin levels) measured at 0, 48, 96, and 168 hours. Results: Among 167 randomized patients (mean [SD] age, 54.8 years [16.7]; 90 men [54%]), 103 (62%) completed the study to day 60. There were no significant differences between the vitamin C and placebo groups in the primary end points of change in mean modified Sequential Organ Failure Assessment score from baseline to 96 hours (from 9.8 to 6.8 in the vitamin C group [3 points] and from 10.3 to 6.8 in the placebo group [3.5 points]; difference, -0.10; 95% CI, -1.23 to 1.03; P =.86) or in C-reactive protein levels (54.1 vs 46.1 μg/mL; difference, 7.94 μg/mL; 95% CI, -8.2 to 24.11; P =.33) and thrombomodulin levels (14.5 vs 13.8 ng/mL; difference, 0.69 ng/mL; 95% CI, -2.8 to 4.2; P =.70) at 168 hours. Conclusions and Relevance: In this preliminary study of patients with sepsis and ARDS, a 96-hour infusion of vitamin C compared with placebo did not significantly improve organ dysfunction scores or alter markers of inflammation and vascular injury. Further research is needed to evaluate the potential role of vitamin C for other outcomes in sepsis and ARDS. Trial Registration: ClinicalTrials.gov Identifier: NCT02106975.

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Fowler AA, Truwit JD, Hite RD, Morris PE, Dewilde C, Priday A et al. 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 - Journal of the American Medical Association. 2019 Oct 1;322(13):1261-1270. doi: 10.1001/jama.2019.11825

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

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