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Phase I safety trial of intravenous ascorbic acid in patients with severe sepsis

BACKGROUND: Parenterally administered ascorbic acid modulates sepsis-induced inflammation and coagulation in experimental animal models. The objective of this randomized, double-blind, placebo-controlled, phase I trial was to determine the safety of intravenously infused ascorbic acid in patients wi...

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Autores principales: Fowler, Alpha A, Syed, Aamer A, Knowlson, Shelley, Sculthorpe, Robin, Farthing, Don, DeWilde, Christine, Farthing, Christine A, Larus, Terri L, Martin, Erika, Brophy, Donald F, Gupta, Seema, Fisher, Bernard J, Natarajan, Ramesh
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3937164/
https://www.ncbi.nlm.nih.gov/pubmed/24484547
http://dx.doi.org/10.1186/1479-5876-12-32
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author Fowler, Alpha A
Syed, Aamer A
Knowlson, Shelley
Sculthorpe, Robin
Farthing, Don
DeWilde, Christine
Farthing, Christine A
Larus, Terri L
Martin, Erika
Brophy, Donald F
Gupta, Seema
Fisher, Bernard J
Natarajan, Ramesh
author_facet Fowler, Alpha A
Syed, Aamer A
Knowlson, Shelley
Sculthorpe, Robin
Farthing, Don
DeWilde, Christine
Farthing, Christine A
Larus, Terri L
Martin, Erika
Brophy, Donald F
Gupta, Seema
Fisher, Bernard J
Natarajan, Ramesh
author_sort Fowler, Alpha A
collection PubMed
description BACKGROUND: Parenterally administered ascorbic acid modulates sepsis-induced inflammation and coagulation in experimental animal models. The objective of this randomized, double-blind, placebo-controlled, phase I trial was to determine the safety of intravenously infused ascorbic acid in patients with severe sepsis. METHODS: Twenty-four patients with severe sepsis in the medical intensive care unit were randomized 1:1:1 to receive intravenous infusions every six hours for four days of ascorbic acid: Lo-AscA (50 mg/kg/24 h, n = 8), or Hi-AscA (200 mg/kg/24 h, n = 8), or Placebo (5% dextrose/water, n = 8). The primary end points were ascorbic acid safety and tolerability, assessed as treatment-related adverse-event frequency and severity. Patients were monitored for worsened arterial hypotension, tachycardia, hypernatremia, and nausea or vomiting. In addition Sequential Organ Failure Assessment (SOFA) scores and plasma levels of ascorbic acid, C-reactive protein, procalcitonin, and thrombomodulin were monitored. RESULTS: Mean plasma ascorbic acid levels at entry for the entire cohort were 17.9 ± 2.4 μM (normal range 50-70 μM). Ascorbic acid infusion rapidly and significantly increased plasma ascorbic acid levels. No adverse safety events were observed in ascorbic acid-infused patients. Patients receiving ascorbic acid exhibited prompt reductions in SOFA scores while placebo patients exhibited no such reduction. Ascorbic acid significantly reduced the proinflammatory biomarkers C-reactive protein and procalcitonin. Unlike placebo patients, thrombomodulin in ascorbic acid infused patients exhibited no significant rise, suggesting attenuation of vascular endothelial injury. CONCLUSIONS: Intravenous ascorbic acid infusion was safe and well tolerated in this study and may positively impact the extent of multiple organ failure and biomarkers of inflammation and endothelial injury. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT01434121.
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spelling pubmed-39371642014-02-28 Phase I safety trial of intravenous ascorbic acid in patients with severe sepsis Fowler, Alpha A Syed, Aamer A Knowlson, Shelley Sculthorpe, Robin Farthing, Don DeWilde, Christine Farthing, Christine A Larus, Terri L Martin, Erika Brophy, Donald F Gupta, Seema Fisher, Bernard J Natarajan, Ramesh J Transl Med Research BACKGROUND: Parenterally administered ascorbic acid modulates sepsis-induced inflammation and coagulation in experimental animal models. The objective of this randomized, double-blind, placebo-controlled, phase I trial was to determine the safety of intravenously infused ascorbic acid in patients with severe sepsis. METHODS: Twenty-four patients with severe sepsis in the medical intensive care unit were randomized 1:1:1 to receive intravenous infusions every six hours for four days of ascorbic acid: Lo-AscA (50 mg/kg/24 h, n = 8), or Hi-AscA (200 mg/kg/24 h, n = 8), or Placebo (5% dextrose/water, n = 8). The primary end points were ascorbic acid safety and tolerability, assessed as treatment-related adverse-event frequency and severity. Patients were monitored for worsened arterial hypotension, tachycardia, hypernatremia, and nausea or vomiting. In addition Sequential Organ Failure Assessment (SOFA) scores and plasma levels of ascorbic acid, C-reactive protein, procalcitonin, and thrombomodulin were monitored. RESULTS: Mean plasma ascorbic acid levels at entry for the entire cohort were 17.9 ± 2.4 μM (normal range 50-70 μM). Ascorbic acid infusion rapidly and significantly increased plasma ascorbic acid levels. No adverse safety events were observed in ascorbic acid-infused patients. Patients receiving ascorbic acid exhibited prompt reductions in SOFA scores while placebo patients exhibited no such reduction. Ascorbic acid significantly reduced the proinflammatory biomarkers C-reactive protein and procalcitonin. Unlike placebo patients, thrombomodulin in ascorbic acid infused patients exhibited no significant rise, suggesting attenuation of vascular endothelial injury. CONCLUSIONS: Intravenous ascorbic acid infusion was safe and well tolerated in this study and may positively impact the extent of multiple organ failure and biomarkers of inflammation and endothelial injury. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT01434121. BioMed Central 2014-01-31 /pmc/articles/PMC3937164/ /pubmed/24484547 http://dx.doi.org/10.1186/1479-5876-12-32 Text en Copyright © 2014 Fowler et al.; licensee BioMed Central Ltd. http://creativecommons.org/licenses/by/2.0 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Research
Fowler, Alpha A
Syed, Aamer A
Knowlson, Shelley
Sculthorpe, Robin
Farthing, Don
DeWilde, Christine
Farthing, Christine A
Larus, Terri L
Martin, Erika
Brophy, Donald F
Gupta, Seema
Fisher, Bernard J
Natarajan, Ramesh
Phase I safety trial of intravenous ascorbic acid in patients with severe sepsis
title Phase I safety trial of intravenous ascorbic acid in patients with severe sepsis
title_full Phase I safety trial of intravenous ascorbic acid in patients with severe sepsis
title_fullStr Phase I safety trial of intravenous ascorbic acid in patients with severe sepsis
title_full_unstemmed Phase I safety trial of intravenous ascorbic acid in patients with severe sepsis
title_short Phase I safety trial of intravenous ascorbic acid in patients with severe sepsis
title_sort phase i safety trial of intravenous ascorbic acid in patients with severe sepsis
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3937164/
https://www.ncbi.nlm.nih.gov/pubmed/24484547
http://dx.doi.org/10.1186/1479-5876-12-32
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