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

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          Abstract

          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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          Most cited references22

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          Phase I clinical trial of i.v. ascorbic acid in advanced malignancy.

          L.J. Hoffer, M. Levine, S. Assouline … (2008)
          Ascorbic acid is a widely used and controversial alternative cancer treatment. In millimolar concentrations, it is selectively cytotoxic to many cancer cell lines and has in vivo anticancer activity when administered alone or together with other agents. We carried out a dose-finding phase I and pharmacokinetic study of i.v. ascorbic acid in patients with advanced malignancies. Patients with advanced cancer or hematologic malignancy were assigned to sequential cohorts infused with 0.4, 0.6, 0.9 and 1.5 g ascorbic acid/kg body weight three times weekly. Adverse events and toxicity were minimal at all dose levels. No patient had an objective anticancer response. High-dose i.v. ascorbic acid was well tolerated but failed to demonstrate anticancer activity when administered to patients with previously treated advanced malignancies. The promise of this approach may lie in combination with cytotoxic or other redox-active molecules.
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            Adult-population incidence of severe sepsis in Australian and New Zealand intensive care units.

            Simon Finfer, Rinaldo Bellomo, Jeffrey Lipman … (2004)
            To determine the population incidence and outcome of severe sepsis occurring in adult patients treated in Australian and New Zealand intensive care units (ICUs), and compare with recent retrospective estimates from the USA and UK. Inception cohort study. Twenty-three closed multi-disciplinary ICUs of 21 hospitals (16 tertiary and 5 university affiliated) in Australia and New Zealand. A total of 5878 consecutive ICU admission episodes. Main outcome measures were population-based incidence of severe sepsis, mortality at ICU discharge, mortality at 28 days after onset of severe sepsis, and mortality at hospital discharge. A total of 691 patients, 11.8 (95% confidence intervals 10.9-12.6) per 100 ICU admissions, were diagnosed with 752 episodes of severe sepsis. Site of infection was pulmonary in 50.3% of episodes and abdominal in 19.3% of episodes. The calculated incidence of severe sepsis in adults treated in Australian and New Zealand ICUs is 0.77 (0.76-0.79) per 1000 of population. 26.5% of patients with severe sepsis died in ICU, 32.4% died within 28 days of the diagnosis of severe sepsis and 37.5% died in hospital. In this prospective study, 11.8 patients per 100 ICU admissions were diagnosed with severe sepsis and the calculated annual incidence of severe sepsis in adult patients treated in Australian and New Zealand ICUs is 0.77 per 1000 of population. This figure for the population incidence falls in the lower range of recent estimates from retrospective studies in the U.S. and the U.K.
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              Brazilian Sepsis Epidemiological Study (BASES study)

              Eliézer Silva, Marcelo Pedro, Ana Sogayar … (2004)
              Introduction Consistent data about the incidence and outcome of sepsis in Latin American intensive care units (ICUs), including Brazil, are lacking. This study was designed to verify the actual incidence density and outcome of sepsis in Brazilian ICUs. We also assessed the association between the Consensus Conference criteria and outcome Methods This is a multicenter observational cohort study performed in five private and public, mixed ICUs from two different regions of Brazil. We prospectively followed 1383 adult patients consecutively admitted to those ICUs from May 2001 to January 2002, until their discharge, 28th day of stay, or death. For all patients we collected the following data at ICU admission: age, gender, hospital and ICU admission diagnosis, APACHE II score, and associated underlying diseases. During the following days, we looked for systemic inflammatory response syndrome (SIRS), sepsis, severe sepsis, and septic shock criteria, as well as recording the sequential organ failure assessment score. Infection was diagnosed according to CDC criteria for nosocomial infection, and for community-acquired infection, clinical, radiological and microbiological parameters were used. Results For the whole cohort, median age was 65.2 years (49–76), median length of stay was 2 days (1–6), and the overall 28-day mortality rate was 21.8%. Considering 1383 patients, the incidence density rates for sepsis, severe sepsis and septic shock were 61.4, 35.6 and 30.0 per 1000 patient-days, respectively. The mortality rate of patients with SIRS, sepsis, severe sepsis and septic shock increased progressively from 24.3% to 34.7%, 47.3% and 52.2%, respectively. For patients with SIRS without infection the mortality rate was 11.3%. The main source of infection was lung/respiratory tract. Conclusion Our preliminary data suggest that sepsis is a major public health problem in Brazilian ICUs, with an incidence density about 57 per 1000 patient-days. Moreover, there was a close association between ACCP/SCCM categories and mortality rate.
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                Author and article information

                Journal
                Journal ID (nlm-ta): J Transl Med
                Journal ID (iso-abbrev): J Transl Med
                Title: Journal of Translational Medicine
                Publisher: BioMed Central
                ISSN (Electronic): 1479-5876
                Publication date Collection: 2014
                Publication date (Electronic): 31 January 2014
                Volume: 12
                Page: 32
                Affiliations
                [1 ]Division of Pulmonary Disease and Critical Care Medicine, Department of Internal Medicine, School of Medicine, Virginia Commonwealth University, PO Box 980050, Richmond, VA 23298-0050, USA
                [2 ]Department of Critical Care Nursing, Virginia Commonwealth University Health System, Richmond, Virginia, USA
                [3 ]Investigational Drug Services, Department of Pharmacy Services, School of Pharmacy, Virginia Commonwealth University, Richmond, Virginia, USA
                [4 ]Division of Nephrology, Department of Internal Medicine, School of Medicine, Virginia Commonwealth University, Richmond, Virginia, USA
                [5 ]Department of Pharmacotherapy & Outcomes Science, School of Pharmacy, Virginia Commonwealth University, Richmond, Virginia, USA
                [6 ]Health Diagnostic Laboratory, Richmond, Virginia, USA
                Author notes
                Medical Respiratory Intensive Care Unit Nursing
                Article
                Publisher ID: 1479-5876-12-32
                DOI: 10.1186/1479-5876-12-32
                PMC ID: 3937164
                PubMed ID: 24484547
                SO-VID: e1adeb4e-8fcd-4274-ba5e-36199140879c
                Copyright © Copyright © 2014 Fowler et al.; licensee BioMed Central Ltd.
                License:

                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.

                History
                Date received : 12 November 2013
                Date accepted : 2 January 2014
                Categories
                Subject: Research

                ScienceOpen disciplines: Medicine
                Keywords: multiple organ failure,organ dysfunction scores,sepsis,biological markers,clinical trials phase i as topic,ascorbic acid
                Data availability:
                ScienceOpen disciplines: Medicine
                Keywords: multiple organ failure, organ dysfunction scores, sepsis, biological markers, clinical trials phase i as topic, ascorbic acid

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