
==== Front
Indian J Crit Care Med
Indian J Crit Care Med
IJCCM
Indian Journal of Critical Care Medicine : Peer-reviewed, Official Publication of Indian Society of Critical Care Medicine
0972-5229
1998-359X
Jaypee Brothers Medical Publishers

10.5005/jp-journals-10071-24636
Letter to the Editor
To C or not to C? Designing a Pragmatic Trial to Deploy a Novel Immunomodulatory Therapy to Fight Organ Dysfunction in Sepsis
Angadi Varun M 1https://orcid.org/0009-0001-0148-1526

Jindal Atul 2https://orcid.org/0000-0002-0504-1077

1,2 Department of Pediatrics, All India Institute of Medical Sciences, Raipur, Chhattisgarh, India
Varun M Angadi, Department of Pediatrics, All India Institute of Medical Sciences, Raipur, Chhattisgarh, India, Phone: +91 9538636135, e-mail: angadi.varun@gmail.com
3 2024
29 2 2024
28 3 311311
Copyright © 2024; The Author(s).
2024
https://creativecommons.org/licenses/by-nc/4.0/ © The Author(s). 2024 Open Access. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by-nc/4.0/), which permits unrestricted use, distribution, and non-commercial 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.
How to cite this article

Angadi VM, Jindal A. To C or not to C? Designing a Pragmatic Trial to Deploy a Novel Immunomodulatory Therapy to Fight Organ Dysfunction in Sepsis. Indian J Crit Care Med 2024;28(3):311.

Keywords

Immunomodulation
Organ dysfunction
Sepsis
Vitamin C
==== Body
pmc Dear Editor,

We read the article by Venkataraman et al.,1 on the usefulness of intravenous vitamin C in lessening organ dysfunction in critically ill adult patients with sepsis. The paradigm shift in viewing sepsis as an entity of ‘dysregulated immune response’ and not merely an ill-effect of the invading micro-organism has opened up new opportunities in research to look for immune-modulating interventions.2 Vitamin C, being one such tested intervention with equivocal results is being put to test in the index study and we attempt to critically analyze this topic in the light of available evidence.3,4

Starting with the baseline characteristics, the author has provided a comparison of the physiological scores of the patients enrolled in the two groups. However, it would've been prudent to use inferential statistics instead of descriptive statistics for such a comparison where the variables of interest (organ dysfunction scores at admission) are likely to have an impact on the outcome of interest persistent organ dysfunction (POD) in the study. It is impractical to deduce the impact of admission APACHE-II and SOFA scores (with interquartile range) on POD merely based on median values.

The ‘Use of corticosteroids’ – an intervention carried out at the discretion of the treating physician in this study is an important confounding factor in critically ill patients with sepsis. Significant mortality benefits and a decrease in organ dysfunction have been noted by the use of corticosteroids in patients with sepsis.5 To negate such confounding effects, a pragmatic study design would be one using matched controls or providing comparative analysis using inferential statistics.

As a process variable, adherence to protocol is the only parameter put to the test. However, a better design would incorporate an objective measure assessing the adequacy of supplementation. Serum levels of vitamin C or a suitable surrogate marker should've been used in this trial before deriving any conclusions regarding its impact on morbidity and mortality.6,7

The authors’ efforts in designing the trial to test a novel therapy and ensuring complete adherence to the protocol amidst the pandemic are commendable. Though this pilot trial couldn't produce results favoring vitamin C role in sepsis, it is a pioneer to drive concerted efforts in this direction. With a more pragmatic design, more trials testing the benefits of immunomodulation shall come up in this cohort of patients.

Orcid

Varun M Angadi https://orcid.org/0009-0001-0148-1526

Atul Jindal https://orcid.org/0000-0002-0504-1077

Source of support: Nil

Conflict of interest: None
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References

1. Venkataraman R Sprague S Ramakrishnan N Ramachandran P Jayakumar D Vijayaraghavan BKT et al. A pilot feasibility randomized controlled trial of intravenous vitamin C in adults with sepsis in the intensive care unit: The lessening organ dysfunction with vitamin C-India (LOVIT-India) trial Indian J Crit Care Med 2023 27 12 910 916 10.5005/jp-journals-10071-24587 38074959
2. Toft P Tønnesen E Immune-modulating interventions in critically ill septic patients: Pharmacological options Expert Rev Clin Pharmacol 2011 4 4 491 501 10.1586/ecp.11.25 22114858
3. 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 2019 322 13 1261 1270 10.1001/jama.2019.11825 31573637
4. Lamontagne F Masse MH Menard J Sprague S Pinto R Heyland DK et al. Intravenous vitamin c in adults with sepsis in the intensive care unit N Engl J Med 2022 386 25 2387 2398 10.1056/NEJMoa2200644 35704292
5. Annane D Renault A Brun-Buisson C Megarbane B Quenot JP Siami S et al. Hydrocortisone plus fludrocortisone for adults with septic shock N Engl J Med 2018 378 9 809 818 10.1056/NEJMoa1705716 29490185
6. Collie JTB Greaves RF Jones OAH Eastwood G Bellomo R Vitamin C measurement in critical illness: Challenges, methodologies and quality improvements Clin Chem Lab Med CCLM 2020 58 4 460 470 10.1515/cclm-2019-0912 31829967
7. Rozemeijer S van der Horst FAL de Man AME Measuring vitamin C in critically ill patients: Clinical importance and practical difficulties—Is it time for a surrogate marker? Crit Care 2021 25 1 310 10.1186/s13054-021-03670-x 34461968
