Ascorbic acid, corticosteroids, and thiamine in sepsis: a review of the biologic rationale and the present state of clinical evaluation

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Abstract

The combination of thiamine, ascorbic acid, and hydrocortisone has recently emerged as a potential adjunctive therapy to antibiotics, infectious source control, and supportive care for patients with sepsis and septic shock. In the present manuscript, we provide a comprehensive review of the pathophysiologic basis and supporting research for each element of the thiamine, ascorbic acid, and hydrocortisone drug combination in sepsis. In addition, we describe potential areas of synergy between these therapies and discuss the strengths/weaknesses of the two studies to date which have evaluated the drug combination in patients with severe infection. Finally, we describe the current state of current clinical practice as it relates to the thiamine, ascorbic acid, and hydrocortisone combination and present an overview of the randomized, placebo-controlled, multi-center Ascorbic acid, Corticosteroids, and Thiamine in Sepsis (ACTS) trial and other planned/ongoing randomized clinical trials.

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Most cited references 44

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Epidemiology of severe sepsis

Florian Mayr, Sachin Yende, Derek C Angus (2013)

Severe sepsis is a leading cause of death in the United States and the most common cause of death among critically ill patients in non-coronary intensive care units (ICU). Respiratory tract infections, particularly pneumonia, are the most common site of infection, and associated with the highest mortality. The type of organism causing severe sepsis is an important determinant of outcome, and gram-positive organisms as a cause of sepsis have increased in frequency over time and are now more common than gram-negative infections. Recent studies suggest that acute infections worsen pre-existing chronic diseases or result in new chronic diseases, leading to poor long-term outcomes in acute illness survivors. People of older age, male gender, black race, and preexisting chronic health conditions are particularly prone to develop severe sepsis; hence prevention strategies should be targeted at these vulnerable populations in future studies.

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Mechanisms and treatment of organ failure in sepsis

Christophe Lelubre, Jean-Louis Vincent (2018)

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Mechanisms of cardiac and renal dysfunction in patients dying of sepsis.

R Eliot Fagley, Deborah L Janks, Paul E Swanson … (2013)

The mechanistic basis for cardiac and renal dysfunction in sepsis is unknown. In particular, the degree and type of cell death is undefined. To evaluate the degree of sepsis-induced cardiomyocyte and renal tubular cell injury and death. Light and electron microscopy and immunohistochemical staining for markers of cellular injury and stress, including connexin-43 and kidney-injury-molecule-1 (Kim-1), were used in this study. Rapid postmortem cardiac and renal harvest was performed in 44 septic patients. Control hearts were obtained from 12 transplant and 13 brain-dead patients. Control kidneys were obtained from 20 trauma patients and eight patients with cancer. Immunohistochemistry demonstrated low levels of apoptotic cardiomyocytes (<1-2 cells per thousand) in septic and control subjects and revealed redistribution of connexin-43 to lateral membranes in sepsis (P < 0.020). Electron microscopy showed hydropic mitochondria only in septic specimens, whereas mitochondrial membrane injury and autophagolysosomes were present equally in control and septic specimens. Control kidneys appeared relatively normal by light microscopy; 3 of 20 specimens showed focal injury in approximately 1% of renal cortical tubules. Conversely, focal acute tubular injury was present in 78% of septic kidneys, occurring in 10.3 ± 9.5% and 32.3 ± 17.8% of corticomedullary-junction tubules by conventional light microscopy and Kim-1 immunostains, respectively (P < 0.01). Electron microscopy revealed increased tubular injury in sepsis, including hydropic mitochondria and increased autophagosomes. Cell death is rare in sepsis-induced cardiac dysfunction, but cardiomyocyte injury occurs. Renal tubular injury is common in sepsis but presents focally; most renal tubular cells appear normal. The degree of cell injury and death does not account for severity of sepsis-induced organ dysfunction.

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Author and article information

Contributors

Ari Moskowitz: amoskowi@bidmc.harvard.edu

Lars W. Andersen: lwanders@bidmc.harvard.edu

David T. Huang: huangdt@ccm.upmc.edu

Katherine M. Berg: kberg@bidmc.harvard.edu

Anne V. Grossestreuer: agrosses@bidmc.harvard.edu

Paul E. Marik: marikPE@evms.edu

Robert L. Sherwin: rsherwin@dmc.org

Peter C. Hou: phou@bwh.harvard.edu

Lance B. Becker: lance.becker@northwell.edu

Michael N. Cocchi: mcocchi@bidmc.harvard.edu

Pratik Doshi: PratikBDoshi@uth.tmc.edu

Jonathan Gong: JGong1@northwell.edu

Ayan Sen: Sen.Ayan@mayo.edu

Michael W. Donnino: 617-754-2323 , mdonnino@bidmc.harvard.edu , amoskowi@bidmc.harvard.edu

Journal

Journal ID (nlm-ta): Crit Care

Title: Critical Care

Publisher: BioMed Central (London )

ISSN (Print): 1364-8535

ISSN (Electronic): 1466-609X

Publication date (Electronic): 29 October 2018

Publication date PMC-release: 29 October 2018

Publication date Collection: 2018

Volume: 22

Electronic Location Identifier: 283

Affiliations

[1 ]Beth Israel Deaconess Medical Center, Department of Medicine, Division of Pulmonary, Critical Care, and Sleep Medicine, Boston, MA USA

[2 ]ISNI 0000 0000 9011 8547, GRID grid.239395.7, Beth Israel Deaconess Medical Center, Department of Emergency Medicine, ; Boston, MA USA

[3 ]ISNI 0000 0004 0512 597X, GRID grid.154185.c, Research Center for Emergency Medicine, , Aarhus University Hospital, ; Aarhus, Denmark

[4 ]ISNI 0000 0004 0512 597X, GRID grid.154185.c, Department of Anesthesiology, , Aarhus University Hospital, ; Aarhus, Denmark

[5 ]ISNI 0000 0004 1936 9000, GRID grid.21925.3d, Department of Critical Care Medicine, , University of Pittsburgh, ; Pittsburgh, PA USA

[6 ]ISNI 0000 0004 1936 9000, GRID grid.21925.3d, Department of Emergency Medicine, , University of Pittsburgh, ; Pittsburgh, PA USA

[7 ]ISNI 0000 0001 2182 3733, GRID grid.255414.3, Department of Internal Medicine, , Eastern Virginia Medical School, ; Norfolk, VA USA

[8 ]ISNI 0000 0001 1456 7807, GRID grid.254444.7, Department of Emergency Medicine, , Wayne State University School of Medicine/Detroit Receiving Hospital, ; Detroit, MI USA

[9 ]ISNI 0000 0004 0378 8294, GRID grid.62560.37, Division of Emergency Critical Care Medicine, Department of Emergency Medicine, , Brigham and Women’s Hospital, ; Boston, MA USA

[10 ]Department of Emergency Medicine, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY USA

[11 ]ISNI 0000 0000 9566 0634, GRID grid.250903.d, Feinstein Institute for Medical Research, ; Manhasset, NY USA

[12 ]ISNI 0000 0000 9011 8547, GRID grid.239395.7, Department of Anesthesia Critical Care, Division of Critical Care, , Beth Israel Deaconess Medical Center, ; Boston, MA USA

[13 ]ISNI 0000 0000 9206 2401, GRID grid.267308.8, Department of Emergency Medicine and Internal Medicine, , University of Texas Health Science Center at Houston, ; Houston, TX USA

[14 ]Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Northwell Health System, New Hyde Park, NY USA

[15 ]ISNI 0000 0000 8875 6339, GRID grid.417468.8, Department of Critical Care Medicine, , Mayo Clinic, ; Phoenix, AZ USA

[16 ]ISNI 0000 0000 9011 8547, GRID grid.239395.7, Beth Israel Deaconess Medical Center, Emergency Medicine, ; One Deaconess Rd, W/CC 2, Boston, MA 02215 USA

Article

Publisher ID: 2217

DOI: 10.1186/s13054-018-2217-4

PMC ID: 6206928

PubMed ID: 30373647

SO-VID: 7d3110eb-8cfe-4818-9d79-38057bb72991

License:

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. 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 : 9 August 2018

Date accepted : 3 October 2018

Funding

Funded by: FundRef http://dx.doi.org/10.13039/100000002, National Institutes of Health;

Award ID: K23GM128005-01

Award ID: 1K23HL128814-01

Award ID: UO1HL122989-03

Award Recipient : Ari Moskowitz Katherine M. Berg Peter C. Hou

Funded by: FundRef http://dx.doi.org/10.13039/100000968, American Heart Association;

Award ID: 15SDG22420010

Award Recipient : Michael N. Cocchi

Funded by: Open Philanthropy

Award ID: n/a

Award Recipient : Michael W. Donnino

Funded by: Harvard Catalyst (US)

Award ID: KL2 TR001100

Custom metadata

ScienceOpen disciplines: Emergency medicine & Trauma

Keywords: thiamine,ascorbic acid,corticosteroids,metabolic resuscitation,sepsis

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ScienceOpen disciplines: Emergency medicine & Trauma

Keywords: thiamine, ascorbic acid, corticosteroids, metabolic resuscitation, sepsis

Ascorbic acid, corticosteroids, and thiamine in sepsis: a review of the biologic rationale and the present state of clinical evaluation

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Abstract

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Irish Journal of Paramedicine

Most cited references 44

Epidemiology of severe sepsis

Mechanisms and treatment of organ failure in sepsis

Mechanisms of cardiac and renal dysfunction in patients dying of sepsis.

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